Lane Medical Library

Researchers' Individual Publication Rate Has Not Increased in a Century.

PLoS One. 2016;11(3):e0149504

Authors: Fanelli D, Larivière V

Abstract
Debates over the pros and cons of a "publish or perish" philosophy have inflamed academia for at least half a century. Growing concerns, in particular, are expressed for policies that reward "quantity" at the expense of "quality," because these might prompt scientists to unduly multiply their publications by fractioning ("salami slicing"), duplicating, rushing, simplifying, or even fabricating their results. To assess the reasonableness of these concerns, we analyzed publication patterns of over 40,000 researchers that, between the years 1900 and 2013, have published two or more papers within 15 years, in any of the disciplines covered by the Web of Science. The total number of papers published by researchers during their early career period (first fifteen years) has increased in recent decades, but so has their average number of co-authors. If we take the latter factor into account, by measuring productivity fractionally or by only counting papers published as first author, we observe no increase in productivity throughout the century. Even after the 1980s, adjusted productivity has not increased for most disciplines and countries. These results are robust to methodological choices and are actually conservative with respect to the hypothesis that publication rates are growing. Therefore, the widespread belief that pressures to publish are causing the scientific literature to be flooded with salami-sliced, trivial, incomplete, duplicated, plagiarized and false results is likely to be incorrect or at least exaggerated.

PMID: 26960191 [PubMed - as supplied by publisher]

Molecular Interaction between Stress and Pain.

Anesthesiology. 2016 Mar 10;

Authors: Flood P, Clark JD

PMID: 26959842 [PubMed - as supplied by publisher]

Telephone Problem-Solving Treatment Improves Sleep Quality in Service Members With Combat-Related Mild Traumatic Brain Injury: Results From a Randomized Clinical Trial.

J Head Trauma Rehabil. 2016 Mar-Apr;31(2):147-157

Authors: Vuletic S, Bell KR, Jain S, Bush N, Temkin N, Fann JR, Stanfill KE, Dikmen S, Brockway JA, He F, Ernstrom K, Raman R, Grant G, Stein MB, Gahm GA, CONTACT Investigators

Abstract
OBJECTIVE: Evaluate sleep quality, its correlates, and the effect of telephone-based problem-solving treatment (PST) in active duty postdeployment service members with mild traumatic brain injury (mTBI) SETTING:: Randomized clinical trial.
PARTICIPANTS: Active duty service members with combat-related mTBI.
STUDY DESIGN: Education-only (EO) and PST groups (N = 178 each) received printed study materials and 12 educational brochures. The PST group additionally received up to 12 PST telephone calls addressing participant-selected issues. Outcomes were evaluated postintervention (6 months) and at 12 months.
MAIN MEASURE: Pittsburgh Sleep Quality Index.
RESULTS: Sleep quality was manifestly poor in both groups at baseline (Pittsburgh Sleep Quality Index = 12.5 ± 4). Overall sleep quality was significantly different between the PST and EO groups at 6 months (P = .003) but not at 12 months. Longitudinally, PST significantly improved sleep quality at 6 months (P = .001) but not over the follow-up. Low sleep quality was associated with concussion symptoms, pain, depression, and posttraumatic stress disorder at all time points (P < .0001).
CONCLUSIONS: Sleep disorders, common in postdeployment service members with mTBI, are strongly associated with the presence of pain, posttraumatic stress disorder, and depression. Telephone-based PST may be an effective therapeutic approach for reducing sleep disorders in this population. Research should focus on maintenance of treatment gains.

PMID: 26959668 [PubMed - as supplied by publisher]

Concordance of Actigraphy With Polysomnography in Traumatic Brain Injury Neurorehabilitation Admissions.

J Head Trauma Rehabil. 2016 Mar-Apr;31(2):117-125

Authors: Kamper JE, Garofano J, Schwartz DJ, Silva MA, Zeitzer J, Modarres M, Barnett SD, Nakase-Richardson R

Abstract
OBJECTIVE: To examine concordance of accelerometer-based actigraphy (ACG) with polysomnography (PSG) in the determination of sleep states in inpatients with traumatic brain injury (TBI), and examine the impact of injury severity and comorbid conditions (spasticity, apnea) on concordance.
PARTICIPANTS: This was a convenience sample of 50 participants with primarily severe TBI.
DESIGN: This was a retrospective chart review of concurrent administration of PSG with ACG in nonconsecutive rehabilitation admissions with TBI.
MAIN MEASURES: Total sleep time and sleep efficiency were measured by PSG and ACG.
RESULTS: Moderate to strong correlations between ACG and PSG were observed for total sleep time (r = 0.78, P < .01) and sleep efficiency (r = 0.66, P < .01). PSG and ACG estimates of total sleep time (316 minutes vs 325 minutes, respectively) and sleep efficiency (78% vs 77%, respectively) were statistically indistinguishable.
CONCLUSIONS: Actigraphy is a valid proxy for monitoring of sleep in this population across injury severity and common comorbidity groups. However, further research with larger sample sizes to examine concordance in patients with TBI with disorder of consciousness and spasticity is recommended.

PMID: 26959665 [PubMed - as supplied by publisher]

Deconstructing Dietary Restriction: A Case for Systems Approaches in Aging.

Cell Metab. 2016 Mar 8;23(3):395-396

Authors: Yeo R, Brunet A

Abstract
Dietary restriction is a robust and conserved intervention to slow aging and extend lifespan. In this issue of Cell Metabolism, Hou et al. (2016) use a systems biology approach in C. elegans to uncover key molecular nodes underlying the transcriptomic response to dietary restriction and predict novel regulators of lifespan.

PMID: 26959179 [PubMed - as supplied by publisher]

Intrinsic Selectivity and Structure Sensitivity of Rhodium Catalysts for C2+ Oxygenate Production.

J Am Chem Soc. 2016 Mar 9;

Authors: Yang N, Medford AJ, Liu X, Studt F, Bligaard T, Bent SF, Nørskov JK

Abstract
Synthesis gas (CO + H2) conversion is a promising route to converting coal, natural gas, or biomass into synthetic liquid fuels. Rhodium has long been studied as it is the only elemental catalyst that has demonstrated selectivity to ethanol and other C2+ oxygenates. However, the fundamentals of syngas conversion over rhodium are still debated. In this work a microkinetic model is developed for conversion of CO and H2 into methane, ethanol, and acetaldehyde on the Rh (211) and (111) surfaces, chosen to describe steps and close-packed facets on catalyst particles. The model is based on DFT calculations using the BEEF-vdW functional. The mean-field kinetic model includes lateral adsorbate-adsorbate interactions, and the BEEF-vdW error estimation ensemble is used to propagate error from the DFT calculations to the predicted rates. The model shows the Rh(211) surface to be ∼6 orders of magnitude more active than the Rh(111) surface, but highly selective toward methane, while the Rh(111) surface is intrinsically selective toward acetaldehyde. A variety of Rh/SiO2 catalysts are synthesized, tested for catalytic oxygenate production, and characterized using TEM. The experimental results indicate that the Rh(111) surface is intrinsically selective toward acetaldehyde, and a strong inverse correlation between catalytic activity and oxygenate selectivity is observed. Furthermore, iron impurities are shown to play a key role in modulating the selectivity of Rh/SiO2 catalysts toward ethanol. The experimental observations are consistent with the structure-sensitivity predicted from theory. This work provides an improved atomic-scale understanding and new insight into the mechanism, active site, and intrinsic selectivity of syngas conversion over rhodium catalysts and may also guide rational design of alloy catalysts made from more abundant elements.

PMID: 26958997 [PubMed - as supplied by publisher]

Hunting Viral Receptors Using Haploid Cells.

Annu Rev Virol. 2015 Nov 9;2(1):219-239

Authors: Pillay S, Carette JE

Abstract
Viruses have evolved intricate mechanisms to gain entry into the host cell. Identification of host proteins that serve as viral receptors has enabled insights into virus particle internalization, host and tissue tropism, and viral pathogenesis. In this review we discuss the most commonly employed methods for virus receptor discovery, specifically highlighting the use of forward genetic screens in human haploid cells. The ability to generate true knockout alleles at high saturation provides a sensitive means to study virus-host interactions. To illustrate the power of such haploid genetic screens, we highlight the discovery of the lysosomal proteins NPC1 and LAMP1 as intracellular receptors for Ebola virus and Lassa virus, respectively. From these studies emerges the notion that receptor usage by these viruses is highly dynamic, involving a programmed switch from cell surface receptor to intracellular receptor. Broad application of genetic knockout approaches will chart functional landscapes of receptors and endocytic pathways hijacked by viruses.

PMID: 26958914 [PubMed - as supplied by publisher]

Crystal structures of the M1 and M4 muscarinic acetylcholine receptors.

Nature. 2016 Mar 9;

Authors: Thal DM, Sun B, Feng D, Nawaratne V, Leach K, Felder CC, Bures MG, Evans DA, Weis WI, Bachhawat P, Kobilka TS, Sexton PM, Kobilka BK, Christopoulos A

Abstract
Muscarinic M1-M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer's disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains.

PMID: 26958838 [PubMed - as supplied by publisher]

Identification of the dominant photochemical pathways and mechanistic insights to the ultrafast ligand exchange of Fe(CO)5 to Fe(CO)4EtOH.

Struct Dyn. 2016 Jul;3(4):043204

Authors: Kunnus K, Josefsson I, Rajkovic I, Schreck S, Quevedo W, Beye M, Weniger C, Grübel S, Scholz M, Nordlund D, Zhang W, Hartsock RW, Gaffney KJ, Schlotter WF, Turner JJ, Kennedy B, Hennies F, de Groot FM, Techert S, Odelius M, Wernet P, Föhlisch A

Abstract
We utilized femtosecond time-resolved resonant inelastic X-ray scattering and ab initio theory to study the transient electronic structure and the photoinduced molecular dynamics of a model metal carbonyl photocatalyst Fe(CO)5 in ethanol solution. We propose mechanistic explanation for the parallel ultrafast intra-molecular spin crossover and ligation of the Fe(CO)4 which are observed following a charge transfer photoexcitation of Fe(CO)5 as reported in our previous study [Wernet et al., Nature 520, 78 (2015)]. We find that branching of the reaction pathway likely happens in the (1)A1 state of Fe(CO)4. A sub-picosecond time constant of the spin crossover from (1)B2 to (3)B2 is rationalized by the proposed (1)B2 → (1)A1 → (3)B2 mechanism. Ultrafast ligation of the (1)B2 Fe(CO)4 state is significantly faster than the spin-forbidden and diffusion limited ligation process occurring from the (3)B2 Fe(CO)4 ground state that has been observed in the previous studies. We propose that the ultrafast ligation occurs via (1)B2 → (1)A1 → (1)A' Fe(CO)4EtOH pathway and the time scale of the (1)A1 Fe(CO)4 state ligation is governed by the solute-solvent collision frequency. Our study emphasizes the importance of understanding the interaction of molecular excited states with the surrounding environment to explain the relaxation pathways of photoexcited metal carbonyls in solution.

PMID: 26958587 [PubMed]

NCCN Guidelines Insights: Non-Small Cell Lung Cancer, Version 4.2016.

J Natl Compr Canc Netw. 2016 Mar;14(3):255-64

Authors: Ettinger DS, Wood DE, Akerley W, Bazhenova LA, Borghaei H, Camidge DR, Cheney RT, Chirieac LR, D'Amico TA, Dilling TJ, Dobelbower MC, Govindan R, Hennon M, Horn L, Jahan TM, Komaki R, Lackner RP, Lanuti M, Lilenbaum R, Lin J, Loo BW, Martins R, Otterson GA, Patel JD, Pisters KM, Reckamp K, Riely GJ, Schild SE, Shapiro TA, Sharma N, Stevenson J, Swanson SJ, Tauer K, Yang SC, Gregory K, Hughes M

Abstract
These NCCN Guidelines Insights focus on recent updates in the 2016 NCCN Guidelines for Non-Small Cell Lung Cancer (NSCLC; Versions 1-4). These NCCN Guidelines Insights will discuss new immunotherapeutic agents, such as nivolumab and pembrolizumab, for patients with metastatic NSCLC. For the 2016 update, the NCCN panel recommends immune checkpoint inhibitors as preferred agents (in the absence of contraindications) for second-line and beyond (subsequent) therapy in patients with metastatic NSCLC (both squamous and nonsquamous histologies). Nivolumab and pembrolizumab are preferred based on improved overall survival rates, higher response rates, longer duration of response, and fewer adverse events when compared with docetaxel therapy.

PMID: 26957612 [PubMed - in process]

Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple Negative Breast Cancer.

Clin Cancer Res. 2016 Mar 8;

Authors: Telli ML, Timms KM, Reid JE, Hennessy B, Mills GB, Jensen KC, Szallasi Z, Barry WT, Winer EP, Tung N, Isakoff SJ, Ryan PD, Greene-Colozzi A, Gutin A, Sangale Z, Iliev D, Neff C, Abkevich V, Jones JT, Lanchbury JS, Hartman AR, Garber JE, Ford JM, Silver DP, Richardson AL

Abstract
PURPOSE: <i>BRCA1/2</i> mutated and some sporadic triple negative breast cancers (TNBCs) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed based on loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST).
EXPERIMENTAL DESIGN: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score {greater than or equal to}42 or <i>BRCA1/2</i> mutation, with response to platinum-based therapy.
RESULTS: In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted Residual Cancer Burden score of 0 or 1 (RCB 0/1) and pathologic complete response (pCR) (OR=4.96, p=0.0036; OR=6.52, p=0.0058). HR deficiency remained a significant predictor of RCB 0/1 when adjusted for clinical variables (OR=5.86, p=0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/1 and pCR (OR=10.18, p=0.0011; OR=17.00, p=0.0066). In a multivariable model of RCB 0/1, HR deficiency retained significance when clinical variables were included (OR=12.08, p=0.0017). When restricted to <i>BRCA1/2</i> non-mutated tumors, response was higher in patients with high HRD scores: RCB 0/1 p=0.062, pCR p=0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/1 p=0.0039, pCR p=0.018 in the neoadjuvant cisplatin trials.
CONCLUSIONS: HR deficiency identifies TNBC tumors, including <i>BRCA1/2</i> non-mutated tumors more likely to respond to platinum-containing therapy.

PMID: 26957554 [PubMed - as supplied by publisher]

Trends in Enrollment, Clinical Characteristics, Treatment, and Outcomes According to Age in Non-ST-Segment Elevation Acute Coronary Syndromes Clinical Trials.

Circulation. 2016 Mar 8;

Authors: Kragholm K, Goldstein SA, Yang Q, Lopes RD, Schulte PJ, Bernacki GM, White HD, Mahaffey KW, Giugliano RP, Armstrong PW, Harrington RA, Tricoci P, Van de Werf F, Alexander JH, Alexander KP, Newby LK

Abstract
BACKGROUND: -Representation by age ensures appropriate translation of clinical trial results to practice, but historically, older patients were underrepresented in clinical trial populations. As the general population has aged, it is unknown whether clinical trial enrollment has changed in parallel.
METHODS AND RESULTS: -We studied time trends in enrollment, clinical characteristics, treatment, and outcomes by age among 76,141 NSTE ACS patients enrolled in 11 phase III clinical trials over 17 years (1994-2010). Overall, 19.7% of patients were ≥75 years; this proportion increased from 16% during 1994-1997 to 21% during 1998-2001 and 23.2% during 2002-2005, but declined to 20.2% in 2006-2010. The number of comorbidities increased with successive time periods irrespective of age. There were substantial increases in use of evidence-based medication in-hospital and at discharge regardless of age. While predicted 6-month mortality increased slightly over time, observed 6-month mortality declined significantly in all age strata (1994-1997 vs. 2006-2010: <65 years: 3.0% vs. 1.9%; 65-74 years: 7.5% vs. 3.4%; 75-79 years: 13.0% vs. 6.5%; 80-84 years: 17.6% vs. 8.2%; and ≥85 years: 24.8% vs. 12.6%).
CONCLUSIONS: -The distribution of enrollment by age in phase III NSTE ACS trials was unchanged over time. Irrespective of age, post-myocardial infarction mortality decreased significantly over time, concurrent with increased evidence-based care and despite increasing comorbidities. Clinical Trial Registration Information-ClinicalTrials.gov. Identifier: NCT00089895.

PMID: 26957532 [PubMed - as supplied by publisher]

The Kidney in Critical Cardiac Disease: Proceedings From the 10th International Conference of the Pediatric Cardiac Intensive Care Society.

World J Pediatr Congenit Heart Surg. 2016 Mar;7(2):152-63

Authors: Cooper DS, Basu RK, Price JF, Goldstein SL, Krawczeski CD

Abstract
The field of cardiac intensive care continues to advance in tandem with congenital heart surgery. The focus of intensive care unit care has now shifted to that of morbidity reduction and eventual elimination. Acute kidney injury (AKI) after cardiac surgery is associated with adverse outcomes, including prolonged intensive care and hospital stays, diminished quality of life, and increased long-term mortality. Acute kidney injury occurs frequently, complicating the care of both postoperative patients and those with heart failure. Patients who become fluid overloaded and/or require dialysis are at high risk of mortality, but even minor degrees of AKI portend a significant increase in mortality and morbidity. Clinicians continue to seek methods of early diagnosis and risk stratification of AKI to prevent its adverse sequelae. Previous conventional wisdom that survivors of AKI fully recover renal function without subsequent consequences may be flawed.

PMID: 26957397 [PubMed - in process]

New mechanism of lymphoma-induced bone marrow aplasia.

Ann Hematol. 2016 Mar 9;

Authors: Pierini A, Mancusi A, Terenzi A, Massei MS, Del Papa B, Zei T, Iacucci R, Falzetti F, Aversa F, Falini B, Ruggeri L, Velardi A

PMID: 26957358 [PubMed - as supplied by publisher]

Tools to facilitate the teaching and enhance the practice of psychopharmacology.

Asian J Psychiatr. 2016 Feb;19:21-2

Authors: Glick ID, Rush AJ

PMID: 26957331 [PubMed - in process]

Oxidation Effects in Rare Earth Doped Topological Insulator Thin Films.

Sci Rep. 2016;6:22935

Authors: Figueroa AI, van der Laan G, Harrison SE, Cibin G, Hesjedal T

Abstract
The breaking of time-reversal symmetry (TRS) in topological insulators is a prerequisite for unlocking their exotic properties and for observing the quantum anomalous Hall effect (QAHE). The incorporation of dopants which exhibit magnetic long-range order is the most promising approach for TRS-breaking. REBiTe3, wherein 50% of the Bi is substitutionally replaced by a RE atom (RE = Gd, Dy, and Ho), is a predicted QAHE system. Despite the low solubility of REs in bulk crystals of a few %, highly doped thin films have been demonstrated, which are free of secondary phases and of high crystalline quality. Here we study the effects of exposure to atmosphere of rare earth-doped Bi2(Se, Te)3 thin films using x-ray absorption spectroscopy. We demonstrate that these RE dopants are all trivalent and effectively substitute for Bi(3+) in the Bi2(Se, Te)3 matrix. We find an unexpected high degree of sample oxidation for the most highly doped samples, which is not restricted to the surface of the films. In the low-doping limit, the RE-doped films mostly show surface oxidation, which can be prevented by surface passivation, encapsulation, or in-situ cleaving to recover the topological surface state.

PMID: 26956771 [PubMed - in process]

Contraception in the Developing World: Special Considerations.

Semin Reprod Med. 2016 Mar 8;

Authors: Schivone GB, Blumenthal PD

Abstract
The United States Agency for International Development (USAID) estimates that there are 225 million women and girls with unmet contraceptive need yearly. Unmet need for contraception is defined as women who desire a delay in childbearing and are not using a modern method of contraception. It is projected that providing contraception to these women would avert 36 million abortions, 70,000 maternal deaths, and 52 million unintended pregnancies overall. In the past 30 years, there has been an increase both in population and in contraception use in the developing world. As a result, it is estimated that in 2015 there were 500 million contraceptive users in developing countries, which is nearly double the prevalence in 2000. Unfortunately, women and girls in developing nations still face many obstacles in obtaining modern methods of contraception. Particular challenges in the developing world include lack of access due to inadequate number of trained providers, fewer method options, and "stock-outs" of contraceptive supplies. Innovative strategies for decreasing unmet need will have to address these challenges, and will necessarily involve programmatic solutions such as community-based distribution and social marketing campaigns. Additionally, increasing uptake of long-acting reversible contraceptive methods will be essential for achieving the goal of decreasing unmet need.

PMID: 26956690 [PubMed - as supplied by publisher]

Understanding non-performance reports for instrumental activity of daily living items in population analyses: a cross sectional study.

BMC Geriatr. 2016;16(1):64

Authors: Stineman MG, Xie D, Pan Q, Kurichi JE, Saliba D, Rose SM, Streim JE

Abstract
BACKGROUND: Concerns about using Instrumental Activities of Daily Living (IADLs) in national surveys come up frequently in geriatric and rehabilitation medicine due to high rates of non-performance for reasons other than health. We aim to evaluate the effect of different strategies of classifying "does not do" responses to IADL questions when estimating prevalence of IADL limitations in a national survey.
METHODS: Cross-sectional analysis of a nationally representative sample of 13,879 non-institutionalized adult Medicare beneficiaries included in the 2010 Medicare Current Beneficiary Survey (MCBS). Sample persons or proxies were asked about difficulties performing six IADLs. Tested strategies to classify non-performance of IADL(s) for reasons other than health were to 1) derive through multiple imputation, 2) exclude (for incomplete data), 3) classify as "no difficulty," or 4) classify as "difficulty." IADL stage prevalence estimates were compared across these four strategies.
RESULTS: In the sample, 1853 sample persons (12.4 % weighted) did not do one or more IADLs for reasons other than physical problems or health. Yet, IADL stage prevalence estimates differed little across the four alternative strategies. Classification as "no difficulty" led to slightly lower, while classification as "difficulty" raised the estimated population prevalence of disability.
CONCLUSIONS: These analyses encourage clinicians, researchers, and policy end-users of IADL survey data to be cognizant of possible small differences that can result from alternative ways of handling unrated IADL information. At the population-level, the resulting differences appear trivial when applying MCBS data, providing reassurance that IADL items can be used to estimate the prevalence of activity limitation despite high rates of non-performance.

PMID: 26956616 [PubMed - in process]

Quantitative CRISPR interference screens in yeast identify chemical-genetic interactions and new rules for guide RNA design.

Genome Biol. 2016;17(1):45

Authors: Smith JD, Suresh S, Schlecht U, Wu M, Wagih O, Peltz G, Davis RW, Steinmetz LM, Parts L, St Onge RP

Abstract
BACKGROUND: Genome-scale CRISPR interference (CRISPRi) has been used in human cell lines; however, the features of effective guide RNAs (gRNAs) in different organisms have not been well characterized. Here, we define rules that determine gRNA effectiveness for transcriptional repression in Saccharomyces cerevisiae.
RESULTS: We create an inducible single plasmid CRISPRi system for gene repression in yeast, and use it to analyze fitness effects of gRNAs under 18 small molecule treatments. Our approach correctly identifies previously described chemical-genetic interactions, as well as a new mechanism of suppressing fluconazole toxicity by repression of the ERG25 gene. Assessment of multiple target loci across treatments using gRNA libraries allows us to determine generalizable features associated with gRNA efficacy. Guides that target regions with low nucleosome occupancy and high chromatin accessibility are clearly more effective. We also find that the best region to target gRNAs is between the transcription start site (TSS) and 200 bp upstream of the TSS. Finally, unlike nuclease-proficient Cas9 in human cells, the specificity of truncated gRNAs (18 nt of complementarity to the target) is not clearly superior to full-length gRNAs (20 nt of complementarity), as truncated gRNAs are generally less potent against both mismatched and perfectly matched targets.
CONCLUSIONS: Our results establish a powerful functional and chemical genomics screening method and provide guidelines for designing effective gRNAs, which consider chromatin state and position relative to the target gene TSS. These findings will enable effective library design and genome-wide programmable gene repression in many genetic backgrounds.

PMID: 26956608 [PubMed - in process]

Location of metastases in cancer of unknown primary are not random and signal familial clustering.

Sci Rep. 2016;6:22891

Authors: Hemminki K, Sundquist K, Sundquist J, Hemminki A, Ji J

Abstract
Cancer of unknown primary (CUP) is a fatal disease diagnosed through metastases. It shows intriguing familial clustering with certain defined primary cancers. Here we examine whether metastatic location in CUP patients is related to primary non-CUP cancers in relatives based on the Swedish Cancer Registry. Standardized incidence ratios (SIRs) were calculated for CUP patients defined by metastatic location depending on cancer in their first degree relatives. SIRs for CUP were high in association with liver (3.94), ovarian (3.41), lung (2.43) and colorectal cancers (1.83) in relatives. The SIR was 1.63 for CUP with metastases in the abdomen when a relative was diagnosed with ovarian cancer. CUP with liver metastases associated with liver (1.44) cancer in relatives. CUP with head and neck region metastases associated with relatives' esophageal (2.87) cancer. CUP metastases in the thorax associated with a relative's cancers in the upper aerodigestive tract (2.14) and lung (1.74). The findings, matching metastatic location in CUP and primary cancer in relatives, could be reconciled if these cases of CUP constitute a phenotypically modified primary lacking tissue identification, resulting from epitope immunoediting. Alternatively, CUP metastases arise in a genetically favored tissue environment (soil) promoting growth of both primary cancers and metastases (seeds).

PMID: 26956545 [PubMed - in process]

Lack of cortistatin or somatostatin differentially influences DMBA-induced mammary gland tumorigenesis in mice in an obesity-dependent mode.

Breast Cancer Res. 2016;18(1):29

Authors: Luque RM, Villa-Osaba A, L-López F, Pozo-Salas AI, Sánchez-Sánchez R, Ortega-Salas R, de Lecea L, Álvarez-Benito M, López-Miranda J, Gahete MD, Castaño JP

Abstract
BACKGROUND: Somatostatin (SST) and cortistatin (CORT), two structurally and functionally related peptides, share a family of widespread receptors (sst1-5) to exert apparently similar biological actions, including endocrine/metabolic regulation and suppression of tumor cell proliferation. However, despite their therapeutic potential, attempts to apply SST-analogs to treat breast cancer have yielded unsatisfactory results. Actually, the specific roles of SST and CORT in mammary gland tumorigenesis (MGT), particularly in relation to metabolic dysregulation (i.e. obesity), remain unknown.
METHODS: The role of endogenous SST and CORT in carcinogen-induced MGT was investigated under normal (lean) and obesity conditions. To that end, SST- and CORT-knockout (KO) mice and their respective littermate-controls, fed low-fat (LF) or high-fat (HF) diets, were treated with 7,12-dimethyl-benza-anthracene (DMBA) once a week (wk) for 3 wk, and MGT was monitored for 25 wk. Additionally, we examined the effect of SST or CORT removal in the development of the mammary gland.
RESULTS: Lack of SST did not alter DMBA-induced MGT incidence under lean conditions; conversely, lack of endogenous CORT severely aggravated DMBA-induced MGT in LF-fed mice. These differences were not attributable to altered mammary gland development. HF-diet modestly increased the sensitivity to DMBA-induced carcinogenesis in control mice, whereas, as observed in LF-fed CORT-KO, HF-fed CORT-KO mice exhibited aggravated tumor incidence, discarding a major influence of obesity on these CORT actions. In marked contrast, HF-fed SST-KO mice exhibited much higher tumor incidence than LF-fed SST-KO mice, which could be associated with higher mammary complexity.
CONCLUSIONS: Endogenous SST and CORT distinctly impact on DMBA-induced MGT, in a manner that is strongly dependent on the metabolic/endocrine milieu (lean vs. obese status). Importantly, CORT, rather than SST, could represent a major inhibitor of MGT under normal/lean-conditions, whereas both neuropeptides would similarly influence MGT under obesity conditions. The mechanisms mediating these different effects likely involve mammary development and hormones, but the precise underlying factors are still to be fully elucidated. However, our findings comprise suggestive evidence that CORT-like molecules, rather than classic SST-analogs, may help to identify novel tools for the medical treatment of breast cancer.

PMID: 26956474 [PubMed - in process]

Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia.

Nat Commun. 2016;7:10933

Authors: Berndt SI, Camp NJ, Skibola CF, Vijai J, Wang Z, Gu J, Nieters A, Kelly RS, Smedby KE, Monnereau A, Cozen W, Cox A, Wang SS, Lan Q, Teras LR, Machado M, Yeager M, Brooks-Wilson AR, Hartge P, Purdue MP, Birmann BM, Vajdic CM, Cocco P, Zhang Y, Giles GG, Zeleniuch-Jacquotte A, Lawrence C, Montalvan R, Burdett L, Hutchinson A, Ye Y, Call TG, Shanafelt TD, Novak AJ, Kay NE, Liebow M, Cunningham JM, Allmer C, Hjalgrim H, Adami HO, Melbye M, Glimelius B, Chang ET, Glenn M, Curtin K, Cannon-Albright LA, Diver WR, Link BK, Weiner GJ, Conde L, Bracci PM, Riby J, Arnett DK, Zhi D, Leach JM, Holly EA, Jackson RD, Tinker LF, Benavente Y, Sala N, Casabonne D, Becker N, Boffetta P, Brennan P, Foretova L, Maynadie M, McKay J, Staines A, Chaffee KG, Achenbach SJ, Vachon CM, Goldin LR, Strom SS, Leis JF, Weinberg JB, Caporaso NE, Norman AD, De Roos AJ, Morton LM, Severson RK, Riboli E, Vineis P, Kaaks R, Masala G, Weiderpass E, Chirlaque MD, Vermeulen RC, Travis RC, Southey MC, Milne RL, Albanes D, Virtamo J, Weinstein S, Clavel J, Zheng T, Holford TR, Villano DJ, Maria A, Spinelli JJ, Gascoyne RD, Connors JM, Bertrand KA, Giovannucci E, Kraft P, Kricker A, Turner J, Ennas MG, Ferri GM, Miligi L, Liang L, Ma B, Huang J, Crouch S, Park JH, Chatterjee N, North KE, Snowden JA, Wright J, Fraumeni JF, Offit K, Wu X, de Sanjose S, Cerhan JR, Chanock SJ, Rothman N, Slager SL

Abstract
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10(-11)), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10(-8)) and 3q28 (rs9815073, LPP, P=3.62 × 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10(-11)) in the combined analysis. We find suggestive evidence (P<5 × 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

PMID: 26956414 [PubMed - in process]

Aberrant excitatory rewiring of layer V pyramidal neurons early after neocortical trauma.

Neurobiol Dis. 2016 Mar 5;

Authors: Takahashi DK, Gu F, Parada I, Vyas S, Prince DA

Abstract
Lesioned neuronal circuits form new functional connections after a traumatic brain injury (TBI). In humans and animal models, aberrant excitatory connections that form after TBI may contribute to the pathogenesis of post-traumatic epilepsy. Partial neocortical isolation ("undercut" or "UC") leads to altered neuronal circuitry and network hyperexcitability recorded in vivo and in brain slices from chronically lesioned neocortex. Recent data suggest a critical period for maladaptive excitatory circuit formation within the first 3days post UC injury (Graber and Prince 1999, 2004; Li et al. 2011, 2012b). The present study focuses on alterations in excitatory connectivity within this critical period. Immunoreactivity (IR) for growth-associated protein (GAP)-43 was increased in the UC cortex 3days after injury. Some GAP-43-expressing excitatory terminals targeted the somata of layer V pyramidal (Pyr) neurons, a domain usually innervated predominantly by inhibitory terminals. Immunocytochemical analysis of pre- and postsynaptic markers showed that putative excitatory synapses were present on somata of these neurons in UC neocortex. Excitatory postsynaptic currents from UC layer V Pyr cells displayed properties consistent with perisomatic inputs and also reflected an increase in the number of synaptic contacts. Laser scanning photostimulation (LSPS) experiments demonstrated reorganized excitatory connectivity after injury within the UC. Concurrent with these changes, spontaneous epileptiform bursts developed in UC slices. Results suggest that aberrant reorganization of excitatory connectivity contributes to early neocortical hyperexcitability in this model. The findings are relevant for understanding the pathophysiology of neocortical post-traumatic epileptogenesis and are important in terms of the timing of potential prophylactic treatments.

PMID: 26956396 [PubMed - as supplied by publisher]

[18F]FDG PET/MRI of patients with chronic pain alters management: early experience.

EJNMMI Phys. 2015 Dec;2(Suppl 1):A84

Authors: Biswal S, Behera D, Yoon DH, Holley D, Ith MA, Carroll I, Smuck M, Hargreaves B

PMID: 26956346 [PubMed]

Correlation between arterial spin labeling MRI and dynamic FDG on PET-MR in Alzheimer's disease and non-Alzhiemer's disease patients.

EJNMMI Phys. 2015 Dec;2(Suppl 1):A83

Authors: Douglas D, Goubran M, Wilson E, Xu G, Tripathi P, Holley D, Chao S, Wintermark M, Quon A, Zeineh M, Vasanawala M, Zaharchuk G

PMID: 26956345 [PubMed]

The potential of TOF PET-MRI for reducing artifacts in PET images.

EJNMMI Phys. 2015 Dec;2(Suppl 1):A77

Authors: Iagaru A, Minamimoto R, Levin C, Barkhodari A, Jamali M, Holley D, Greg Z

PMID: 26956338 [PubMed]

Assessment of PET & ASL metabolism in the hippocampal subfields of MCI and AD using simultaneous PET-MR.

EJNMMI Phys. 2015 Dec;2(Suppl 1):A73

Authors: Goubran M, Douglas D, Chao S, Quon A, Tripathi P, Holley D, Vasanawala M, Zaharchuk G, Zeineh M

PMID: 26956334 [PubMed]

Imaging patients with breast and prostate cancers using combined 18F NaF/18F FDG and TOF simultaneous PET/ MRI.

EJNMMI Phys. 2015 Dec;2(Suppl 1):A65

Authors: Iagaru A, Minamimoto R, Jamali M, Barkodhodari A, Gambhir SS, Vasanawala S

PMID: 26956325 [PubMed]

Whole-body simultaneous time-of-flight PET-MRI: early experience with clinical studies.

EJNMMI Phys. 2015 Dec;2(Suppl 1):A64

Authors: Minamimoto R, Iagaru A, Jamali M, Barkodhodari A, Holley D, Vasanawala S, Zaharchuk G

PMID: 26956324 [PubMed]

Dynamic brain PET/MR using TOF reconstruction.

EJNMMI Phys. 2015 Dec;2(Suppl 1):A60

Authors: Khalighi MM, Delso G, Tohme M, Iagaru A, Zaharchuk G

PMID: 26956320 [PubMed]

Successful demonstration of simultaneous PET/MR Imaging with a RF-penetrable PET insert.

EJNMMI Phys. 2015 Dec;2(Suppl 1):A17

Authors: Lee B, Grant A, Chang CM, Glover G, Levin C

PMID: 26956272 [PubMed]

Impaired Arm Function and Finger Dexterity in a Nonhuman Primate Model of Stroke: Motor and Cognitive Assessments.

Stroke. 2016 Mar 8;

Authors: McEntire CR, Choudhury GR, Torres A, Steinberg GK, Redmond DE, Daadi MM

Abstract
BACKGROUND AND PURPOSE: Ischemic stroke is the leading cause of upper extremity motor impairments. Although several well-characterized experimental stroke models exist, modeling of upper extremity motor impairments, which are unique to primates, is not well established. Cortical representation of dexterous movements in nonhuman primates is functionally and topographically similar to that in humans. In this study, we characterize the African green monkey model of focal ischemia reperfusion with a defined syndrome, impaired dexterous movements.
METHODS: Cerebral ischemia was induced by transient occlusion of the M3 segment of the left middle cerebral artery. Motor and cognitive functions after stroke were evaluated using the object retrieval task with barrier-detour. Postmortem magnetic resonance imaging and histopathology were performed to map and characterize the infarct.
RESULTS: The middle cerebral artery occlusion consistently produced a necrotic infarct localized in the sensorimotor cortex in the middle cerebral artery territory. The infarction was reproducible and resulted in significant loss of fine motor function characterized by impaired dexterity. No significant cognitive impairment was detected. Magnetic resonance imaging and histopathology demonstrated consistent and significant loss of tissue on the left parietal cortex by the central sulcus covering the sensorimotor area. The results suggest that this species has less collateralization, which closely resembles humans.
CONCLUSIONS: The reported nonhuman primate model produces a defined and reproducible syndrome relevant to our understanding of ischemic stroke, cortical representation, and sensorimotor integration controlling dexterous movements. This model will be useful in basic and translational research addressing loss of arm function and dexterity.

PMID: 26956259 [PubMed - as supplied by publisher]

Nuclear DNA damage signalling to mitochondria in ageing.

Nat Rev Mol Cell Biol. 2016 Mar 9;

Authors: Fang EF, Scheibye-Knudsen M, Chua KF, Mattson MP, Croteau DL, Bohr VA

Abstract
Mitochondrial dysfunction is a hallmark of ageing, and mitochondrial maintenance may lead to increased healthspan. Emerging evidence suggests a crucial role for signalling from the nucleus to mitochondria (NM signalling) in regulating mitochondrial function and ageing. An important initiator of NM signalling is nuclear DNA damage, which accumulates with age and may contribute to the development of age-associated diseases. DNA damage-dependent NM signalling constitutes a network that includes nuclear sirtuins and controls genomic stability and mitochondrial integrity. Pharmacological modulation of NM signalling is a promising novel approach for the prevention and treatment of age-associated diseases.

PMID: 26956196 [PubMed - as supplied by publisher]

Identification of human juvenile chondrocyte-specific factors that stimulate stem cell growth.

Tissue Eng Part A. 2016 Mar 9;

Authors: Taylor SE, Lee J, Smeriglio P, Razzaque A, Smith RL, Dragoo JL, Maloney W, Bhutani N

Abstract
Although regeneration of human cartilage is inherently inefficient, age is an important risk factor for Osteoarthritis (OA). Recent reports have provided compelling evidence that juvenile chondrocytes (from donors below 13 years of age) are more efficient at generating articular cartilage as compared to adult chondrocytes. However, the molecular basis for such a superior regenerative capability is not understood. In order to identify the cell-intrinsic differences between juvenile and adult cartilage, we have systematically profiled global gene expression changes between a small cohort of human neonatal/juvenile and adult chondrocytes. No such study is available for human chondrocytes although 'young' and 'old' bovine and equine cartilage have been recently profiled. Our studies have identified and validated new factors enriched in juvenile chondrocytes as compared to adult chondrocytes including secreted ECM factors Chordin-like 1 (CHRDL1) and Microfibrillar-associated protein 4 (MFAP4). Network analyses identified cartilage development pathways, epithelial to mesenchymal transition and innate immunity pathways to be overrepresented in juvenile-enriched genes. Finally, CHRDL1 was observed to aid the proliferation and survival of human bone-marrow derived mesenchymal stem cells (MSC) while maintaining their stem cell potential. These studies therefore provide a mechanism for how young cartilage factors can potentially enhance stem cell function in cartilage repair.

PMID: 26955889 [PubMed - as supplied by publisher]

Reviewer acknowledgement.

Neural Dev. 2016;11(1):6

Authors: Doe CQ, Harris W, Shen K, Wong R

Abstract
CONTRIBUTING REVIEWERS: The editors of Neural Development would like to thank all the reviewers who have contributed to the journal in Volume 10 (2015).

PMID: 26955875 [PubMed - in process]

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF.

J Am Heart Assoc. 2016;5(3)

Authors: Pokorney SD, Piccini JP, Stevens SR, Patel MR, Pieper KS, Halperin JL, Breithardt G, Singer DE, Hankey GJ, Hacke W, Becker RC, Berkowitz SD, Nessel CC, Mahaffey KW, Fox KA, Califf RM, ROCKET AF Steering Committee & Investigators, ROCKET AF Steering Committee Investigators

Abstract
BACKGROUND: Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions.
METHODS AND RESULTS: In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS2 score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P<0.0001) were associated with higher all-cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C-index 0.677).
CONCLUSIONS: In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

PMID: 26955859 [PubMed - in process]

Emotional expressiveness and avoidance in narratives of unaccompanied refugee minors.

Eur J Psychotraumatol. 2016;7:29163

Authors: Huemer J, Nelson K, Karnik N, Völkl-Kernstock S, Seidel S, Ebner N, Ryst E, Friedrich M, Shaw RJ, Realubit C, Steiner H, Skala K

Abstract
OBJECTIVE: The aim of this study was to examine a cohort of unaccompanied refugee minors (URMs) by means of psycholinguistic methods in order to obtain a more subtle picture of their degree of traumatization.
METHODS: Twenty-eight participants were included in the Stress-Inducing Speech Task (SIST) consisting of a free association (FA) and a stress (STR) condition. Narratives were examined by means of (1) quantitative parameters (word count); (2) psycholinguistic variables (temporal junctures, TJs), narrative structure, referential activity (RA)-a measure of emotional expressivity; and (3) content analysis ratings.
RESULTS: Word count was significantly lower than in age-matched norms. In the FA condition, TJs were lower, but in the STR condition, rates were comparable. RA was significantly higher in both conditions. Content analysis ratings showed that the experiences described by these youths were potentially traumatic in nature.
CONCLUSIONS: This pattern of narrative shows a mixture of fulfilling the task demand, while containing an emotionally charged narrative. Narrative structure was absent in the FA condition, but preserved in the STR condition, as URMs struggled with the description of non-normative events. This indicates that these youths have not yet emotionally dealt with and fully integrated their trauma experiences.

PMID: 26955827 [PubMed]

Real-Time PCR Assay for the Identification of the Brown Marmorated Stink Bug (Halyomorpha halys).

Front Mol Biosci. 2016;3:5

Authors: Dhami MK, Dsouza M, Waite DW, Anderson D, Li D

Abstract
The brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae), is a gregarious crop pest that has rapidly spread across the world in the last two decades. It is an excellent hitchhiker species, especially as an over-wintering adult. During this period it is often associated with non-biological commodities such as shipping containers and machinery that travel long distances. Inadequate identification keys and similarity to common species has assisted its spread across Europe, while accurate identification from immature stages or eggs is not possible. We developed a real-time TaqMan PCR assay for the accurate and sensitive detection of the brown marmorated stink bug from all life stages. The assay performance against required diagnostic criterion and within a quarantine framework are described.

PMID: 26955631 [PubMed]

Stereotactic laser ablation of the splenium for intractable epilepsy.

Epilepsy Behav Case Rep. 2016;5:23-6

Authors: Ho AL, Miller KJ, Cartmell S, Inoyama K, Fisher RS, Halpern CH

Abstract
Partial or complete corpus callosotomies have been applied, traditionally via open surgical or radiosurgical approaches, for the treatment of epilepsy in patients with multifocal tonic, atonic, or myoclonic seizures. Minimally invasive methods, such as MRI-guided laser interstitial thermal ablation (MTLA), are being employed to functionally remove or ablate seizure foci in the treatment of epilepsy. This therapy can achieve effectiveness similar to that of traditional resection, but with reduced morbidity compared with open surgery. Here, we present a patient with a history of prior partial corpus callosotomy who continued to suffer from medically refractory epilepsy with bisynchronous onset. We report on the utilization of laser ablation of the splenium in this patient to achieve full corpus callosotomy. Adequate ablation of the splenial remnant was confirmed by postoperative MRI imaging, and at four-month follow-up, the patient's seizure frequency had dropped more than 50%. This is the first reported instance of laser ablation of the splenium to achieve full corpus callosotomy following a previous unsuccessful anterior callosotomy in a patient with intractable generalized epilepsy.

PMID: 26955518 [PubMed]

The effects of dopamine on digit span in Parkinson's disease.

J Clin Mov Disord. 2016;3:5

Authors: Warden C, Hwang J, Marshall A, Fenesy M, Poston KL

Abstract
BACKGROUND: Parkinson's disease patients are at an elevated risk of developing cognitive impairment. Although cognitive impairment is one of the strongest predictors of quality of life, dopaminergic anti-parkinsonian medications are designed to target motor symptoms. However, there is substantial evidence that dopamine also impacts cognition, in particular working memory. It is therefore critical for movement disorders physicians to understand the potential dopaminergic effects on working memory when prescribing these medications. Verbal digit span tasks offer a potentially straightforward and quick assessment of baseline working memory. Moreover, Digit Span Backward was recently validated as a screening tool for mild cognitive impairment in Parkinson's disease when participants were medicated. Research indicates that the interaction between dopamine and working memory follows an Inverted-U shaped curve, but the effect of dopamine on Digit Span has not been well studied. Our study seeks to: (1) determine the validity of verbal Digit Spans for detecting cognitive impairment in Parkinson's disease patients both ON and OFF medications; and (2) ascertain the effects of dopaminergic medications on verbal Digit Span.
METHODS: We recruited 64 Parkinson's disease patients and 22 age-and education-matched controls. Parkinson's patients completed Digit Span Backward and Digit Span Forward ON and OFF medications, while healthy controls completed them once. All participants were categorized by cognitive diagnosis using level-II consensus criteria.
RESULTS: Digit Span Backward successfully identified mild cognitive impairment in Parkinson's disease, both ON and OFF medications. Combining patients with and without cognitive impairment, we found that dopamine significantly improved performance on Digit Span Backward, but not Forward. In a secondary analysis, we found this dopaminergic improvement was restricted to the Low baseline working memory group; the High baseline working memory group was unaffected.
CONCLUSIONS: This study provides evidence for Digit Span Backward as a screening tool for working memory impairment in Parkinson's disease and for its utility in measuring baseline working memory. Moreover, it reveals a partial beneficial effect of dopamine on Digit Span in Parkinson's disease patients.

PMID: 26955482 [PubMed]

Do Ground-Dwelling Vertebrates Promote Diversity in a Neotropical Forest? Results from a Long-Term Exclosure Experiment.

Bioscience. 2015 Sep 1;65(9):862-870

Authors: Kurten EL, Carson WP

Abstract
Using a decade-long exclosure experiment in Panama, we tested the hypothesis that ground-dwelling vertebrate herbivores and seed predators are crucial determinants of tropical tree diversity and abundance within the understory. Our exclosure experiment is a community-level test of the Janzen-Connell hypothesis. Therefore, we predicted that vertebrate exclusion would (a) increase plant densities and (b) lower richness, diversity, and evenness. Excluding vertebrates caused a 38%-46% increase in plant densities, which, in contrast to our predictions, caused species richness to increase by 12%-15%. Because vertebrate exclusion causes plant species richness to increase, not decrease, vertebrates are unlikely to be causal agents of Janzen-Connell effects. We synthesized this and previous studies to explore why plant richness responds differently to defaunation and exclosures in tropical forests worldwide. Likely because of their contrasting effects on mesoconsumers, defaunation and exclosures cause decreases and increases in plant density respectively, which in turn cause corresponding changes in richness.

PMID: 26955084 [PubMed - as supplied by publisher]

High Time for Conservation: Adding the Environment to the Debate on Marijuana Liberalization.

Bioscience. 2015 Aug 1;65(8):822-829

Authors: Carah JK, Howard JK, Thompson SE, Short Gianotti AG, Bauer SD, Carlson SM, Dralle DN, Gabriel MW, Hulette LL, Johnson BJ, Knight CA, Kupferberg SJ, Martin SL, Naylor RL, Power ME

Abstract
The liberalization of marijuana policies, including the legalization of medical and recreational marijuana, is sweeping the United States and other countries. Marijuana cultivation can have significant negative collateral effects on the environment that are often unknown or overlooked. Focusing on the state of California, where by some estimates 60%-70% of the marijuana consumed in the United States is grown, we argue that (a) the environmental harm caused by marijuana cultivation merits a direct policy response, (b) current approaches to governing the environmental effects are inadequate, and

PMID: 26955083 [PubMed - as supplied by publisher]

Strategic Actions to Value, Conserve, and Restore the Natural Capital of Megadiversity Countries: The Case of Mexico.

Bioscience. 2015 Feb 1;65(2):164-173

Authors: Sarukhán J, Urquiza-Haas T, Koleff P, Carabias J, Dirzo R, Ezcurra E, Cerdeira-Estrada S, Soberón J

Abstract
Decisionmakers need updated, scientifically sound and relevant information to implement appropriate policy measures and make innovative commitments to halt biodiversity loss and improve human well-being. Here, we present a recent science-based synthesis on the biodiversity and ecosystem services of Mexico, intended to be a tool for policymakers. We describe the methodological approach used to undertake such an assessment and highlight the major findings. Organized into five volumes and originally written in Spanish (Capital Natural de México), it summarizes the available knowledge on the components, structure, and functioning of the biodiversity of Mexico; the threats and trajectories of anthropogenic impact, together with its conservation status; and the policies, institutions, and instruments available for its sustainable management. We stress the lessons learned that can be useful for similar exercises in other megadiverse developing countries and identify major gaps and strategic actions to conserve the natural capital in light of the challenges of the Anthropocene.

PMID: 26955077 [PubMed - as supplied by publisher]

Should We Excise Native Breast Skin Envelope to Achieve Symmetric Scars in Bilateral Autologous Breast Reconstruction?-A Survey of Surgeon and Patient Preference.

Ann Plast Surg. 2016 Mar 5;

Authors: Garza RM, Chen TA, Lee GK

Abstract
BACKGROUND: Given the multiple possible scar patterns in autologous breast reconstruction and combinations of such patterns in bilateral reconstruction, the present study aimed to determine the importance of scar symmetry in achieving aesthetically pleasing results.
METHODS: A survey was administered to 128 participants including plastic surgeons and female breast reconstruction patients. In part A of the survey, participants were provided with photos of bilateral autologous breast reconstructions, and scar placement was varied to represent bilateral (1) immediate, (2) delayed symmetric, (3) delayed asymmetric, and (4) a mixture of immediate and delayed free flap reconstructions. Participants were asked to rank the photos in order of best to worst aesthetic outcome. In part B, pairs of the same reconstruction before and after nipple-areolar complex (NAC) reconstruction were presented, and participants were asked to assign a score to each photo according to aesthetic outcome.
RESULTS: In part A, immediate reconstructions that included the smallest flap skin paddles ranked best among 52.5% ± 30% of participants, followed by delayed symmetric reconstructions that ranked best in 46.7% ± 29.6%. Mixed reconstructions ranked worst among 53.6% ± 37.6% of participants, followed by delayed asymmetric reconstructions (42.5% ± 37.9%). When NAC reconstruction was added to 1 set of the photos in part A, the same immediate reconstruction was ranked best, a significantly higher proportion of the time (36.3% increase, P < 0.001). This was accompanied by a significant decrease in top ranking for the delayed symmetric reconstruction (37.9% decrease, P < 0.001). In part B, addition of NAC increased each reconstruction's score by an average of 1.36 points on a 5-point scale with patients citing less improvement between the conditions (0.93 ± 0.03) than plastic surgeons (1.13 ± 0.49) (P = 0.03).
CONCLUSIONS: More symmetric breast scars led to higher aesthetic ranking of bilateral autologous breast reconstructions. Participants in our survey preferred symmetric scars, even if achieving such a scar pattern would require excision of native breast skin and inclusion of more flap skin. Furthermore, NAC reconstruction alone improves aesthetic outcome, and improvement was most notable among immediate reconstructions.

PMID: 26954739 [PubMed - as supplied by publisher]

Double-Chamber Tissue Expanders Optimize Lower Pole Expansion in Immediate Breast Reconstruction Requiring Adjuvant Radiation Therapy.

Ann Plast Surg. 2016 Mar 5;

Authors: Fischer LH, Nguyen D

Abstract
INTRODUCTION: Tissue expander-based reconstruction in the irradiated breast has been associated with significant complications, including infection, skin breakdown and implant extrusion, and poor aesthetic outcome. These complications may be attributed to inadequate lower pole expansion causing increased pressure on the suture line. Achieving and maintaining adequate lower pole expansion in the reconstructed breast requiring adjuvant radiation therapy may reduce the pressure/strain on the suture line and preserve the natural appearance of the breast. We describe the effective use of a double-chamber tissue expander to control lower pole expansion in immediate breast reconstruction requiring adjuvant radiation therapy.
METHODS: We performed a retrospective chart review of patients who underwent postoperative radiation therapy after immediate breast reconstruction using Sientra's double-chamber tissue expander, performed by a single plastic surgeon from 2012 to 2014.
RESULTS: A total of 22 patients met our inclusion criteria. Seventeen patients had bilateral, and 5 patients had unilateral reconstruction (n = 39 total breasts). All patients were over expanded by 20% on the side affected by cancer before the start of radiation, which started by the sixth postoperative week. There was no expansion during radiation therapy. Two patients had further expansion after radiation therapy was completed. The tissue expanders were exchanged for shaped silicone gel implants 3 to 4 months after completion of radiation.A total of 2 complications occurred in 2 patients (9.0%) and 2 breasts (5.1%). These included an infection in one patient and a tissue expander leak in another. No patient developed Baker grade 3 or 4 capsular contracture, seroma, or device malposition. Good lower pole contour and projection was maintained in all breasts at 9 to 12 months of follow-up.
CONCLUSIONS: The double-chamber tissue expander is effective in controlling shape, contour, and position of the breast following immediate tissue expander reconstruction requiring adjuvant radiation therapy, with decreased complication rates compared to standard expanders. These results suggest that double-chamber tissue expanders may be the preferred expander option in patients requiring adjuvant radiation therapy. Prospective clinical studies are needed to better evaluate the advantages of this reconstructive approach.

PMID: 26954736 [PubMed - as supplied by publisher]

Association Between Hypertensive Disorders of Pregnancy and Later Risk of Cardiomyopathy.

JAMA. 2016 Mar 8;315(10):1026-33

Authors: Behrens I, Basit S, Lykke JA, Ranthe MF, Wohlfahrt J, Bundgaard H, Melbye M, Boyd HA

Abstract
IMPORTANCE: Women with hypertensive disorders of pregnancy, preeclampsia in particular, have an increased risk of cardiomyopathy during the peripartum period. Whether hypertensive disorders of pregnancy are also associated with cardiomyopathy later in life is unknown.
OBJECTIVE: To determine whether hypertensive disorders of pregnancy are associated with cardiomyopathy beyond the peripartum period.
DESIGN, SETTING, AND PARTICIPANTS: Nationwide register-based cohort study using Cox regression to compare rates of cardiomyopathy in women with and without a history of hypertensive disorders of pregnancy in a cohort of 1,075,763 women with at least 1 pregnancy ending in live birth or stillbirth in Denmark, 1978-2012, with follow-up through December 31, 2012.
EXPOSURES: A hypertensive disorder of pregnancy (severe or moderate preeclampsia or gestational hypertension) registered in the National Patient Register.
MAIN OUTCOMES AND MEASURES: Cardiomyopathy more than 5 months after delivery (outside the peripartum period) up to 34 years 7 months.
RESULT: The women in the primary cohort had 2,067,633 eligible pregnancies during the study period, 76,108 of which were complicated by a hypertensive disorder of pregnancy. During follow-up, 1577 women (mean age, 48.5 years at cardiomyopathy diagnosis; 2.6% with multiple pregnancies) developed cardiomyopathy. Compared with women with normotensive pregnancies (18,211,603 person-years of follow-up; n = 1408 cardiomyopathy events, 7.7/100,000 person-years [95% CI, 7.3-8.2]), women with a history of hypertensive disorders of pregnancy had significantly increased rates of cardiomyopathy (in 173,062 person-years of follow-up among women with severe preeclampsia, n = 27 cardiomyopathy events; 15.6/100,000 person-years [95% CI, 10.7-22.7]; adjusted hazard ratio [HR], 2.20 [95% CI, 1.50-3.23]; in 697,447 person-years of follow-up among women with moderate preeclampsia, n = 102 cardiomyopathy events; 14.6/100,000 person-years [95% CI, 12.0-17.8]; adjusted HR, 1.89 [95% CI, 1.55-2.23]; in 213,197 person-years of follow-up among women with gestational hypertension, n = 40 cardiomyopathy events; 17.3/100,000 person-years [95% CI, 12.7-23.6]; adjusted HR, 2.06 [95% CI, 1.50-2.82]). These increases persisted more than 5 years after the latest pregnancy. Mediation analyses suggested that only about 50% of the association was an indirect association through postpregnancy chronic hypertension. In this cohort, 11% of all cardiomyopathy events occurred in women with a history of hypertensive disorders of pregnancy.
CONCLUSIONS AND RELEVANCE: Women with a history of hypertensive disorders of pregnancy, compared with women without such a history, had a small but statistically significant increased risk of cardiomyopathy more than 5 months after delivery. Further research is necessary to understand whether there is a causal mechanism behind this association.

PMID: 26954411 [PubMed - in process]

Toxin Immunoassays and Clostridium difficile Infection.

JAMA Intern Med. 2016 Mar 1;176(3):413

Authors: Banaei N, Schroeder LF

PMID: 26954049 [PubMed - in process]

Health Coaching and COPD Re-hospitalization: a Randomized Study.

Am J Respir Crit Care Med. 2016 Mar 8;

Authors: Benzo R, Vickers K, Novotny PJ, Tucker S, Hoult J, Neuenfeldt P, Connett J, Lorig K, McEvoy C

Abstract
RATIONALE: Hospital readmission in Chronic Obstructive Pulmonary Disease (COPD) has attracted attention due to the burden to patients and the Health Care system. There is a knowledge gap on approaches to reduce COPD readmissions.
OBJECTIVE: Determine the effect of comprehensive Health Coaching, on the rate of COPD readmissions. Methods 215 hospitalized for a COPD exacerbation were randomized at hospital discharged to Motivational Interviewing based Health Coaching plus a written action plan for exacerbations and a brief exercise advice versus usual care. Measures Rate of COPD related hospitalization during the year-followup.
RESULTS: The Absolute Risk Reduction of COPD related re-hospitalization by health coaching was 7.5% p=0.01, 11.0% p=0.02, 11.6% p=0.03, 11.4% p=0.05 and 5.4% p=0.24 at 1, 3, 6, 9, and 12 months compared to the control group. The Odds Ratio for COPD Hospitalization on the Intervention Arm Compared to the Control was 0.08 (CI 0.01-0.70) at 1 month post discharge, 0.35 (CI 0.13-0.93) at 3 months post discharge, 0.30 (CI 0.12-0.73) at 6 months and 0.49 (CI 012-1.11) at 1 year post discharge. Missing value rate for the primary outcome was 0.4% (1 patient). Disease specific quality of life improved significantly in the health coaching group compared to the control group at 6 and 12 months by the Chronic Respiratory Questionnaire (CRQ) Emotional Score (Emotion-Mastery) and Physical Score (Dyspnea-Fatigue) p<0.05. There were no differences in the physical activity measured at any time points between groups. Conclusion Health Coaching may represent a feasible and possibly effective intervention to reduce COPD readmissions. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01058486.

PMID: 26953637 [PubMed - as supplied by publisher]

Evaluation Of A Maternal Health Program In Uganda And Zambia Finds Mixed Results On Quality Of Care And Satisfaction.

Health Aff (Millwood). 2016 Mar 1;35(3):510-9

Authors: Kruk ME, Vail D, Austin-Evelyn K, Atuyambe L, Greeson D, Grépin KA, Kibira SP, Macwan'gi M, Masvawure TB, Rabkin M, Sacks E, Simbaya J, Galea S

Abstract
Saving Mothers, Giving Life is a multidonor program designed to reduce maternal mortality in Uganda and Zambia. We used a quasi-random research design to evaluate its effects on provider obstetric knowledge, clinical confidence, and job satisfaction, and on patients' receipt of services, perceived quality, and satisfaction. Study participants were 1,267 health workers and 2,488 female patients. Providers' knowledge was significantly higher in Ugandan and Zambian intervention districts than in comparison districts, and in Uganda there were similar positive differences for providers' clinical confidence and job satisfaction. Patients in Ugandan intervention facilities were more likely to give high ratings for equipment availability, providers' knowledge and communication skills, and care quality, among other factors, than patients in comparison facilities. There were fewer differences between Zambian intervention and comparison facilities. Country differences likely reflect differing intensity of program implementation and the more favorable geography of intervention districts in Uganda than in Zambia. National investments in the health system and provider training and the identification of intervention components most associated with improved performance will be required for scaling up and sustaining the program.

PMID: 26953307 [PubMed - in process]

BAF chromatin remodelling complex is an epigenetic regulator of lineage specification in the early mouse embryo.

Development. 2016 Mar 7;

Authors: Panamarova M, Cox A, Wicher K, Butler R, Bulgakova N, Jeon S, Rosen B, Seong RH, Skarnes W, Crabtree G, Zernicka-Goetz M

Abstract
Dynamic control of gene expression is essential for development of a totipotent zygote into an embryo with defined cell lineages. The accessibility of genes responsible for cell specification to transcriptional machinery is dependent on chromatin remodelling complexes such as the SWI\SNF (BAF) complex. However, the role of the BAF complex in the early mouse development has remained unclear. Here we demonstrate that BAF155, a major BAF complex subunit, regulates the assembly of the BAF complex in vivo, and regulates lineage specification of a mouse blastocyst. We find that associations of BAF155 with other BAF complex subunits become enriched in extra-embryonic lineages just prior to implantation. This enrichment is attributed to decreased mobility of BAF155 in extra-embryonic compared to embryonic lineage. Down-regulation of BAF155 leads to increased expression of the pluripotency marker Nanog and its ectopic expression in extra-embryonic lineages, whereas up-regulation of BAF155 leads to up-regulation of differentiation markers. Finally, we show that arginine methyltransferase CARM1 methylates BAF155, which influences assembly of the BAF complex between the lineages and expression of pluripotency markers. Together our results indicate a novel role of BAF-dependent chromatin remodelling in mouse development via regulation of lineage specification.

PMID: 26952987 [PubMed - as supplied by publisher]

Developmental origin of lung macrophage diversity.

Development. 2016 Mar 7;

Authors: Tan SY, Krasnow MA

Abstract
Macrophages are specialized phagocytic cells, present in all tissues, which engulf and digest pathogens, infected and dying cells, and debris, and can recruit and regulate other immune cells and the inflammatory response and aid in tissue repair. Macrophage subpopulations play distinct roles in these processes and in disease, and are typically recognized by differences in marker expression, immune function, or tissue of residency. Although macrophage subpopulations in the brain have been found to have distinct developmental origins, the extent to which development contributes to macrophage diversity of other tissues and within tissues is not well understood. Here we investigate the development and maintenance of mouse lung macrophages by marker expression patterns, genetic lineage tracing and parabiosis. We show that macrophages populate the lung in three developmental waves, each giving rise to a distinct lineage. These lineages express different markers, reside in different locations, renew in different ways, and show little or no interconversion. Thus, development contributes significantly to lung macrophage diversity and targets each lineage to a different anatomical domain.

PMID: 26952982 [PubMed - as supplied by publisher]

Epigenetic response to environmental stress: Assembly of BRG1-G9a/GLP-DNMT3 repressive chromatin complex on Myh6 promoter in pathologically stressed hearts.

Biochim Biophys Acta. 2016 Mar 4;

Authors: Han P, Li W, Yang J, Shang C, Lin CH, Cheng W, Hang CT, Cheng HL, Chen CH, Wong J, Xiong Y, Zhao M, Drakos SG, Ghetti A, Li DY, Bernstein D, Chen HV, Quertermous T, Chang CP

Abstract
Chromatin structure is determined by nucleosome positioning, histone modifications, and DNA methylation. How chromatin modifications are coordinately altered under pathological conditions remains elusive. Here we describe a stress-activated mechanism of concerted chromatin modification in the heart. In mice, pathological stress activates cardiomyocytes to express Brg1 (nucleosome-remodeling factor), G9a/Glp (histone methyltransferase), and Dnmt3 (DNA methyltransferase). Once activated, Brg1 recruits G9a and then Dnmt3 to sequentially assemble repressive chromatin-marked by H3K9 and CpG methylation-on a key molecular motor gene (Myh6), thereby silencing Myh6 and impairing cardiac contraction. Disruption of Brg1, G9a or Dnmt3 erases repressive chromatin marks and de-represses Myh6, reducing stress-induced cardiac dysfunction. In human hypertrophic hearts, BRG1-G9a/GLP-DNMT3 complex is also activated; its level correlates with H3K9/CpG methylation, Myh6 repression, and cardiomyopathy. Our studies demonstrate a new mechanism of chromatin assembly in stressed hearts and novel therapeutic targets for restoring Myh6 and ventricular function. The stress-induced Brg1-G9a-Dnmt3 interactions and sequence of repressive chromatin assembly on Myh6 illustrates a molecular mechanism by which the heart epigenetically responds to environmental signals. This article is part of a Special Issue entitled:Cardiomyocyte Biology: Integration of Develomental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

PMID: 26952936 [PubMed - as supplied by publisher]

High throughput physiological screening of iPSC-derived cardiomyocytes for drug development.

Biochim Biophys Acta. 2016 Mar 4;

Authors: Del Álamo JC, Lemons D, Serrano R, Savchenko A, Cerignoli F, Bodmer R, Mercola M

Abstract
Cardiac drug discovery is hampered by the reliance on non-human animal and cellular models with inadequate throughput and physiological fidelity to accurately identify new targets and test novel therapeutic strategies. Similarly, adverse drug effects on the heart are challenging to model, contributing to costly failure of drugs during development and even after market launch. Human induced pluripotent stem cell derived cardiac tissue represents a potentially powerful means to model aspects of heart physiology relevant to disease and adverse drug effects, providing both the human context and throughput needed to improve the efficiency of drug development. Here we review emerging technologies for high throughput measurements of cardiomyocyte physiology, and comment on the promises and challenges of using iPSC-derived cardiomyocytes to model disease and introduce the human context into early stages of drug discovery.This article is part of a Special Issue entitled:Cardiomyocyte Biology: Integration of Develomental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

PMID: 26952934 [PubMed - as supplied by publisher]

PROMIS(®) Measures of Pain, Fatigue, Negative Affect, Physical Function and Social Function Demonstrate Clinical Validity across a Range of Chronic Conditions.

J Clin Epidemiol. 2016 Mar 4;

Authors: Cook KF, Jensen SE, Schalet BD, Beaumont JL, Amtmann D, Czajkowski S, Dewalt DA, Fries JF, Pilkonis PA, Reeve BB, Stone AA, Weinfurt K, Cella D

Abstract
OBJECTIVE: To present an overview of a series of studies in which the clinical validity of the National Institutes of Health's Patient Reported Outcome Measurement Information System (NIH; PROMIS®) measures was evaluated, by domain, across six clinical populations.
STUDY DESIGN AND SETTING: Approximately 1500 individuals at baseline and 1300 at follow-up completed PROMIS measures. The analyses reported in this issue were conducted post hoc, pooling data across six previous studies and accommodating the different designs of the six, within-condition, parent studies. Changes in T-scores, standardized response means, and effect sizes were calculated in each study. When a parent study design allowed, known groups validity was calculated using a linear mixed model.
RESULTS: The results provide substantial support for the clinical validity of nine PROMIS measures in a range of chronic conditions.
CONCLUSION: The cross-condition focus of the analyses provided a unique and multi-faceted perspective on how PROMIS measures function in "real world" clinical settings and provides external anchors that can support comparative effectiveness research. The current body of clinical validity evidence for the nine PROMIS measures indicates the success of NIH PROMIS in developing measures that are effective across a range of chronic conditions.

PMID: 26952842 [PubMed - as supplied by publisher]

In vitro fertilization outcomes after fresh and frozen blastocyst transfer in South Asian compared with white women.

Fertil Steril. 2016 Mar 4;

Authors: Shah M, Caballes M, Lathi RB, Baker VL, Westphal LM, Milki A

Abstract
OBJECTIVE: To study pregnancy outcomes between South Asian and white women undergoing frozen blastocyst transfer cycles.
DESIGN: Retrospective cohort study.
SETTING: Not applicable.
PATIENT(S): White and South Asian patients undergoing frozen blastocyst transfer between January 2011 and December 2014.
INTERVENTION(S): Not applicable.
MAIN OUTCOME MEASURE(S): Live birth rate.
RESULT(S): A total of 196 white and 117 South Asian women were included in our study. Indians were on average 2.2 years younger than white women (34.9 vs. 37.1 years), and were more likely to be nulliparous (59% vs. 43%). All other baseline characteristics were similar. In women undergoing their first frozen ET cycle, implantation rate (49% vs. 47%), clinical pregnancy rate (PR; 54% vs. 49%), and live birth rate (43% vs. 43%) were similar between South Asians and whites, respectively. In patients who underwent a prior fresh blastocyst transfer, the live birth rate was significantly lower in South Asian versus white women (21% vs. 37%).
CONCLUSION(S): Our data demonstrate that IVF outcomes are better in frozen versus fresh cycles among South Asian women. The IVF clinics may wish to consider these findings when counseling South Asian patients about the timing of ET.

PMID: 26952781 [PubMed - as supplied by publisher]

A Unified Approach to Outcomes Assessment for Distal Radius Fractures.

J Hand Surg Am. 2016 Mar 5;

Authors: Waljee JF, Ladd A, MacDermid JC, Rozental TD, Wolfe SW, Distal Radius Outcomes Consortium

Abstract
Distal radius fractures are one of the most common upper extremity injuries. Currently, outcome assessment after treatment of these injuries varies widely with respect to the measures that are used, timing of assessment, and the end points that are considered. A more consistent approach to outcomes assessment would provide a standard by which to assess treatment options and best practices. In this summary, we review the consensus regarding outcomes assessment after distal radius fractures and propose a systematic approach that integrates performance, patient-reported outcomes, pain, complications, and radiographs.

PMID: 26952734 [PubMed - as supplied by publisher]

Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.

Lancet. 2016 Mar 4;

Authors: Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, Dawson N, O'Donnell PH, Balmanoukian A, Loriot Y, Srinivas S, Retz MM, Grivas P, Joseph RW, Galsky MD, Fleming MT, Petrylak DP, Perez-Gracia JL, Burris HA, Castellano D, Canil C, Bellmunt J, Bajorin D, Nickles D, Bourgon R, Frampton GM, Cui N, Mariathasan S, Abidoye O, Fine GD, Dreicer R

Abstract
BACKGROUND: Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population.
METHODS: For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov, number NCT02108652.
FINDINGS: Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients later did not meet eligibility criteria and were not dosed with study drug). The PD-L1 expression status on infiltrating immune cells (ICs) in the tumour microenvironment was defined by the percentage of PD-L1-positive immune cells: IC0 (<1%), IC1 (≥1% but <5%), and IC2/3 (≥5%). The primary analysis (data cutoff May 5, 2015) showed that compared with a historical control overall response rate of 10%, treatment with atezolizumab resulted in a significantly improved RECIST v1.1 objective response rate for each prespecified immune cell group (IC2/3: 27% [95% CI 19-37], p<0·0001; IC1/2/3: 18% [13-24], p=0·0004) and in all patients (15% [11-20], p=0·0058). With longer follow-up (data cutoff Sept 14, 2015), by independent review, objective response rates were 26% (95% CI 18-36) in the IC2/3 group, 18% (13-24) in the IC1/2/3 group, and 15% (11-19) overall in all 310 patients. With a median follow-up of 11·7 months (95% CI 11·4-12·2), ongoing responses were recorded in 38 (84%) of 45 responders. Exploratory analyses showed The Cancer Genome Atlas (TCGA) subtypes and mutation load to be independently predictive for response to atezolizumab. Grade 3-4 treatment-related adverse events, of which fatigue was the most common (five patients [2%]), occurred in 50 (16%) of 310 treated patients. Grade 3-4 immune-mediated adverse events occurred in 15 (5%) of 310 treated patients, with pneumonitis, increased aspartate aminotransferase, increased alanine aminotransferase, rash, and dyspnoea being the most common. No treatment-related deaths occurred during the study.
INTERPRETATION: Atezolizumab showed durable activity and good tolerability in this patient population. Increased levels of PD-L1 expression on immune cells were associated with increased response. This report is the first to show the association of TCGA subtypes with response to immune checkpoint inhibition and to show the importance of mutation load as a biomarker of response to this class of agents in advanced urothelial carcinoma.
FUNDING: F Hoffmann-La Roche Ltd.

PMID: 26952546 [PubMed - as supplied by publisher]

Timing reproduction in teleost fish: cues and mechanisms.

Curr Opin Neurobiol. 2016 Mar 4;38:57-62

Authors: Juntti SA, Fernald RD

Abstract
Fish comprise half of extant vertebrate species and use a rich variety of reproductive strategies that have yielded insights into the basic mechanisms that evolved for sex. To maximize the chances of fertilization and survival of offspring, fish species time reproduction to occur at optimal times. For years, ethologists have performed painstaking experiments to identify sensory inputs and behavioral outputs of the brain during mating. Here we review known mechanisms that generate sexual behavior, focusing on the factors that govern the timing of these displays. The development of new technologies, including high-throughput sequencing and genome engineering, has the potential to provide novel insights into how the vertebrate brain consummates mating at the appropriate time.

PMID: 26952366 [PubMed - as supplied by publisher]

Evaluation of the first open-access hepatitis B and safe injection online training course for health professionals in China.

BMC Med Educ. 2016;16(1):81

Authors: Wang J, Feng Q, Tam A, Sun T, Zhou P, So S

Abstract
BACKGROUND: Despite the high prevalence of chronic hepatitis B virus (HBV) infection in China, HBV infection prevention and long-term care knowledge of health professionals is inadequate. To address this knowledge gap, we developed an open-access evidence-based online training course, "KnowHBV", to train health professionals on prevention of HBV transmission and safe injections. We conducted an evaluation of the course with health professionals in China to examine its effectiveness in improving knowledge and learner's satisfaction of the course.
METHODS: Between July and December 2011, 1015 health professionals from selected hospitals and disease control institutions of Shandong province registered for the course and 932 (92 %) completed the three-module course. Participants' demographic information, pre- and post-course knowledge test results and learner's feedback were collected through the course website.
RESULTS: Pre-course knowledge assessment confirmed gaps in HBV transmission routes, prevention and long-term care knowledge. Only 50.4 % of participants correctly identified all of the transmission routes of HBV, and only 40.7 % recognized all of the recommended tests to monitor chronically infected persons. The number of participants that answered all six multi-part multiple-choice knowledge questions correctly increased from 183 (19.7 %) before taking the course to 395 (42.4 %) on their first attempt upon completion of the course. Over 90 % of the 898 participants who completed the learner-feedback questionnaire rated the course as 'good' or 'very good'; over 94 % found the course instructional design helpful; 57.5 %, 65.7 % and 68.5 % reported that half or more than half of the course content in modules 1, 2 and 3 respectively provided new information; and 93.2 % of the participants indicated they preferred the online learning over traditional face-to-face classroom learning.
CONCLUSIONS: The "KnowHBV" online training course appears to be an effective online training tool to improve HBV prevention and care knowledge of the health professionals in China.

PMID: 26952079 [PubMed - in process]

Coronary Artery Bypass Surgery Is Not Underutilized!

Circulation. 2016 Mar 8;133(10):1027-35

Authors: Fearon WF, Harrington RA

PMID: 26951822 [PubMed - in process]

Behavioral response inhibition and maturation of goal representation in prefrontal cortex after puberty.

Proc Natl Acad Sci U S A. 2016 Mar 7;

Authors: Zhou X, Zhu D, King SG, Lees CJ, Bennett AJ, Salinas E, Stanford TR, Constantinidis C

Abstract
Executive functions including behavioral response inhibition mature after puberty, in tandem with structural changes in the prefrontal cortex. Little is known about how activity of prefrontal neurons relates to this profound cognitive development. To examine this, we tracked neuronal responses of the prefrontal cortex in monkeys as they transitioned from puberty into adulthood and compared activity at different developmental stages. Performance of the antisaccade task greatly improved in this period. Among neural mechanisms that could facilitate it, reduction of stimulus-driven activity, increased saccadic activity, or enhanced representation of the opposing goal location, only the latter was evident in adulthood. Greatly accentuated in adults, this neural correlate of vector inversion may be a prerequisite to the formation of a motor plan to look away from the stimulus. Our results suggest that the prefrontal mechanisms that underlie mature performance on the antisaccade task are more strongly associated with forming an alternative plan of action than with suppressing the neural impact of the prepotent stimulus.

PMID: 26951656 [PubMed - as supplied by publisher]

Excellent Patient Care Processes in Poor Hospitals? Why Hospital-Level and Patient-Level Care Quality-Outcome Relationships Can Differ.

J Gen Intern Med. 2016 Mar 7;

Authors: Finney JW, Humphreys K, Kivlahan DR, Harris AH

Abstract
Studies finding weak or nonexistent relationships between hospital performance on providing recommended care and hospital-level clinical outcomes raise questions about the value and validity of process of care performance measures. Such findings may cause clinicians to question the effectiveness of the care process presumably captured by the performance measure. However, one cannot infer from hospital-level results whether patients who received the specified care had comparable, worse or superior outcomes relative to patients not receiving that care. To make such an inference has been labeled the "ecological fallacy," an error that is well known among epidemiologists and sociologists, but less so among health care researchers and policy makers. We discuss such inappropriate inferences in the health care performance measurement field and illustrate how and why process measure-outcome relationships can differ at the patient and hospital levels. We also offer recommendations for appropriate multilevel analyses to evaluate process measure-outcome relationships at the patient and hospital levels and for a more effective role for performance measure bodies and research funding organizations in encouraging such multilevel analyses.

PMID: 26951280 [PubMed - as supplied by publisher]

Opportunities to Enhance Value-Related Research in the U.S. Department of Veterans Affairs.

J Gen Intern Med. 2016 Mar 7;

Authors: Wagner TH, Burstin H, Frakt AB, Krein SL, Lorenz K, Maciejewski ML, Pizer SD, Weiner M, Yoon J, Zulman DM, Asch SM

PMID: 26951279 [PubMed - as supplied by publisher]

Are Improvements in Measured Performance Driven by Better Treatment or "Denominator Management"?

J Gen Intern Med. 2016 Mar 7;

Authors: Harris AH, Chen C, Rubinsky AD, Hoggatt KJ, Neuman M, Vanneman ME

Abstract
BACKGROUND: Process measures of healthcare quality are usually formulated as the number of patients who receive evidence-based treatment (numerator) divided by the number of patients in the target population (denominator). When the systems being evaluated can influence which patients are included in the denominator, it is reasonable to wonder if improvements in measured quality are driven by expanding numerators or contracting denominators.
OBJECTIVE: In 2003, the US Department of Veteran Affairs (VA) based executive compensation in part on performance on a substance use disorder (SUD) continuity-of-care quality measure. The first goal of this study was to evaluate if implementing the measure in this way resulted in expected improvements in measured performance. The second goal was to examine if the proportion of patients with SUD who qualified for the denominator contracted after the quality measure was implemented, and to describe the facility-level variation in and correlates of denominator contraction or expansion.
DESIGN: Using 40 quarters of data straddling the implementation of the performance measure, an interrupted time series design was used to evaluate changes in two outcomes.
PARTICIPANTS: All veterans with an SUD diagnosis in all VA facilities from fiscal year 2000 to 2009.
MAIN MEASURES: The two outcomes were 1) measured performance-patients retained/patients qualified and 2) denominator prevalence-patients qualified/patients with SUD program contact.
KEY RESULTS: Measured performance improved over time (P < 0.001). Notably, the proportion of patients with SUD program contact who qualified for the denominator decreased more rapidly after the measure was implemented (p = 0.02). Facilities with higher pre-implementation denominator prevalence had steeper declines in denominator prevalence after implementation (p < 0.001).
CONCLUSIONS: These results should motivate the development of measures that are less vulnerable to denominator management, and also the exploration of "shadow measures" to monitor and reduce undesirable denominator management.

PMID: 26951270 [PubMed - as supplied by publisher]

Measuring What Matters in Health: Lessons from the Veterans Health Administration State of the Art Conference.

J Gen Intern Med. 2016 Mar 7;

Authors: Asch SM, Kerr EA

PMID: 26951269 [PubMed - as supplied by publisher]

Tracheoesophageal fistula length decreases over time.

Eur Arch Otorhinolaryngol. 2016 Mar 7;

Authors: Jiang N, Kearney A, Damrose EJ

Abstract
The objectives of this study were to demonstrate that the length of the tracheoesophageal voice prosthesis changes over time and to determine whether the prosthesis length over time increased, decreased, or showed no predictable change in size. A retrospective chart review was performed at a tertiary care referral center. Patients who underwent either primary or secondary tracheoesophageal puncture between January 2006 and August 2014 were evaluated. Patients were excluded if the tracheoesophageal prosthesis size was not consistently recorded or if they required re-puncturing for an extruded prosthesis. Data analyzed included patient demographics and the length of the tracheoesophageal voice prosthesis at each change. A total of 37 patients were identified. The mean age was 64 years. Seventy-six percent were male. 24 % underwent primary tracheoesophageal puncture and 76 % underwent secondary tracheoesophageal puncture. The length of the prosthesis decreased over time (median Kendall correlation coefficient = -0.60; mean = -0.44) and this correlation between length and time was significant (p = 0.00085). Therefore, in conclusion, tracheoesophageal prosthesis length is not constant over time. The tracheoesophageal wall thins, necessitating placement of shorter prostheses over time. Patients with a tracheoesophageal voice prosthesis will require long-term follow-up and repeat sizing of their prosthesis. Successful tracheoesophageal voicing will require periodic reevaluation of these devices, and insurers must, therefore, understand that long-term professional care will be required to manage these patients and their prostheses.

PMID: 26951219 [PubMed - as supplied by publisher]

Screening for Impaired Visual Acuity in Older Adults: US Preventive Services Task Force Recommendation Statement.

JAMA. 2016 Mar 1;315(9):908-14

Authors: US Preventive Services Task Force (USPSTF), Siu AL, Bibbins-Domingo K, Grossman DC, Baumann LC, Davidson KW, Ebell M, García FA, Gillman M, Herzstein J, Kemper AR, Krist AH, Kurth AE, Owens DK, Phillips WR, Phipps MG, Pignone MP

Abstract
DESCRIPTION: Update of the US Preventive Services Task Force (USPSTF) recommendation on screening for impaired visual acuity in older adults.
METHODS: The USPSTF reviewed the evidence on screening for visual acuity impairment associated with uncorrected refractive error, cataracts, and age-related macular degeneration among adults 65 years or older in the primary care setting; the benefits and harms of screening; the accuracy of screening; and the benefits and harms of treatment of early vision impairment due to uncorrected refractive error, cataracts, and age-related macular degeneration.
POPULATION: This recommendation applies to asymptomatic adults 65 years or older who do not present to their primary care clinician with vision problems.
RECOMMENDATION: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for impaired visual acuity in older adults. (I statement).

PMID: 26934260 [PubMed - indexed for MEDLINE]

The peptidergic control circuit for sighing.

Nature. 2016 Feb 18;530(7590):293-7

Authors: Li P, Janczewski WA, Yackle K, Kam K, Pagliardini S, Krasnow MA, Feldman JL

Abstract
Sighs are long, deep breaths expressing sadness, relief or exhaustion. Sighs also occur spontaneously every few minutes to reinflate alveoli, and sighing increases under hypoxia, stress, and certain psychiatric conditions. Here we use molecular, genetic, and pharmacologic approaches to identify a peptidergic sigh control circuit in murine brain. Small neural subpopulations in a key breathing control centre, the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG), express bombesin-like neuropeptide genes neuromedin B (Nmb) or gastrin-releasing peptide (Grp). These project to the preBötzinger Complex (preBötC), the respiratory rhythm generator, which expresses NMB and GRP receptors in overlapping subsets of ~200 neurons. Introducing either neuropeptide into preBötC or onto preBötC slices, induced sighing or in vitro sigh activity, whereas elimination or inhibition of either receptor reduced basal sighing, and inhibition of both abolished it. Ablating receptor-expressing neurons eliminated basal and hypoxia-induced sighing, but left breathing otherwise intact initially. We propose that these overlapping peptidergic pathways comprise the core of a sigh control circuit that integrates physiological and perhaps emotional input to transform normal breaths into sighs.

PMID: 26855425 [PubMed - indexed for MEDLINE]

Interactions of Prosthetic and Natural Vision in Animals With Local Retinal Degeneration.

Invest Ophthalmol Vis Sci. 2015 Nov;56(12):7444-50

Authors: Lorach H, Lei X, Galambos L, Kamins T, Mathieson K, Dalal R, Huie P, Harris J, Palanker D

Abstract
PURPOSE: Prosthetic restoration of partial sensory loss leads to interactions between artificial and natural inputs. Ideally, the rehabilitation should allow perceptual fusion of the two modalities. Here we studied the interactions between normal and prosthetic vision in a rodent model of local retinal degeneration.
METHODS: Implantation of a photovoltaic array in the subretinal space of normally sighted rats induced local degeneration of the photoreceptors above the chip, and the inner retinal neurons in this area were electrically stimulated by the photovoltaic implant powered by near-infrared (NIR) light. We studied prosthetic and natural visually evoked potentials (VEP) in response to simultaneous stimulation by NIR and visible light patterns.
RESULTS: We demonstrate that electrical and natural VEPs summed linearly in the visual cortex, and both responses decreased under brighter ambient light. Responses to visible light flashes increased over 3 orders of magnitude of contrast (flash/background), while for electrical stimulation the contrast range was limited to 1 order of magnitude. The maximum amplitude of the prosthetic VEP was three times lower than the maximum response to a visible flash over the same area on the retina.
CONCLUSIONS: Ambient light affects prosthetic responses, albeit much less than responses to visible stimuli. Prosthetic representation of contrast in the visual scene can be encoded, to a limited extent, by the appropriately calibrated stimulus intensity, which also depends on the ambient light conditions. Such calibration will be important for patients combining central prosthetic vision with natural peripheral sight, such as in age-related macular degeneration.

PMID: 26618643 [PubMed - indexed for MEDLINE]

Network Analysis Identifies Mitochondrial Regulation of Epidermal Differentiation by MPZL3 and FDXR.

Dev Cell. 2015 Nov 23;35(4):444-57

Authors: Bhaduri A, Ungewickell A, Boxer LD, Lopez-Pajares V, Zarnegar BJ, Khavari PA

Abstract
Current gene expression network approaches commonly focus on transcription factors (TFs), biasing network-based discovery efforts away from potentially important non-TF proteins. We developed proximity analysis, a network reconstruction method that uses topological constraints of scale-free, small-world biological networks to reconstruct relationships in eukaryotic systems, independent of subcellular localization. Proximity analysis identified MPZL3 as a highly connected hub that is strongly induced during epidermal differentiation. MPZL3 was essential for normal differentiation, acting downstream of p63, ZNF750, KLF4, and RCOR1, each of which bound near the MPZL3 gene and controlled its expression. MPZL3 protein localized to mitochondria, where it interacted with FDXR, which was itself also found to be essential for differentiation. Together, MPZL3 and FDXR increased reactive oxygen species (ROS) to drive epidermal differentiation. ROS-induced differentiation is dependent upon promotion of FDXR enzymatic activity by MPZL3. ROS induction by the MPZL3 and FDXR mitochondrial proteins is therefore essential for epidermal differentiation.

PMID: 26609959 [PubMed - indexed for MEDLINE]

Multiphase CT Angiography: A Poor Man's Perfusion CT?

Radiology. 2015 Dec;277(3):922-4

Authors: Aviv RI, Parsons M, Bivard A, Jahromi B, Wintermark M

PMID: 26599931 [PubMed - indexed for MEDLINE]

Proteomics of Primary Cilia by Proximity Labeling.

Dev Cell. 2015 Nov 23;35(4):497-512

Authors: Mick DU, Rodrigues RB, Leib RD, Adams CM, Chien AS, Gygi SP, Nachury MV

Abstract
While cilia are recognized as important signaling organelles, the extent of ciliary functions remains unknown because of difficulties in cataloguing proteins from mammalian primary cilia. We present a method that readily captures rapid snapshots of the ciliary proteome by selectively biotinylating ciliary proteins using a cilia-targeted proximity labeling enzyme (cilia-APEX). Besides identifying known ciliary proteins, cilia-APEX uncovered several ciliary signaling molecules. The kinases PKA, AMPK, and LKB1 were validated as bona fide ciliary proteins and PKA was found to regulate Hedgehog signaling in primary cilia. Furthermore, proteomics profiling of Ift27/Bbs19 mutant cilia correctly detected BBSome accumulation inside Ift27(-/-) cilia and revealed that β-arrestin 2 and the viral receptor CAR are candidate cargoes of the BBSome. This work demonstrates that proximity labeling can be applied to proteomics of non-membrane-enclosed organelles and suggests that proteomics profiling of cilia will enable a rapid and powerful characterization of ciliopathies.

PMID: 26585297 [PubMed - indexed for MEDLINE]

"Big Data" in Laboratory Medicine.

Clin Chem. 2015 Dec;61(12):1433-40

Authors: Tolan NV, Parnas ML, Baudhuin LM, Cervinski MA, Chan AS, Holmes DT, Horowitz G, Klee EW, Kumar RB, Master SR

PMID: 26487761 [PubMed - indexed for MEDLINE]

Plant stilbenes induce endoplasmic reticulum stress and their anti-cancer activity can be enhanced by inhibitors of autophagy.

Exp Cell Res. 2015 Nov 15;339(1):147-53

Authors: Papandreou I, Verras M, McNeil B, Koong AC, Denko NC

Abstract
BACKGROUND: Environmental conditions or chemical agents can interfere with the function of the endoplasmic reticulum, and the resulting endoplasmic reticulum (ER) stress can be toxic to the cell if it is not relieved. The classical compensatory response to ER stress is the unfolded protein response (UPR) that reduces protein load in the ER. However, autophagy may also compensate by removing large insoluble protein aggregates. Agents that stress the ER can have anti-cancer activity, and novel applications of ER stress inducing agents are being investigated. Plant stilbenes are a class of stress responsive molecules that includes resveratrol, which are being investigated as potential therapeutics in humans for conditions such as aging or cancer.
RESULTS: We performed a screen of 1726 small, drug like molecules to identify those that could activate an ER-stress responsive luciferase gene. After secondary screening, we determined that the plant stilbenes pterostilbene and piceatannol were the most potent inducers of ER stress from this group. ER stress can be particularly toxic to cells with high ER load, so we examined their effect on cells expressing the Wnt family of secreted glycoprotein growth factors. Molecular analysis determined that these ER stress-inducing stilbenes could block Wnt processing and also induce autophagy in acute lymphoblastic leukemia cells expressing Wnt16. Combining pterostilbene (to induce ER stress) with chloroquine (to inhibit autophagy) lead to significant cellular toxicity in cells from aggressive acute lymphoblastic leukemia.
CONCLUSIONS: Plant stilbenes are potent inducers of ER stress. However, their toxicity is more pronounced in cancer cells expressing Wnt growth factors. The toxicity of stilbenes in these ALL cells can be potentiated by the addition of autophagy inhibitors, suggesting a possible therapeutic application.

PMID: 26477823 [PubMed - indexed for MEDLINE]

Novel cytogenic and neurovascular niches due to blood-brain barrier compromise in the chronic pain brain.

Mol Pain. 2015;11:63

Authors: Tajerian M, Clark JD

Abstract
BACKGROUND: The mechanisms by which painful injuries are linked to the multitude of pain-related comorbidities and neuroplastic changes in the brain remain poorly understood. Here we propose a model that relies on epi-neuronal communication through the vascular system to effect various brain structures. Specifically, we hypothesize that the differential vulnerability of the blood-brain barrier (BBB) in different brain regions is associated with region-specific neuroplastic and neurovascular changes that are in turn associated with particular pain-related comorbidities.
PRESENTATION OF THE HYPOTHESIS: We will present our hypothesis by focusing on two main points: (A) chronic pain (CP) is associated with differential BBB compromise. (B) Circulating mediators leaking through the BBB create cytogenic and neovascular niches associated with pain-related co-morbidities.
TESTING THE HYPOTHESIS: Pre-clinically, our hypothesis can be tested by observing, in parallel, BBB compromise, (neo)vascularization, neurogenesis, and their co-localization in animal pain models using imaging, microscopy, biochemical and other tools. Furthermore, the BBB can be experimentally damaged in specific brain regions, and the consequences of those lesions studied on nociception and associated comorbidities. Recently developed imaging techniques allow the analysis of blood brain barrier integrity in patients providing a route for translation of the laboratory findings. Though perhaps more limited, post-mortem examination of brains with available pain histories constitutes a second approach to addressing this hypothesis.
IMPLICATIONS OF THE HYPOTHESIS: Understanding changes in BBB permeability in chronic pain conditions has clear implications both for understanding the pathogenesis of chronic pain and for the design of novel treatments to prevent chronic pain and its consequences. More broadly, this hypothesis may help us to understand how peripheral injuries impact the brain via mechanisms other than commonly studied efferent sensory pathways.

PMID: 26453186 [PubMed - indexed for MEDLINE]

Safety of Spectacles for Children's Vision: A Cluster-Randomized Controlled Trial.

Am J Ophthalmol. 2015 Nov;160(5):897-904

Authors: Ma X, Congdon N, Yi H, Zhou Z, Pang X, Meltzer ME, Shi Y, He M, Liu Y, Rozelle S

Abstract
PURPOSE: To study safety of children's glasses in rural China, where fear that glasses harm vision is an important barrier for families and policy makers.
DESIGN: Exploratory analysis from a cluster-randomized, investigator-masked, controlled trial.
METHODS: Among primary schools (n = 252) in western China, children were randomized by school to 1 of 3 interventions: free glasses provided in class, vouchers for free glasses at a local facility, or glasses prescriptions only (Control group). The main outcome of this analysis is uncorrected visual acuity after 8 months, adjusted for baseline acuity.
RESULTS: Among 19 934 children randomly selected for screening, 5852 myopic (spherical equivalent refractive error ≤-0.5 diopters) eyes of 3001 children (14.7%, mean age 10.5 years) had VA ≤6/12 without glasses correctable to >6/12 with glasses, and were eligible. Among these, 1903 (32.5%), 1798 (30.7%), and 2151 (36.8%) were randomized to Control, Voucher, and Free Glasses, respectively. Intention-to-treat analyses were performed on all 1831 (96.2%), 1699 (94.5%), and 2007 (93.3%) eyes of children with follow-up in Control, Voucher, and Free Glasses groups. Final visual acuity for eyes of children in the treatment groups (Free Glasses and Voucher) was significantly better than for Control children, adjusting only for baseline visual acuity (difference of 0.023 logMAR units [0.23 vision chart lines, 95% CI: 0.03, 0.43]) or for other baseline factors as well (0.025 logMAR units [0.25 lines, 95% CI 0.04, 0.45]).
CONCLUSION: We found no evidence that spectacles promote decline in uncorrected vision with aging among children.

PMID: 26284747 [PubMed - indexed for MEDLINE]

Impact of Free Glasses and a Teacher Incentive on Children's Use of Eyeglasses: A Cluster-Randomized Controlled Trial.

Am J Ophthalmol. 2015 Nov;160(5):889-896.e1

Authors: Yi H, Zhang H, Ma X, Zhang L, Wang X, Jin L, Naidoo K, Minto H, Zou H, Lu L, Rozelle S, Congdon N

Abstract
PURPOSE: To study the effect of free glasses combined with teacher incentives on in-school glasses wear among Chinese urban migrant children.
DESIGN: Cluster-randomized controlled trial.
METHODS: Children with visual acuity (VA) ≤6/12 in either eye owing to refractive error in 94 randomly chosen primary schools underwent randomization by school to receive free glasses, education on their use, and a teacher incentive (Intervention), or glasses prescriptions only (Control). Intervention group teachers received a tablet computer if ≥80% of children given glasses wore them during unannounced visits 6 weeks and 6 months (main outcome) after intervention.
RESULTS: Among 4376 children, 728 (16.7%, mean age 10.9 years, 51.0% boys) met enrollment criteria and were randomly allocated, 358 (49.2%, 47 schools) to Intervention and 370 (50.8%, 47 schools) to Control. Among these, 693 children (95.2%) completed the study and underwent analysis. Spectacle wear was significantly higher at 6 months among Intervention children (Observed [main outcome]: 68.3% vs 23.9%, adjusted odds ratio [OR] = 11.5, 95% confidence interval [CI] 5.91-22.5, P < .001; Self-reported: 90.6% vs 32.1%, OR = 43.7, 95% CI = 21.7-88.5, P < .001). Other predictors of observed wear at 6 months included baseline spectacle wear (P < .001), uncorrected VA <6/18 (P = .01), and parental spectacle wear (P = .02). The 6-month observed wear rate was only 41% among similar-aged children provided free glasses in our previous trial without teacher incentives.
CONCLUSIONS: Free spectacles and teacher incentives maintain classroom wear in the large majority of children needing glasses over a school year. Low wear among Control children demonstrates the need for interventions.

PMID: 26275472 [PubMed - indexed for MEDLINE]

Dynamics of water, methanol, and ethanol in a room temperature ionic liquid.

J Chem Phys. 2015 Jun 7;142(21):212408

Authors: Kramer PL, Giammanco CH, Fayer MD

Abstract
The dynamics of a series of small molecule probes with increasing alkyl chain length: water, methanol, and ethanol, diluted to low concentration in the room temperature ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, was investigated with 2D infrared vibrational echo (2D IR) spectroscopy and polarization resolved pump-probe (PP) experiments on the deuterated hydroxyl (O-D) stretching mode of each of the solutes. The long timescale spectral diffusion observed by 2D IR, capturing complete loss of vibrational frequency correlation through structural fluctuation of the medium, shows a clear but not dramatic slowing as the probe alkyl chain length is increased: 23 ps for water, 28 ps for methanol, and 34 ps for ethanol. Although in each case, only a single population of hydroxyl oscillators contributes to the infrared line shapes, the isotropic pump-probe decays (normally caused by population relaxation) are markedly nonexponential at short times. The early time features correspond to the timescales of the fast spectral diffusion measured with 2D IR. These fast isotropic pump-probe decays are produced by unequal pumping of the OD absorption band to a nonequilibrium frequency dependent population distribution caused by significant non-Condon effects. Orientational correlation functions for these three systems, obtained from pump-probe anisotropy decays, display several periods of restricted angular motion (wobbling-in-a-cone) followed by complete orientational randomization. The cone half-angles, which characterize the angular potential, become larger as the experimental frequency moves to the blue. These results indicate weakening of the angular potential with decreasing hydrogen bond strength. The slowest components of the orientational anisotropy decays are frequency-independent and correspond to the complete orientational randomization of the solute molecule. These components slow appreciably with increasing chain length: 25 ps for water, 42 ps for methanol, and 88 ps for ethanol. The shape and volume of the probe, therefore, impact reorientation far more severely than they do spectral diffusion at long times, though these two processes occur on similar timescales at earlier times.

PMID: 26049428 [PubMed - indexed for MEDLINE]

Right Heart Score for Predicting Outcome in Idiopathic, Familial, or Drug- and Toxin-Associated Pulmonary Arterial Hypertension.

JACC Cardiovasc Imaging. 2015 Jun;8(6):627-38

Authors: Haddad F, Spruijt OA, Denault AY, Mercier O, Brunner N, Furman D, Fadel E, Bogaard HJ, Schnittger I, Vrtovec B, Wu JC, de Jesus Perez V, Vonk-Noordegraaf A, Zamanian RT

Abstract
OBJECTIVES: This study sought to determine whether a simple score combining indexes of right ventricular (RV) function and right atrial (RA) size would offer good discrimination of outcome in patients with pulmonary arterial hypertension (PAH).
BACKGROUND: Identifying a simple score of outcome could simplify risk stratification of patients with PAH and potentially lead to improved tailored monitoring or therapy.
METHODS: We recruited patients from both Stanford University (derivation cohort) and VU University Medical Center (validation cohort). The composite endpoint for the study was death or lung transplantation. A Cox proportional hazard with bootstrap CI adjustment model was used to determine independent correlates of death or transplantation. A predictive score was developed using the beta coefficients of the multivariable models.
RESULTS: For the derivation cohort (n = 95), the majority of patients were female (79%), average age was 43 ± 11 years, mean pulmonary arterial pressure was 54 ± 14 mm Hg, and pulmonary vascular resistance index was 25 ± 12 Wood units × m(2). Over an average follow-up of 5 years, the composite endpoint occurred in 34 patients, including 26 deaths and 8 patients requiring lung transplant. On multivariable analysis, RV systolic dysfunction grade (hazard ratio [HR]: 3.4 per grade; 95% confidence interval [CI]: 2.0 to 7.8; p < 0.001), severe RA enlargement (HR: 3.0; 95% CI: 1.3 to 8.1; p = 0.009), and systemic blood pressure <110 mm Hg (HR: 3.3; 95% CI: 1.5 to 9.4; p < 0.001) were independently associated with outcome. A right heart (RH) score constructed on the basis of these 3 parameters compared favorably with the National Institutes of Health survival equation (0.88; 95% CI: 0.79 to 0.94 vs. 0.60; 95% CI: 0.49 to 0.71; p < 0.001) but was not statistically different than the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) score c-statistic of 0.80 (95% CI: 0.69 to 0.88) with p = 0.097. In the validation cohort (n = 87), the RH score remained the strongest independent correlate of outcome.
CONCLUSIONS: In patients with prevalent PAH, a simple RH score may offer good discrimination of long-term outcome.

PMID: 25981508 [PubMed - indexed for MEDLINE]

2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope.

Heart Rhythm. 2015 Jun;12(6):e41-63

Authors: Sheldon RS, Grubb BP, Olshansky B, Shen WK, Calkins H, Brignole M, Raj SR, Krahn AD, Morillo CA, Stewart JM, Sutton R, Sandroni P, Friday KJ, Hachul DT, Cohen MI, Lau DH, Mayuga KA, Moak JP, Sandhu RK, Kanjwal K

PMID: 25980576 [PubMed - indexed for MEDLINE]

Simple Real-Time PCR and Amplicon Sequencing Method for Identification of Plasmodium Species in Human Whole Blood.

J Clin Microbiol. 2015 Jul;53(7):2251-7

Authors: Lefterova MI, Budvytiene I, Sandlund J, Färnert A, Banaei N

Abstract
Malaria is the leading identifiable cause of fever in returning travelers. Accurate Plasmodium species identification has therapy implications for P. vivax and P. ovale, which have dormant liver stages requiring primaquine. Compared to microscopy, nucleic acid tests have improved specificity for species identification and higher sensitivity for mixed infections. Here, we describe a SYBR green-based real-time PCR assay for Plasmodium species identification from whole blood, which uses a panel of reactions to detect species-specific non-18S rRNA gene targets. A pan-Plasmodium 18S rRNA target is also amplified to allow species identification or confirmation by sequencing if necessary. An evaluation of assay accuracy, performed on 76 clinical samples (56 positives using thin smear microscopy as the reference method and 20 negatives), demonstrated clinical sensitivities of 95.2% for P. falciparum (20/21 positives detected) and 100% for the Plasmodium genus (52/52), P. vivax (20/20), P. ovale (9/9), and P. malariae (6/6). The sensitivity of the P. knowlesi-specific PCR was evaluated using spiked whole blood samples (100% [10/10 detected]). The specificities of the real-time PCR primers were 94.2% for P. vivax (49/52) and 100% for P. falciparum (51/51), P. ovale (62/62), P. malariae (69/69), and P. knowlesi (52/52). Thirty-three specimens were used to test species identification by sequencing the pan-Plasmodium 18S rRNA PCR product, with correct identification in all cases. The real-time PCR assay also identified two samples with mixed P. falciparum and P. ovale infection, which was confirmed by sequencing. The assay described here can be integrated into a malaria testing algorithm in low-prevalence areas, allowing definitive Plasmodium species identification shortly after malaria diagnosis by microscopy.

PMID: 25972416 [PubMed - indexed for MEDLINE]

Coordination of peptidoglycan synthesis and outer membrane constriction during Escherichia coli cell division.

Elife. 2015;4

Authors: Gray AN, Egan AJ, Van't Veer IL, Verheul J, Colavin A, Koumoutsi A, Biboy J, Altelaar AF, Damen MJ, Huang KC, Simorre JP, Breukink E, den Blaauwen T, Typas A, Gross CA, Vollmer W

Abstract
To maintain cellular structure and integrity during division, Gram-negative bacteria must carefully coordinate constriction of a tripartite cell envelope of inner membrane, peptidoglycan (PG), and outer membrane (OM). It has remained enigmatic how this is accomplished. Here, we show that envelope machines facilitating septal PG synthesis (PBP1B-LpoB complex) and OM constriction (Tol system) are physically and functionally coordinated via YbgF, renamed CpoB (Coordinator of PG synthesis and OM constriction, associated with PBP1B). CpoB localizes to the septum concurrent with PBP1B-LpoB and Tol at the onset of constriction, interacts with both complexes, and regulates PBP1B activity in response to Tol energy state. This coordination links PG synthesis with OM invagination and imparts a unique mode of bifunctional PG synthase regulation by selectively modulating PBP1B cross-linking activity. Coordination of the PBP1B and Tol machines by CpoB contributes to effective PBP1B function in vivo and maintenance of cell envelope integrity during division.

PMID: 25951518 [PubMed - indexed for MEDLINE]

Automated band annotation for RNA structure probing experiments with numerous capillary electrophoresis profiles.

Bioinformatics. 2015 Sep 1;31(17):2808-15

Authors: Lee S, Kim H, Tian S, Lee T, Yoon S, Das R

Abstract
MOTIVATION: Capillary electrophoresis (CE) is a powerful approach for structural analysis of nucleic acids, with recent high-throughput variants enabling three-dimensional RNA modeling and the discovery of new rules for RNA structure design. Among the steps composing CE analysis, the process of finding each band in an electrophoretic trace and mapping it to a position in the nucleic acid sequence has required significant manual inspection and remains the most time-consuming and error-prone step. The few available tools seeking to automate this band annotation have achieved limited accuracy and have not taken advantage of information across dozens of profiles routinely acquired in high-throughput measurements.
RESULTS: We present a dynamic-programming-based approach to automate band annotation for high-throughput capillary electrophoresis. The approach is uniquely able to define and optimize a robust target function that takes into account multiple CE profiles (sequencing ladders, different chemical probes, different mutants) collected for the RNA. Over a large benchmark of multi-profile datasets for biological RNAs and designed RNAs from the EteRNA project, the method outperforms prior tools (QuSHAPE and FAST) significantly in terms of accuracy compared with gold-standard manual annotations. The amount of computation required is reasonable at a few seconds per dataset. We also introduce an 'E-score' metric to automatically assess the reliability of the band annotation and show it to be practically useful in flagging uncertainties in band annotation for further inspection.
AVAILABILITY AND IMPLEMENTATION: The implementation of the proposed algorithm is included in the HiTRACE software, freely available as an online server and for download at http://hitrace.stanford.edu.
CONTACT: sryoon@snu.ac.kr or rhiju@stanford.edu
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 25943472 [PubMed - indexed for MEDLINE]

Examining kinesin processivity within a general gating framework.

Elife. 2015;4

Authors: Andreasson JO, Milic B, Chen GY, Guydosh NR, Hancock WO, Block SM

Abstract
Kinesin-1 is a dimeric motor that transports cargo along microtubules, taking 8.2-nm steps in a hand-over-hand fashion. The ATP hydrolysis cycles of its two heads are maintained out of phase by a series of gating mechanisms, which lead to processive runs averaging ~1 μm. A key structural element for inter-head coordination is the neck linker (NL), which connects the heads to the stalk. To examine the role of the NL in regulating stepping, we investigated NL mutants of various lengths using single-molecule optical trapping and bulk fluorescence approaches in the context of a general framework for gating. Our results show that, although inter-head tension enhances motor velocity, it is crucial neither for inter-head coordination nor for rapid rear-head release. Furthermore, cysteine-light mutants do not produce wild-type motility under load. We conclude that kinesin-1 is primarily front-head gated, and that NL length is tuned to enhance unidirectional processivity and velocity.

PMID: 25902401 [PubMed - indexed for MEDLINE]

Dealing With Longitudinal Data.

PM R. 2015 Jun;7(6):649-53

Authors: Sainani KL

PMID: 25892355 [PubMed - indexed for MEDLINE]

Measuring Rab GTPase-activating protein (GAP) activity in live cells and extracts.

Methods Mol Biol. 2015;1298:61-71

Authors: Nottingham RM, Pfeffer SR

Abstract
Mammalian cells encode a diverse set of Rab GTPases and their corresponding regulators. In vitro biochemical screening has proven invaluable in assigning particular Rabs as substrates for their cognate GTPase-activating proteins. However, in vitro activity does not always reflect substrate specificity in cells. This method describes a functional test of GAP activity in cells or extracts that takes into account the presence of other factors or conditions that might change observed in vitro specificity.

PMID: 25800832 [PubMed - indexed for MEDLINE]

Feasibility and safety of uninterrupted periprocedural apixaban administration in patients undergoing radiofrequency catheter ablation for atrial fibrillation: Results from a multicenter study.

Heart Rhythm. 2015 Jun;12(6):1162-8

Authors: Di Biase L, Lakkireddy D, Trivedi C, Deneke T, Martinek M, Mohanty S, Mohanty P, Prakash S, Bai R, Reddy M, Gianni C, Horton R, Bailey S, Sigmund E, Derndorfer M, Schade A, Mueller P, Szoelloes A, Sanchez J, Al-Ahmad A, Hranitzky P, Gallinghouse GJ, Hongo RH, Beheiry S, Pürerfellner H, Burkhardt JD, Natale A

Abstract
BACKGROUND: Periprocedural anticoagulation management with uninterrupted warfarin and a "therapeutic" international normalized ratio is the best approach for reducing both thromboembolic and bleeding complications in the setting of catheter ablation for atrial fibrillation (AF).
OBJECTIVE: The purpose of this study was to evaluate the safety and feasibility of uninterrupted apixaban in this setting.
METHODS: This was a prospective multicenter registry of AF patients undergoing radiofrequency catheter ablation at 4 institutions in United States and Europe with uninterrupted apixaban. These patients were compared with an equal number of patients, matched for age, gender, and type of AF, undergoing AF ablation on uninterrupted warfarin. The apixaban group was comprised of consecutive patients who had taken their last dose of apixaban the morning of the procedure. A subset of 29 patients in the apixaban group underwent diffusion magnetic resonance imaging (dMRI) to detect silent cerebral ischemia.
RESULTS: A total of 400 patients (200 patients in each group) were included in the study. The average age was 65.9 ± 9.9 years, 286 (71.5%) were male, and 334 (83.5%) had nonparoxysmal AF. There were no statistical differences with regard to major complications (1% vs 0.5%, P = 1), minor complications (3.5% vs 2.5%, P = .56), or total bleeding complications (4.5% vs 3%, P = .43) between the apixaban and warfarin groups. There were no symptomatic thromboembolic complications. All dMRIs were negative for "new" silent cerebral ischemia in the apixaban group.
CONCLUSION: Uninterrupted apixaban administration in patients undergoing AF ablation seems to be feasible and effective in preventing clinical and silent thromboembolic events without increasing the risk of major bleeding.

PMID: 25728754 [PubMed - indexed for MEDLINE]

Whole genome sequencing in critically ill children.

Lancet Respir Med. 2015 Apr;3(4):264-6

Authors: Char DS, Cho M, Magnus D

PMID: 25704991 [PubMed - indexed for MEDLINE]

Sensitivity of fNIRS measurement to head motion: an applied use of smartphones in the lab.

J Neurosci Methods. 2015 Apr 30;245:37-43

Authors: Cui X, Baker JM, Liu N, Reiss AL

Abstract
BACKGROUND: Powerful computing capabilities in small, easy to use hand-held devices have made smart technologies such as smartphones and tablets ubiquitous in today's society. The capabilities of these devices provide scientists with many tools that can be used to improve the scientific method.
METHOD: Here, we demonstrate how smartphones may be used to quantify the sensitivity of functional near-infrared spectroscopy (fNIRS) signal to head motion. By attaching a smartphone to participants' heads during the fNIRS scan, we were able to capture data describing the degree of head motion.
RESULTS: Our results demonstrate that data recorded from an off-the-shelf smartphone accelerometer may be used to identify correlations between head-movement and fNIRS signal change. Furthermore, our results identify correlations between the magnitudes of head-movement and signal artifact, as well as a relationship between the direction of head movement and the location of the resulting signal noise.
CONCLUSIONS: These data provide a valuable proof-of-concept for the use of off-the-shelf smart technologies in neuroimaging applications.

PMID: 25687634 [PubMed - indexed for MEDLINE]

Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer.

J Control Release. 2015 Apr 10;203:99-108

Authors: Wang TY, Choe JW, Pu K, Devulapally R, Bachawal S, Machtaler S, Chowdhury SM, Luong R, Tian L, Khuri-Yakub B, Rao J, Paulmurugan R, Willmann JK

Abstract
Ultrasound induced microbubble cavitation can cause enhanced permeability across natural barriers of tumors such as vessel walls or cellular membranes, allowing for enhanced therapeutic delivery into the target tissues. While enhanced delivery of small (<1nm) molecules has been shown at acoustic pressures below 1MPa both in vitro and in vivo, the delivery efficiency of larger (>100nm) therapeutic carriers into cancer remains unclear and may require a higher pressure for sufficient delivery. Enhanced delivery of larger therapeutic carriers such as FDA approved pegylated poly(lactic-co-glycolic acid) nanoparticles (PLGA-PEG-NP) has significant clinical value because these nanoparticles have been shown to protect encapsulated drugs from degradation in the blood circulation and allow for slow and prolonged release of encapsulated drugs at the target location. In this study, various acoustic parameters were investigated to facilitate the successful delivery of two nanocarriers, a fluorescent semiconducting polymer model drug nanoparticle as well as PLGA-PEG-NP into human colon cancer xenografts in mice. We first measured the cavitation dose produced by various acoustic parameters (pressure, pulse length, and pulse repetition frequency) and microbubble concentration in a tissue mimicking phantom. Next, in vivo studies were performed to evaluate the penetration depth of nanocarriers using various acoustic pressures, ranging between 1.7 and 6.9MPa. Finally, a therapeutic microRNA, miR-122, was loaded into PLGA-PEG-NP and the amount of delivered miR-122 was assessed using quantitative RT-PCR. Our results show that acoustic pressures had the strongest effect on cavitation. An increase of the pressure from 0.8 to 6.9MPa resulted in a nearly 50-fold increase in cavitation in phantom experiments. In vivo, as the pressures increased from 1.7 to 6.9MPa, the amount of nanoparticles deposited in cancer xenografts was increased from 4- to 14-fold, and the median penetration depth of extravasated nanoparticles was increased from 1.3-fold to 3-fold, compared to control conditions without ultrasound, as examined on 3D confocal microscopy. When delivering miR-122 loaded PLGA-PEG-NP using optimal acoustic settings with minimum tissue damage, miR-122 delivery into tumors with ultrasound and microbubbles was 7.9-fold higher compared to treatment without ultrasound. This study demonstrates that ultrasound induced microbubble cavitation can be a useful tool for delivery of therapeutic miR loaded nanocarriers into cancer in vivo.

PMID: 25687306 [PubMed - indexed for MEDLINE]

Potential effector and immunoregulatory functions of mast cells in mucosal immunity.

Mucosal Immunol. 2015 May;8(3):444-63

Authors: Reber LL, Sibilano R, Mukai K, Galli SJ

Abstract
Mast cells (MCs) are cells of hematopoietic origin that normally reside in mucosal tissues, often near epithelial cells, glands, smooth muscle cells, and nerves. Best known for their contributions to pathology during IgE-associated disorders such as food allergy, asthma, and anaphylaxis, MCs are also thought to mediate IgE-associated effector functions during certain parasite infections. However, various MC populations also can be activated to express functional programs--such as secreting preformed and/or newly synthesized biologically active products--in response to encounters with products derived from diverse pathogens, other host cells (including leukocytes and structural cells), damaged tissue, or the activation of the complement or coagulation systems, as well as by signals derived from the external environment (including animal toxins, plant products, and physical agents). In this review, we will discuss evidence suggesting that MCs can perform diverse effector and immunoregulatory roles that contribute to homeostasis or pathology in mucosal tissues.

PMID: 25669149 [PubMed - indexed for MEDLINE]

Letter to the editor.

J Occup Environ Hyg. 2015;12(6):D86-7

Authors: Weill D, Chatfield E, Cox A, Gamble J, Gibbs G, Wylie A

PMID: 25617231 [PubMed - indexed for MEDLINE]

Femoral Neck Stress Fractures and Imaging Features of Femoroacetabular Impingement.

PM R. 2015 Jun;7(6):584-92

Authors: Goldin M, Anderson CN, Fredericson M, Safran MR, Stevens KJ

Abstract
BACKGROUND: Prior literature has suggested an association between the radiographic signs of femoroacetabular impingement (FAI) and femoral neck stress fractures (FNSF) or femoral neck stress reactions (FNSR). At the time of the writing of this article, no study has described the association of FAI and FNSF/FNSR along with the need for surgical intervention and outcomes.
OBJECTIVE: To determine the prevalence of radiographic features of FAI in patients diagnosed with FNSF.
DESIGN: Retrospective case series.
SETTING: Tertiary care, institutional setting.
PATIENTS: A medical records search program (Stanford Translational Research Integrated Database Environment, Stanford University, California) was used to retrospectively search for patients 18-40 years old with a history of FNSF or FNSR. The records were obtained from the period July 25, 2003, to September 23, 2011.
METHODS: For assessment of risk factors, plain radiographs and magnetic resonance imaging studies were reviewed for features of cam or pincer FAI. Medical records were reviewed to determine whether patients required operative intervention.
MAIN OUTCOME MEASURES: Incidence of abnormal alpha (α) angle, abnormal anterior offset ratio, abnormal femoral head-neck junction, coxa profunda, positive crossover sign, and abnormal lateral center-to-edge angle.
RESULTS: Twenty-one female and 3 male participants (mean age 27 years, range 19-39 years) were identified with magnetic resonance imaging evidence of femoral neck stress injury. Cam morphology was seen in 10 patients (42%). Pincer morphology could be assessed in 18 patients, with coxa profunda in 14 (78%) and acetabular retroversion in 6 (14%). Features of combined pincer and cam impingement were observed in 4 patients (17%). Seven patients (29%) had operative intervention, with 3 (12%) requiring internal fixation of their femoral neck fractures, and all had radiographic evidence of fracture union after surgery. Four patients (17%) had persistent symptoms after healing of their FNSF with conservative treatment and eventually required surgery for FAI, 3 had no pain at final follow-up 1 year post-surgery, and one patient was lost to follow-up.
CONCLUSION: The results of the current study suggest that patients in the general population with femoral neck stress injuries have a higher incidence of bony abnormalities associated with pincer impingement, including coxa profunda and acetabular retroversion, although it is unclear whether pincer FAI is a true risk factor in the development of FNSF.

PMID: 25591871 [PubMed - indexed for MEDLINE]

Augmentative repetitive Transcranial Magnetic Stimulation (rTMS) in the acute treatment of poor responder depressed patients: a comparison study between high and low frequency stimulation.

Eur Psychiatry. 2015 Feb;30(2):271-6

Authors: Dell'Osso B, Oldani L, Camuri G, Dobrea C, Cremaschi L, Benatti B, Arici C, Grancini B, Altamura AC

Abstract
BACKGROUND: While the efficacy of repetitive transcranial magnetic stimulation (rTMS) in Major Depressive Disorder (MDD) is well established, the debate is still open in relation to bipolar depression and to a possible different effectiveness of high vs. low stimulation. The present study was aimed to assess and compare the efficacy and tolerability of different protocols of augmentative rTMS in a sample of patients with current Major Depressive Episode (MDE), poor drug response/treatment resistance and a diagnosis of MDD or bipolar disorder.
METHODS: Thirty-three patients were recruited in a 4-week, blind-rater, rTMS trial and randomised to the following three groups of stimulation: (1) (n=10) right dorsolateral prefrontal cortex (DLPFC) 1 HZ, 110% of the motor threshold (MT), 420 stimuli/day; (2) (n=10) right DLPFC, 1Hz, 110% MT, 900 stimuli/day; (3) (n=13) left DLPFC, 10Hz, 80% MT, 750 stimuli/day.
RESULTS: Twenty-nine patients completed the treatment, showing a significant reduction of primary outcome measures (HAM-D, MADRS and CGI-S total scores: t=8.1, P<0.001; t=8.6, P<0.001; t=4.6, P<0.001 respectively). No significant differences in terms of efficacy and tolerability were found between high vs. low frequency and between unipolar and bipolar patients. Side effects were reported by 21% of the sample. One of the 4 dropouts was caused by a hypomanic switch.
CONCLUSIONS: Augmentative rTMS appeared to be effective and well tolerated for the acute treatment of unipolar and bipolar depression with features of poor drug response/treatment resistance, showing a comparable effectiveness profile between protocols of high and low frequency stimulation.

PMID: 25572482 [PubMed - indexed for MEDLINE]

Inference of gorilla demographic and selective history from whole-genome sequence data.

Mol Biol Evol. 2015 Mar;32(3):600-12

Authors: McManus KF, Kelley JL, Song S, Veeramah KR, Woerner AE, Stevison LS, Ryder OA, Ape Genome Project G, Kidd JM, Wall JD, Bustamante CD, Hammer MF

Abstract
Although population-level genomic sequence data have been gathered extensively for humans, similar data from our closest living relatives are just beginning to emerge. Examination of genomic variation within great apes offers many opportunities to increase our understanding of the forces that have differentially shaped the evolutionary history of hominid taxa. Here, we expand upon the work of the Great Ape Genome Project by analyzing medium to high coverage whole-genome sequences from 14 western lowland gorillas (Gorilla gorilla gorilla), 2 eastern lowland gorillas (G. beringei graueri), and a single Cross River individual (G. gorilla diehli). We infer that the ancestors of western and eastern lowland gorillas diverged from a common ancestor approximately 261 ka, and that the ancestors of the Cross River population diverged from the western lowland gorilla lineage approximately 68 ka. Using a diffusion approximation approach to model the genome-wide site frequency spectrum, we infer a history of western lowland gorillas that includes an ancestral population expansion of 1.4-fold around 970 ka and a recent 5.6-fold contraction in population size 23 ka. The latter may correspond to a major reduction in African equatorial forests around the Last Glacial Maximum. We also analyze patterns of variation among western lowland gorillas to identify several genomic regions with strong signatures of recent selective sweeps. We find that processes related to taste, pancreatic and saliva secretion, sodium ion transmembrane transport, and cardiac muscle function are overrepresented in genomic regions predicted to have experienced recent positive selection.

PMID: 25534031 [PubMed - indexed for MEDLINE]

[99mTc]Annexin V-128 SPECT Monitoring of Splenic and Disseminated Listeriosis in Mice: a Model of Imaging Sepsis.

Mol Imaging Biol. 2015 Jun;17(3):345-54

Authors: Hardy JW, Levashova Z, Schmidt TL, Contag CH, Blankenberg FG

Abstract
PURPOSE: Here, we evaluate [(99m)Tc]annexin V-128, an in vivo marker of apoptosis, for single photon emission computed tomography (SPECT) imaging of localization and antibiotic treatment of disseminated bacterial infection, using a well-described mouse model that employs bioluminescent Listeria monocytogenes.
PROCEDURES: Sixteen groups of five mice in six separate experiments were infected with bioluminescent Listeria, and in vivo bioluminescence imaging (BLI) was performed each day, to assess the location and extent of infection and response to antibiotics. [(99m)Tc]annexin V-128 was then injected for SPECT imaging, and the two sets of images were correlated and validated.
RESULTS: Signals from BLI and [(99m)Tc]annexin V-128 SPECT co-localized within the spleen and other organs including bone marrow, intestine, nasopharynx, and brain. Decreases in [(99m)Tc]annexin V-128 uptake and BLI signal within the spleen directly reflected the reduction of bacterial infection by ampicillin treatment.
CONCLUSIONS: Tc-99m-Annexin V-128 uptake as observed by SPECT allowed for the detection of systemic listeriosis and ampicillin treatment in mice. [(99m)Tc]annexin V-128 should be further explored for the assessment of bacterial spread and antibiotic efficacy in patients with disseminated bacterial infection.

PMID: 25416406 [PubMed - indexed for MEDLINE]

Diffuse high intensity PD-L1 staining in thymic epithelial tumors.

J Thorac Oncol. 2015 Mar;10(3):500-8

Authors: Padda SK, Riess JW, Schwartz EJ, Tian L, Kohrt HE, Neal JW, West RB, Wakelee HA

Abstract
INTRODUCTION: Blockade of the immune checkpoint programmed death receptor ligand-1 (PD-L1)/PD-1 pathway has well-established clinical activity across many tumor types. PD-L1 protein expression by immunohistochemistry is emerging as a predictive biomarker of response to these therapies. Here, we examine PD-L1 expression in a thymic epithelial tumor (TET) tissue microarray (TMA).
METHODS: The TMA contained 69 TETs and 17 thymic controls, with each case represented by triplicate cores. The TMA was stained with rabbit monoclonal antibody (clone 15; Sino Biological, Beijing, China) to human PD-L1. PD-L1 staining was scored based on intensity as follows: 0 = none, 1 = equivocal/uninterpretable, 2 = weak, and 3 = intermediate-strong. Those cases with all cores scoring three in the epithelial component were categorized as PD-L1 high and the remaining as PD-L1 low.
RESULTS: PD-L1 high scores were more frequent in TETs than in controls (68.1% versus 17.6%; p = 0.0036). PD-L1 scores and histology were significantly correlated, with higher intensity staining in World Health Organization (WHO). B2/B3/C TETs. Only 14.8% of TETs had PD-L1 staining of associated lymphocytes. In an adjusted analysis (age/sex), PD-L1 high TETs had a significantly worse overall survival (hazard ratio: 5.40, 95% confidence interval: 1.13-25.89; p = 0.035) and a trend for worse event-free survival (hazard ratio: 2.94, 95% confidence interval: 0.94-9.24; p = 0.064).
CONCLUSIONS: PD-L1 expression was present in all cases of TETs within the epithelial component but only in a minority in the lymphocytic component. TETs stained more intensely for PD-L1 than in controls, and PD-L1 high TETs were associated with more aggressive histology and worse prognosis. This study lends rationale to a clinical trial with anti-PD-1/PD-L1 therapy in this rare tumor type.

PMID: 25402569 [PubMed - indexed for MEDLINE]

Multidisciplinary treatment for thoracic and abdominopelvic endometriosis.

JSLS. 2014 Jul-Sep;18(3)

Authors: Nezhat C, Main J, Paka C, Nezhat A, Beygui RE

Abstract
BACKGROUND AND OBJECTIVES: Thoracic endometriosis is a rare form of extragenital endometriosis with important clinical ramifications. Up to 80% of women with thoracic endometriosis have concomitant abdominopelvic endometriosis, yet the surgical treatment is usually performed with separate procedures. This is the largest published series of the combination of video-assisted thoracoscopic surgery and traditional laparoscopy for the treatment of abdominopelvic and thoracic endometriosis. The objectives of this series are to further evaluate the manifestations of thoracic endometriosis, assess the multidisciplinary surgical approach, and discuss our institution's protocols.
METHODS: This is a retrospective, institutional review board-approved case series of 25 consecutive women who underwent combined video-assisted thoracoscopic surgery and traditional laparoscopy for the treatment of abdominopelvic, diaphragmatic, and thoracic endometriosis from January 1, 2008, to September 30, 2013. All surgeries were performed at a tertiary referral center by the same primary surgeons. Data were collected by chart review.
RESULTS: Twenty-five patients were included, with a mean age of 37.7 years. Eighty percent of patients had catamenial chest pain, and in 40% this was their only chest complaint. Shoulder pain was noted in 40% of patients, catamenial pneumothorax in 24%, and hemoptysis in 12%. One hundred percent of patients were found to have endometriosis in the pelvis, 100% in the diaphragm, 64% in the chest wall, and 40% in the parenchyma. There were 2 major postoperative complications: 1 diaphragmatic hernia and 1 vaginal cuff hematoma.
CONCLUSION: Clinical suspicion and preoperative assessment are crucial in the diagnosis of thoracic endometriosis and allow for a multidisciplinary approach. The combination of video-assisted thoracoscopic surgery and traditional laparoscopy for the treatment of endometriosis optimally addresses the pelvis, diaphragm, and thoracic cavity in a single operation.

PMID: 25392636 [PubMed - indexed for MEDLINE]

Advanced gynecologic laparoscopy in a fast-track ambulatory surgery center.

JSLS. 2014 Jul-Sep;18(3)

Authors: Nezhat C, Main J, Paka C, Soliemannjad R, Parsa MA

Abstract
BACKGROUND/OBJECTIVES: It has been shown that major gynecologic laparoscopy is safe in hospital ambulatory settings, but there is little data to suggest the same in freestanding ambulatory surgery centers. This study evaluates the safety and efficacy of advanced gynecologic laparoscopic surgery using a fast-track model in freestanding ambulatory surgery centers and discusses our institution protocols.
METHODS: Retrospective, multicenter review was conducted of major gynecologic surgeries from August 1st 2010 to September 30th 2011 in 3 surgical centers with one primary surgeon. All patients were treated for symptomatic uterine leiomyomas and/or endometriosis. Primary outcome measures were unplanned admissions and discharge within 23 hours.
RESULTS: One hundred and thirty-four patients underwent major laparoscopic gynecologic surgery with a total of 160 procedures: 77 stage IV endometriosis treatment including 7 disk excisions of endometriosis from the large bowel, 3 ureteroneocystostomies and 1 partial bladder resection, 38 myomectomies, and 34 hysterectomies including 12 modified radical hysterectomies. The overall unplanned admission rate was 4.5%. One hundred and thirty-one patients (97.7%) were discharged within 24 hours after surgery. Three patients (2.2%) were transferred to the hospital postoperatively: 1 patient for observation of postoperative anemia and 2 patients for postoperative fever. Three patients (2.2%) were admitted to the hospital after discharge: 1 patient for postoperative ileus, 1 patient for postoperative fever, and 1 patient with septic pelvic thrombophlebitis. These postoperative issues all resolved without complication, and all patients had an uneventful follow-up.
CONCLUSIONS: With appropriate resources and an experienced surgeon, advanced laparoscopic surgery can be safely performed in a fast-track ambulatory surgery center with a high rate of discharge within 23 hours and low unplanned readmission rate.

PMID: 25392631 [PubMed - indexed for MEDLINE]

Maturation of mast cell progenitors to mucosal mast cells during allergic pulmonary inflammation in mice.

Mucosal Immunol. 2015 May;8(3):596-606

Authors: Bankova LG, Dwyer DF, Liu AY, Austen KF, Gurish MF

Abstract
In contrast to resident constitutive mast cells (CMCs), mucosal MCs (MMCs) appear in the lung and trachea of sensitized mice only following inhalation challenge. We monitored the influx and maturation of MCs by their expression of Kit, FcɛRI, β7-integrin and side scatter (SSC) by flow cytometry. Influx of MC progenitors (MCps) (FcɛRI(lo), Kit(int), β7(hi), and SSC(lo)) peaks 1 day after challenges and subsides to baseline by day 7 after challenge. The mature MMCs appear as a distinct population on day 7 and peak at day 14 with higher SSC and FcɛRI expression, but lower β7 and Kit expression. A distinct transitional population is present between 1 and 7 days after challenge. Maturation occurs more rapidly in the trachea. The resident tracheal CMCs had higher SSC, FcɛRI, and Kit and lower β7-integrin expression than the MMCs. By histology, the MMCs follow similar kinetics to the flow cytometry-identified mature MMCs and are notably persistent for >42 days. Steroid treatment reduced inflammation and MCp influx but had no effect on established MMCs. Thus, changes in SSC, FcɛRI, and Kit together with the expression of αE/α4:β7-integrins characterizes the development of induced MMCs from MCps and distinguishes them from resident CMCs in the trachea and large airways.

PMID: 25291985 [PubMed - indexed for MEDLINE]