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Salmonella enterica serovar Enteritidis is one of the most frequent causes of Salmonellosis globally and is commonly transmitted from animals to humans by the consumption of contaminated foodstuffs. In the UK and many other countries in the Global North, a significant proportion of cases are caused by the consumption of imported food products or contracted during foreign travel, therefore, making the rapid identification of the geographical source of new infections a requirement for robust public health outbreak investigations. Herein, we detail the development and application of a hierarchical machine learning model to rapidly identify and trace the geographical source of S. Enteritidis infections from whole genome sequencing data. 2313 S. Enteritidis genomes, collected by the UKHSA between 2014–2019, were used to train a ‘local classifier per node’ hierarchical classifier to attribute isolates to four continents, 11 sub-regions, and 38 countries (53 classes). The highest classification accuracy was achieved at the continental level followed by the sub-regional and country levels (macro F1: 0.954, 0.718, 0.661, respectively). A number of countries commonly visited by UK travelers were predicted with high accuracy (hF1: >0.9). Longitudinal analysis and validation with publicly accessible international samples indicated that predictions were robust to prospective external datasets. The hierarchical machine learning framework provided granular geographical source prediction directly from sequencing reads in

In the management of otitis media (OM), identification of causative bacterial pathogens and knowledge of their biofilm formation can provide more targeted treatment approaches. Current clinical diagnostic methods rely on the visualization of the tympanic membrane and lack real-time assessment of the causative pathogen(s) and the nature of any biofilm that may reside behind the membrane and within the middle ear cavity. In recent years, optical coherence tomography (OCT) has been demonstrated as an improved in vivo diagnostic tool for visualization and morphological characterization of OM biofilms and middle ear effusions; but lacks specificity about the causative bacterial species. This study proposes the combination of OCT and Raman spectroscopy (RS) to examine differences in the refractive index, optical attenuation, and biochemical composition of Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, and Pseudomonas aeruginosa; four of the leading otopathogens in OM. This combination provides a dual optical approach for identifying and differentiating OM-causing bacterial species under three different in vitro growth environments (i.e., agar-grown colonies, planktonic cells from liquid cultures, and biofilms). This study showed that RS was able to identify key biochemical variations to differentiate all four OM-causing bacteria. Additionally, biochemical spectral changes (RS) and differences in the mean attenuation coefficient (OCT) were able to distinguish the growth environment for each bacterial species.

ABSTRACT Reviewing the genetics underlying the arms race between bacteria and bacteriophages can offer an interesting insight into the development of bacterial resistance and phage co-evolution. This study shows how the natural development of resistances to the K1F bacteriophage, a phage which targets the K1 capsule of pathogenic Escherichia coli, can come about through insertion sequences (IS). Of the K1F resistant mutants isolated, two were of particular interest. The first of these showed full resistance to K1F and was found to have disruptions to kpsE, the product of which is involved in polysialic acid translocation. The second, after showing an initial susceptibility to K1F which then developed to full resistance, had disruptions to neuC, a gene involved in one of the early steps of polysialic acid biosynthesis. Both of these mutations came with a fitness cost and produced considerable phenotypic differences in the completeness and location of the K1 capsule when compared with the wild type. Sequential treatment of these two K1F resistant mutants with T7 resulted in the production of a variety of isolates, many of which showed a renewed susceptibility to K1F, indicating that these insertion sequence mutations are reversible, as well as one isolate that developed resistance to both phages. IMPORTANCE Bacteriophages have many potential uses in industry and the clinical environment as an antibacterial control measure. One of their uses, phage therapy, is an appealing alternative to antibiotics due to their high specificity. However, as with the rise in antimicrobial resistance (AMR), it is critical to improve our understanding of how resistance develops against these viral agents. In the same way as bacteria will evolve and mutate antibiotic receptors so they can no longer be recognized, resistance to bacteriophages can come about via mutations to phage receptors, preventing phage binding and infection. We have shown that Escherichia coli will become resistant to the K1F bacteriophage via insertion element reshufflings causing null mutations to elements of the polysialic acid biosynthetic cluster. Exposure to the T7 bacteriophage then resulted in further changes in the position of these IS elements, further altering their resistance and sensitivity profiles.

The excavated architecture of the exceptional prehistoric site of Akrotiri on the Greek island of Thera/Santorini is endangered by gradual decay, damage due to accidents, and seismic shocks, being located on an active volcano in an earthquake-prone area. Therefore, in 2013 and 2014 a digital documentation project has been conducted with support of the National Geographic Society in order to generate a detailed digital model of Akrotiri’s architecture using terrestrial laser scanning and image-based modeling. Additionally, non-invasive geophysical prospection has been tested in order to investigate its potential to explore and map yet buried archaeological remains. This article describes the project and the generated results.

Objectives: Compare SARS-CoV-2 infection and work absence rates between vaccinated and unvaccinated employees during a two-year pandemic period., Methods: Cross-sectional study with 2,107 participants. Primary outcome: total days missed; main exposure: vaccination status. Analyses included t-tests to compare absence days and ANOVA to evaluate confounders. Mixed-effects logistic regression assessed infection risk, incorporating community prevalence as a fixed effect and work location as a random effect., Results: Vaccinated employees missed slightly fewer days (0.16 days), though not statistically significant (p = 0.574). Symptom severity and job status were linked to higher absenteeism. Vaccination had a small but significant protective effect (p = 0.045). Remote work correlated moderately with reduced absenteeism., Conclusion: Vaccination lowered infection risk but not absenteeism due to uniform quarantine policies. Remote work reduced absenteeism and should be integrated into future interventions to support vulnerable workers., Competing Interests: Conflict of Interest: None Declared, (Copyright © 2024 American College of Occupational and Environmental Medicine.)

Purpose: In patients with urologic chronic pelvic pain syndrome (UCPPS), the presence of widespread pain appears to identify a distinct phenotype, with a different symptom trajectory and potentially different response to treatment than patients with pelvic pain only., Materials and Methods: A 76-site body map was administered four times, at weekly intervals, to 568 male and female UCPPS participants in the MAPP Network protocol. The 76 sites were classified into 13 regions (1 pelvic region and 12 nonpelvic regions). The degree of widespread pain was scored from 0 to 12 based on the number of reported nonpelvic pain regions. This continuous body map score was regressed over other measures of widespread pain, with UCPPS symptom severity, and with psychosocial variables to measure level of association. These models were repeated using an updated body map score (0-12) that incorporated a threshold of pain ≥ 4 at each site., Results: Body map scores showed limited variability over the 4 weekly assessments, indicating that a single baseline assessment was sufficient. The widespread pain score correlated highly with other measures of widespread pain and correlated with worsened UCPPS symptom severity and psychosocial functioning. Incorporating a pain severity threshold ≥4 resulted in only marginal increases in these correlations., Conclusions: These results support the use of this 13-region body map in the baseline clinical assessment of UCPPS patients. It provides reliable data about the presence of widespread pain and does not require measurement of pain severity, making it relatively simple to use for clinical purposes., (© 2024 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Study Design: Retrospective Cohort Study., Introduction: The 11-item modified Frailty index (mFI-11) by the ACS-NSQIP database was used to predict which patients are high risk for complications and inpatient mortality. ACS-NSQIP now has switched to the 5-item MFI. However, there are no studies on how these frailty indices fare against each other and their prognostic value of functional independence in patients with spinal cord injury (SCI)., Objective: To compare the mFI-5 and mFI-11 in order to standardize frailty assessment in the SCI population., Methods: Retrospective analysis of 272,174 patients with SCI from 2010 to 2020 from the Pennsylvania Trauma Systems Foundation (PTSF) registry. Multivariable logistic regression was used to determine the predictive value of mFI for functional independence as determined by locomotion and transfer mobility., Results: A total of 1907 patients were included with a mean age of 46.9 ± 15.1 years. The 3 most common MFI factors were hypertension (32.2%), diabetes mellitus (13.7%) and chronic obstructive pulmonary disease (8.5%). Multivariable logistic regression analyses using MFI-5 and MFI-11 showed that a higher frailty score in MFI-5 (OR 1.375, P < .001) and in MFI-11 (OR 1.366, P < .001) were each predictive of poor functional status at discharge. ROC curves for the MFI-5 (AUC = .818, P < .001) and MFI-11 (AUC = .819, P < .001) demonstrated excellent diagnostic accuracy., Conclusion: The new MFI-5 is equivalent to its predecessor, the MFI-11, and predictive of functional outcomes in patients with SCI. MFI-5 can serve as the preferred frailty index at the point of care and in research contexts., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Author ContributionsNM, TL, and JJ designed the study. NM, TL were involved with data collection and analysis. NM, TL, CY, KL, DF, KH, KL were involved with data collection, manuscript preparation, critical revision, and data interpretation. AS, SP, JH, JSH, JJ were responsible for manuscript preparation, and critical revision.

Background: There is a lack of data on whether intracranial pressure (ICP)-guided therapy with an intraparenchymal fiberoptic monitor (IPM) or an external ventricular drain (EVD) leads to superior outcomes. Our goal is to determine the relationship between ICP-guided therapy with an EVD or IPM and mortality., Methods: Retrospective analysis of severe traumatic brain injury cases that required IPM or EVD placement for ICP-guided therapy from January 1, 2010 to December 31, 2020. The data were obtained from the Pennsylvania Trauma Systems Foundation registry., Results: A total of 2305 patients met the inclusion criteria, with 1048 (45.5%) IPM and 1257 (54.5%) EVD placed. Inpatient mortality occurred in 337 (32.2%) and 334 (26.6%) patients in the IPM and EVD cohorts, respectively (P = 0.003). Even among those treated medically only, inpatient mortality occurred in 171 (30.8%) of those with an IPM and in 100 (23.4%) of those with an EVD (P = 0.010). Multivariable logistic regression analysis showed that older age (odds ratio [OR] 1.03, P < 0.001), lower Glasgow Coma Scale (GCS) score (OR 1.16, P < 0.001), requiring surgery (OR 1.22, P = 0.049), and an IPM (OR 1.40, P = 0.001) were significant predictors of mortality. Propensity score-adjusted analysis using inverse probability of treatment weighted method revealed a 28% decrease in mortality and a 14% decrease in length of hospital stay with EVD use when adjusting for age, sex, GCS, Injury Severity Score, surgery, and Hispanic ethnicity., Conclusions: A significant mortality benefit was associated with the use of EVD compared to IPM. This mortality benefit was observed regardless of whether patients required surgery or not., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Clinical trials of pain are notoriously difficult and inefficient in demonstrating efficacy even for known efficacious treatments. Determining the appropriate pain phenotype to study can be problematic. Recent work has identified the extend of widespread pain as an important factor in the likelihood of response to therapy, but has not been tested in clinical trials. Using data from three previously published negative studies of the treatment of interstitial cystitis/ bladder pain with data on the extent of widespread pain, we examined the response of patients to different therapies base on the amount of pain beyond the pelvis. Participants with predominately local but not widespread pain responded to therapy targeting local symptoms. Participants with widespread and local pain responded to therapy targeting widespread pain. Differentiating patients with and without widespread pain phenotypes may be a key feature of designing future pain clinical trials to demonstrate treatments that are effective versus not., Competing Interests: John T Farrar reports over the past 3 years funding from NIH-NCATS – UL1 Grant (Co-I), NIH-NIDDK - U01 Grants (CoI), from NIH-NINDS - U24 Grant (PI), and two FDA-BAA Contracts; and compensation for serving on two NIH DSMBs. Has served on advisory boards as a consultant on clinical trial methods from Vertex and Lilly. Kenneth T Locke reports no relevant conflicts J Quentin Clemens reports no relevant conflicts James W. Griffith reports no relevant conflicts Steven E Harte reports no relevant conflicts Ziya Kirkali reports no relevant conflicts Karl J Kreder reports no relevant conflicts John N Krieger reports no relevant conflicts H Henry Lai reports no relevant conflicts Robert Moldwin reports no relevant conflicts Chris Mullins reports no relevant conflicts Bruce D Naliboff reports no relevant conflicts Michael A Pontari reports being a site for a clinical trial with Lipella Pharmaceuticals Inc. Larissa V Rodriguez reports no relevant conflicts Anthony J Schaeffer reports no relevant conflicts Andrew Schrepf reports no relevant conflicts Alisa J Stephens-Shields reports no relevant conflicts Siobhan Sutcliffe reports no relevant conflicts Bayley J Taple reports no relevant conflicts David A Williams reports consultant relationship with Swing Therapeutics, Inc., and Community Health Focus, Inc. J. Richard Landis reports no relevant conflicts

Background: Hypoxic brain injury is the leading cause of death in comatose patients following resuscitation from cardiac arrest. Neurological outcome can be difficult to prognosticate following resuscitation, and goals of care discussions are often informed by multiple prognostic tools. One tool that has shown promise is the SLANT score, which encompasses five metrics including initial nonshockable rhythm, leukocyte count after targeted temperature management, total adrenaline dose during resuscitation, lack of bystander cardiopulmonary resuscitation, and time to return of spontaneous circulation. This cohort study aimed to provide an external validation of this score by using a database of comatose cardiac arrest survivors from our institution., Methods: We retrospectively queried our database of cardiac arrest survivors, selecting for patients with coma, sustained return of spontaneous circulation, and use of targeted temperature management to have a comparable sample to the index study. We calculated SLANT scores for each patient and separated them into risk levels, both according to the original study and according to a Youden index analysis. The primary outcome was poor neurologic outcome (defined by a cerebral performance category score of 3 or greater at discharge), and the secondary outcome was in-hospital mortality. Univariable and multivariable analyses, as well as a receiver operator characteristic curve, were used to assess the SLANT score for independent predictability and diagnostic accuracy for poor outcomes., Results: We demonstrate significant association between a SLANT group with increased risk and poor neurologic outcome on univariable (p = 0.005) and multivariable analysis (odds ratio 1.162, 95% confidence interval 1.003-1.346, p = 0.046). A receiver operating characteristic analysis indicates that SLANT scoring is a fair prognostic test for poor neurologic outcome (area under the curve 0.708, 95% confidence interval 0.536-0.879, p = 0.024). Among this cohort, the most frequent SLANT elements were initial nonshockable rhythm (84.5%) and total adrenaline dose ≥ 5 mg (63.9%). There was no significant association between SLANT score and in-hospital mortality (p = 0.064)., Conclusions: The SLANT score may independently predict poor neurologic outcome but not in-hospital mortality. Including the SLANT score as part of a multimodal approach may improve our ability to accurately prognosticate comatose survivors of cardiac arrest., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Purpose: We assessed the reliability and validity of an efficient severity assessment for pelvic pain and urinary symptoms in urological chronic pelvic pain syndrome, which consists of interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome., Materials and Methods: A total of 578 patients were assessed using brief, empirically derived self-report scales for pelvic pain severity (PPS) and urinary symptom severity (USS) 4 times during a 1-month period and baseline clinic visit that included urological, pain and illness-impact measures. Mild, moderate and severe categories on each dimension were examined for measurement stability and construct validity., Results: PPS and USS severity categories had adequate reliability and both discriminant validity (differential relationships with specific clinical and self-report measures) and convergent validity (common association with nonurological somatic symptoms). For example, increasing PPS was associated with pelvic tenderness and widespread pelvic pain, whereas USS was associated with urgency during a bladder filling test and increased sensory sensitivity. PPS and USS categories were independently associated with nonurological pain and emotional distress. A descriptive analysis identified higher likelihood characteristics associated with having moderate to severe PPS or USS or both. Lack of sex interactions indicated that the measures are comparable in interstitial cystitis/bladder pain syndrome and chronic prostatitis/chronic pelvic pain syndrome., Conclusions: Women and men with urological chronic pelvic pain syndrome can be reliably subgrouped using brief self-report measures of mild, moderate or severe pelvic pain and urinary symptoms. Comparisons with a broad range of clinical variables demonstrate the validity and potential clinical utility of these classifications, including use in clinical trials, health services and biological research.

Clinical research networks (CRNs), made up of multiple healthcare systems each with patient data from several care sites, are beneficial for studying rare outcomes and increasing generalizability of results. While CRNs encourage sharing aggregate data across healthcare systems, individual systems within CRNs often cannot share patient-level data due to privacy regulations, prohibiting multi-site regression which requires an analyst to access all individual patient data pooled together. Meta-analysis is commonly used to model data stored at multiple institutions within a CRN but can result in biased estimation, most notably in rare-event contexts. We present a communication-efficient, privacy-preserving algorithm for modeling multi-site zero-inflated count outcomes within a CRN. Our method, a one-shot distributed algorithm for performing hurdle regression (ODAH), models zero-inflated count data stored in multiple sites without sharing patient-level data across sites, resulting in estimates closely approximating those that would be obtained in a pooled patient-level data analysis. We evaluate our method through extensive simulations and two real-world data applications using electronic health records: examining risk factors associated with pediatric avoidable hospitalization and modeling serious adverse event frequency associated with a colorectal cancer therapy. In simulations, ODAH produced bias less than 0.1% across all settings explored while meta-analysis estimates exhibited bias up to 12.7%, with meta-analysis performing worst in settings with high zero-inflation or low event rates. Across both applied analyses, ODAH estimates had less than 10% bias for 18 of 20 coefficients estimated, while meta-analysis estimates exhibited substantially higher bias. Relative to existing methods for distributed data analysis, ODAH offers a highly accurate, computationally efficient method for modeling multi-site zero-inflated count data., (© 2021. The Author(s).)

Neurotropic viral infections continue to pose a serious threat to human and animal wellbeing. Host responses combatting the invading virus in these infections often cause irreversible damage to the nervous system, resulting in poor prognosis. Rabies is the most lethal neurotropic virus, which specifically infects neurons and spreads through the host nervous system by retrograde axonal transport. The key pathogenic mechanisms associated with rabies infection and axonal transmission in neurons remains unclear. Here we studied the pathogenesis of different field isolates of lyssavirus including rabies using ex-vivo model systems generated with mouse primary neurons derived from the peripheral and central nervous systems. In this study, we show that neurons activate selective and compartmentalized degeneration of their axons and dendrites in response to infection with different field strains of lyssavirus. We further show that this axonal degeneration is mediated by the loss of NAD and calpain-mediated digestion of key structural proteins such as MAP2 and neurofilament. We then analysed the role of SARM1 gene in rabies infection, which has been shown to mediate axonal self-destruction during injury. We show that SARM1 is required for the accelerated execution of rabies induced axonal degeneration and the deletion of SARM1 gene significantly delayed axonal degeneration in rabies infected neurons. Using a microfluidic-based ex-vivo neuronal model, we show that SARM1-mediated axonal degeneration impedes the spread of rabies virus among interconnected neurons. However, this neuronal defense mechanism also results in the pathological loss of axons and dendrites. This study therefore identifies a potential host-directed mechanism behind neurological dysfunction in rabies infection. This study also implicates a novel role of SARM1 mediated axonal degeneration in neurotropic viral infection., Competing Interests: The authors have declared that no competing interests exist.

More than half of spinal cord injury (SCI) cases occur in the cervical region, leading to respiratory dysfunction due to damaged neural circuitry that controls critically important muscles such as the diaphragm. The C3-C5 spinal cord is the location of phrenic motor neurons (PhMNs) that are responsible for diaphragm activation; PhMNs receive bulbospinal excitatory drive predominately from supraspinal neurons of the rostral ventral respiratory group (rVRG). Cervical SCI results in rVRG axon damage, PhMN denervation, and consequent partial-to-complete paralysis of hemidiaphragm. In a rat model of C2 hemisection SCI, we expressed the axon guidance molecule, brain-derived neurotrophic factor (BDNF), selectively at the location of PhMNs (ipsilateral to lesion) to promote directed growth of rVRG axons toward PhMN targets by performing intraspinal injections of adeno-associated virus serotype 2 (AAV2)-BDNF vector. AAV2-BDNF promoted significant functional diaphragm recovery, as assessed by in vivo electromyography. Within the PhMN pool ipsilateral to injury, AAV2-BDNF robustly increased sprouting of both spared contralateral-originating rVRG axons and serotonergic fibers. Furthermore, AAV2-BDNF significantly increased numbers of putative monosynaptic connections between PhMNs and these sprouting rVRG and serotonergic axons. These findings show that targeting circuit plasticity mechanisms involving the enhancement of synaptic inputs from spared axon populations is a powerful strategy for restoring respiratory function post-SCI.-Charsar, B. A., Brinton, M. A., Locke, K., Chen, A. Y., Ghosh, B., Urban, M. W., Komaravolu, S., Krishnamurthy, K., Smit, R., Pasinelli, P., Wright, M. C., Smith, G. M., Lepore, A. C. AAV2-BDNF promotes respiratory axon plasticity and recovery of diaphragm function following spinal cord injury.

Current trends suggest that significant gender disparities exist within Science, Technology, Engineering, and Mathematics (STEM) education at university, with female students being underrepresented in physics, but more equally represented in life sciences (e.g., biology, medicine). To understand these trends, it is important to consider the context in which students make decisions about which university courses to enrol in. The current study seeks to investigate gender differences in STEM through a unique approach that combines network analysis of student enrollment data with an interpretive lens based on the sociological theory of Pierre Bourdieu. We generate a network of courses taken by around 9000 undergraduate physics students (from 2009 to 2014) to quantify Bourdieu's concept of field. We identify the fields in which physics students participate by constructing a weighted co-enrollment network and finding communities within it. We then use odds ratios to report gender differences in transverse movements between different academic fields, and non-parametric tests to assess gender differences in vertical movements (changes in students' achievement rankings within a field). Odds ratios comparing the likelihood of progression from one field to another indicate that female students were more likely to make transverse movements into life science fields. We also found that university physics did a poor job in attracting high achieving students, and especially high achieving female students. Of the students who did choose to study physics at university, low and middle achieving female high school students were more likely to decrease their relative rank in their first year compared to their male counterparts. Low achieving female students were also less likely to continue with physics after their first year compared to their male counterparts. Results and implications are discussed in the context of Bourdieu's theory, and previous research. We argue that in order to remove constraints on female students' study choices, the field of physics needs to provide a culture in which all students feel like they belong., Competing Interests: The authors have declared that no competing interests exist.

The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure-activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets.

The cannabinoid receptor CB2 is predominately expressed in the immune system, and selective modulation of CB2 without the psychoactivity of CB1 has therapeutic potential in inflammatory, fibrotic, and neurodegenerative diseases. Here, we report the crystal structure of human CB2 in complex with a rationally designed antagonist, AM10257, at 2.8 Å resolution. The CB2-AM10257 structure reveals a distinctly different binding pose compared with CB1. However, the extracellular portion of the antagonist-bound CB2 shares a high degree of conformational similarity with the agonist-bound CB1, which led to the discovery of AM10257's unexpected opposing functional profile of CB2 antagonism versus CB1 agonism. Further structural analysis using mutagenesis studies and molecular docking revealed the molecular basis of their function and selectivity for CB2 and CB1. Additional analyses of our designed antagonist and agonist pairs provide important insight into the activation mechanism of CB2. The present findings should facilitate rational drug design toward precise modulation of the endocannabinoid system., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The objective of this study was to develop an artificial stomach-duodenum (ASD) dissolution model as an in vitro evaluation tool that would simulate the gastrointestinal physiology of gastric pH-reduced dogs as a method to assess formulations for a poorly soluble free acid compound with ng/mL solubility. After establishing the ASD model with well-controlled duodenum pH, 5 formulations each applying different solubilization principles were developed and their performance in the ASD model and in vivo in dogs was evaluated. Excellent correlations were obtained between dog area under the curve (AUC) and ASD AUC of 5 formulations evaluated with simulated intestinal fluid (r 2  = 0.987) and fasted-state simulated intestinal fluid (r 2  = 0.989) as the duodenum dissolution medium, indicating that the approach of infusing NaOH into duodenum compartment to maintain duodenum pH of an ASD worked properly in simulating gastric pH-reduced dog. Raman spectroscopy was used to study drug dissolution kinetics associated with different solubilization principles and the results suggested that the solubilization principles performed as designed. Spectroscopic results also identified that the compound formed a gel during dissolution and hypromellose maintained the drug-gelled state to avoid further solid form conversion. The implication of the compound physical gelation to drug dissolution kinetics and in vivo exposure are discussed., (Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array. Optimization of this produced the first known micromolar inhibitors of the ATAD2 bromodomain.

The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored.

Background: Effective clinical communication is critical to providing high-quality patient care. Hospitals have used different types of interventions to improve communication between care teams, but there have been few studies of their effectiveness., Objectives: To describe the effects of different communication interventions and their problems., Design: Prospective observational case study using a mixed methods approach of quantitative and qualitative methods., Setting: General internal medicine (GIM) inpatient wards at five tertiary care academic teaching hospitals., Participants: Clinicians consisting of residents, attending physicians, nurses, and allied health (AH) staff working on the GIM wards., Methods: Ethnographic methods and interviews with clinical staff (doctors, nurses, medical students, and AH professionals) were conducted over a 16-month period from 2009 to 2010., Results: We identified four categories that described the intended and unintended consequences of communication interventions: impacts on senders, receivers, interprofessional collaboration, and the use of informal communication processes. The use of alphanumeric pagers, smartphones, and web-based communication systems had positive effects for senders and receivers, but unintended consequences were seen with all interventions in all four categories., Conclusions: Interventions that aimed to improve clinical communications solved some but not all problems, and unintended effects were seen with all systems.

Purpose: To evaluate the effects of selective rod and/or cone loss on frequency-domain optical coherence tomography (fdOCT) measures of photoreceptor structure in patients with retinal degenerative diseases., Methods: Six patients with cone dystrophy (CD) and eight patients with retinitis pigmentosa (RP) were recruited from the Southwest Eye Registry on the basis of diagnosis and ERG findings. fdOCT horizontal line scans were segmented to obtain the thicknesses of the outer segments plus RPE (OS+) and the outer nuclear layer (ONL). The normalized product ONL*OS was obtained after dividing by mean ONL*OS values of 23 normal individuals. Visual field sensitivity profiles were obtained with a modified retinal perimeter, from the horizontal midline with short- and long-wave stimuli under dark- and light-adapted conditions., Results: Patients with CD and normal rod-mediated sensitivity, but decreased cone-mediated sensitivity, showed normal ONL*OS outside the fovea. The total receptor layer was thinned in the fovea, consistent with loss in cone nuclei and Henle's fiber layer. Patients with RP and sensitivity in the dark that was mediated by cones showed ONL*OS thickness that was linearly related to cone sensitivity. ONL*OS thickness was linearly related to rod sensitivity in regions with greater loss of cone than rod sensitivity., Conclusions: Both rods and cones can support an intact IS/OS junction and normal photoreceptor thickness measures. The product of ONL and OS thicknesses is proportional to the sensitivity mediated by the less abnormal type of photoreceptor.

Hdac3 is essential for efficient DNA replication and DNA damage control. Deletion of Hdac3 impaired DNA repair and greatly reduced chromatin compaction and heterochromatin content. These defects corresponded to increases in histone H3K9,K14ac; H4K5ac; and H4K12ac in late S phase of the cell cycle, and histone deposition marks were retained in quiescent Hdac3-null cells. Liver-specific deletion of Hdac3 culminated in hepatocellular carcinoma. Whereas HDAC3 expression was downregulated in only a small number of human liver cancers, the mRNA levels of the HDAC3 cofactor NCOR1 were reduced in one-third of these cases. siRNA targeting of NCOR1 and SMRT (NCOR2) increased H4K5ac and caused DNA damage, indicating that the HDAC3/NCOR/SMRT axis is critical for maintaining chromatin structure and genomic stability., (Copyright © 2010 Elsevier Inc. All rights reserved.)

This study reports results from the first International Body Project (IBP-I), which surveyed 7,434 individuals in 10 major world regions about body weight ideals and body dissatisfaction. Participants completed the female Contour Drawing Figure Rating Scale (CDFRS) and self-reported their exposure to Western and local media. Results indicated there were significant cross-regional differences in the ideal female figure and body dissatisfaction, but effect sizes were small across high-socioeconomic-status (SES) sites. Within cultures, heavier bodies were preferred in low-SES sites compared to high-SES sites in Malaysia and South Africa (ds = 1.94-2.49) but not in Austria. Participant age, body mass index (BMI), and Western media exposure predicted body weight ideals. BMI and Western media exposure predicted body dissatisfaction among women. Our results show that body dissatisfaction and desire for thinness is commonplace in high-SES settings across world regions, highlighting the need for international attention to this problem.

The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.

A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.

Objective: Our objective was to investigate the influence of oxaliplatin on the pharmacokinetics of 5-fluorouracil (5FU) administered in a bolus plus infusional regimen., Patients and Methods: All patients had advanced/metastatic colorectal cancer. In study 1, 19 patients were studied after bolus (400 mg/m(2)) plus a 22-hour infusion (600 mg/m(2)) of 5FU/leucovorin in the standard de Gramont regimen or the same regimen with oxaliplatin (85 mg/m(2)) given before 5FU. In study 2, 12 patients were studied for 2 treatment cycles, with 5FU given in a modified de Gramont regimen comprising bolus (400 mg/m(2)) plus a 46-hour infusion (2400 mg/m(2)) of 5FU. During 1 of these cycles, oxaliplatin (85 mg/m(2)) was given before 5FU., Results: The coadministration of oxaliplatin did not significantly alter 5FU area under the plasma concentration-time curve from 0 to 1 hour, area under the plasma concentration-time curve from time 0 to the last time point, or steady-state concentration in either the de Gramont (11.6 +/- 3.8 mg/L x h(-1), 14.9 +/- 4.2 mg x h/L, and 0.17 +/- 0.06 mg/L, respectively, for 5FU alone versus 9.4 +/- 2.6 mg/L x h(-1), 13.3 +/- 2.3 mg x h/L, and 0.16 +/- 0.04, respectively, for 5FU plus oxaliplatin) or modified de Gramont regimens (13.4 +/- 2.2 mg x h/L, 35.4 +/- 4.2 mg x h/L, and 0.46 +/- 0.08 mg/L, respectively, for 5FU alone versus 13.9 +/- 3.3 mg x h/L, 38.1 +/- 7.4 mg x h/L, and 0.53 +/- 0.12, respectively, for 5FU plus oxaliplatin). The inclusion of oxaliplatin coadministration as a covariate in a NONMEM analysis did not result in any change in the objective function or mean values for the following derived parameters: maximum velocity (1590 mg x h(-1)), day 1 Michaelis-Menten constant (7.8 mg x h(-1)), and day 2 Michaelis-Menten constant (11.9 mg x h(-1))., Conclusions: The coadministration of oxaliplatin in either the standard or modified de Gramont regimen does not significantly affect the pharmacokinetics of 5FU.

The mechanism by which ligands of nuclear receptors show differential effects on gene transcription is not fully understood, but is believed to result in part from the preferential recruitment and/or displacement of coactivators and corepressors. We have explored the interaction of several known ligands and the nuclear receptor (peroxisome proliferator activated receptor alpha, PPARalpha) using scintillation proximity assay (SPA) and the interaction of LXXLL containing peptides derived from three coactivators (SRC-1, CBP and PGC-1) with PPARalpha in the presence of PPARalpha agonist ligands using fluorescence resonance energy transfer (FRET). The EC(50)s of the individual ligands for recruitment showed the same rank order regardless of the coactivator peptide used, with GW2331

This study evaluates the effect of maternal depression on neonatal health status in premature infants during their initial hospitalization. Infants younger than 34 weeks' gestation born to nondrug abusing mothers were enrolled in the study. Thirty-one mother-infant pairs were identified. Maternal depression was evaluated by the Center for Epidemiologic Studies-Depression Scale (CES-D). Scores > or = 16 defined maternal depression. Initial infant physiologic health status was determined by the Score for Neonatal Acute Physiology (SNAP). In-hospital health status was assessed by the following variables: days receiving supplemental oxygen, days on mechanical ventilation (VENT), and days not on enteral feeding (NPO). Health status variables evaluated for long-term outcome included bronchopulmonary dysplasia at 28 days (BPD), BPD at 34 weeks' postmenstrual age (BPD-34), and intraventricular hemorrhage (IVH). Seventeen (55%) of 31 mothers manifested depression on the CES-D. No epidemiologic differences were found between this group and the nondepressed mothers. No differences in gestation or birth weight was detected between the preterm infants of depressed versus nondepressed mothers. The CES-D scores correlated significantly with SNAP (r = .36, P < .02). Infants of depressed mothers experienced significantly worse outcomes in the occurrence of BPD (P = .015), BPD-34 (P = .049), and IVH (P = .055). This study confirms that maternal depression occurs frequently in mothers of preterm infants and adversely affects the presenting neonatal health status of their babies during the initial hospitalization. Maternal depression was related to the severity of the initial neonatal illness and was significantly related to IVH and BPD. These factors may have long-term consequences for subsequent growth, neurodevelopment, and recurrence of related health problems.

A new reagent, 1-(9-anthracenylmethyl)piperzine (MAP), was used for the derivatization of airborne 1,6-hexamethylene diisocyanate (HDI) and polyisocyanates generated during spray-painting operations. The new reagent, which offers enhanced sensitivity and uniformity of response to both the monomeric and oligomeric forms of HDI, was compared directly with 1-(2-methoxyphenyl)piperazine (MOP), the currently employed derivatizing reagent used in the National Institute for Occupational Safety and Health Method 5521. Both the validity of the side-by-side sampling protocol and the efficacy of two derivatizing reagents were evaluated in field studies. The analytical results indicate that there is no significant difference at the 95% confidence level in the concentration of polyisocyanate in the aerosol as determined by two impingers containing MAP and a third containing MOP when these are positioned in a side-by-side-by-side arrangement.