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Background/Objective: Teriparatide, an osteoanabolic agent similar to parathyroid hormone in properties, is used to manage severe osteoporosis. Aortic valve stenosis is a common valve condition observed in the elderly. Its natural history includes gradual progression toward severity. We present a case of a patient who had rapidly progressive aortic stenosis after teriparatide initiation. Case Report: An 84-year-old woman who was diagnosed with osteoporosis was treated with oral bisphosphonates. When she had spinal compression fractures, she was found to have primary hyperparathyroidism. She underwent parathyroidectomy and was treated with denosumab infusions every 6 months. However, after she experienced bilateral atypical femoral fractures, she was switched to teriparatide daily injections. Her laboratory test results showed a calcium level of 10 mg/dL (reference range, 8.5-10.2 mg/dL), 25-hydroxyvitamin D level of 38.2 ng/mL (reference range, 31.0-80.0 ng/mL), and phosphorus level of 3.3 mg/dL (reference, range, 2.7-4.8 mg/dL). On reviewing echocardiograms before and after teriparatide initiation, we found a rapid progression of her aortic stenosis from moderate to severe based on the mean gradients (23 to 40 mm Hg) and peak velocities (3.09 to 4 m/s), over a span of 10 months. She eventually required valve replacement. Discussion: Natural progression of mild to severe aortic stenosis typically occurs at the rate of 3 to 7 mm Hg per year over several years. Chronic exposure of human valvular endothelial cells to parathyroid hormone can trigger endothelial dysfunction and valvular calcification. Conclusion: In patients with preexisting aortic stenosis, coordination of care with cardiology and echocardiographic monitoring while on therapy may be considered.

Summary: Background: While many patients seem to recover from SARS-CoV-2 infections, many patients report experiencing SARS-CoV-2 symptoms for weeks or months after their acute COVID-19 ends, even developing new symptoms weeks after infection. These long-term effects are called post-acute sequelae of SARS-CoV-2 (PASC) or, more commonly, Long COVID. The overall prevalence of Long COVID is currently unknown, and tools are needed to help identify patients at risk for developing long COVID. Methods: A working group of the Rapid Acceleration of Diagnostics-radical (RADx-rad) program, comprised of individuals from various NIH institutes and centers, in collaboration with REsearching COVID to Enhance Recovery (RECOVER) developed and organized the Long COVID Computational Challenge (L3C), a community challenge aimed at incentivizing the broader scientific community to develop interpretable and accurate methods for identifying patients at risk of developing Long COVID. From August 2022 to December 2022, participants developed Long COVID risk prediction algorithms using the National COVID Cohort Collaborative (N3C) data enclave, a harmonized data repository from over 75 healthcare institutions from across the United States (U.S.). Findings: Over the course of the challenge, 74 teams designed and built 35 Long COVID prediction models using the N3C data enclave. The top 10 teams all scored above a 0.80 Area Under the Receiver Operator Curve (AUROC) with the highest scoring model achieving a mean AUROC of 0.895. Included in the top submission was a visualization dashboard that built timelines for each patient, updating the risk of a patient developing Long COVID in response to clinical events. Interpretation: As a result of L3C, federal reviewers identified multiple machine learning models that can be used to identify patients at risk for developing Long COVID. Many of the teams used approaches in their submissions which can be applied to future clinical prediction questions. Funding: Research reported in this RADx® Rad publication was supported by the National Institutes of Health. Timothy Bergquist, Johanna Loomba, and Emily Pfaff were supported by Axle Subcontract: NCATS-STSS-P00438.

The neutron-rich rare isotope 190W is discussed as a candidate for a prolate-oblate transitional nucleus with maximum γ-softness. The collectivity of this isotope is assessed for the first time by the measurement of the reduced E2 transition probability of its first 2+ state to the ground state. The experiment employed the FAst TIming Array (FATIMA), comprised of 36 LaBr3(Ce) scintillators, which was part of the DESPEC setup at GSI, Darmstadt. The 41+ and 21+ states of 190W were populated subsequently to the decay of its 127(12) μs isomeric Jπ=10− state. The mean lifetime of the 21+ state was determined to be τ=274(28) ps, which corresponds to a B(E2;21+→01+) value of 95(10) W.u. The results motivated a revision of previous calculations within an energy-density functional-based interacting boson model-2 approach, yielding E2 transition properties and spectroscopic quadrupole moments for tungsten isotopes. From comparison to theory, the new data suggest that 190W is at the transition from prolate to oblate structure along the W isotopic chain, which had previously been discussed as a nuclear shape-phase transition.

Background: This study reports the detailed management and outcomes of women treated with Primary Endocrine Therapy (PET) in a large prospective UK cohort of older women (≥70) with breast cancer. Methods: This was an unplanned secondary analysis of a prospective, multicentre, observational study (The Age Gap study). Data were collected at baseline and regular intervals on patient, tumour and treatment characteristics with tumour RECIST response category recorded. Direct study follow-up was 24 months with longer-term survival data obtained from the UK cancer registry. Results: The Age Gap study recruited 3316 women across 56 breast units. Primary endocrine therapy (PET) was initiated for 505/3316 (15 %) women; median age was 84 (IQR 79–88) with median follow-up 41.9 months (IQR 27–60). Death occurred in 205/505(40.6 %) patients, 160/205; 78 % non- Breast Cancer related, 45/205; 21.9 % Breast Cancer related. Multivariate analysis identified older age (HR-1.055(95 % Confidence Interval: 1.029–1.084); P 0.05). Conclusion: Early disease response and change of endocrine therapy are not significantly associated with overall survival, conversion to surgery is linked to improved outcome. Prognosis is largely determined by age and comorbidity in older women treated with PET.

Reduced transition probabilities have been extracted between excited, yrast states in the N=Z+2 nucleus 94Pd. The transitions of interest were observed following decays of the Iπ=14+, Ex=2129-keV isomeric state, which was populated following the projectile fragmentation of a 124Xe primary beam at the GSI Helmholtzzentrum für Schwerionenforschung accelerator facility as part of FAIR Phase-0. Experimental information regarding the reduced E2 transition strengths for the decays of the yrast 8+ and 6+ states was determined following isomer-delayed Eγ1−Eγ2−△T2,1 coincidence method, using the LaBr3(Ce)-based FATIMA fast-timing coincidence gamma-ray array, which allowed direct determination of lifetimes of states in 94Pd using the Generalized Centroid Difference (GCD) method. The experimental value for the half-life of the yrast 8+ state of 755(106) ps results in a reduced transition probability of B(E2:8→+6+) = 205−25+34 e2fm4, which enables a precise verification of shell-model calculations for this unique system, lying directly between the N=Z line and the N=50 neutron shell closure. The determined B(E2) value provides an insight into the purity of (g9/2)n configurations in competition with admixtures from excitations between the (lower) N=3pf and (higher) N=4gds orbitals for the first time. The results indicate weak collectivity expected for near-zero quadrupole deformation and an increasing importance of the T=0 proton-neutron interaction at N=48.

Background: Obesity increases risk of atrial fibrillation (AF) at least in part due to pro-inflammatory effects, but has been paradoxically associated with improved mortality. Although statins have pleiotropic anti-inflammatory properties, their interaction with obesity and clinical outcomes in AF is unknown. We explored the relationship between BMI, statin use, and all-cause mortality and AF/congestive heart failure (CHF)-related encounters, hypothesizing that statin exposure may be differentially associated with improved outcomes in overweight/obesity. Methods: This was a single center retrospective cohort study of adults with AF diagnosed between 2011–2018. Patients were grouped by body mass index (BMI) and statin use at time of AF diagnosis. Outcomes included all-cause mortality and ED or inpatient encounters for AF or CHF. Results and Conclusions: A total of 2503 subjects were included (median age 66 years, 43.4 % female, median BMI 29.8 kg/m2, 54.6 % on baseline statin therapy). Increasing BMI was associated with decreased mortality hazard but not associated with AF/CHF encounter risk. Adjusting for statin-BMI interaction, demographics, and cardiovascular comorbidities, overweight non-statin users experienced improved mortality (adjusted hazard ratio [aHR] 0.55, 95 % CI 0.35–0.84) compared to statin users (aHR 0.98, 95 % CI 0.69–1.40; interaction P-value = 0.013). Mortality hazard was consistently lower in obese non-statin users than in statin users, however interaction was insignificant. No significant BMI-statin interactions were observed in AF/CHF encounter risk. In summary, statin use was not differentially associated with improved mortality or hospitalization risk in overweight/obese groups. These findings do not support statins for secondary prevention of adverse outcomes based on overweight/obesity status alone.

The response of objects engulfed in, and adjacent to, large-scale pool fires is of interest in accident and safety assessments. In this study, Fuego, a low-Mach turbulent reacting flow code was used to study conjugate heat transfer in a 7.9 m diameter JP-8 pool fire. Simulations were designed to replicate past experimental measurements (Blanchat et al., 2006) of incident heat flux to three cylindrical calorimeters in and around the pool fire. Two turbulent combustion models were compared directly - the eddy dissipation concept and a more recently developed unsteady flamelet model. First and second order spatial and temporal discretization schemes were also compared to assess the performance of low-dissipation numerical operators. Heat flux predictions to the transportation size calorimeter outside the fire were within experimental uncertainties. Inside the fire, experimental measurements were higher than predicted values and may have been a consequence of soot deposition and augmented participating media radiation from soot and fuel vapor. Simulation predictions improved in cases where turbulent kinetic energy and mixing were more resolved. This work, and others referenced herein, suggest that spatial resolution on the order of 0.5–1.0 cm may be required to fully resolve fluid instabilities, vortex production between fire plumes and crosswind, soot production, and fuel-air mixing. This presents a substantial computational challenge for safety assessments of engulfed objects in fully turbulent pool fires.

Background: Trait mindfulness—the tendency to attend to present-moment experiences without judgment—is negatively correlated with adolescent anxiety and depression. Understanding the neural mechanisms that underlie trait mindfulness may inform the neural basis of psychiatric disorders. However, few studies have identified brain connectivity states that are correlated with trait mindfulness in adolescence, and they have not assessed the reliability of such states. Methods: To address this gap in knowledge, we rigorously assessed the reliability of brain states across 2 functional magnetic resonance imaging scans from 106 adolescents ages 12 to 15 (50% female). We performed both static and dynamic functional connectivity analyses and evaluated the test-retest reliability of how much time adolescents spent in each state. For the reliable states, we assessed associations with self-reported trait mindfulness. Results: Higher trait mindfulness correlated with lower anxiety and depression symptoms. Static functional connectivity (intraclass correlation coefficients 0.31–0.53) was unrelated to trait mindfulness. Among the dynamic brains states that we identified, most were unreliable within individuals across scans. However, one state, a hyperconnected state of elevated positive connectivity between networks, showed good reliability (intraclass correlation coefficient = 0.65). We found that the amount of time that adolescents spent in this hyperconnected state positively correlated with trait mindfulness. Conclusions: By applying dynamic functional connectivity analysis on over 100 resting-state functional magnetic resonance imaging scans, we identified a highly reliable brain state that correlated with trait mindfulness. This brain state may reflect a state of mindfulness, or awareness and arousal more generally, which may be more pronounced in people who are higher in trait mindfulness.

Natural fiber composites offer an advantage in terms of weight saving for many automotive applications; however, many natural fiber composites lack properties to justify substitution for synthetic composites. Hybridizing the natural fiber composites by adding a fraction of synthetic fibers is an innovative approach to provide a balance between composite's performance and weight savings. In this study, coir fiber (40 wt%)-reinforced polypropylene (PP) composites were hybridized by substituting a fraction of coir fiber with glass fiber (0–30 wt%). The composites were prepared using a novel wet-laid technique followed by compression molding, where the fiber length is preserved. The composites prepared by hybridizing PP/coir fibers with glass fibers were light in weight (6–20% lighter compared to 40 wt% glass fiber reinforced PP) with significantly enhanced tensile (strength – 49–182%, modulus – 54–130%), flexural (strength – 41–104%, modulus – 64–193%), and impact properties (157 - 474%) compared to 40 wt% coir fiber reinforced PP composites. Furthermore, the addition of glass fiber (10–30 wt%) to coir fiber reduced the water-absorbing tendency (by 18–74%) of PP/coir fiber composites. All in all, this work has potential applications in automotive, mass transit, and truck applications where natural fiber composites are being investigated as alternatives to metal and/or fully synthetic composites.

Summary: Protein kinase A (PKA) is a conserved kinase crucial for fundamental biological processes linked to growth, development, and metabolism. The PKA catalytic subunit is expressed as multiple isoforms in diverse eukaryotes; however, their contribution to ensuring signaling specificity in response to environmental cues remains poorly defined. Catalytic subunit activity is classically moderated via interaction with an inhibitory regulatory subunit. Here, a quantitative mass spectrometry approach is used to examine heat-stress-induced changes in the binding of yeast Tpk1–3 catalytic subunits to the Bcy1 regulatory subunit. We show that Tpk3 is not regulated by Bcy1 binding but, instead, is deactivated upon heat stress via reversible sequestration into cytoplasmic granules. These “Tpk3 granules” are enriched for multiple PKA substrates involved in various metabolic processes, with the Hsp42 sequestrase required for their formation. Hence, regulated sequestration of Tpk3 provides a mechanism to control isoform-specific kinase signaling activity during stress conditions.

Aging is associated with impaired strength and power during isometric and shortening contractions, however, during lengthening (i.e., eccentric) contractions, strength is maintained. During daily movements, muscles undergo stretch-shortening cycles (SSCs). It is unclear whether the age-related maintenance of eccentric strength offsets age-related impairments in power generation during SSCs owing to the utilization of elastic energy or other cross-bridge based mechanisms. Here we investigated how aging influences SSC performance at the single muscle fibre level and whether performing active lengthening prior to shortening protects against age-related impairments in power generation. Single muscle fibres from the psoas major of young (∼8 months; n = 31 fibres) and old (∼32 months; n = 41 fibres) male F344BN rats were dissected and chemically permeabilized. Fibres were mounted between a force transducer and length controller and maximally activated (pCa 4.5). For SSCs, fibres were lengthened from average sarcomere lengths of 2.5 to 3.0 μm and immediately shortened back to 2.5 μm at both fast and slow (0.15 and 0.60 Lo/s) lengthening and shortening speeds. The magnitude of the SSC effect was calculated by comparing work and power during shortening to an active shortening contraction not preceded by active lengthening. Absolute isometric force was ∼37 % lower in old compared to young rat single muscle fibres, however, when normalized to cross-sectional area (CSA), there was no longer a significant difference in isometric force between age groups, meanwhile there was an ∼50 % reduction in absolute power in old as compared with young. We demonstrated that SSCs significantly increased power production (75–110 %) in both young and old fibres when shortening occurred at a fast speed and provided protection against power-loss with aging. Therefore, in older adults during everyday movements, power is likely ‘protected’ in part due to the stretch-shortening cycle as compared with isolated shortening contractions.

Background: Type 2 diabetes elevates the risk of severe outcomes in COVID-19 patients, with multiple studies reporting higher case fatality rates. Metformin is a widely used medication for glycemic management. We hypothesize that improved adherence to metformin may lower COVID-19 post-infection mortality risk in this group. Utilizing data from the Mexican Social Security Institute (IMSS), we investigate the relationship between metformin adherence and mortality following COVID-19 infection in patients with chronic metformin prescriptions. Methods: This is a retrospective cohort study consisting of 61,180 IMSS beneficiaries who received a positive polymerase chain reaction (PCR) or rapid test for SARS-CoV-2 and had at least two consecutive months of metformin prescriptions prior to the positive test. The hypothetical intervention is improved adherence to metformin, measured by proportion of days covered (PDC), with the comparison being the observed metformin adherence values. The primary outcome is all-cause mortality following COVID-19 infection. We defined the causal parameter using shift intervention, an example of modified treatment policies. We used the targeted learning framework for estimation of the target estimand. Findings: Among COVID-19 positive patients with chronic metformin prescriptions, we found that a 5% and 10% absolute increase in metformin adherence is associated with a respective 0.26% (95% CI: −0.28%, 0.79%) and 1.26% (95% CI: 0.72%, 1.80%) absolute decrease in mortality risk. Interpretation: Subject to the limitations of a real-world data study, our results indicate a causal association between improved metformin adherence and reduced COVID-19 post-infection mortality risk.

Providing bedding or access to an outdoor run are husbandry aspects intended to improve pig welfare, which is currently financially supported through animal welfare schemes in several European countries. However, they may significantly affect the environment through changes in feed efficiency and manure management. Therefore, the aim of this paper was to compare farms differing in animal welfare relevant husbandry aspects regarding (1) the welfare of growing-finishing pigs and (2) environmental impact categories such as global warming (GW), acidification (AC), and freshwater (FE) and marine eutrophication (ME), by employing an attributional Life Cycle Assessment. We collected data on 50 farms with growing-finishing pigs in seven European countries. Ten animal-based welfare indicators were aggregated into three pig welfare indices using principal component analysis. Cluster analysis of farms based on husbandry aspects resulted in three clusters: NOBED (31 farms without bedding or outdoor run), BED (11 farms with bedding only) and BEDOUT (eight farms with bedding and outdoor run). Pigs on farms with bedding (BED and BEDOUT) manipulated enrichment more often (P

Summary: Background: Although immunomodulators have established benefit against the new coronavirus disease (COVID-19) in general, it is uncertain whether such agents improve outcomes without increasing the risk of secondary infections in the specific subgroup of previously immunocompromised patients. We assessed the effect of immunomodulators on outcomes of immunocompromised patients hospitalized for COVID-19. Methods: The protocol was prospectively registered with PROSPERO (CRD42022335397). MEDLINE, Cochrane Central Register of Controlled Trials and references of relevant articles were searched up to 01-06-2022. Authors of potentially eligible randomized controlled trials were contacted to provide data on immunocompromised patients randomized to immunomodulators vs control (i.e., placebo or standard-of-care). Findings: Eleven randomized controlled trials involving 397 immunocompromised patients hospitalized for COVID-19 were included. Ten trials had low risk of bias. There was no difference between immunocompromised patients randomized to immunomodulators vs control regarding mortality [30/182 (16.5%) vs 41/215 (19.1%); RR 0.93, 95% CI 0.61–1.41; p = 0.74], secondary infections (RR 1.00, 95% CI 0.64–1.58; p = 0.99) and change in World Health Organization ordinal scale from baseline to day 15 (weighed mean difference 0.27, 95% CI -0.09–0.63; p = 0.15). In subgroup analyses including only patients with hematologic malignancy, only trials with low risk of bias, only trials administering IL-6 inhibitors, or only trials administering immunosuppressants, there was no difference between comparators regarding mortality. Interpretation: Immunomodulators, compared to control, were not associated with harmful or beneficial outcomes, including mortality, secondary infections, and change in ordinal scale, when administered to immunocompromised patients hospitalized for COVID-19. Funding: Hellenic Foundation for Research and Innovation.

Purpose: In parent-child trios with genome sequencing data, we investigated inherited biallelic deletions to identify known and novel genetic disorders. Methods: We developed a copy-number variations analysis pipeline based on autosomal genome sequencing read depth of Genomics England 100,000 Genomes Project data from 11,754 parent-child trios and additional 18,875 non-trios. A control cohort of 15,440 cancer patients provided independent deletion frequencies. Results: Autosomal recessive (AR) modeling detected 34 distinct rare deletions that were homozygous in the proband and heterozygous in both parents. These inherited biallelic deletions were only detected in 52 trios. These “knockout” regions included 37 genes, having among them 8 with an Online Mendelian Inheritance in Man AR annotation. Deletions of NPHP1, followed by OTOA, both within segmental duplications, were the only recurrent findings explaining phenotypes in a total of 10 and 3 patients, respectively. Recurrent heterozygous NPHP1 deletions were detected in 0.3%-0.5% of controls. We reviewed “knockout” patients for the remaining 29 genes without disease associations and identified SLC66A1 as a likely novel cause for AR rod-cone dystrophy in 4 families. Conclusion: A tailored copy-number variations analysis of genome sequencing trio data shows that biallelic inherited gene deletions are rare, with NPHP1 biallelic deletions causing nephronophthisis the leading finding. We propose SLC66A1 as a novel cause for AR retinopathy.

Rationale and objectives: To improve the image quality of CT pulmonary angiography (CTPA) using a patient-specific timing protocol. Material and methods: A total of 24 swine (48.5 ± 14.3 kg) underwent continuous contrast-enhanced dynamic CT acquisition over 30 s to capture the pulmonary arterial input function (AIF). Multiple contrast injections were made under different cardiac outputs (1.4–5.1 L/min), resulting in a total of 154 AIF curves. The volume scans with maximal enhancement in these AIF curves were retrospectively selected as the reference standard (group A). Two prospective CTPA protocols with bolus-tracking were then simulated using these AIF curves: one used a fixed delay of 5 s between triggering and CTPA acquisition (group B), while the other used a specific delay based on one-half of the contrast injection duration (group C). The mean attenuation, signal-to-noise (SNR) and contrast-to-noise ratios (CNR) between the three groups were then compared using independent sample t-test. Subjective image quality scores were also compared using Wilcoxon-Mann-Whitney test. Results: The mean attenuation of pulmonary arteries for group A, B and C (expressed in [HU]) were 870.1 ± 242.5 HU, 761.1 ± 246.7 HU and 825.2 ± 236.8 HU, respectively. The differences in the mean SNR and CNR between Group A and Group C were not significant (SNR: 65.2 vs. 62.4, CNR: 59.6 vs. 56.4, both p > 0.05), while Group B was significantly lower than Group A (p < 0.05). Conclusion: The image quality of CT pulmonary angiography is significantly improved with a timing protocol determined using contrast injection delivery time, as compared with a standard timing protocol with a fixed delay between bolus triggering and image acquisition.

Background: Clinicians have limited time during patient encounters which can result in patients' concerns not being addressed. This study's objective was to test whether an electronic patient-reported outcome quality of life tool (PROQOL) in which patients identify their primary concern during clinic visits improves cancer patient quality of life (QOL). Patients and methods: This single center non-blinded prospective clinical trial randomized patients (2:1) to PROQOL versus usual care (UC). Two patient cohorts were enrolled: those with hematologic malignancies (multiple myeloma [MM] or light chain amyloidosis [AL]) and solid tumors (head and neck [H/N] or gynecologic [GYN] malignancies). Primary endpoint was patient-reported QOL at 12 months measured by a single-item Linear Analog Self-Assessment. Value to patients and impact on clinician workflow was measured using a “was it worth it” survey. The study was powered to detect a 0.5 standard deviation difference between groups. Results: Overall 383 patients were enrolled, 171 with MM, 62 AL, 113 GYN, and 37 H/N between July 2016 and April 2018, with 12-month follow-up. There were 171 (44.6%) male patients and median age was 62 years (range 31–87). The most often selected concern was physical health (30.9%), and second was cancer diagnosis and treatment (29.1%). Mean QOL was 7.12 for PROQOL and 6.98 for UC (0–10 scale) at 12 months, with no between-group difference overall (p = 0.56) or within hematologic or solid tumor cohorts, respectively. Among patients, 74% thought the PROQOL tool was worthwhile, 86% would choose PROQOL again, and 81% would recommend it to others. Among clinicians, 95% responded that PROQOL was worthwhile and did not think that PROQOL negatively impacted their workflow. Conclusions: Although we did not demonstrate a QOL difference between PROQOL and UC groups; the PROQOL tool held considerable value in identifying patients' main concerns over time and was worthwhile for patients and clinicians.

The rollout of 5G wireless service has been much anticipated by consumers across the U.S. since it will bring faster data download speeds and expanded service; however, the impact to aviation and air travel are as a major issue and the potential impact to aviation has not been estimated or assessed. This paper fills that gap and provides the first analysis of the potential number of flights impacted by 5G at ten of the busiest airports in the U.S. Using detailed historical weather and flight data in 2019 at 10 large hub airports, we find that nearly 15,700 flight arrivals could be directly impacted annually, at the ten airports considered. The geographical and seasonal impact varies significantly with more flights affected by the potential for 5G interference at airports in Seattle and Dallas Fort-Worth and relatively few flights affected at airports in Phoenix and Las Vegas. A case study examining ten years of data at Chicago O’Hare International, a hub for two major airlines, suggests that over 2,400 flights every year could be impacted by 5G interference. Fortunately, there has been increasing cooperation between the cell phone industry and aviation stakeholders to ensure a safe rollout of 5G C-band; this paper provides a significant contribution by documenting the issues and context for aviation operations.

Purpose: To describe spectral-domain OCT (SD-OCT) features, age, gender, and systemic variables that may be used in machine/deep learning studies to identify high-risk patient subpopulations with high risk of progression to geographic atrophy (GA) and visual acuity (VA) loss in the short term. Design: Prospective, longitudinal study. Participants: We analyzed imaging data from patients with intermediate age-related macular degeneration (iAMD) (N = 316) enrolled in the Age-Related Eye Disease Study 2 (AREDS2) Ancillary SD-OCT with adequate SD-OCT imaging for repeated measures. Methods: Qualitative and quantitative multimodal variables from the database were derived at each yearly visit over 5 years. Based on statistical analyses developed in the field of cardiology, an algorithm was developed and used to select person-years without GA on color fundus photography or SD-OCT at baseline. The analysis used machine learning approaches to generate classification trees. Eyes were stratified as low, average, above average, and high risk in 1 or 2 years, based on OCT and demographic features by the risk of GA development or decreased VA by 5+ and 10+ letters. Main Outcome Measures: New onset of SD-OCT–determined GA and VA loss. Results: We identified multiple retinal and subretinal SD-OCT and demographic features from the baseline visit, each of which independently conveyed low to high risk of new-onset GA or VA loss on each of the follow-up visits at 1 or 2 years. Conclusions: We propose a risk-stratified classification of iAMD based on the combination of OCT-derived retinal features, age, gender, and systemic variables for progression to OCT-determined GA or VA loss. After external validation, the composite early end points may be used as exclusion or inclusion criteria for future clinical studies of iAMD focused on prevention of GA progression or VA loss.

Abstract Background Traumatic brain injury (TBI) results in neurovascular damage that initiates intrinsic mechanisms of hypercoagulation, which can contribute to the development of life‐threatening complications, such as coagulopathy and delayed thrombosis. Clinical studies have hypothesized that tissue factor (TF) induces hypercoagulability after TBI; however, none have directly shown this relationship. Objectives In the current study, we took a stepwise approach to understand what factors are driving thrombin generation following experimental TBI. Methods We employed the contusion‐producing controlled cortical impact (CCI) model and the diffuse closed head injury (CHI) model to investigate these mechanisms as a function of injury severity and modality. Whole blood was collected at 6 hours and 24 hours after injury, and platelet‐poor plasma was used to measure thrombin generation and extracellular vesicle (EV) TF. Results We found that plasma thrombin generation, dependent on TF present in the plasma, was greater in CCI‐injured animals compared to sham at both 6 hours (120.4 ± 36.9 vs 0.0 ± 0.0 nM*min endogenous thrombin potential) and 24 hours (131.0 ± 34.0 vs 32.1 ± 20.6 nM*min) after injury. This was accompanied by a significant increase in EV TF at 24 hours (328.6 ± 62.1 vs 167.7 ± 20.8 fM) after CCI. Further, EV TF is also increased at 6 hours (126.6 ± 17.1 vs 63.3 ± 14.4 fM) but not 24 hours following CHI. Conclusion TF‐mediated thrombin generation is time‐dependent after injury and TF increases resolve earlier following CHI as compared to CCI. Taken together, these data support a TF‐mediated pathway of thrombin generation after TBI and pinpoint TF as a major player in TBI‐induced coagulopathy.

Epigenetic aging biomarkers are associated with increased morbidity and mortality. We evaluated if occupational exposure to three established chemical carcinogens is associated with acceleration of epigenetic aging. We studied workers in China occupationally exposed to benzene, trichloroethylene (TCE) or formaldehyde by measuring personal air exposures prior to blood collection. Unexposed controls matched by age and sex were selected from nearby factories. We measured leukocyte DNA methylation (DNAm) in peripheral white blood cells using the Infinium HumanMethylation450 BeadChip to calculate five epigenetic aging clocks and DNAmTL, a biomarker associated with leukocyte telomere length and cell replication. We tested associations between exposure intensity and epigenetic age acceleration (EAA), defined as the residuals of regressing the DNAm aging biomarker on chronological age, matching factors and potential confounders. Median differences in EAA between exposure groups were tested using a permutation test with exact p-values. Epigenetic clocks were strongly correlated with age (Spearman r > 0.8) in all three occupational studies. There was a positive exposure-response relationship between benzene and the Skin-Blood Clock EAA biomarker: median EAA was −0.91 years in controls (n = 44), 0.78 years in workers exposed to

Study objective: Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk for atherosclerotic cardiovascular disease (ASCVD) events in patients with diabetes and ASCVD. We assessed factors associated with initiating either medication among patients with diabetes and a prior myocardial infarction (MI). Setting/participants: US adults ≥19 years old with private health insurance (MarketScan) or government health insurance (Medicare) who had diabetes and a prior MI and initiated a PCSK9i or an SGLT2i in 2017 or 2018. Main outcome measures: PCSK9i or SGLT2i initiation was identified using pharmacy claims. Results: Overall, 8102 patients initiated a PCSK9i (n = 1501; 18.5%) or an SGLT2i (n = 6601; 81.5%). Patients with 2 and ≥3 versus 1 prior MI (risk ratio [RR]: 1.32 [95%CI: 1.17–1.48] and 1.68 [1.41–2.01], respectively), prior coronary revascularization (1.47 [1.31–1.64]), prior stroke (1.28 [1.06–1.56]), history of peripheral artery disease (1.27 [1.14–1.41]), receiving cardiologist care (1.51 [1.36–1.67]) or taking ezetimibe (2.57 [2.35–2.82]) were more likely to initiate a PCSK9i versus an SGLT2i. Patients with a history of short-term (RR 1.07 [95%CI 1.05–1.09]) or long-term (1.07 [1.04–1.09]) diabetes complications, and taking a low/moderate- and high-intensity statin dosage (1.61 [1.51–1.70] and 1.68 [1.58–1.77], respectively) were more likely to initiate an SGLT2i versus a PCSK9i. Among patients who initiated a PCSK9i, 2.9% subsequently initiated an SGLT2i; 0.8% who initiated an SGLT2i subsequently initiated a PCSK9i. Conclusion: The decision to initiate PCSK9i or SGLT2i is explained by having very high cardiovascular disease risk for those initiating PCSK9i and diabetes complications for those initiating SGLT2i.

Traumatic pancreatic injuries are relatively uncommon in the setting of trauma, however, early detection of these injuries can alter patient management and overall prognosis. Computed tomography is the first line imaging modality in major trauma. Because failure to recognize pancreatic or main pancreatic duct injuries can lead to mismanagement, magnetic resonance imaging (MRI) can be a useful adjunct study in appropriate patients. In this report, we present a case in which MRI was used to diagnose traumatic avulsion and devascularization of the entire pancreas in a patient following a motor vehicle accident and we also include a review of the literature on this topic. It is our conclusion from this case report that MRI is the most effective imaging modality—specifically the subtraction post processing sequences—to evaluate severe pancreatic injury. Keywords: Magnetic resonance imaging, Subtraction imaging, Traumatic pancreatic injury

Background: Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants formed from incomplete combustion of organic matter; some PAHs are carcinogens. Smoking, diet, and other activities contribute to exposure to PAHs. Exposure data to PAHs among combustible tobacco product users (e.g. cigarette smokers) exist; however, among non-combustible tobacco products users (e.g., e-cigarette users), such data are rather limited. Objectives: We sought to evaluate exposure to PAHs among participants in Wave 1 (2013–2014) of the Population Assessment of Tobacco and Health (PATH) Study based on the type of tobacco product (combustible vs non-combustible), and frequency and intensity of product use. Methods: We quantified seven PAH urinary biomarkers in 11,519 PATH Study participants. From self-reported information, we categorized 8327 participants based on their use of tobacco products as never-tobacco user (never user, n = 1700), exclusive current established combustible products user (combustible products user, n = 5767), and exclusive current established non-combustible products user (non-combustible products user, n = 860). We further classified tobacco users as exclusive cigarette user (cigarette user, n = 3964), exclusive smokeless product user (SLT user, n = 509), and exclusive e-cigarette user (e-cigarette user, n = 280). Last, we categorized frequency of product use (everyday vs some days) and time since use (last hour, within 3 days, over 3 days). We calculated geometric mean (GM) concentrations, and evaluated associations between tobacco product user categories and PAH biomarkers concentrations. Results: Combustible products users had significantly higher GMs of all biomarkers than non-combustible products users and never users; non-combustible products users had significantly higher GMs than never users for four of seven biomarkers. For all biomarkers examined, cigarette users had the highest GMs compared to other tobacco-product users. Interestingly, GMs of 2-hydroxyfluorene, 3-hydroxyfluorene and ∑2,3-hydroxyphenanthrene were significantly higher in SLT users than in e-cigarette users; 3-hydroxyfluorene and 1-hydroxypyrene were also significantly higher in e-cigarette and SLT users than in never users. Everyday cigarette and SLT users had significantly higher GMs for most biomarkers than some days' users; cigarette and SLT users who used the product in the last hour had significantly higher GMs of most biomarkers than other occasional cigarette or SLT users respectively. By contrast, everyday e-cigarette users' GMs of most biomarkers did not differ significantly from those in some days' e-cigarette users; we did not observe clear trends by time of last use among e-cigarette users. Conclusions: Users of tobacco products had higher PAH urinary biomarker concentrations compared to never users, and concentrations differed by type and frequency of tobacco product use.

Pollen from trees, grasses, and weeds can trigger asthma exacerbation in sensitized individuals. However, there are gaps in knowledge about the effects, such as the relative risks from different plant taxa and threshold levels of effect. We aimed to describe the local association between pollen and asthma exacerbation among children in the City of Philadelphia, and to evaluate whether effects are modified by children’s characteristics and clinical factors (e.g., child’s age, race/ethnicity, comorbidities). We conducted a time-stratified case-crossover study of pediatric (age

The evidence for periods of increased volcanic activity following deglaciation, such as following ice sheet retreat after the Last Glacial Maximum, has been examined in several formerly glaciated areas, including Iceland, Alaska, and the Andean Southern Volcanic Zone. Here we present new evidence supporting the theory that during episodes of cooling in the Holocene, Icelandic volcanic activity decreased. By examining proximal and distal tephra records from Iceland spanning the last 12,500 years, we link two observed tephra minima to documented periods of climatic cooling and glacial advance, at 8.3 to 8 and 5.2 to 4.9 cal kyr BP. We simulate these periods in atmosphere-ocean and ice sheet models to assess the potential validity of the postglacial ‘unloading effect’ on Icelandic volcanic systems. We conclude that an increase in glacial cover may have decreased shallow magma ascent rates, thus limiting eruption potential and producing apparent quiescent periods in proximal and distal tephra records. However, several major uncertainties remain regarding the theory, including geographical and temporal preservation biases and the importance of any unloading effects against other factors, and these will require more prolonged investigation in future research.

Previous observational studies have shown that the endocrine disrupting chemical bisphenol A (BPA) is associated with type 2 diabetes, but few studies have examined direct effects of BPA on human health. The purpose of this study is to determine whether orally administered BPA at the US Environmental Protection Agency (EPA) safe dose of 50 μg/kg body weight has an adverse effect on hepatic glucose production and skeletal muscle insulin sensitivity. Forty, non-habitually active, healthy adults of normal weight will be enrolled. Participants will begin with a 2-day baseline energy balance diet low in bisphenols in which urine and blood will be collected, and standard tests performed to assess the primary outcome measures of hepatic glucose production (via [6,6-2H] glucose infusion) and skeletal muscle insulin sensitivity (via euglycemic hyperinsulinemic clamp technique). Secondary outcome measures are fasting hormones/endocrine factors (insulin, glucose, C-peptide, Pro-insulin, adiponectin, 17-beta-estradiol, free fatty acids) related to the pathogenesis of type 2 diabetes. Participants will then be randomly assigned to a 4-day energy balance diet plus oral administration of BPA at 50 μg/kg body weight (Diet + BPA) or 4-day energy balance diet plus oral administration of placebo (Diet + No BPA); all outcome measures will be reassessed after 4 days. Findings from this study will provide a framework for other studies in this area, and provide much needed experimental evidence using gold standard measures as to whether oral BPA administration over several days poses any risk of type 2 diabetes. Keywords: Bisphenol A, Administration, Diabetes, Insulin sensitivity, Glucose

Facial recognition ability declines in adult aging, but the neural basis for this decline remains unknown. Cortical areas involved in face recognition exhibit lower dopamine (DA) receptor availability and lower blood-oxygen-level-dependent (BOLD) signal during task performance with advancing adult age. We hypothesized that changes in the relationship between these two neural systems are related to age differences in face-recognition ability. To test this hypothesis, we leveraged positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to measure D1 receptor binding potential (BPND) and BOLD signal during face-recognition performance. Twenty younger and 20 older participants performed a face-recognition task during fMRI scanning. Face recognition accuracy was lower in older than in younger adults, as were D1 BPND and BOLD signal across the brain. Using linear regression, significant relationships between DA and BOLD were found in both age-groups in face-processing regions. Interestingly, although the relationship was positive in younger adults, it was negative in older adults (i.e., as D1 BPND decreased, BOLD signal increased). Ratios of BOLD:D1 BPND were calculated and relationships to face-recognition performance were tested. Multiple linear regression revealed a significant Group × BOLD:D1 BPND Ratio interaction. These results suggest that, in the healthy system, synchrony between neurotransmitter (DA) and hemodynamic (BOLD) systems optimizes the level of BOLD activation evoked for a given DA input (i.e., the gain parameter of the DA input-neural activation function), facilitating task performance. In the aged system, however, desynchronization between these brain systems would reduce the gain parameter of this function, adversely impacting task performance and contributing to reduced face recognition in older adults.

The Connectomes Related to Human Diseases (CRHD) initiative was developed with the Human Connectome Project (HCP) to provide high-resolution, open-access, multi-modal MRI data to better understand the neural correlates of human disease. Here, we present an introduction to a CRHD project, the Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA) study, which is collecting multimodal neuroimaging, clinical, and neuropsychological data from 225 adolescents (ages 14–17), 150 of whom are expected to have a diagnosis of depression and/or anxiety. Our transdiagnostic recruitment approach samples the full spectrum of depressed/anxious symptoms and their comorbidity, consistent with NIMH Research Domain Criteria (RDoC). We focused on an age range that is critical for brain development and for the onset of mental illness. This project sought to harmonize imaging sequences, hardware, and functional tasks with other HCP studies, although some changes were made to canonical HCP methods to accommodate our study population and questions. We present a thorough overview of our imaging sequences, hardware, and scanning protocol. We detail similarities and differences between this study and other HCP studies. We evaluate structural-, diffusion-, and functional-image-quality measures that may be influenced by clinical factors (e.g., disorder, symptomatology). Signal-to-noise and motion estimates from the first 140 adolescents suggest minimal influence of clinical factors on image quality. We anticipate enrollment of an additional 85 participants, most of whom are expected to have a diagnosis of anxiety and/or depression. Clinical and neuropsychological data from the first 140 participants are currently freely available through the National Institute of Mental Health Data Archive (NDA).

We present a Human Connectome Project study tailored toward adolescent anxiety and depression. This study is one of the first studies of the Connectomes Related to Human Diseases initiative and is collecting structural, functional, and diffusion-weighted brain imaging data from up to 225 adolescents (ages 14–17 years), 150 of whom are expected to have a current diagnosis of an anxiety and/or depressive disorder. Comprehensive clinical and neuropsychological evaluations and longitudinal clinical data are also being collected. This article provides an overview of task functional magnetic resonance imaging (fMRI) protocols and preliminary findings (N = 140), as well as clinical and neuropsychological characterization of adolescents. Data collection is ongoing for an additional 85 adolescents, most of whom are expected to have a diagnosis of an anxiety and/or depressive disorder. Data from the first 140 adolescents are projected for public release through the National Institutes of Health Data Archive (NDA) with the timing of this manuscript. All other data will be made publicly-available through the NDA at regularly scheduled intervals. This article is intended to serve as an introduction to this project as well as a reference for those seeking to clinical, neurocognitive, and task fMRI data from this public resource.

Targeted gene therapy strategies utilizing homology-driven repair (HDR) allow for greater control over transgene integration site, copy number, and expression—significant advantages over traditional vector-mediated gene therapy with random genome integration. However, the relatively low efficiency of HDR-based strategies limits their clinical application. Here, we used HDR to knock in a mutant dihydrofolate reductase (mDHFR) selection gene at the gene-edited CCR5 locus in primary human CD4+ T cells and selected for mDHFR-modified cells in the presence of methotrexate (MTX). Cells were transfected with CCR5-megaTAL nuclease mRNA and transduced with adeno-associated virus containing an mDHFR donor template flanked by CCR5 homology arms, leading to up to 40% targeted gene insertion. Clinically relevant concentrations of MTX led to a greater than 5-fold enrichment for mDHFR-modified cells, which maintained a diverse TCR repertoire over the course of expansion and drug selection. Our results demonstrate that mDHFR/MTX-based selection can be used to enrich for gene-modified T cells ex vivo, paving the way for analogous approaches to increase the percentage of HIV-resistant, autologous CD4+ T cells infused into HIV+ patients, and/or for in vivo selection of gene-edited T cells for the treatment of cancer. Keywords: gene editing, chemoselection, T cell gene therapy, lentiviral vectors, homology-directed repair, methotrexate, dihydrofolate reductase, adeno-associated viruses, HIV, cancer

Abstract: Hematopoietic stem-cell gene therapy is a promising treatment of X-linked severe combined immunodeficiency disease (SCID-X1), but currently, it requires recipient conditioning, extensive cell manipulation, and sophisticated facilities. With these limitations in mind, we explored a simpler therapeutic approach to SCID-X1 treatment by direct IV administration of foamy virus (FV) vectors in the canine model. FV vectors were used because they have a favorable integration site profile and are resistant to serum inactivation. Here, we show improved efficacy of our in vivo gene therapy platform by mobilization with granulocyte colony-stimulating factor (G-CSF) and AMD3100 before injection of an optimized FV vector incorporating the human phosphoglycerate kinase enhancerless promoter. G-CSF/AMD3100 mobilization before FV vector delivery accelerated kinetics of CD3+ lymphocyte recovery, promoted thymopoiesis, and increased immune clonal diversity. Gene-corrected T lymphocytes exhibited a normal CD4:CD8 ratio and a broad T-cell receptor repertoire and showed restored γC-dependent signaling function. Treated animals showed normal primary and secondary antibody responses to bacteriophage immunization and evidence for immunoglobulin class switching. These results demonstrate safety and efficacy of an accessible, portable, and translatable platform with no conditioning regimen for the treatment of SCID-X1 and other genetic diseases.

Self-rated health (SRH) is an independent predictor of mortality; studies have investigated correlates of SRH to explain this predictive capability. However, the interplay of a broad array of factors that influence health status may not be adequately captured with parametric multivariate regression. This study investigated associations between several health determinants and SRH using recursive partitioning methods. This non-parametric analytic approach aimed to reflect the social-ecological model of health, emphasizing relationships between multiple health determinants, including biological, behavioral, and from social/physical environments. The study sample of 3648 men and women was drawn from the year 15 (2000–2001) data collection of the CARDIA Study, USA, in order to study a young adult sample. Classification tree analysis identified 15 distinct, mutually exclusive, subgroups (eight with a larger proportion of individuals with higher SRH, and seven with a larger proportion of lower SRH), and multi-domain risk and protective factors associated with subgroup membership. Health determinant profiles were not uniform between subgroups, even for those with similar health status. The subgroup with the largest proportion of higher SRH was characterized by several protective factors, whilst that with the largest proportion of lower SRH, with several negative risk factors; certain factors were associated with both higher and lower SRH subgroups. In the full sample, physical activity, education and income were highest ranked by variable importance (random forests analysis) in association with SRH. This exploratory study demonstrates the utility of recursive partitioning methods in studying the joint impact of multiple health determinants. The findings indicate that factors do not affect SRH in the same way across the whole sample. Multiple factors from different domains, and with varying relative importance, are associated with SRH in different subgroups. This has implications for developing and prioritizing appropriate interventions to target conditions and factors that improve self-rated health status. Keywords: Self-rated health, Health determinants, Recursive partitioning methods, Classification tree analysis, Random forests

Objective: Regulation of energy balance depends on pro-opiomelanocortin (POMC)-derived peptides and melanocortin-4 receptor (MC4R). Alpha-melanocyte stimulating hormone (α-MSH) is the predicted natural POMC-derived peptide that regulates energy balance. Desacetyl-α-MSH, the precursor for α-MSH, is present in brain and blood. Desacetyl-α-MSH is considered to be unimportant for regulating energy balance despite being more potent (compared with α-MSH) at activating the appetite-regulating MC4R in vitro. Thus, the physiological role for desacetyl-α-MSH is still unclear. Methods: We created a novel mouse model to determine whether desacetyl-α-MSH plays a role in regulating energy balance. We engineered a knock in targeted QKQR mutation in the POMC protein cleavage site that blocks the production of both desacetyl-α-MSH and α-MSH from adrenocorticotropin (ACTH1-39). Results: The mutant ACTH1-39 (ACTHQKQR) functions similar to native ACTH1-39 (ACTHKKRR) at the melanocortin 2 receptor (MC2R) in vivo and MC4R in vitro. Male and female homozygous mutant ACTH1-39 (Pomctm1/tm1) mice develop the characteristic melanocortin obesity phenotype. Replacement of either desacetyl-α-MSH or α-MSH over 14 days into Pomctm1/tm1 mouse brain significantly reverses excess body weight and fat mass gained compared to wild type (WT) (Pomcwt/wt) mice. Here, we identify both desacetyl-α-MSH and α-MSH peptides as regulators of energy balance and highlight a previously unappreciated physiological role for desacetyl-α-MSH. Conclusions: Based on these data we propose that there is potential to exploit the naturally occurring POMC-derived peptides to treat obesity but this relies on first understanding the specific function(s) for desacetyl-α-MSH and α-MSH. Keywords: POMC, Obesity, Desacetyl-α-MSH, α-MSH, Obese mouse model

Worse health outcomes among those living in poverty are due in part to lower rates of health insurance and barriers to care. As the Affordable Care Act reduced financial barriers, identifying persistent barriers to accessible health care continues to be important. We examined whether the built environment as reflected by Walk Score™ (a measure of walkability to neighborhood resources) and Transit Score™ (a measure of transit access) is associated with having a usual source of care among low-income adults, newly enrolled in Medicaid. We received responses from 312 out of 1000 new Medicaid enrollees in Philadelphia, a large, densely populated urban area, who were surveyed between 2015 and 2016 to determine if they had identified a usual source of outpatient primary care. Respondents living at an address with a low Walk Scores (

Summary: We have performed an in-depth single-cell phenotypic characterization of high-grade serous ovarian cancer (HGSOC) by multiparametric mass cytometry (CyTOF). Using a CyTOF antibody panel to interrogate features of HGSOC biology, combined with unsupervised computational analysis, we identified noteworthy cell types co-occurring across the tumors. In addition to a dominant cell subset, each tumor harbored rarer cell phenotypes. One such group co-expressed E-cadherin and vimentin (EV), suggesting their potential role in epithelial mesenchymal transition, which was substantiated by pairwise correlation analyses. Furthermore, tumors from patients with poorer outcome had an increased frequency of another rare cell type that co-expressed vimentin, HE4, and cMyc. These poorer-outcome tumors also populated more cell phenotypes, as quantified by Simpson’s diversity index. Thus, despite the recognized genomic complexity of the disease, the specific cell phenotypes uncovered here offer a focus for therapeutic intervention and disease monitoring.

Highly hydrophilic hollow polycaprolactone (PCL) microfibres were developed as building elements to create tissue-mimicking test objects (phantoms) for validation of diffusion magnetic resonance imaging (MRI). These microfibres were fabricated by the co-electrospinning of PCL-polysiloxane-based surfactant (PSi) mixture as shell and polyethylene oxide as core. The addition of PSi had a significant effect on the size of resultant electrospun fibres and the formation of hollow microfibres. The presence of PSi in both co-electrospun PCL microfibre surface and cross-section, revealed by X-ray energy dispersive spectroscopy (EDX), enabled water to wet these fibres completely (i.e., zero contact angle) and remained active for up to 12 months after immersing in water. PCL and PCL-PSi fibres with uniaxial orientation were constructed into water-filled phantoms. MR measurement revealed that water molecules diffuse anisotropically in the PCL-PSi phantom. Co-electrospun hollow PCL-PSi microfibres have desirable hydrophilic properties for the construction of a new generation of tissue-mimicking dMRI phantoms. Keywords: Axon mimic, Polycaprolactone, Hydrophilic hollow microfibres, Co-electrospinning, Diffusion magnetic resonance imaging

An understanding of factors influencing health in socioeconomic groups is required to reduce health inequalities. This study investigated combinations of health determinants associated with self-rated health (SRH), and their relative importance, in income-based groups.Cross-sectional data from year 15 (2000−2001) of the CARDIA study (Coronary Artery Risk Development in Young Adults, USA) - 3648 men and women (mean 40 years) - were split into 5 income-based groups. SRH responses were categorized as ‘higher’/‘lower’. Health determinants (medical, lifestyle, and social factors, living conditions) associated with SRH in each group were analyzed using classification tree analysis (CTA).Income and SRH were positively associated (p

Concerns are heightened from detecting environmentally persistent man-made per- and polyfluoroalkyl substances (PFAS) in drinking water systems around the world. Many PFAS, including perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), remain in the human body for years. Since 1999–2000, assessment of exposure to PFOS, PFOA, and other select PFAS in the U.S. general population has relied on measuring PFAS serum concentrations in participants of the National Health and Nutrition Examination Survey (NHANES). Manufacturers have replaced select chemistries (“legacy” PFAS) with PFAS with shorter biological half-lives (e.g., GenX, perfluorobutanoate [PFBA]) which may efficiently eliminate in urine. However, knowledge regarding exposure to these compounds is limited. We analyzed 2682 urine samples for 17 legacy and alternative PFAS in 2013–2014 NHANES participants ≥6 years of age. Concentrations of some of these PFAS, measured previously in paired serum samples from the same NHANES participants, suggested universal exposure to PFOS and PFOA, and infrequent or no exposure to two short-chain PFAS, perfluorobutane sulfonate and perfluoroheptanoate. Yet, in urine, PFAS were seldom detected; the frequency of not having detectable concentrations of any of the 17 PFAS was 67.5%. Only two were detected in >1.5% of the population: PFBA (13.3%) and perfluorohexanoate (PFHxA, 22.6%); the 90th percentile urine concentrations were 0.1 μg/L (PFBA), and 0.3 μg/L (PFHxA). These results suggest that exposures to short-chain PFAS are infrequent or at levels below those that would result in detectable concentrations in urine. As such, these findings do not support biomonitoring of short-chain PFAS or fluorinated alternatives in the general population using urine, and highlight the importance of selecting the adequate biomonitoring matrix. Keywords: Biomonitoring, NHANES, PFAS

Summary: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several pathogenic mutations have been identified, the vast majority of ALS cases have no family history of disease. Thus, for most ALS cases, the disease may be a product of multiple pathways contributing to varying degrees in each patient. Using machine learning algorithms, we stratify the transcriptomes of 148 ALS postmortem cortex samples into three distinct molecular subtypes. The largest cluster, identified in 61% of patient samples, displays hallmarks of oxidative and proteotoxic stress. Another 19% of the samples shows predominant signatures of glial activation. Finally, a third group (20%) exhibits high levels of retrotransposon expression and signatures of TARDBP/TDP-43 dysfunction. We further demonstrate that TDP-43 (1) directly binds a subset of retrotransposon transcripts and contributes to their silencing in vitro, and (2) pathological TDP-43 aggregation correlates with retrotransposon de-silencing in vivo. : Tam et al. present transcriptome profiling results from a large set of amyotrophic lateral sclerosis (ALS) patient cortex samples, finding 3 distinct groups. Two ALS subtypes are marked by gene pathways previously associated with ALS disease, while a third group shows elevated retrotransposon expression linked to TDP-43 pathology. Keywords: amyotrophic lateral sclerosis, retrotransposons, transposable elements, TDP-43, neurodegenerative disease, neurodegeneration, genetics and genomics of ALS

The accumulation of damage caused by oxidative stress has been linked to aging and to the etiology of numerous age-related diseases. The longevity gene, sirtuin 6 (SIRT6), promotes genome stability by facilitating DNA repair, especially under oxidative stress conditions. Here we uncover the mechanism by which SIRT6 is activated by oxidative stress to promote DNA double-strand break (DSB) repair. We show that the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), phosphorylates SIRT6 on serine 10 in response to oxidative stress. This post-translational modification facilitates the mobilization of SIRT6 to DNA damage sites and is required for efficient recruitment of poly (ADP-ribose) polymerase 1 (PARP1) to DNA break sites and for efficient repair of DSBs. Our results demonstrate a post-translational mechanism regulating SIRT6, and they provide the link between oxidative stress signaling and DNA repair pathways that may be critical for hormetic response and longevity assurance.

An electrical method to measure extracellular bioelectrical activity in vitro is presented. This method exploits the Helmholtz capacitive double-layer established at the electrode surface. Small extracellular voltage variations in the order of μVs induce through the double-layer capacitor a displacement current that is measured. This current is then enhanced by a gain factor proportional to the electrode capacitance. In addition, when measurements are carried out at low frequencies in current mode the electrode contribution to the noise can be minimized. The performance of the electrodes and the method is demonstrated using zebrafish hearts and glioma cell cultures. We propose that this electrical method is an ideal tool to measure in vitro slow and temporally synchronized events that are often involved in long range intracellular signaling. Keywords: Extracellular electrodes, Bioelectrical signals, Displacement current, Electrical double-layer, Intercellular signaling

Cognitive slowing is a prevalent symptom observed in Gulf War Illness (GWI). The present study assessed the extent to which functional connectivity between dorsolateral prefrontal cortex (DLPFC) and other task-relevant brain regions was predictive of GWI-related cognitive slowing. GWI patients (n = 54) and healthy veteran controls (n = 29) were assessed on performance of a processing speed task (the Digit Symbol Substitution Task; DSST) while undergoing functional magnetic resonance imaging (fMRI). GWI patients were slower on the DSST relative to controls. Bilateral DLPFC connectivity with task-relevant nodes was altered in GWI patients compared to healthy controls during DSST performance. Moreover, hyperconnectivity in these networks predicted GWI-related increases in reaction time on the DSST, whereas hypoconnectivity did not. These results suggest that GWI-related cognitive slowing reflects reduced efficiency in cortical networks.

Bacteria associated with corn roots inoculated with soils collected from the Canadian woodlands were isolated and characterized. Genus-level identification based on 16S rRNA sequence analysis classified the 161 isolates in 19 genera. The majority (64%) of the isolates were affiliated with the genus Pseudomonas. Further analysis of the Pseudomonas isolates based on BLASTn and rpoD-rpoB-gyrB concatenated gene phylogeny revealed three unique clusters that could not be assigned to known species. This study reports the taxonomic description of one of the distinct lineages represented by two strains (S1E40T and S1E44) with P. lurida LMG 21995T, P. costantinii LMG 22119T, P. palleroniana LMG 23076T, P. simiae CCUG 50988T and P. extremorientalis LMG 19695T as the closest taxa. Both strains showed low ANIm (

Summary: Background: Poor nutrition and exposure to faecal contamination are associated with diarrhoea and growth faltering, both of which have long-term consequences for child health. We aimed to assess whether water, sanitation, handwashing, and nutrition interventions reduced diarrhoea or growth faltering. Methods: The WASH Benefits cluster-randomised trial enrolled pregnant women from villages in rural Kenya and evaluated outcomes at 1 year and 2 years of follow-up. Geographically-adjacent clusters were block-randomised to active control (household visits to measure mid-upper-arm circumference), passive control (data collection only), or compound-level interventions including household visits to promote target behaviours: drinking chlorinated water (water); safe sanitation consisting of disposing faeces in an improved latrine (sanitation); handwashing with soap (handwashing); combined water, sanitation, and handwashing; counselling on appropriate maternal, infant, and young child feeding plus small-quantity lipid-based nutrient supplements from 6–24 months (nutrition); and combined water, sanitation, handwashing, and nutrition. Primary outcomes were caregiver-reported diarrhoea in the past 7 days and length-for-age Z score at year 2 in index children born to the enrolled pregnant women. Masking was not possible for data collection, but analyses were masked. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704105. Findings: Between Nov 27, 2012, and May 21, 2014, 8246 women in 702 clusters were enrolled and randomly assigned an intervention or control group. 1919 women were assigned to the active control group; 938 to passive control; 904 to water; 892 to sanitation; 917 to handwashing; 912 to combined water, sanitation, and handwashing; 843 to nutrition; and 921 to combined water, sanitation, handwashing, and nutrition. Data on diarrhoea at year 1 or year 2 were available for 6494 children and data on length-for-age Z score in year 2 were available for 6583 children (86% of living children were measured at year 2). Adherence indicators for sanitation, handwashing, and nutrition were more than 70% at year 1, handwashing fell to less than 25% at year 2, and for water was less than 45% at year 1 and less than 25% at year 2; combined groups were comparable to single groups. None of the interventions reduced diarrhoea prevalence compared with the active control. Compared with active control (length-for-age Z score −1·54) children in nutrition and combined water, sanitation, handwashing, and nutrition were taller by year 2 (mean difference 0·13 [95% CI 0·01–0·25] in the nutrition group; 0·16 [0·05–0·27] in the combined water, sanitation, handwashing, and nutrition group). The individual water, sanitation, and handwashing groups, and combined water, sanitation, and handwashing group had no effect on linear growth. Interpretation: Behaviour change messaging combined with technologically simple interventions such as water treatment, household sanitation upgrades from unimproved to improved latrines, and handwashing stations did not reduce childhood diarrhoea or improve growth, even when adherence was at least as high as has been achieved by other programmes. Counselling and supplementation in the nutrition group and combined water, sanitation, handwashing, and nutrition interventions led to small growth benefits, but there was no advantage to integrating water, sanitation, and handwashing with nutrition. The interventions might have been more efficacious with higher adherence or in an environment with lower baseline sanitation coverage, especially in this context of high diarrhoea prevalence. Funding: Bill & Melinda Gates Foundation, United States Agency for International Development.

Summary: Background: Diarrhoea and growth faltering in early childhood are associated with subsequent adverse outcomes. We aimed to assess whether water quality, sanitation, and handwashing interventions alone or combined with nutrition interventions reduced diarrhoea or growth faltering. Methods: The WASH Benefits Bangladesh cluster-randomised trial enrolled pregnant women from villages in rural Bangladesh and evaluated outcomes at 1-year and 2-years' follow-up. Pregnant women in geographically adjacent clusters were block-randomised to one of seven clusters: chlorinated drinking water (water); upgraded sanitation (sanitation); promotion of handwashing with soap (handwashing); combined water, sanitation, and handwashing; counselling on appropriate child nutrition plus lipid-based nutrient supplements (nutrition); combined water, sanitation, handwashing, and nutrition; and control (data collection only). Primary outcomes were caregiver-reported diarrhoea in the past 7 days among children who were in utero or younger than 3 years at enrolment and length-for-age Z score among children born to enrolled pregnant women. Masking was not possible for data collection, but analyses were masked. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCC01590095. Findings: Between May 31, 2012, and July 7, 2013, 5551 pregnant women in 720 clusters were randomly allocated to one of seven groups. 1382 women were assigned to the control group; 698 to water; 696 to sanitation; 688 to handwashing; 702 to water, sanitation, and handwashing; 699 to nutrition; and 686 to water, sanitation, handwashing, and nutrition. 331 (6%) women were lost to follow-up. Data on diarrhoea at year 1 or year 2 (combined) were available for 14 425 children (7331 in year 1, 7094 in year 2) and data on length-for-age Z score in year 2 were available for 4584 children (92% of living children were measured at year 2). All interventions had high adherence. Compared with a prevalence of 5·7% (200 of 3517 child weeks) in the control group, 7-day diarrhoea prevalence was lower among index children and children under 3 years at enrolment who received sanitation (61 [3·5%] of 1760; prevalence ratio 0·61, 95% CI 0·46–0·81), handwashing (62 [3·5%] of 1795; 0·60, 0·45–0·80), combined water, sanitation, and handwashing (74 [3·9%] of 1902; 0·69, 0·53–0·90), nutrition (62 [3·5%] of 1766; 0·64, 0·49–0·85), and combined water, sanitation, handwashing, and nutrition (66 [3·5%] of 1861; 0·62, 0·47–0·81); diarrhoea prevalence was not significantly lower in children receiving water treatment (90 [4·9%] of 1824; 0·89, 0·70–1·13). Compared with control (mean length-for-age Z score −1·79), children were taller by year 2 in the nutrition group (mean difference 0·25 [95% CI 0·15–0·36]) and in the combined water, sanitation, handwashing, and nutrition group (0·13 [0·02–0·24]). The individual water, sanitation, and handwashing groups, and combined water, sanitation, and handwashing group had no effect on linear growth. Interpretation: Nutrient supplementation and counselling modestly improved linear growth, but there was no benefit to the integration of water, sanitation, and handwashing with nutrition. Adherence was high in all groups and diarrhoea prevalence was reduced in all intervention groups except water treatment. Combined water, sanitation, and handwashing interventions provided no additive benefit over single interventions. Funding: Bill & Melinda Gates Foundation.

To meet the greater demand for skilled personnel in Emergency Medicine (EM) in Ghana, the authors developed an in-service course in basic acute care for Physician Assistants (PAs) working in district hospitals. Methods: An initial training of trainers course was held for twenty-two PAs. From this initial group, ten were selected as Senior Trainers. Following a refresher course, Senior Trainers facilitated an in-service training and refresher course for other PAs from their regions. The course was organised into modules consisting of didactic lectures and interactive small group sessions. Assessment included testing, observation, case review, and simulations. Results: All groups showed improvement in knowledge. The majority learned information sequentially, inconsistently used physical examinations for diagnosis, and rarely reassessed following interventions. Practical skills were more easily acquired than clinical decision-making skills. The case discussions and simulations were the most helpful learning tools. Symptom-based algorithms were useful for daily practice. Conclusion: The greatest successes of this programme were providing the participants with greater confidence in basic life-saving skills and increasing their knowledge of and advocacy for EM. For continued success of this programme, a formal course with greater emphasis on filling Senior Trainer knowledge gaps, increased coordination with administrative authorities, and specific measurable clinical outcomes are needed.

Objective: Low physical activity and high sedentary behavior levels are major concerns in persons with multiple sclerosis (MS) and these differ depending on the level of mobility disability. However, the manner in which daily activity is accumulated is currently unknown in this population. Methods: A secondary analysis was performed on a combined data set of persons with MS from two previous investigations of physical activity and symptomatic or quality of life outcomes in the United States over a two year period (2007–2009). Mobility disability status was determined using the Patient Determined Disease Steps (PDDS) while activity behavior was objectively monitored using an ActiGraph accelerometer for 7 days. Results: Persons with MS who have mobility disability were involved in sedentary behavior, light and moderate intensity activity for 65%, 34% and 1% of the day, respectively compared to 60%, 37%, and 3%, respectively in those without mobility disability (p