Proton pump inhibitors and 180-day mortality in the elderly after Clostridium difficile treatment

Background: There is a reported association between proton pump inhibitor (PPI) exposure and increased risk of Clostridium difficile infection (CDI), but less is known about how this class of medications taken during treatment might influence mortality after CDI. Here we examine 180-day mortality rates in a cohort of CDI elders and its association with exposure to PPIs. We conducted a retrospective cohort study of elderly patients ( \u3e 65 years of age) diagnosed and treated for CDI in the years 2014-2016 (n = 874) in the Umass Memorial Health Care system, which represents both academic and community healthcare. Patient characteristics and medication use was extracted from the electronic medical record (EMR) and 6 month mortality data was obtained via the Center for Disease Control National Death Index. A Cox proportional hazards model was used to estimate hazard ratios associated with medication exposures and other relevant variables. Results: Of the 874 elderly adults treated for CDI, 180-day all-cause mortality was 12.4%. Exposure to a PPI was associated with a 55% reduced risk of mortality (adjusted hazard ratio (aHR) 0.45; 95% confidence interval (CI) 0.28-0.72). In our Cox model, increasing age (aHR 1.45; 95% CI 1.14-1.84), those with severe CDI infections (aHR 1.87; 95% CI 1.22-2.88), and those with hospital acquired CDI (aHR 3.01; 95% CI 1.81-4.99) also had increased 180 day mortality risk. There were similar associations noted with both 90 day and 1-year mortality. Conclusion: Use of PPIs during CDI treatment in elderly patients is associated with decreased 180-day mortality. Although use of PPIs has been associated with an increased risk of CDI, it appears to be protective against mortality when used during the treatment phase

Comparative assessment of performance and genome dependence among phylogenetic profiling methods

BACKGROUND: The rapidly increasing speed with which genome sequence data can be generated will be accompanied by an exponential increase in the number of sequenced eukaryotes. With the increasing number of sequenced eukaryotic genomes comes a need for bioinformatic techniques to aid in functional annotation. Ideally, genome context based techniques such as proximity, fusion, and phylogenetic profiling, which have been so successful in prokaryotes, could be utilized in eukaryotes. Here we explore the application of phylogenetic profiling, a method that exploits the evolutionary co-occurrence of genes in the assignment of functional linkages, to eukaryotic genomes. RESULTS: In order to evaluate the performance of phylogenetic profiling in eukaryotes, we assessed the relative performance of commonly used profile construction techniques and genome compositions in predicting functional linkages in both prokaryotic and eukaryotic organisms. When predicting linkages in E. coli with a prokaryotic profile, the use of continuous values constructed from transformed BLAST bit-scores performed better than profiles composed of discretized E-values; the use of discretized E-values resulted in more accurate linkages when using S. cerevisiae as the query organism. Extending this analysis by incorporating several eukaryotic genomes in profiles containing a majority of prokaryotes resulted in similar overall accuracy, but with a surprising reduction in pathway diversity among the most significant linkages. Furthermore, the application of phylogenetic profiling using profiles composed of only eukaryotes resulted in the loss of the strong correlation between common KEGG pathway membership and profile similarity score. Profile construction methods, orthology definitions, ontology and domain complexity were explored as possible sources of the poor performance of eukaryotic profiles, but with no improvement in results. CONCLUSION: Given the current set of completely sequenced eukaryotic organisms, phylogenetic profiling using profiles generated from any of the commonly used techniques was found to yield extremely poor results. These findings imply genome-specific requirements for constructing functionally relevant phylogenetic profiles, and suggest that differences in the evolutionary history between different kingdoms might generally limit the usefulness of phylogenetic profiling in eukaryotes

Survey of endoscopic skull base surgery practice patterns among otolaryngologists

Background Endoscopic skull base surgery (ESBS) is a rapidly expanding field. Despite divergent reported preferences for reconstructive techniques and perioperative management, limited data exist regarding contemporary practice patterns among otolaryngologists performing ESBS. This study aims to elucidate current practice patterns, primarily the volumes of cases performed and secondarily a variety of other perioperative preferences. Methods An anonymous 32-item electronic survey examining perioperative ESBS preferences was distributed to the American Rhinologic Society membership. Statistical significance between variables was determined utilizing Student t, chi-square, and Fisher exact tests. Results Seventy otolaryngologists completed the survey. The effective response rate was approximately 22.5%. Sixty percent of respondents were in full-time academic practice and 70% had completed rhinology/skull base fellowships. Annually, 43.3 mean ESBS cases were performed (29.1 private practice vs. 52.9 academic practice, P = .009). Academic practice averaged 24.1 expanded cases versus only 11 in private practice (P = .01). Of respondents, 55.7% stood on the same side as the neurosurgeon and 72.9% remained present for the entire case. Current procedural terminology coding and antibiotic regimens were widely divergent; 31.4% never placed lumbar drains preoperatively, while 41.4% did so for anticipated high-flow cerebrospinal fluid leaks. While considerable variation in reconstructive techniques were noted, intradural defect repairs utilized vascularized flaps 86.3% of the time versus only 51.3% for extradural repairs (P < 0.001). Major complications were rare. Postoperative restrictions varied considerably, with most activity limitations between 2–8 weeks and positive airway pressure use for 2–6 weeks. Most respondents started saline irrigations 0–2 weeks postoperatively. Conclusions Based on responses from fellowship- and non-fellowship-trained otolaryngologists in various practice settings, there remains considerable variation in the perioperative management of patients undergoing ESBS. Level of Evidence

CHILES: HI morphology and galaxy environment at z=0.12 and z=0.17

We present a study of 16 HI-detected galaxies found in 178 hours of observations from Epoch 1 of the COSMOS HI Large Extragalactic Survey (CHILES). We focus on two redshift ranges between 0.108 <= z <= 0.127 and 0.162 <= z <= 0.183 which are among the worst affected by radio frequency interference (RFI). While this represents only 10% of the total frequency coverage and 18% of the total expected time on source compared to what will be the full CHILES survey, we demonstrate that our data reduction pipeline recovers high quality data even in regions severely impacted by RFI. We report on our in-depth testing of an automated spectral line source finder to produce HI total intensity maps which we present side-by-side with significance maps to evaluate the reliability of the morphology recovered by the source finder. We recommend that this become a common place manner of presenting data from upcoming HI surveys of resolved objects. We use the COSMOS 20k group catalogue, and we extract filamentary structure using the topological DisPerSE algorithm to evaluate the \hi\ morphology in the context of both local and large-scale environments and we discuss the shortcomings of both methods. Many of the detections show disturbed HI morphologies suggesting they have undergone a recent interaction which is not evident from deep optical imaging alone. Overall, the sample showcases the broad range of ways in which galaxies interact with their environment. This is a first look at the population of galaxies and their local and large-scale environments observed in HI by CHILES at redshifts beyond the z=0.1 Universe.Comment: 23 pages, 12 figures, 1 interactive 3D figure, accepted to MNRA

A high affinity, partial antagonist effect of 3,4-diaminopyridine mediates action potential broadening and enhancement of transmitter release at NMJs

3,4-Diaminopyridine (3,4-DAP) increases transmitter release from neuromuscular junctions (NMJs), and low doses of 3,4-DAP (estimated to reach ∼1 μM in serum) are the Food and Drug Administration (FDA)-Approved treatment for neuro muscular weakness caused by Lambert-Eaton myasthenic syn drome. Canonically, 3,4-DAP is thought to block voltage-gated potassium (Kv) channels, resulting in prolongation of the pre synaptic action potential (AP). However, recent reports have shown that low millimolar concentrations of 3,4-DAP have an off-Target agonist effect on the Cav1 subtype ( L-Type ) of voltage-gated calcium (Cav) channels and have speculated that this agonist effect might contribute to 3,4-DAP effects on transmitter release at the NMJ. To address 3,4-DAPs mecha nism(s) of action, we first used the patch-clamp electrophysi ology to characterize the concentration-dependent block of 3,4-DAP on the predominant presynaptic Kv channel subtypes found at the mammalian NMJ (Kv3.3 and Kv3.4). We identified a previously unreported high-Affinity (1-10 μM) partial antag onist effect of 3,4-DAP in addition to the well-known low-Af finity (0.1-1 mM) antagonist activity. We also showed that 1.5-μM DAP had no effects on Cav1.2 or Cav2.1 current. Next, we used voltage imaging to show that 1.5-or 100-μM 3,4-DAP broadened the AP waveform in a dose-dependent manner, in dependent of Cav1 calcium channels. Finally, we demonstrated that 1.5-or 100-μM 3,4-DAP augmented transmitter release in a dose-dependent manner and this effect was also independent of Cav1 channels. From these results, we conclude that low micromolar concentrations of 3,4-DAP act solely on Kv chan nels to mediate AP broadening and enhance transmitter release at the NMJ

Haploinsufficiency of SIRT1 Enhances Glutamine Metabolism and Promotes Cancer Development

SIRT1, the most conserved mammalian NAD+-dependent protein deacetylase, plays a vital role in the regulation of metabolism, stress responses, and genome stability. However, the role of SIRT1 in the multi-step process leading to transformation and/or tumorigenesis, as either a tumor suppressor or tumor promoter, is complex and maybe dependent upon the context in which SIRT1 activity is altered, and the role of SIRT1 in tumor metabolism is unknown. Here we demonstrate that SIRT1 dose-dependently regulates cellular glutamine metabolism and apoptosis, which in turn differentially impact cell proliferation and cancer development. Heterozygous deletion of Sirt1 induces c-Myc expression, enhancing glutamine metabolism and subsequent proliferation, autophagy, stress resistance and cancer formation. In contrast, homozygous deletion of Sirt1 triggers cellular apoptotic pathways, increases cell death, diminishes autophagy, and reduces cancer formation. Consistent with the observed dose-dependence in cells, intestine-specific Sirt1 heterozygous mice have enhanced intestinal tumor formation, whereas intestine-specific Sirt1 homozygous knockout mice have reduced development of colon cancer. Furthermore, SIRT1 reduction but not deletion is associated with human colorectal tumors, and colorectal cancer patients with low protein expression of SIRT1 have a poor prognosis. Taken together, our findings indicate that the dose-dependent regulation of tumor metabolism and possibly apoptosis by SIRT1 mechanistically contributes to the observed dual roles of SIRT1 in tumorigenesis. Our study highlights the importance of maintenance of a suitable SIRT1 dosage for metabolic and tissue homeostasis, which will have important implications in SIRT1 small molecule activators/inhibitors based therapeutic strategies for cancers

TMC function, dysfunction, and restoration in mouse vestibular organs

Tmc1 and Tmc2 are essential pore-forming subunits of mechanosensory transduction channels localized to the tips of stereovilli in auditory and vestibular hair cells of the inner ear. To investigate expression and function of Tmc1 and Tmc2 in vestibular organs, we used quantitative polymerase chain reaction (qPCR), fluorescence in situ hybridization – hairpin chain reaction (FISH-HCR), immunostaining, FM1-43 uptake and we measured vestibular evoked potentials (VsEPs) and vestibular ocular reflexes (VORs). We found that Tmc1 and Tmc2 showed dynamic developmental changes, differences in regional expression patterns, and overall expression levels which differed between the utricle and saccule. These underlying changes contributed to unanticipated phenotypic loss of VsEPs and VORs in Tmc1 KO mice. In contrast, Tmc2 KO mice retained VsEPs despite the loss of the calcium buffering protein calretinin, a characteristic biomarker of mature striolar calyx-only afferents. Lastly, we found that neonatal Tmc1 gene replacement therapy is sufficient to restore VsEP in Tmc1 KO mice for up to six months post-injection

CMB-S4 Science Book, First Edition

This book lays out the scientific goals to be addressed by the next-generation ground-based cosmic microwave background experiment, CMB-S4, envisioned to consist of dedicated telescopes at the South Pole, the high Chilean Atacama plateau and possibly a northern hemisphere site, all equipped with new superconducting cameras. CMB-S4 will dramatically advance cosmological studies by crossing critical thresholds in the search for the B-mode polarization signature of primordial gravitational waves, in the determination of the number and masses of the neutrinos, in the search for evidence of new light relics, in constraining the nature of dark energy, and in testing general relativity on large scales