Patients With Autoimmune Hepatitis and Nonalcoholic Fatty Liver Disease: Characteristics, Treatment, and Outcomes.

GOAL: The objective of this study was to characterize an autoimmune hepatitis (AIH)/nonalcoholic fatty liver disease (NAFLD) overlap cohort, determine if they received standard of care treatment, and delineate their outcomes in comparison with patients with AIH or NAFLD alone. BACKGROUND: AIH is a relatively rare and heterogeneously presenting liver disease of unknown etiology. NAFLD is a leading cause of liver disease worldwide. AIH treatment includes steroids, which have adverse metabolic effects that can worsen NAFLD. No treatment guidelines are available to mitigate this side on AIH/NAFLD overlap patients. Few studies to date have examined these patients' characteristics, management practices, and outcomes. MATERIALS AND METHODS: A single-center, retrospective chart review study examining biopsy-proven AIH/NAFLD, AIH, and NAFLD patients. Characteristics, treatment, and 1- and 3-year outcomes (all-cause mortality, need for liver transplantation, or decompensated cirrhosis) were evaluated. RESULTS: A total of 72 patients (36.1% AIH/NAFLD, 34.7% AIH, and 29.2% NAFLD) were included. AIH/NAFLD patients were found to be more often Hispanic/Latino, female, and with lower liver aminotransaminases, immunoglobulin G, and anti-smooth muscle antibody positivity. AIH/NAFLD patients were less likely to receive standard of care treatment. No significant differences in outcomes were seen between AIH/NAFLD and either AIH or NAFLD. CONCLUSIONS: Our study demonstrated that AIH/NAFLD patients have unique characteristics and are less likely to receive standard of care treatment compared with patients with AIH alone. Despite this, no difference in outcomes (all-cause mortality, need for liver transplantation, or decompensated cirrhosis) was seen. Given NAFLD's rising prevalence, AIH/NAFLD cases will likely increase, and may benefit from alternative treatment guidelines to prevent worsening of NAFLD.

Temperature responses vary between riffle beetles from contrasting aquatic environments.

Organisms living in environmentally stable ecosystems are hypothesized to exhibit narrow environmental tolerance ranges; however, previous experiments testing this prediction with invertebrates in spring habitats are equivocal. Here we examined the effects of elevated temperatures on four riffle beetle species (family: Elmidae) native to central and west Texas, USA. Two of these, Heterelmis comalensis and Heterelmis cf. glabra are known to occupy habitats immediately adjacent to spring openings and are thought to have stenothermal tolerance profiles. The other two, Heterelmis vulnerata and Microcylloepus pusillus are surface stream species with more cosmopolitan distributions and are assumed to be less sensitive to variation in environmental conditions. We examined performance and survival of elmids in response to increasing temperatures using dynamic and static assays. Additionally, changes in metabolic rate in response to thermal stress were assessed for all four species. Our results indicated that spring-associated H. comalensis is most sensitive while the more cosmopolitan elmid M. pusillus is least sensitive to thermal stress. However, there were differences in temperature tolerances among the two spring-associated species: H. comalensis had relatively narrow thermal tolerance in comparison to H. cf. glabra. This could be due to differences in the climatic and hydrological conditions in the geographical regions which the respective riffle beetle populations reside. However, despite these differences, H. comalensis and H. cf. glabra showed a dramatic increase in their metabolic rates with increasing temperatures indicating that these species are indeed spring specialists and likely have a stenothermal profile.

Subterranean freshwater gastropod biodiversity and conservation in the United States and Mexico.

Many taxonomic groups successfully exploit groundwater environments and have adapted to a subterranean (stygobiotic) existence. Among these groups are freshwater gastropods (stygosnails), which represent a widespread and taxonomically diverse component of groundwater ecosystems in North America. However, owing to sampling difficulty and lack of targeted study, stygosnails remain among the most understudied of all subterranean groups. We conducted a literature review to assess the biodiversity and geographic associations of stygosnails, along with the threats, management activities, and policy considerations related to the groundwater systems they inhabit. We identified 39 stygosnail species known to occur in a range of groundwater habitats from karst regions in the United States and Mexico. Most stygosnails exhibit extreme narrow-range endemism, resulting in a high risk of extinction from a single catastrophic event. We found that anthropogenically driven changes to surface environments have led to changes in local hydrology and degradation of groundwater systems inhabited by stygosnails such as increased sedimentation, introduction of invasive species, groundwater extraction, or physical collapse of water-bearing passages. Consequently, 32 of the 39 described stygosnail species in the United States and Mexico have been assessed as imperiled under NatureServe criteria, and 10 species have been assessed as threatened under International Union for Conservation of Nature criteria. Compared with surface species of freshwater snails, stygosnail conservation is uniquely hindered by difficulties associated with accessing subterranean habitats for monitoring and management. Furthermore, only three species were found to have federal protection in either the United States or Mexico, and current laws regulating wildlife and water pollution at the state and federal level may be inadequate for protecting stygosnail habitats. As groundwater systems continue to be manipulated and relied on by humans, groundwater-restricted fauna such as stygosnails should be studied so unique biodiversity can be protected.

Diversidad y Conservación de Gasterópodos Subterráneos de Agua Dulce en los Estados Unidos y en México Resumen Muchos grupos taxonómicos aprovechan exitosamente los ambientes de aguas subterráneas y se han adaptado eficazmente a una existencia subterránea (estigobiótica). Entre estos grupos están los gasterópodos (estigocaracoles), los cuales representan un componente taxonómicamente diverso y de amplia distribución en los ecosistemas de aguas subterráneas en América del Norte. Sin embargo, debido a la dificultad del muestreo y a la falta de estudios enfocados, los estigocaracoles todavía son de los grupos menos estudiados de los taxones subterráneos. Realizamos una revisión de la literatura para evaluar las asociaciones geográficas y la biodiversidad de los estigocaracoles, junto con las amenazas, actividades de manejo y consideraciones políticas relacionadas con los sistemas de aguas subterráneas que habitan. Identificamos a 39 especies de estigocaracoles que se sabe se encuentran en una gama de hábitats de aguas subterráneas de las regiones kársticas en los Estados Unidos y en México. La mayoría de los estigocaracoles exhiben un endemismo extremo de extensión limitada, lo que resulta en un riesgo elevado de extinción a partir de un evento catastrófico único. Descubrimos que los cambios causados por el hombre en los ambientes superficiales han resultado en cambios en la hidrología local y en la degradación de los sistemas de aguas subterráneas habitadas por los estigocaracoles. Dichos cambios incluyen incremento de la sedimentación, la introducción de especies invasoras, la extracción de aguas subterráneas y el colapso físico de los pasos de agua. Como consecuencia, 32 de las 39 especies descritas de estigocaracoles en los Estados Unidos y en México han sido valoradas como en peligro bajo los criterios de NatureServe, y diez especies han sido valoradas como amenazadas bajo los criterios de la Unión Internacional para la Conservación de la Naturaleza. Comparada con las especies superficiales de caracoles de agua dulce, la conservación de los estigocaracoles está singularmente obstaculizada por las dificultades asociadas con el acceso a los hábitats subterráneos para su monitoreo y manejo. Además, se encontró que sólo tres especies cuentan con protección federal ya sea en Estados Unidos o en México, y puede que las leyes actuales que regulan la vida silvestre y la contaminación del agua a nivel estatal y federal sean inadecuadas para la protección de los hábitats de los estigocaracoles. Mientras los sistemas de aguas subterráneas sigan siendo manipulados y los humanos sigan dependiendo de ellos, la fauna restringida a las aguas subterráneas, como los estigocaracoles, debería ser estudiada para proteger a la biodiversidad tan única.

Reductive carboxylation supports redox homeostasis during anchorage-independent growth.

Cells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM). Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, a property of most malignant cells. Detachment from ECM is associated with enhanced production of reactive oxygen species (ROS) owing to altered glucose metabolism. Here we identify an unconventional pathway that supports redox homeostasis and growth during adaptation to anchorage independence. We observed that detachment from monolayer culture and growth as anchorage-independent tumour spheroids was accompanied by changes in both glucose and glutamine metabolism. Specifically, oxidation of both nutrients was suppressed in spheroids, whereas reductive formation of citrate from glutamine was enhanced. Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because the activity was suppressed in cells homozygous null for IDH1 or treated with an IDH1 inhibitor. This activity occurred in absence of hypoxia, a well-known inducer of reductive metabolism. Rather, IDH1 mitigated mitochondrial ROS in spheroids, and suppressing IDH1 reduced spheroid growth through a mechanism requiring mitochondrial ROS. Isotope tracing revealed that in spheroids, isocitrate/citrate produced reductively in the cytosol could enter the mitochondria and participate in oxidative metabolism, including oxidation by IDH2. This generates NADPH in the mitochondria, enabling cells to mitigate mitochondrial ROS and maximize growth. Neither IDH1 nor IDH2 was necessary for monolayer growth, but deleting either one enhanced mitochondrial ROS and reduced spheroid size, as did deletion of the mitochondrial citrate transporter protein. Together, the data indicate that adaptation to anchorage independence requires a fundamental change in citrate metabolism, initiated by IDH1-dependent reductive carboxylation and culminating in suppression of mitochondrial ROS.

Intraoperative Indocyanine Green Dye Use in Ovarian Torsion: A Feasibility Study.

STUDY OBJECTIVE: To determine the feasibility of  intravenous indocyanine green (ICG) dye use in patients with adnexal torsion to intraoperatively evaluate ovarian perfusion after detorsion. DESIGN: A prospective multicenter single-arm feasibility study. SETTING: A teaching hospital. PATIENTS: A total of 12 nonpregnant patients, 18 to 45 years old with surgically confirmed adnexal torsion. INTERVENTIONS: Torsion was surgically confirmed, the involved adnexa were untwisted laparoscopically, and ICG dye was injected intravenously. The absence or presence of ICG perfusion was documented, and the clinical decision for ovarian conservation or removal was determined by the surgeon. MEASUREMENTS AND MAIN RESULTS: The primary outcome was feasibility of using ICG dye including measures such as time to visualized perfusion and operative time. Secondary outcomes included presence or absence of ovarian preservation and postoperative follow-up measures. Intraoperative visualization of ICG perfusion to the detorsed adnexa was achieved in 10 patients (83%) in a median time of 1 minute (0, 2), resulting in entire (n = 9) or partial (n = 1) ovarian conservation. Perfusion was absent in 2 cases, and postoophorectomy histologic necrosis was confirmed in one case. Median operative time was 74 minutes (48, 94). There were no adverse events related to ICG dye use. CONCLUSION: Intraoperative ICG dye use in this study was logistically feasible and conservation of the entire or partial ovary was observed in 83% of patients, including one case where preoperative Doppler flow was absent.

The Risk of Readmission after Early Postpartum Discharge during the COVID-19 Pandemic.

OBJECTIVE: To determine whether early postpartum discharge during the coronavirus disease 2019 (COVID-19) pandemic was associated with a change in the odds of maternal postpartum readmissions. STUDY DESIGN: This is a retrospective analysis of uncomplicated postpartum low-risk women in seven obstetrical units within a large New York health system. We compared the rate of postpartum readmissions within 6 weeks of delivery between two groups: low-risk women who had early postpartum discharge as part of our protocol during the COVID-19 pandemic (April 1-June 15, 2020) and similar low-risk patients with routine postpartum discharge from the same study centers 1 year prior. Statistical analysis included the use of Wilcoxon's rank-sum and chi-squared tests, Nelson-Aalen cumulative hazard curves, and multivariate logistic regression. RESULTS: Of the 8,206 patients included, 4,038 (49.2%) were patients who had early postpartum discharge during the COVID-19 pandemic and 4,168 (50.8%) were patients with routine postpartum discharge prior to the COVID-19 pandemic. The rates of postpartum readmissions after vaginal delivery (1.0 vs. 0.9%; adjusted odds ratio [OR]: 0.75, 95% confidence interval [CI]: 0.39-1.45) and cesarean delivery (1.5 vs. 1.9%; adjusted OR: 0.65, 95% CI: 0.29-1.45) were similar between the two groups. Demographic risk factors for postpartum readmission included Medicaid insurance and obesity. CONCLUSION: Early postpartum discharge during the COVID-19 pandemic was associated with no change in the odds of maternal postpartum readmissions after low-risk vaginal or cesarean deliveries. Early postpartum discharge for low-risk patients to shorten hospital length of stay should be considered in the face of public health crises. KEY POINTS: · Early postpartum discharge was not associated with an increase in odds of hospital readmissions after vaginal delivery.. · Early postpartum discharge was not associated with an increase in odds of hospital readmissions after cesarean delivery.. · Early postpartum discharge for low-risk patients should be considered during a public health crisis..

Lactate Clearance Is Associated With Improved Survival in Cardiogenic Shock: A Systematic Review and Meta-Analysis of Prognostic Factor Studies.

OBJECTIVE: Elevated blood lactate levels are strongly associated with mortality in patients with cardiogenic shock. Recent evidence suggests that the degree and rate at which blood lactate levels decrease after the initiation of treatment may be equally important in patient prognosis. We performed a systematic review and meta-analysis to evaluate the usefulness of lactate clearance as a prognostic factor in cardiogenic shock. METHODS AND RESULTS: We performed searches of Ovid MEDLINE, Elsevier EMBASE, EBM Reviews-Cochrane Central Register of Controlled Trials, and Web of Science to identify studies comparing lactate clearance between survivors and nonsurvivors at one or more timepoints. Both prospective and retrospective studies were eligible for inclusion. Two study investigators independently screened, extracted data, and assessed the quality of all included studies. Twelve studies were included in the meta-analysis. The median lactate clearance at 6-8 hours was 21.9% (interquartile range [IQR] 14.6%-42.1%) in survivors and 0.6% (IQR -3.7% to 14.6%) in nonsurvivors. At 24 hours, the median lactate clearance was 60.7% (IQR 58.1%-76.3%) and 40.3% (IQR 30.2%-55.8%) in survivors and nonsurvivors, respectively. Accordingly, the pooled mean difference in lactate clearance between survivors and nonsurvivors at 6-8 hours was 17.3% (95% CI 11.6%-23.1%, P < .001) at 6-8 hours and 27.9% (95% CI 14.1%-41.7%, P < .001) at 24 hours. CONCLUSIONS: Survivors had significantly greater lactate clearance at 6-8 hours and at 24 hours compared with nonsurvivors, suggesting that lactate clearance is an important prognostic marker in cardiogenic shock.

Right Ventricular Dysfunction Is Common and Identifies Patients at Risk of Dying in Cardiogenic Shock.

BACKGROUND: Understanding the prognostic impact of right ventricular dysfunction (RVD) in cardiogenic shock (CS) is a key step toward rational diagnostic and treatment algorithms and improved outcomes. Using a large multicenter registry, we assessed (1) the association between hemodynamic markers of RVD and in-hospital mortality, (2) the predictive value of invasive hemodynamic assessment incorporating RV evaluation, and (3) the impact of RVD severity on survival in CS. METHODS AND RESULTS: Inpatients with CS owing to acute myocardial infarction (AMI) or heart failure (HF) between 2016 and 2019 were included. RV parameters (right atrial pressure, right atrial/pulmonary capillary wedge pressure [RA/PCWP], pulmonary artery pulsatility index [PAPI], and right ventricular stroke work index [RVSWI]) were assessed between survivors and nonsurvivors, and between etiology and SCAI stage subcohorts. Multivariable logistic regression analysis determined hemodynamic predictors of in-hospital mortality; the resulting models were compared with SCAI staging alone. Nonsurvivors had a significantly higher right atrial pressure and RA/PCWP and lower PAPI and RVSWI than survivors, consistent with more severe RVD. Compared with AMI, patients with HF had a significantly lower RA/PCWP (0.58 vs 0.66, P = .001) and a higher PAPI (2.71 vs 1.78, P < .001) and RVSWI (5.70 g-m/m2 vs 4.66 g-m/m2, P < .001), reflecting relatively preserved RV function. Paradoxically, multiple RVD parameters (PAPI, RVSWI) were associated with mortality in the HF but not the AMI cohort. RVD was more severe with advanced SCAI stage, although its prognostic value was progressively diluted in stages D and E. Multivariable modelling incorporating the RA/PCWP improved the predictive value of SCAI staging (area under the curve [AUC] 0.78 vs 0.73, P < .001), largely driven by patients with HF (AUC 0.82 vs 0.71, P < .001). CONCLUSIONS: RVD is associated with poor outcomes in CS, with key differences across etiology and shock severity. Further studies are needed to assess the usefulness of RVD assessment in guiding therapy.

Ab Initio Simulations of Poorly and Well Equilibrated (CH3CN)n- Cluster Anions: Assigning Experimental Photoelectron Peaks to Surface-Bound Electrons and Solvated Monomer and Dimer Anions.

Excess electrons in liquid acetonitrile are of particular interest because they exist in two different forms in equilibrium: they can be present as traditional solvated electrons in a cavity, and they can form some type of solvated molecular anion. Studies of small acetonitrile cluster anions in the gas phase show two isomers with distinct vertical detachment energies, and it is tempting to presume that the two gas-phase cluster anion isomers are precursors of the two excess electron species present in bulk solution. In this paper, we perform DFT-based ab initio molecular dynamics simulations of acetonitrile cluster anions to understand the electronic species that are present and why they have different binding energies. Using a long-range-corrected density functional that was optimally tuned to describe acetonitrile cluster anion structures, we have theoretically explored the chemistry of (CH3CN)n- cluster anions with sizes n = 5, 7, and 10. Because the temperature of the experimental cluster anions is not known, we performed two sets of simulations that investigated how the way in which the cluster anions are prepared affects the excess electron binding motif: one set of simulations simply attached excess electrons to neutral (CH3CN)n clusters, providing little opportunity for the clusters to relax in the presence of the excess electron, while the other set allowed the cluster anions to thermally equilibrate near room temperature. We find that both sets of simulations show three distinct electron binding motifs: electrons can attach to the surface of the cluster (dipole-bound) or be present either as solvated monomer anions, CH3CN-, or as solvated molecular dimer anions, (CH3CN)2-. All three species have higher binding energies at larger cluster sizes. Thermal equilibration strongly favors the formation of the valence-bound molecular anions relative to surface-bound excess electrons, and the dimer anion becomes more stable than the monomer anion and surface-bound species as the cluster size increases. The calculated photoelectron spectra from our simulations in which there was poor thermal equilibration are in good agreement with experiment, suggesting assignment of the two experimental cluster anion isomers as the surface-bound electron and the solvated molecular dimer anion. The simulations also suggest that the shoulder seen experimentally on the low-energy isomer's detachment peak is not part of a vibronic progression but instead results from molecular monomer anions. Nowhere in the size range that we explore do we see evidence for a nonvalence, cavity-bound interior-solvated electron, indicating that this species is likely only accessible at larger sizes with good thermal equilibration.

Accelerated transsulfuration metabolically defines a discrete subclass of amyotrophic lateral sclerosis patients.

Amyotrophic lateral sclerosis is a disease characterized by progressive paralysis and death. Most ALS-cases are sporadic (sALS) and patient heterogeneity poses challenges for effective therapies. Applying metabolite profiling on 77-sALS patient-derived-fibroblasts and 43-controls, we found ~25% of sALS cases (termed sALS-1) are characterized by transsulfuration pathway upregulation, where methionine-derived-homocysteine is channeled into cysteine for glutathione synthesis. sALS-1 fibroblasts selectively exhibited a growth defect under oxidative conditions, fully-rescued by N-acetylcysteine (NAC). [U13C]-glucose tracing showed transsulfuration pathway activation with accelerated glucose flux into the Krebs cycle. We established a four-metabolite support vector machine model predicting sALS-1 metabotype with 97.5% accuracy. Both sALS-1 metabotype and growth phenotype were validated in an independent cohort of sALS cases. Importantly, plasma metabolite profiling identified a system-wide cysteine metabolism perturbation as a hallmark of sALS-1. Findings reveal that sALS patients can be stratified into distinct metabotypes with differential sensitivity to metabolic stress, providing novel insights for personalized therapy.

Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study.

BACKGROUND: Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD. METHODS AND FINDINGS: A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n = 23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI -0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort. Key limitations to the study were the open-label design, and use of external comparators. CONCLUSIONS: We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve individuals over an 18-month treatment period. We found that fewer physician-reported AEs occurred with vamorolone than have been reported for treatment with prednisone and deflazacort, and that vamorolone treatment did not cause the stunting of growth seen with these corticosteroids. This Phase IIa study provides Class III evidence to support benefit of motor function in young boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable safety profile. A Phase III RCT is underway to further investigate safety and efficacy. TRIAL REGISTRATION: Clinical trials were registered at www.clinicaltrials.gov, and the links to each trial are as follows (as provided in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE [NCT03038399].

Tunable Dopants with Intrinsic Counterion Separation Reveal the Effects of Electron Affinity on Dopant Intercalation and Free Carrier Production in Sequentially Doped Conjugated Polymer Films.

Carrier mobility in doped conjugated polymers is limited by Coulomb interactions with dopant counterions. This complicates studying the effect of the dopant's oxidation potential on carrier generation because different dopants have different Coulomb interactions with polarons on the polymer backbone. Here, dodecaborane (DDB)-based dopants are used, which electrostatically shield counterions from carriers and have tunable redox potentials at constant size and shape. DDB dopants produce mobile carriers due to spatial separation of the counterion, and those with greater energetic offsets produce more carriers. Neutron reflectometry indicates that dopant infiltration into conjugated polymer films is redox-potential-driven. Remarkably, X-ray scattering shows that despite their large 2-nm size, DDBs intercalate into the crystalline polymer lamellae like small molecules, indicating that this is the preferred location for dopants of any size. These findings elucidate why doping conjugated polymers usually produces integer, rather than partial charge transfer: dopant counterions effectively intercalate into the lamellae, far from the polarons on the polymer backbone. Finally, it is shown that the IR spectrum provides a simple way to determine polaron mobility. Overall, higher oxidation potentials lead to higher doping efficiencies, with values reaching 100% for driving forces sufficient to dope poorly crystalline regions of the film.

Early postpartum discharge during the COVID-19 pandemic.

Objectives To report our experience with early postpartum discharge to decrease hospital length of stay among low-risk puerperium patients in a large obstetrical service during the COVID-19 pandemic in New York. Methods Retrospective analysis of all uncomplicated postpartum women in seven obstetrical units within a large health system between December 8th, 2019 and June 20th, 2020. Women were stratified into two groups based on date of delivery in relation to the start of the COVID-19 pandemic in New York (Mid-March 2020); those delivering before or during the COVID-19 pandemic. We compared hospital length of stay, defined as time interval from delivery to discharge in hours, between the two groups and correlated it with the number of COVID-19 admissions to our hospitals. Statistical analysis included use of Wilcoxon rank sum test and Chi-squared test with significance defined as p-value<0.05. Results Of the 11,770 patients included, 5,893 (50.1%) delivered prior to and 5,877 (49.9%) delivered during the COVID-19 pandemic. We detected substantial shortening in postpartum hospital length of stay after vaginal delivery (34 vs. 48 h, p≤0.0001) and cesarean delivery (51 vs. 74 h, p≤0.0001) during the COVID-19 pandemic. Conclusions We report successful implementation of early postpartum discharge for low-risk patients resulting in a significantly shorter hospital stay during the COVID-19 pandemic in New York. The impact of this strategy on resource utilization, patient satisfaction and adverse outcomes requires further study.

The care of pregnant women during the COVID-19 pandemic - response of a large health system in metropolitan New York.

The rapid progression of the coronavirus disease 2019 (COVID-19) outbreak presented extraordinary challenges to the US health care system, particularly straining resources in hard hit areas such as the New York metropolitan region. As a result, major changes in the delivery of obstetrical care were urgently needed, while maintaining patient safety on our maternity units. As the largest health system in the region, with 10 hospitals providing obstetrical services, and delivering over 30,000 babies annually, we needed to respond to this crisis in an organized, deliberate fashion. Our hospital footprint for Obstetrics was dramatically reduced to make room for the rapidly increasing numbers of COVID-19 patients, and established guidelines were quickly modified to reduce potential staff and patient exposures. New communication strategies were developed to facilitate maternity care across our hospitals, with significantly limited resources in personnel, equipment, and space. The lessons learned from these unexpected challenges offered an opportunity to reassess the delivery of obstetrical care without compromising quality and safety. These lessons may well prove valuable after the peak of the crisis has passed.

Ultrafast transient absorption spectroscopy of doped P3HT films: distinguishing free and trapped polarons.

It is generally presumed that the vast majority of carriers created by chemical doping of semiconducting polymer films are coulombically trapped by the counteranion, with only a small fraction that are free and responsible for the increased conductivity essential for organic electronic applications. At higher doping levels, it is also possible for bipolarons to form, which are expected to be less conductive than single polarons. Unfortunately, there is no simple way to distinguish free polarons, trapped polarons and bipolarons using steady-state spectroscopy. Thus, in this work, we use ultrafast transient absorption spectroscopy to study the dynamics of polarons in 2,3,5,6-tetrafluoro-7,7,8,8-tetracyanoquinodimethane (F4TNCQ)-doped films of poly(3-hexylthiophene-2,5-diyl) (P3HT) as a function of dopant concentration and excitation wavelength. When exciting on the red side of the polaron P1 transition, our transient absorption spectra and kinetics match well with what is expected for free 2-D-delocalized polarons; the measurements are not consistent with a recent theory of doped conjugated polymer electronic structure that suggests that the half-filled state lies deeper in the conduction band rather than in the bandgap. As we tune the excitation wavelength to the blue, our measurements reveal an increasing amount of slower transient kinetics that are consistent with the presence of coulombically-trapped polarons rather than bipolarons. Taking advantage of their distinct ultrafast relaxation kinetics as a type of action spectroscopy, we are able to extract the steady-state absorption spectra of free and trapped polarons as a function of dopant concentration. By comparing the results to theoretical models, we determine that in F4TCNQ-doped P3HT films, trapped polarons sit ∼0.4 nm away from the anion while free polarons reside between 0.7 and 0.9 nm from the counteranion. Perhaps counterintuitively, the ratio of trapped to free polarons increases at higher doping levels, an observation that is consistent with a plateau in the concentration-dependent conductivity of F4TCNQ-doped P3HT films.

Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug.

We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.

Clinically Divergent Mutation Effects on the Structure and Function of the Human Cardiac Tropomyosin Overlap.

The progression of genetically inherited cardiomyopathies from an altered protein structure to clinical presentation of disease is not well understood. One of the main roadblocks to mechanistic insight remains a lack of high-resolution structural information about multiprotein complexes within the cardiac sarcomere. One example is the tropomyosin (Tm) overlap region of the thin filament that is crucial for the function of the cardiac sarcomere. To address this central question, we devised coupled experimental and computational modalities to characterize the baseline function and structure of the Tm overlap, as well as the effects of mutations causing divergent patterns of ventricular remodeling on both structure and function. Because the Tm overlap contributes to the cooperativity of myofilament activation, we hypothesized that mutations that enhance the interactions between overlap proteins result in more cooperativity, and conversely, those that weaken interaction between these elements lower cooperativity. Our results suggest that the Tm overlap region is affected differentially by dilated cardiomyopathy-associated Tm D230N and hypertrophic cardiomyopathy-associated human cardiac troponin T (cTnT) R92L. The Tm D230N mutation compacts the Tm overlap region, increasing the cooperativity of the Tm filament, contributing to a dilated cardiomyopathy phenotype. The cTnT R92L mutation causes weakened interactions closer to the N-terminal end of the overlap, resulting in decreased cooperativity. These studies demonstrate that mutations with differential phenotypes exert opposite effects on the Tm-Tn overlap, and that these effects can be directly correlated to a molecular level understanding of the structure and dynamics of the component proteins.

Hybrid MRI-Ultrasound acquisitions, and scannerless real-time imaging.

PURPOSE: To combine MRI, ultrasound, and computer science methodologies toward generating MRI contrast at the high frame rates of ultrasound, inside and even outside the MRI bore. METHODS: A small transducer, held onto the abdomen with an adhesive bandage, collected ultrasound signals during MRI. Based on these ultrasound signals and their correlations with MRI, a machine-learning algorithm created synthetic MR images at frame rates up to 100 per second. In one particular implementation, volunteers were taken out of the MRI bore with the ultrasound sensor still in place, and MR images were generated on the basis of ultrasound signal and learned correlations alone in a "scannerless" manner. RESULTS: Hybrid ultrasound-MRI data were acquired in eight separate imaging sessions. Locations of liver features, in synthetic images, were compared with those from acquired images: The mean error was 1.0 pixel (2.1 mm), with best case 0.4 and worst case 4.1 pixels (in the presence of heavy coughing). For results from outside the bore, qualitative validation involved optically tracked ultrasound imaging with/without coughing. CONCLUSION: The proposed setup can generate an accurate stream of high-speed MR images, up to 100 frames per second, inside or even outside the MR bore. Magn Reson Med 78:897-908, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

A Nutrition Education Program in Rural Bangladesh Was Associated with Improved Feeding Practices but Not with Child Growth.

Background: Childhood undernutrition is a major public health problem in Bangladesh. Evaluating child nutrition programs is a priority.Objective: The objective of this study was to evaluate a community-based nutrition education program (implemented from 2011 to 2013) aimed at improving infant and young child feeding (IYCF) practices and growth in rural Bangladesh.Methods: A cohort-based evaluation was conducted that included 2400 women (1200 from Karimganj, the intervention subdistrict, and 1200 from Katiadi, the control subdistrict) enrolled at 28-31 wk gestation in 3 waves between January and October 2011. Follow-up occurred at 3, 9, 16, and 24 mo of offspring age. The main outcomes were exclusive breastfeeding (EBF), measured at 3 mo, timing of complementary feeding (CF) initiation and minimum acceptable diet (MAD), measured at 9 mo, and child growth [assessed via length-for-age z score (LAZ) and weight-for-length z score], measured at all follow-ups. The main exposures were subdistrict of residence and wave of enrollment. For IYCF practices as outcome, logistic regressions were used. Generalized estimating equations were used for child growth as outcome.Results: EBF rates at 3 mo remained unchanged between waves 1 and 3 in Karimganj (55.6% compared with 57.3%), but the proportion of infants receiving timely CF initiation and MAD at 9 mo increased significantly (CF: 27.1-54.7%; MAD: 8.4-35.3%). Mean LAZ at 24 mo remained unchanged between waves 1 and 3 in Karimganj (-2.18 compared with -1.98).Conclusions: The program was successful in improving the quality of infant diet at 9 mo and timely CF initiation, but not EBF at 3 mo or LAZ. These findings support the case for implementing simple messages in all programs aimed at improving infant diet, especially in settings in which supplementing overall household diet may not be feasible.

New IDH1 mutant inhibitors for treatment of acute myeloid leukemia.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML. Our study provides proof of concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia.