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Abstract Background As previously published, the MMPOWER-3 clinical trial did not demonstrate a significant benefit of elamipretide treatment in a genotypically diverse population of adults with primary mitochondrial myopathy (PMM). However, the prespecified subgroup of subjects with disease-causing nuclear DNA (nDNA) pathogenic variants receiving elamipretide experienced an improvement in the six-minute walk test (6MWT), while the cohort of subjects with mitochondrial DNA (mtDNA) pathogenic variants showed no difference versus placebo. These published findings prompted additional genotype-specific post hoc analyses of the MMPOWER-3 trial. Here, we present these analyses to further investigate the findings and to seek trends and commonalities among those subjects who responded to treatment, to build a more precise Phase 3 trial design for further investigation in likely responders. Results Subjects with mtDNA pathogenic variants or single large-scale mtDNA deletions represented 74% of the MMPOWER-3 population, with 70% in the mtDNA cohort having either single large-scale mtDNA deletions or MT-TL1 pathogenic variants. Most subjects in the nDNA cohort had pathogenic variants in genes required for mtDNA maintenance (mtDNA replisome), the majority of which were in POLG and TWNK. The mtDNA replisome post-hoc cohort displayed an improvement on the 6MWT, trending towards significant, in the elamipretide group when compared with placebo (25.2 ± 8.7 m versus 2.0 ± 8.6 m for placebo group; p = 0.06). The 6MWT results at week 24 in subjects with replisome variants showed a significant change in the elamipretide group subjects who had chronic progressive external ophthalmoplegia (CPEO) (37.3 ± 9.5 m versus − 8.0 ± 10.7 m for the placebo group; p = 0.0024). Pharmacokinetic (exposure–response) analyses in the nDNA cohort showed a weak positive correlation between plasma elamipretide concentration and 6MWT improvement. Conclusions Post hoc analyses indicated that elamipretide had a beneficial effect in PMM patients with mtDNA replisome disorders, underscoring the importance of considering specific genetic subtypes in PMM clinical trials. These data serve as the foundation for a follow-up Phase 3 clinical trial (NuPOWER) which has been designed as described in this paper to determine the efficacy of elamipretide in patients with mtDNA maintenance-related disorders. Classification of evidence Class I ClinicalTrials.gov identifier NCT03323749

Background The TaqMan Array Card (TAC) is an arrayed, high-throughput qPCR platform that can simultaneously detect multiple targets in a single reaction. However, the manual post-run analysis of TAC data is time consuming and subject to interpretation. We sought to automate the post-run analysis of TAC data using machine learning models. Methods We used 165,214 qPCR amplification curves from two studies to train and test two eXtreme Gradient Boosting (XGBoost) models. Previous manual analyses of the amplification curves by experts in qPCR analysis were used as the gold standard. First, a classification model predicted whether amplification occurred or not, and if so, a second model predicted the cycle threshold (Ct) value. We used 5-fold cross-validation to tune the models and assessed performance using accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and mean absolute error (MAE). For external validation, we used 1,472 reactions previously analyzed by 17 laboratory scientists as part of an external quality assessment for a multisite study. Results In internal validation, the classification model achieved an accuracy of 0.996, sensitivity of 0.997, specificity of 0.993, PPV of 0.998, and NPV of 0.991. The Ct prediction model achieved a MAE of 0.590. In external validation, the automated analysis achieved an accuracy of 0.997 and a MAE of 0.611, and the automated analysis was more accurate than manual analyses by 14 of the 17 laboratory scientists. Conclusions We automated the post-run analysis of highly-arrayed qPCR data using machine learning models with high accuracy in comparison to a manual gold standard. This approach has the potential to save time and improve reproducibility in laboratories using the TAC platform and other high-throughput qPCR approaches.

Abstract To compare the efficacy and safety of the proposed aflibercept biosimilar SCD411 and reference aflibercept in patients with neovascular age-related macular degeneration, this randomized, double-masked, parallel-group, multicenter study was conducted in 14 countries from 13 August 2020 to 8 September 2022. Patients with neovascular age-related macular degeneration. With subfoveal, juxtafoveal, or extrafoveal choroidal neovascularization were aged 50 years or older. Intravitreal injection of SCD411 or aflibercept (2.0 mg) were administered every 4 weeks for the first three injections and every 8 weeks until week 48. The primary efficacy endpoint was the change in best-corrected visual acuity from baseline to week 8 with an adjusted equivalence margin of ± 3.0 letters. Patients were randomly assigned to receive either SCD411 (n = 288) or reference aflibercept (n = 288). A total of 566 participants (98.3%) completed week 8 of the study. The least-squares mean difference of change in best-corrected visual acuity from baseline to week 8 (SCD411—aflibercept) was − 0.4 letters (90% confidence interval = − 1.6 to 0.9). The incidence of ocular (69 of 287 [24.0%] vs. 71 of 286 [24.8%]) and serious ocular (5 of 287 [1.7%] vs. 3 of 286 [1.0%]) treatment-emergent adverse effects were similar between the SCD411 and aflibercept groups. Immunogenicity analysis revealed a low incidence of neutralizing antibody formation in both groups. In conclusion, SCD411 has equivalent efficacy compared with reference aflibercept in patients with neovascular age-related macular degeneration and has a comparable safety profile. The results support the potential use of SCD411 for the treatment of neovascular age-related macular degeneration.

The purpose of this study was to evaluate the reliability and validity of the raw accelerometry output from research-grade and consumer wearable devices compared to accelerations produced by a mechanical shaker table. Raw accelerometry data from a total of 40 devices (i.e., n = 10 ActiGraph wGT3X-BT, n = 10 Apple Watch Series 7, n = 10 Garmin Vivoactive 4S, and n = 10 Fitbit Sense) were compared to reference accelerations produced by an orbital shaker table at speeds ranging from 0.6 Hz (4.4 milligravity-mg) to 3.2 Hz (124.7mg). Two-way random effects absolute intraclass correlation coefficients (ICC) tested inter-device reliability. Pearson product moment, Lin's concordance correlation coefficient (CCC), absolute error, mean bias, and equivalence testing were calculated to assess the validity between the raw estimates from the devices and the reference metric. Estimates from Apple, ActiGraph, Garmin, and Fitbit were reliable, with ICCs = 0.99, 0.97, 0.88, and 0.88, respectively. Estimates from ActiGraph, Apple, and Fitbit devices exhibited excellent concordance with the reference CCCs = 0.88, 0.83, and 0.85, respectively, while estimates from Garmin exhibited moderate concordance CCC = 0.59 based on the mean aggregation method. ActiGraph, Apple, and Fitbit produced similar absolute errors = 16.9mg, 21.6mg, and 22.0mg, respectively, while Garmin produced higher absolute error = 32.5mg compared to the reference. ActiGraph produced the lowest mean bias 0.0mg (95%CI = -40.0, 41.0). Equivalence testing revealed raw accelerometry data from all devices were not statistically significantly within the equivalence bounds of the shaker speed. Findings from this study provide evidence that raw accelerometry data from Apple, Garmin, and Fitbit devices can be used to reliably estimate movement; however, no estimates were statistically significantly equivalent to the reference. Future studies could explore device-agnostic and harmonization methods for estimating physical activity using the raw accelerometry signals from the consumer wearables studied herein.

The Coronavirus Disease 2019 (COVID-19) pandemic has disproportionately impacted people who use drugs (PWUD). This study explored relationships between drug use, COVID-19 testing, vaccination, and infection. This cross-sectional study was conducted in Miami, Florida between March 2021 and October 2022 as part of the National Institutes of Health (NIH) Rapid Acceleration of Diagnostics-Underserved Populations (RADx-UP) initiative and the Miami Adult Studies on HIV (MASH) cohort. Users of cannabis, cocaine/crack, heroin/fentanyl, methamphetamines, hallucinogens, and/or prescription drug misuse in the previous 12 months were considered PWUD. Sociodemographic data, COVID-19 testing history, and vaccination-related beliefs were self-reported. Vaccinations were confirmed with medical records and positivity was determined with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. Statistical analyses included chi-square tests and logistic regression. Of 1,780 participants, median age was 57 years, 50.7% were male, 50.2% Non-Hispanic Black, and 66.0% reported an annual income less than $15,000. Nearly 28.0% used drugs. PWUD were less likely than non-users to self-report ever testing positive for SARS-CoV-2 (14.7% vs. 21.0%, p = 0.006). However, 2.6% of participants tested positive for SARS-CoV-2, with no significant differences between PWUD and non-users (3.7% vs. 2.2%, p = 0.076). PWUD were more likely than non-users to experience difficulties accessing testing (10.2% vs. 7.1%, p = 0.033), vaccine hesitancy (58.9% vs. 43.4%, p = 0.002) and had lower odds of receiving any dose of a COVID-19 vaccine compared to non-users (aOR, 0.63; 95% CI, 0.49-0.81; p

Community collaboration is a cornerstone of modern public health efforts. This work aimed to use community-engaged research to explore COVID-19 vaccination, testing, and infection in a minoritized community. This study was conducted in Miami, Florida, from March 2021 to February 2022 in community partner sites and the Miami Adult Studies on HIV (MASH) cohort. Sociodemographic characteristics, vaccination and testing beliefs, and COVID-19 challenges were self-reported. COVID-19 vaccinations were verified with medical records, testing history was self-reported, and severe acute respiratory syndrome coronavirus 2 positivity was determined via real-time reverse transcription–polymerase chain reaction (rt-PCR). Of 1689 participants, the median age was 57, 51% were male, 49% were non-Hispanic Black, 66% reported an income < USD 15,000/year, and 75.9% received at least one dose of a COVID-19 vaccine. Belief that COVID-19 vaccination is effective was associated with lower odds of COVID-19 positivity and was the strongest predictor of vaccination. Challenges accessing health care, housing, food, and transportation were associated with lower odds of vaccination. Employment, health insurance, higher education, and greater perceived test accuracy were associated with greater odds of COVID-19 testing. Social determinants of health and the belief that vaccines are effective and tests are accurate predicted behaviors and thus should be considered during public health crises in vulnerable communities.

Negative body image often occurs as a result of social evaluation of the physique in men. Social self-preservation theory (SSPT) holds that social-evaluative threats (SETs) elicit consistent psychobiological responses (i.e., salivary cortisol and shame) to protect one’s social-esteem, status, and standing. Actual body image SETs have resulted in psychobiological changes consistent with SSPT in men; however, responses in athletes have yet to be examined. These responses may differ as athletes tend to experience fewer body image concerns compared with non-athletes. The purpose of the current study was to examine psychobiological (i.e., body shame and salivary cortisol) responses to an acute laboratory body image SET in 49 male varsity athletes from non-aesthetic sports and 63 male non-athletes from a university community. Participants (age range 18–28 years) were randomized into a high or low body image SET condition, stratified by athlete status; measures of body shame and salivary cortisol were taken across the session (i.e., pre, post, 30-min post, 50-min post-intervention). There were no significant time-by-condition interactions, such that athletes and non-athletes had significant increases in salivary cortisol ( F 3,321 = 3.34, p = .02), when controlling for baseline values, and state body shame ( F 2.43,262.57 = 4.58, p = .007) following the high-threat condition only. Consistent with SSPT, body image SETs led to increased state body shame and salivary cortisol, although there were no differences in these responses between non-athletes and athletes.

Abstract Altered composition of gut bacteria and changes to the production of their bioactive metabolites, the short-chain fatty acids (SCFAs), have been implicated in the development of multiple sclerosis (MS). However, the immunomodulatory actions of SCFAs and intermediaries in their ability to influence MS pathogenesis are uncertain. In this study, levels of serum SCFAs were correlated with immune cell abundance and phenotype as well as with other relevant serum factors in blood samples taken at first presentation of Clinically Isolated Syndrome (CIS; an early form of MS) or MS and compared to healthy controls. There was a small but significant reduction in propionate levels in the serum of patients with CIS or MS compared with healthy controls. The frequencies of circulating T follicular regulatory cells and T follicular helper cells were significantly positively correlated with serum levels of propionate. Levels of butyrate associated positively with frequencies of IL-10-producing B-cells and negatively with frequencies of class-switched memory B-cells. TNF production by polyclonally-activated B-cells correlated negatively with acetate levels. Levels of serum SCFAs associated with changes in circulating immune cells and biomarkers implicated in the development of MS.

Summary: Background: Late distant recurrence is a challenge for the treatment of invasive lobular carcinoma (ILC) of the breast. Despite in-depth characterisation of primary ILC, the molecular landscape of metastatic ILC is still only partially understood. Methods: We retrospectively identified 38 ILC patients from the tissue banks of six European institutions. DNA extracted from patient matched primary and metastatic FFPE tissue blocks was whole genome sequenced to compute somatic copy number aberrations. This, in turn, was used to infer the evolutionary history of these patients. Findings: The data show different metastatic seeding patterns, with both an early and late divergence of the metastatic lineage observed in ILC. Additionally, cascading dissemination from a metastatic precursor was a dominant rule. Alterations in key cancer driver genes, such as TP53 or CCND1, were acquired early while additional aberrations were present only in the metastatic branch. In about 30% of the patients, the metastatic lineage harboured less aberrations than the primary tumour suggesting a period of tumour dormancy or prolonged adaptation at the distant site. This phenomenon was mostly observed in tumours from de novo metastatic patients. Interpretation: Our results provide insights into ILC evolution and offer potential paths for optimised ILC care. Funding: This work has received financial support from Les Amis de l'Institut Bordet, MEDIC, the Breast Cancer Research Foundation (BCRF) and the Belgian Fonds National de la Recherche Scientifique (F.R.S-FNRS).

Abstract Background Genome wide association studies have identified > 200 susceptibility loci accounting for much of the heritability of multiple sclerosis (MS). Epstein-Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS. The molecular and immunological basis for this has not been established. Infected B cell proliferation is driven by signalling through the EBV produced cell surface protein LMP1, a homologue of the MS risk gene CD40. Methods We have investigated transcriptomes of B cells and EBV-infected B cells at Latency III (LCLs) and identified MS risk genes with altered expression on infection and with expression levels associated with the MS risk genotype (LCLeQTLs). The association of LCLeQTL genomic burden with EBV phenotypes in vitro and in vivo was examined. The risk genotype effect on LCL proliferation with CD40 stimulation was assessed. Results These LCLeQTL MS risk SNP:gene pairs (47 identified) were over-represented in genes dysregulated between B and LCLs (p

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibody neutralization response and its evasion by emerging viral variants and variant of concern (VOC) are unknown, but critical to understand reinfection risk and breakthrough infection following vaccination. Antibody immunoreactivity against SARS-CoV-2 antigens and Spike variants, inhibition of Spike-driven virus-cell fusion, and infectious SARS-CoV-2 neutralization were characterized in 807 serial samples from 233 reverse transcription polymerase chain reaction (RT-PCR)-confirmed Coronavirus Disease 2019 (COVID-19) individuals with detailed demographics and followed up to 7 months. A broad and sustained polyantigenic immunoreactivity against SARS-CoV-2 Spike, Membrane, and Nucleocapsid proteins, along with high viral neutralization, was associated with COVID-19 severity. A subgroup of "high responders" maintained high neutralizing responses over time, representing ideal convalescent plasma donors. Antibodies generated against SARS-CoV-2 during the first COVID-19 wave had reduced immunoreactivity and neutralization potency to emerging Spike variants and VOC. Accurate monitoring of SARS-CoV-2 antibody responses would be essential for selection of optimal responders and vaccine monitoring and design.

Introduction Front-line health workers in remote health facilities are the first contact of the formal health sector and are confronted with life-saving decisions. Health information systems (HIS) support the collection and use of health related data. However, HIS focus on reporting and are unfit to support decisions. Since data tools are paper-based in most primary healthcare settings, we have produced an innovative Paper-based Health Information System in Comprehensive Care (PHISICC) using a human-centred design approach. We are carrying out a cluster randomised controlled trial in three African countries to assess the effects of PHISICC compared with the current systems.Methods and analysis Study areas are in rural zones of Côte d’Ivoire, Mozambique and Nigeria. Seventy health facilities in each country have been randomly allocated to using PHISICC tools or to continuing to use the regular HIS tools. We have randomly selected households in the catchment areas of each health facility to collect outcomes’ data (household surveys have been carried out in two of the three countries and the end-line data collection is planned for mid-2021). Primary outcomes include data quality and use, coverage of health services and health workers satisfaction; secondary outcomes are additional data quality and use parameters, childhood mortality and additional health workers and clients experience with the system. Just prior to the implementation of the trial, we had to relocate the study site in Mozambique due to unforeseen logistical issues. The effects of the intervention will be estimated using regression models and accounting for clustering using random effects.Ethics and dissemination Ethics committees in Côte d’Ivoire, Mozambique and Nigeria approved the trials. We plan to disseminate our findings, data and research materials among researchers and policy-makers. We aim at having our findings included in systematic reviews on health systems interventions and future guidance development on HIS.Trial registration number PACTR201904664660639; Pre-results.

Background: The objective of the study was to assess compliance of the WHO and UNICEF estimates of national immunization coverage (WUENIC) against the 18 criteria of the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER) that define and promote good practice in reporting of global health estimates. Methods: We conducted a desk review of the WUENIC estimation and reporting process vis-à-vis each of the 18 GATHER criteria to complete a self-assessment of compliance with GATHER. Results: Overall, WUENIC estimates are fully compliant with 17 of the GATHER criteria and partially compliant with one criterion—criterion 11, which is related to candidate model evaluation and final model selection. Conclusion: The GATHER criteria provide a useful framework for documenting WUENIC’s compliance with contemporary reporting requirements. Given the role of vaccination coverage estimates in global monitoring and guiding disease control efforts, WHO and UNICEF strive to produce and publish robust estimates of vaccination coverage through a transparent process that emphasizes country involvement.

Introduction: Emergency clinicians on the frontline of the coronavirus pandemic experience a range of emotions including anxiety, fear, and grief. Debriefing can help clinicians process these emotions, but the coronavirus pandemic makes it difficult to create a physically and psychologically safe space in the emergency department (ED) to perform this intervention. In response, we piloted a video-based debriefing program to support emergency clinician well-being. We report the details of our program and results of our evaluation of its acceptability and perceived value to emergency clinicians during the pandemic. Methods: ED attending physicians, resident physicians, and non-physician practitioners (NPP) at our quaternary-care academic medical center were invited to participate in role-based, weekly one-hour facilitated debriefings using Zoom. ED attendings with experience in debriefing led each session and used an explorative approach that focused on empathy and normalizing reactions. At the end of the pilot, we distributed to participants an anonymous 10-point survey that included multiple-answer questions and visual analogue scales. Results: We completed 18 debriefings with 68 unique participants (29 attending physicians, 6 resident physicians, and 33 NPPs. A total of 76% of participants responded to our survey and 77% of respondents participated in at least two debriefings. Emergency clinicians reported that the most common reasons to participate in the debriefings were “to enhance my sense of community and connection” (81%) followed by “to support colleagues” (75%). Debriefing with members of the same role group (92%) and the Zoom platform (81%) were considered to be helpful aspects of the debriefing structure. Although emergency clinicians found these sessions to be useful (78.8 +/− 17.6) interquartile range: 73–89), NPPs were less comfortable speaking up (58.5 +/− 23.6) than attending physicians (77.8 +/− 25.0) (p = < 0.008). Conclusion: Emergency clinicians participating in a video-based debriefing program during the coronavirus pandemic found it to be an acceptable and useful approach to support emotional well-being. Our program provided participants with a platform to support each other and maintain a sense of community and connection. Other EDs should consider implementing a debriefing program to safeguard the emotional well-being of their emergency clinician workforce.

Recent research has shown relationships between health outcomes and residence proximity to unconventional oil and natural gas development (UOGD). The challenge of connecting health outcomes to environmental stressors requires ongoing research with new methodological approaches. We investigated UOGD density and well emissions and their association with symptom reporting by residents of southwest Pennsylvania. A retrospective analysis was conducted on 104 unique, de-identified health assessments completed from 2012-2017 by residents living in proximity to UOGD. A novel approach to comparing estimates of exposure was taken. Generalized linear modeling was used to ascertain the relationship between symptom counts and estimated UOGD exposure, while Threshold Indicator Taxa Analysis (TITAN) was used to identify associations between individual symptoms and estimated UOGD exposure. We used three estimates of exposure: cumulative well density (CWD), inverse distance weighting (IDW) of wells, and annual emission concentrations (AEC) from wells within 5 km of respondents' homes. Taking well emissions reported to the Pennsylvania Department of Environmental Protection, an air dispersion and screening model was used to estimate an emissions concentration at residences. When controlling for age, sex, and smoker status, each exposure estimate predicted total number of reported symptoms (CWD, p

Growth Differentiation Factor-15 (GDF15) is a divergent TGF-beta superfamily cytokine that is overexpressed by most cancers and is induced by anticancer therapy. Transgenic and induced animal models suggest that it protects from cancer development but the mechanisms are uncertain. We investigated the role of immunity in GDF15 induced reduction in prostate cancer (PCa) growth. The C57BL/6 transgenic TRAMP prostate cancer prone mice were bred with mice that were immunodeficient and/or systemically overexpressed GDF15. We developed a novel orthotopic TRAMP PCa model in which primary TRAMP tumor cells were implanted into prostates of mice to reduce the study time. These mice were administered recombinant mouse GDF15, antibody to CD8, PD1 or their respective controls. We found that GDF15 induced protection from tumor growth was reversed by lack of adaptive immunity. Flow cytometric evaluation of lymphocytes within these orthotopic tumors showed that GDF15 overexpression was associated with increased CD8 T cell numbers and an increased number and proportion of recently activated CD8+CD11c+ T cells and a reduced proportion of "exhausted" CD8+PD1+ T cells. Further, depletion of CD8 T cells in tumor bearing mice abolished the GDF15 induced protection from tumor growth. Infusion of GDF15 into mice bearing orthotopic TRAMP tumor, substantially reduced tumor growth that was further reduced by concurrent PD1 antibody administration. GDF15 overexpression or recombinant protein protects from TRAMP tumor growth by modulating CD8 T cell mediated antitumor immunity and augments the positive effects of anti-PD1 blockers.

Introduction: The objective of this study was to investigate the factors associated with first-pass success in pediatric intubation in the emergency department (ED). Methods: We analyzed the data from two multicenter prospective studies of ED intubation in 17 EDs between April 2010 and September 2014. The studies prospectively measured patient’s age, sex, principal indication for intubation, methods (e.g., rapid sequence intubation [RSI]), devices, and intubator’s level of training and specialty. To evaluate independent predictors of first-pass success, we fit logistic regression model with generalized estimating equations. In the sensitivity analysis, we repeated the analysis in children

BACKGROUND:Although periodic cardiac stress testing is commonly used to screen patients on the waiting list for kidney transplantation for ischemic heart disease, there is little evidence to support this practice. We hypothesized that cardiac stress testing in the 18 months prior to kidney transplantation would not reduce postoperative death, total myocardial infarction (MI) or fatal MI. METHODS:Using the United States Renal Data System, we identified ESRD patients ≥40 years old with primary Medicare insurance who received their first kidney transplant between 7/1/2006 and 11/31/2013. Propensity matching created a 1:1 matched sample of patients with and without stress testing in the 18 months prior to kidney transplantation. The outcomes of interest were death, total (fatal and nonfatal) MI or fatal MI within 30 days of kidney transplantation. RESULTS:In the propensity-matched cohort of 17,304 patients, death within 30 days occurred in 72 of 8,652 (0.83%) patients who underwent stress testing and in 65 of 8,652 (0.75%) patients who did not (OR 1.07; 95% CI: 0.79-1.45; P = 0.66). MI within 30 days occurred in 339 (3.9%) patients who had a stress test and in 333 (3.8%) patients who did not (OR 1.03; 95% CI: 0.89-1.21; P = 0.68). Fatal MI occurred in 17 (0.20%) patients who underwent stress testing and 15 (0.17%) patients who did not (OR 0.97; 95% CI: 0.71-1.32; P = 0.84). CONCLUSION:Stress testing in the 18 months prior to kidney transplantation is not associated with a reduction in death, total MI or fatal MI within 30 days of kidney transplantation.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease resulting in non-healing wounds affecting body areas of high hair follicle and sweat gland density. The pathogenesis of HS is not well understood but appears to involve dysbiosis-driven aberrant activation of the innate immune system leading to excessive inflammation. Marked dysregulation of antimicrobial peptides and proteins (AMPs) in HS is observed, which may contribute to this sustained inflammation. Here, we analyzed HS skin transcriptomes from previously published studies and integrated these findings through a comparative analysis with a published wound healing data set and with immunofluorescence and qPCR analysis from new HS patient samples. Among the top differently expressed genes between lesional and non-lesional HS skin were members of the S100 family as well as dermcidin, the latter known as a sweat gland-associated AMP and one of the most downregulated genes in HS lesions. Interestingly, many genes associated with sweat gland function, such as secretoglobins and aquaporin 5, were decreased in HS lesional skin and we discovered that these genes demonstrated opposite expression profiles in healing skin. Conversely, HS lesional and wounded skin shared a common gene signature including genes encoding for S100 proteins, defensins, and genes encoding antiviral proteins. Overall, our results suggest that the pathogenesis of HS may be driven by changes in AMP expression and altered sweat gland function, and may share a similar pathology with chronic wounds.

The portfolio of cytokines is key to the function of macrophages as sentries of the innate immune system as well as being critical for the transition from innate to adaptive immunity. Cytokine bias is critical in the fate of macrophages into a continuum of inflammatory to anti-inflammatory macrophages. Due to advances in the field of toxicology, increasingly advanced multi-cellular in vitro safety assessment models are being developed in order to allow for a better predication of potential adverse effects in humans with many of these models include a macrophage population. The selection of the correct macrophage cells in these advanced in vitro models is critical for a physiologically relevant and realistic immune response. In this study we investigated cytokine response profile (IL1-β, IL6, IL10 and TNF-α) of activated and non-activated THP-1 (immortalized monocyte-like cell line), primary human Kupffer cells (liver resident macrophages) and human primary peripheral blood mononuclear cells following exposure of a panel of nanomaterials or ethanol. The data demonstrated that the THP-1 cell line are not great cytokine producers. The PBMC appear to be a good in vitro surrogate for circulating/pro-inflammatory macrophages but are not a suitable replacement for Kupffer cells. The findings from this study highlight the necessity for the selection of appropriate macrophages populations to meet the specific physiological requirements of in vitro experiment.

Introduction: Our goal was to assess whether use of a standardized clinical protocol improves efficiency for patients who present to the emergency department (ED) with symptoms of transient ischemic attack (TIA). Methods: We performed a structured, retrospective, cohort study at a large, urban, tertiary care academic center. In July 2012 this hospital implemented a standardized protocol for patients with suspected TIA. The protocol selected high-risk patients for admission and low/intermediate-risk patients to an ED observation unit for workup. Recommended workup included brain imaging, vascular imaging, cardiac monitoring, and observation. Patients were included if clinical providers determined the need for workup for TIA. We included consecutive patients presenting during a six-month period prior to protocol implementation, and those presenting between 6–12 months after implementation. Outcomes included ED length of stay (LOS), hospital LOS, use of neuroimaging, and 90-day risk of stroke or TIA. Results: From 01/2012 to 06/2012, 130 patients were evaluated for TIA symptoms in the ED, and from 01/2013 to 06/2013, 150 patients. The final diagnosis was TIA or stroke in 45% before vs. 41% after (p=0.18). Following the intervention, the inpatient admission rate decreased from 62% to 24% (p

Step kinematic variability has been characterized during gait using spatial and temporal kinematic characteristics. However, people can adopt different trajectory paths both between individuals and even within individuals at different speeds. Single point measures such as minimum toe clearance (MTC) and step length (SL) do not necessarily account for the multiple paths that the foot may take during the swing phase to reach the same foot fall endpoint. The purpose of this study was to test a step-by-step foot trajectory area (SBS-FTA) variability measure that is able to characterize sagittal plane foot trajectories of varying areas, and compare this measure against MTC and SL variability at different speeds. We hypothesize that the SBS-FTA variability would demonstrate increased variability with speed. Second, we hypothesize that SBS-FTA would have a stronger curvilinear fit compared with the CV and SD of SL and MTC. Third, we hypothesize SBS-FTA would be more responsive to change in the foot trajectory at a given speed compared to SL and MTC. Fourth, SBS-FTA variability would not strongly co-vary with SL and MTC variability measures since it represents a different construct related to foot trajectory area variability.We studied 15 nonimpaired individuals during walking at progressively faster speeds. We calculated SL, MTC, and SBS-FTA area.SBS-FTA variability increased with speed, had a stronger curvilinear fit compared with the CV and SD of SL and MTC, was more responsive at a given speed, and did not strongly co-vary with SL and MTC variability measures.SBS foot trajectory area variability was sensitive to change with faster speeds, captured a relationship that the majority of the other measures did not demonstrate, and did not co-vary strongly with other measures that are also components of the trajectory.

Emerging evidence indicates that proximity to unconventional oil and gas development (UOGD) is associated with health outcomes. There is intense debate about "How close is too close?" for maintaining public health and safety. The goal of this Delphi study was to elicit expert consensus on appropriate setback distances for UOGD from human activity. Three rounds were used to identify and seek consensus on recommended setback distances. The 18 panelists were health care providers, public health practitioners, environmental advocates, and researchers/scientists. Consensus was defined as agreement of ≥70% of panelists. Content analysis of responses to Round 1 questions revealed four categories: recommend setback distances; do not recommend setback distances; recommend additional setback distances for vulnerable populations; do not recommend additional setback distances for vulnerable populations. In Round 2, panelists indicated their level of agreement with the statements in each category using a five-point Likert scale. Based on emerging consensus, statements within each category were collapsed into seven statements for Round 3: recommend set back distances of

The ability of prokaryotic microbes to produce and respond to neurochemicals that are more often associated with eukaryotic systems is increasingly recognized through the concept of microbial endocrinology. Most studies have described the phenomena of neurochemical production by bacteria, but there remains an incomplete understanding of the mechanisms by which microbe- or host-derived neuroactive substances can be recognized by bacteria. Based on the evolutionary origins of eukaryotic solute carrier transporters, we hypothesized that bacteria may possess an analogous uptake function for neuroactive biogenic amines. Using specific fluorescence-based assays, Lactobacillus salivarius biofilms appear to express both plasma membrane monoamine transporter (PMAT)- and organic cation transporter (OCT)-like uptake of transporter-specific fluorophores. This phenomenon is not distributed throughout the genus Lactobacillus as L. rhamnosus biofilms did not take up these fluorophores. PMAT probe uptake into L. salivarius biofilms was attenuated by the protonophore CCCP, the cation transport inhibitor decynium-22, and the natural substrates norepinephrine, serotonin and fluoxetine. These results provide the first evidence, to our knowledge, for the existence of PMAT- and OCT-like uptake systems in a bacterium. They also suggest the existence of a hitherto unrecognized mechanism by which a probiotic bacterium may interact with host signals and may provide a means to examine microbial endocrinology-based interactions in health and disease that are part of the larger microbiota-gut-brain axis.

Previously, we highlighted induction of an integrated stress response (ISR) gene program in skeletal muscle of pigs treated with a beta-adrenergic agonist. Hence we tested the hypothesis that the ER-stress inhibitor, sodium 4-phenylbutyrate (PBA), would inhibit Clenbuterol-mediated muscle growth and reduce expression of genes that are known indicators of an ISR in mice. Clenbuterol (1mg/kg/day) administered to C57BL6/J mice for 21 days increased body weight (p

BACKGROUND:Home-based records (HBRs), which take many forms, serve as an important tool for frontline health workers by providing a standardized patient history vital to making informed decisions about the need for immunization services. There are increasing concerns around HBRs with recording areas that are functionally irrelevant because records are incomplete or not up-to-date. The aim of this report was to describe HBR ownership and report on the utilization of selected recording areas in HBRs across selected study communities in Kenya. METHODS:The Kenya Missed Opportunities for Vaccination Assessment utilized a mixed-methods approach that included exit interviews, using a standardized questionnaire, among a convenience sample of caregivers of children aged 90% of records. Recording areas were less frequently available for child early eye / vision problems (61%), growth monitoring (74%) and vitamin A (76%); with information marked in 33%, 88% and 60% of records, respectively. CONCLUSIONS:Critical to the reduction of missed opportunities for vaccination, the HBR's importance must be emphasized and the document must be requested by health workers at every health encounter. Health workers must not only ensure that all children receive a HBR and counsel caregivers of its importance, but they must also ensure that all sections of the record are legibly completed to ensure continuity of care. Programmes are encouraged to periodically review and critically assess the HBR to determine whether the document's design and content areas are optimal to end user needs.

Introduction: While emergency department (ED) crowding has myriad causes and negative downstream effects, applying systems engineering science and targeting throughput remains a potential solution to increase functional capacity. However, the most effective techniques for broad application in the ED remain unclear. We examined the hypothesis that Lean-based reorganization of Fast Track process flow would improve length of stay (LOS), percent of patients discharged within one hour, and room use, without added expense. Methods: This study was a prospective, controlled, before-and-after analysis of Fast Track process improvements in a Level 1 tertiary care academic medical center with >95,000 annual patient visits. We included all adult patients seen during the study periods of 6/2010-10/2010 and 6/2011-10/2011, and data were collected from an electronic tracking system. We used concurrent patients seen in another care area used as a control group. The intervention consisted of a simple reorganization of patient flow through existing rooms, based in systems engineering science and modeling, including queuing theory, demand-capacity matching, and Lean methodologies. No modifications to staffing or physical space were made. Primary outcomes included LOS of discharged patients, percent of patients discharged within one hour, and time in exam room. We compared LOS and exam room time using Wilcoxon rank sum tests, and chi-square tests for percent of patients discharged within one hour. Results: Following the intervention, median LOS among discharged patients was reduced by 15 minutes (158 to 143 min, 95%CI 12 to 19 min, p

Epithelial cells represent the first line of host immune defense at mucosal surfaces. Although opioids appear to increase host susceptibility to infection, no studies have examined opioid effects on epithelial immune functions. We tested the hypothesis that morphine alters vectorial cytokine secretion from intestinal epithelial cell (IPEC-J2) monolayers in response to enteropathogens. Both entero-adherent Escherichia coli O157:H7 and entero-invasive Salmonella enterica serovar Typhimurium increased apically-directed IL-6 secretion and bi-directional IL-8 secretion from epithelial monolayers, but only IL-6 secretion evoked by E. coli was reduced by morphine acting through a naloxone-sensitive mechanism. Moreover, the respective type 4 and 5 Toll-like receptor agonists, lipopolysaccharide and flagellin, increased IL-8 secretion from monolayers, which was also attenuated by morphine pretreatment. These results suggest that morphine decreases cytokine secretion and potentially phagocyte migration and activation directed towards the mucosal surface; actions that could increase host susceptibility to some enteric infections.

Introduction: The American College of Emergency Physicians (ACEP) Task Force on Boardingdescribed high-impact initiatives to decrease crowding. Furthermore, some emergencydepartments (EDs) have implemented a novel initiative we term “vertical patient flow,” i.e.segmenting patients who can be safely evaluated, managed, admitted or discharged withoutoccupying a traditional ED room. We sought to determine the degree that ACEP-identified highimpactinitiatives for ED crowding and vertical patient flow have been implemented in academicEDs in the United States (U.S.).Methods: We surveyed the physician leadership of all U.S. academic EDs from March toMay 2010 using a 2-minute online survey. Academic ED was defined by the primary site of anemergency residency program.Results: We had a response rate of 73% (106/145) and a completion rate of 71% (103/145).The most prevalent hospital-based initiative was inpatient discharge coordination (46% [47/103]of respondents) while the least fully initiated was surgical schedule smoothing (11% [11/103]).The most prevalent ED-based initiative was fast track (79% [81/103]) while the least initiated wasphysician triage (12% [12/103]). Vertical patient flow had been implemented in 29% (30/103) ofresponding EDs while an additional 41% (42/103) reported partial/in progress implementation.Conclusion: We found great variability in the extent academic EDs have implemented ACEP’sestablished high-impact ED crowding initiatives, yet most (70%) have adopted to some extentthe novel initiative vertical patient flow. Future studies should examine barriers to implementingthese crowding initiatives and how they affect outcomes such as patient safety, ED throughput andpatient/provider satisfaction.

α-Synuclein misfolding and aggregation is often accompanied by β-amyloid deposition in some neurodegenerative diseases. We hypothesised that α-synuclein promotes β-amyloid production from APP. β-Amyloid levels and APP amyloidogenic processing were investigated in neuronal cell lines stably overexpressing wildtype and mutant α-synuclein. γ-Secretase activity and β-secretase expression were also measured. We show that α-synuclein expression induces β-amyloid secretion and amyloidogenic processing of APP in neuronal cell lines. Certain mutations of α-synuclein potentiate APP amyloidogenic processing. γ-Secretase activity was not enhanced by wildtype α-synuclein expression, however β-secretase protein levels were induced. Furthermore, a correlation between α-synuclein and β-secretase protein was seen in rat brain striata. Iron chelation abolishes the effect of α-synuclein on neuronal cell β-amyloid secretion, whereas overexpression of the ferrireductase enzyme Steap3 is robustly pro-amyloidogenic. We propose that α-synuclein promotes β-amyloid formation by modulating β-cleavage of APP, and that this is potentially mediated by the levels of reduced iron and oxidative stress.

Macrophage inhibitory cytokine-1 (MIC-1), also known as growth differentiation factor 15 (GDF15), is a stress response cytokine. MIC-1/GDF15 is secreted into the cerebrospinal fluid and increased levels of MIC-1/GDF15 are associated with a variety of diseases including cognitive decline. Furthermore, Mic-1/Gdf15 knockout mice (Mic-1 KO) weigh more, have increased adiposity, associated with increased spontaneous food intake, and exhibit reduced basal energy expenditure and physical activity. The current study was designed to comprehensively determine the role of MIC-1/GDF15 on behavioural domains of male and female knockout mice including locomotion, exploration, anxiety, cognition, social behaviours, and sensorimotor gating. Mic-1 KO mice exhibited a task-dependent increase in locomotion and exploration and reduced anxiety-related behaviours across tests. Spatial working memory and social behaviours were not affected by Mic-1/Gdf15 deficiency. Interestingly, knockout mice formed an increased association with the conditioned stimulus in fear conditioning testing and also displayed significantly improved prepulse inhibition. Overall sex effects were evident for social behaviours, fear conditioning, and sensorimotor gating. This is the first study defining the role of Mic-1/Gdf15 in a number of behavioural domains. Whether the observed impact is based on direct actions of Mic-1/Gdf15 deficiency on the CNS or whether the behavioural effects are mediated by indirect actions on e.g. other neurotransmitter systems must be clarified in future studies.