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Background Multisystemic Therapy® (MST®) is an intensive, home‐based intervention for families of youth with social, emotional, and behavioural problems. MST therapists engage family members in identifying and changing individual, family, and environmental factors thought to contribute to problem behaviour. Intervention may include efforts to improve communication, parenting skills, peer relations, school performance, and social networks. MST is widely considered to be a well‐established, evidence‐based programme. Objectives We assessed (1) impacts of MST on out‐of‐home placements, crime and delinquency, and other behavioural and psychosocial outcomes for youth and families; (2) consistency of effects across studies; and (3) potential moderators of effects including study location, evaluator independence, and risks of bias. Search Methods Searches were performed in 2003, 2010, and March to April 2020. We searched PsycINFO, MEDLINE, ERIC, NCJRS Abstracts, ProQuest and WorldCAT dissertations and theses, and 10 other databases, along with government and professional websites. Reference lists of included articles and research reviews were examined. Between April and August 2020 we contacted 22 experts in search of missing data on 16 MST trials. Selection Criteria Eligible studies included youth (ages 10 to 17) with social, emotional, and/or behavioural problems who were randomly assigned to licensed MST programmes or other conditions. There were no restrictions on publication status, language, or geographic location. Data Collection and Analysis Two reviewers independently screened 1802 titles and abstracts, read all available study reports, assessed study eligibility, and extracted data onto structured electronic forms. We assessed risks of bias (ROB) using modified versions of the Cochrane ROB tool and What Works Clearinghouse standards. Where possible, we used random effects models with inverse variance weights to pool results across studies. We used odds ratios for dichotomous outcomes and standardised mean differences for continuous outcomes. We used Hedges g to adjust for small sample sizes. We assessed the heterogeneity of effects with χ2 and I 2. Pairwise meta‐analyses are displayed in forest plots, with studies arranged in subgroups by location (USA or other country) and investigator independence. We provide separate forest plots for conceptually distinct outcomes and endpoints. We assessed differences between subgroups of studies with χ 2 tests. We generated robust variance estimates, using correlated effects (CE) models with small sample corrections to synthesise all available outcome measures within each of nine outcome domains. Exploratory CE analyses assessed potential moderators of effects within these domains. We used GRADE guidelines to assess the certainty of evidence on seven primary outcomes at one year after referral. Main Results Twenty‐three studies met our eligibility criteria; these studies included a total of 3987 participating families. Between 1983 and 2020, 13 trials were conducted in the USA by MST program developers and 10 studies were conducted by independent teams (three in the USA, three in the UK, and one each in Canada, the Netherlands, Norway, and Sweden). These studies examined outcomes of MST for juvenile offenders, sex offenders, offenders with substance abuse problems, youth with conduct or behaviour problems, those with serious mental health problems, autism spectrum disorder, and cases of child maltreatment. We synthesised data from all eligible trials to test the claim that MST is effective across clinical problems and populations. Most trials compared MST to treatment as usual (TAU). In the USA, TAU consisted of relatively little contact and few services for youth and families, compared with more robust public health and social services available to youth in other high‐income countries. One USA study provided “enhanced TAU” to families in the control group, and two USA studies compared MST to individual therapy for youth. The quality of available evidence for MST is mixed. We identified high risks of bias due to: inadequate randomisation procedures (in 9% of studies); lack of comparability between groups at baseline (65%); systematic omission of cases (43%); attrition (39%); confounding factors (e.g., between‐group differences in race, gender, and attention; 43%); selective reporting of outcomes (52%); and conflicts of interest (61%). Most trials (96%) have high risks of bias on at least one indicator. GRADE ratings of the quality of evidence are low or moderate for seven primary outcomes, with high‐quality evidence from non‐USA studies on out‐of‐home placement. Effects of MST are not consistent across studies, outcomes, or endpoints. At one year post randomisation, available evidence shows that MST reduced out‐of‐home placements in the USA (OR 0.52, 95% confidence interval [CI] 0.32 to 0.84; P

BACKGROUND: Experimental studies and small clinical trials have suggested that treatment with intranasal oxytocin may reduce social impairment in persons with autism spectrum disorder. Oxytocin has been administered in clinical practice to many children with autism spectrum disorder. METHODS: We conducted a 24-week, placebo-controlled phase 2 trial of intranasal oxytocin therapy in children and adolescents 3 to 17 years of age with autism spectrum disorder. Participants were randomly assigned in a 1:1 ratio, with stratification according to age and verbal fluency, to receive oxytocin or placebo, administered intranasally, with a total target dose of 48 international units daily. The primary outcome was the least-squares mean change from baseline on the Aberrant Behavior Checklist modified Social Withdrawal subscale (ABC-mSW), which includes 13 items (scores range from 0 to 39, with higher scores indicating less social interaction). Secondary outcomes included two additional measures of social function and an abbreviated measure of IQ. RESULTS: Of the 355 children and adolescents who underwent screening, 290 were enrolled. A total of 146 participants were assigned to the oxytocin group and 144 to the placebo group; 139 and 138 participants, respectively, completed both the baseline and at least one postbaseline ABC-mSW assessments and were included in the modified intention-to-treat analyses. The least-squares mean change from baseline in the ABC-mSW score (primary outcome) was −3.7 in the oxytocin group and −3.5 in the placebo group (least-squares mean difference, −0.2; 95% confidence interval, −1.5 to 1.0; P = 0.61). Secondary outcomes generally did not differ between the trial groups. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: This placebo-controlled trial of intranasal oxytocin therapy in children and adolescents with autism spectrum disorder showed no significant between-group differences in the least-squares mean change from baseline on measures of social or cognitive functioning over a period of 24 weeks. (Funded by the National Institute of Child Health and Human Development; SOARS-B ClinicalTrials.gov number, NCT01944046.)

BackgroundNeutralizing monoclonal antibodies (mAb) targeting SARS-CoV-2 decrease hospitalization and death in patients with mild to moderate Covid-19. Yet, their clinical use is limited, and comparative effectiveness is unknown.MethodsWe present the first results of an ongoing, learning health system adaptive platform trial to expand mAb treatment to all eligible patients and evaluate the comparative effectiveness of available mAbs. The trial launched March 10, 2021. Results are reported as of June 25, 2021 due to the U.S. federal decision to pause distribution of bamlanivimab-etesevimab; patient follow-up concluded on July 23, 2021. Patients referred for mAb who met Emergency Use Authorization criteria were provided a random mAb allocation of bamlanivimab, bamlanivimab-etesevimab, or casirivimab-imdevimab with a therapeutic interchange policy. The primary outcome was hospital-free days (days alive and free of hospital) within 28 days, where patients who died were assigned -1 day. The primary analysis was a Bayesian cumulative logistic model of all patients treated at an infusion center or emergency department, adjusting for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio < 1. Equivalence was defined as a 95% posterior probability that the odds ratio is within a given bound.ResultsPrior to trial launch, 3.1% (502) of 16,345 patients who were potentially eligible by an automated electronic health record (EHR) screen received mAb. During the trial period, 23.2% (1,201) of 5,173 EHR-screen eligible patients were treated, a 7.5-fold increase. After including additional referred patients from outside the health system, a total of 1,935 study patients received mAb therapy (128 bamlanivimab, 885 bamlanivimab-etesevimab, 922 casirivimab-imdevimab). Mean age ranged from 55 to 57 years, half were female (range, 53% to 54%), and 17% were Black (range, 12% to 19%). Median hospital–free days were 28 (IQR, 28 to 28) for each mAb group. Hospitalization varied between groups (bamlanivimab, 12.5%; bamlanivimab-etesevimab, 14.7%, casirivimab-imdevimab, 14.3%). Relative to casirivimab-imdevimab, the median adjusted odds ratios were 0.58 (95% credible interval (CI), 0.30 to 1.16) and 0.94 (95% CI, 0.72 to 1.24) for the bamlanivimab and bamlanivimab-etesevimab groups, respectively. These odds ratios yielded 91% and 94% probabilities of inferiority of bamlanivimab versus bamlanivimab-etesevimab and casirivimab-imdevimab respectively, and an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab, at the prespecified odds ratio bound of 0.25. Twenty-one infusion-related adverse events occurred in 0% (0/128), 1.4% (12/885), and 1.0% (9/922) of patients treated with bamlanivimab, bamlanivimab-etesevimab, and casirivimab-imdevimab, respectively.ConclusionIn non-hospitalized patients with mild to moderate Covid-19, bamlanivimab, compared to bamlanivimab-etesevimab and casirivimab-imdevimab, resulted in 91% and 94% probabilities of inferiority with regards to odds of improvement in hospital-free days within 28 days. There was an 86% probability of equivalence between bamlanivimab-etesevimab and casirivimab-imdevimab at an odds ratio bound of 0.25. However, the trial was unblinded early due to federal distribution decisions, and no mAb met prespecified criteria for statistical inferiority or equivalence. (ClinicalTrials.gov, NCT04790786).

Study question Are the morphokinetic profiles, as assessed using time-lapse technology, of human embryos developed from vitrified oocytes different to those from fresh oocytes. Summary answer Vitrification of oocytes does have an effect on early developmental morphokinetic profiles, but this is normalized by the time the embryo has reached blastocyst. What is known already Vitrification of oocytes is now commonplace, but little is known about the effect this may have on subsequent embryo development. Study design, size, duration This was a retrospective data analysis, from 8 fertility clinics in the UK between 2012 and 2019. Embryos from patients in the vitrified group (n = 557) were matched to fresh patient controls (n = 539). The matching was performed based on the following criteria: type of treatment, patient age, cause of infertility and number of embryos. Participants/materials, setting, methods The embryos in each group were compared for mean morphokinetics of key developmental stages in hours post insemination (hpi). Parameters compared included early cleavage divisions (t2-t8), time to start of compaction (tSC), time to morula (tM), time to start blastulation (tSB), time to full blastocyst (tB) and duration of compaction (tB-tSC). Treatment outcomes were compared between the two groups, including percentage of blastocyst formation, clinical pregnancy rate, implantation rate and live birth rate. Main results and the role of chance The results showed a significant delay across all early cleavage divisions as follows for vitrified and fresh oocytes respectively: 2-cell (28.14 vs 26.10 (p 0.05)). No difference was found in clinical pregnancy, implantation or live birth rates but significantly fewer blastocyst developed from vitrified oocytes compared to fresh (36.09% vs 42.4% (p Limitations, reasons for caution Although this was a matched analysis, it was a retrospective in nature therefore is subject to confounders. However, it would be problematic to perform a prospective randomized controlled trial to address this study question given the need to randomize patients to elective freezing of oocytes prior to embryo creation. Wider implications of the findings: Vitrification of oocytes may affect early developmental morphokinetic profiles, but any effect is normalized by the time the embryo has reached blastocyst. However, fewer blastocysts may develop following oocyte vitrification. This may have implications for oocyte donation banks and those patients choosing to cryopreserve oocytes. Trial registration number NA

Background: The forearm is the most common site of fracture, and perhaps re-fracture, in the pediatric population. Although both bone forearm (BBFA) fractures represent approximately 30% of pediatric upper extremity fractures, little is known about BBFA re-fractures, particularly among youth athletes. Purpose: To evaluate characteristics of BBFA re-fracture and recurrent fractures. Methods: An IRB-approved retrospective chart review based on CPT and ICD-9/10 codes of forearm fractures (ages 10-18 years) treated by a single academic pediatric orthopedic group from June 2009 to May 2020 was conducted. All BBFA, radial, or ulnar fractures with ipsilateral same-site, or non-identical ipsilateral or contralateral forearm fracture were included. Demographics, injury characteristics, length of immobilization, timing of return to activity, and radiographic data (angulation, distance between radius fracture and ulna fracture [in mm], position of fracture within bone, and radiographic healing). An analysis was performed to evaluate associations of ipsilateral same-site re-fracture versus ipsilateral or contra-lateral non-identical site fractures. Results: Twenty-nine of 686 BBFA and distal radius fractures were identified to have recurrent fracture (4.23%), with an average age of 11.5 years and male-to-female ratio of 6.25:1. 67% of ipsilateral same-site re-fractures occurred within one year. The most common mechanisms of primary fracture were contact sports (40%) and tumbling (30%), and re-fracture occurred 182 days after original fracture. 52% percent of recurrent fractures were ipsilateral same-site re-fractures, while 48% occurred in a non-identical site, either ipsilaterally or contralaterally. The most common mechanisms of recurrent fracture were contact sports (38%), falls (38%), and tumbling (14%). Ipsilateral same-site re-fractures compared to other recurrent fractures, were significantly associated with a mid-shaft location (p=0.0029), increased radius to ulna fracture distance (21.14 mm versus 11.3 mm, p=0.0277) [Figure 1], and earlier occurrence following index fracture (re-fracture= 397.33 days versus non-identical recurrent fracture= 884.07 days, p=0.0056). Degree of angulation was not significantly associated with re-fracture. Conclusion: Recurrent fracture may occur at different times and locations following primary injury treatment. Ipsilateral same-site re-fractures tend to occur within the first year of treatment following mid-shaft fractures incurred during contact sports and tumbling, with widely spaced radial and ulnar fracture sites. Further research may be warranted to evaluate biologic, bone health, or personality traits that may lead to recurrent and re-fractures in pediatric forearm fractures. [Figure: see text]

The effectiveness of monoclonal antibodies (mAbs), casirivimab-imdevimab and sotrovimab, is unknown in patients with mild to moderate COVID-19 caused by the SARS-CoV-2 Delta variant.To evaluate the effectiveness of mAb against the Delta variant compared with no mAb treatment and to ascertain the comparative effectiveness of casirivimab-imdevimab and sotrovimab.This study comprised 2 parallel studies: (1) a propensity score-matched cohort study of mAb treatment vs no mAb treatment and (2) a randomized comparative effectiveness trial of casirivimab-imdevimab and sotrovimab. The cohort consisted of patients who received mAb treatment at the University of Pittsburgh Medical Center outpatient infusion centers and emergency departments from July 14 to September 29, 2021. Participants were patients with a positive SARS-CoV-2 test result who were eligible to receive mAbs according to emergency use authorization criteria.For the trial, patients were randomized to either intravenous casirivimab-imdevimab or sotrovimab according to a system therapeutic interchange policy.For the cohort study, risk ratio (RR) estimates for the primary outcome of hospitalization or death by 28 days were compared between mAb treatment and no mAb treatment using propensity score-matched models. For the comparative effectiveness trial, the primary outcome was hospital-free days (days alive and free of hospitalization) within 28 days after mAb treatment, where patients who died were assigned -1 day in a bayesian cumulative logistic model adjusted for treatment location, age, sex, and time. Inferiority was defined as a 99% posterior probability of an odds ratio (OR) less than 1. Equivalence was defined as a 95% posterior probability that the OR was within a given bound.A total of 3069 patients (1023 received mAb treatment: mean [SD] age, 53.2 [16.4] years; 569 women [56%]; 2046 had no mAb treatment: mean [SD] age, 52.8 [19.5] years; 1157 women [57%]) were included in the prospective cohort study, and 3558 patients (mean [SD] age, 54 [18] years; 1919 women [54%]) were included in the randomized comparative effectiveness trial. In propensity score-matched models, mAb treatment was associated with reduced risk of hospitalization or death (RR, 0.40; 95% CI, 0.28-0.57) compared with no treatment. Both casirivimab-imdevimab (RR, 0.31; 95% CI, 0.20-0.50) and sotrovimab (RR, 0.60; 95% CI, 0.37-1.00) were associated with reduced hospitalization or death compared with no mAb treatment. In the clinical trial, 2454 patients were randomized to receive casirivimab-imdevimab and 1104 patients were randomized to receive sotrovimab. The median (IQR) hospital-free days were 28 (28-28) for both mAb treatments, the 28-day mortality rate was less than 1% (n = 12) for casirivimab-imdevimab and less than 1% (n = 7) for sotrovimab, and the hospitalization rate by day 28 was 12% (n = 291) for casirivimab-imdevimab and 13% (n = 140) for sotrovimab. Compared with patients who received casirivimab-imdevimab, those who received sotrovimab had a median adjusted OR for hospital-free days of 0.88 (95% credible interval, 0.70-1.11). This OR yielded 86% probability of inferiority for sotrovimab vs casirivimab-imdevimab and 79% probability of equivalence.In this propensity score-matched cohort study and randomized comparative effectiveness trial, the effectiveness of casirivimab-imdevimab and sotrovimab against the Delta variant was similar, although the prespecified criteria for statistical inferiority or equivalence were not met. Both mAb treatments were associated with a reduced risk of hospitalization or death in nonhospitalized patients with mild to moderate COVID-19 caused by the Delta variant.ClinicalTrials.gov Identifier: NCT04790786.

Objectives The primary objective is to evaluate the comparative effectiveness of COVID-19 specific monoclonal antibodies (mABs) with US Food and Drug Administration (FDA) Emergency Use Authorization (EUA), alongside UPMC Health System efforts to increase patient access to these mABs. Trial design Open-label, pragmatic, comparative effectiveness platform trial with response-adaptive randomization Participants We will evaluate patients who meet the eligibility criteria stipulated by the COVID-19 mAB EUAs who receive mABs within the UPMC Health System, including infusion centers and emergency departments. EUA eligibility criteria include patients with mild to moderate COVID-19, <10 days of symptoms, and who are at high risk for progressing to severe COVID-19 and/or hospitalization (elderly, obese, and/or with specific comorbidities). The EUA criteria exclude patients who require oxygen for the treatment of COVID-19 and patients already hospitalized for the treatment of COVID-19. We will use data collected for routine clinical care, including data entered into the electronic medical record and from follow-up calls. Intervention and comparator The interventions are the COVID-19 specific mABs authorized by the EUAs. All aspects of mAB treatment, including eligibility criteria, dosing, and post-infusion monitoring, are as per the EUAs. As a comparative effectiveness trial, all patients receive mAB treatment, and the interventions are compared against each other. When U.S. government mAB policies change (e.g., FDA grants or revokes EUAs), UPMC Health System policies and the evaluated mAB interventions will accordingly change. From November 2020 to February 2021, FDA issued EUAs for three mAB treatments (bamlanivimab; bamlanivimab and etesevimab; and casirivimab and imdevimab), and at trial launch on March 10, 2021 we evaluated all three. Due to a sustained increase in SARS-CoV-2 variants in the United States resistant to bamlanivimab administered alone, on March 24, 2021 the U.S. Government halted distribution of bamlanivimab alone, and UPMC accordingly halted bamlanivimab monotherapy on March 31, 2021. On April 16, 2021, FDA revoked the EUA for bamlanivimab monotherapy. At the time of manuscript submission, we are therefore evaluating the two mAB treatments authorized by EUAs (bamlanivimab and etesevimab; and casirivimab and imdevimab). Main outcomes The primary outcome is total hospital free days (HFD) at 28 days after mAB administration, calculated as 28 minus the number of days during the index stay (if applicable – e.g., for patients admitted to hospital after mAB administration in the emergency department) minus the number of days readmitted during the 28 days after treatment. This composite endpoint captures the number of days from the day of mAB administration to the 28 days thereafter, during which the patient is alive and free of hospitalization. Death within 28 days is recorded as -1 HFD, as the worst outcome. Randomisation We will start with equal allocation. Due to uncertainty in sample size, we will use a Bayesian adaptive design and response adaptive randomization to ensure ability to provide statistical inference despite variable sample size. When mABs are ordered by UPMC physicians as a generic referral order, the order is filled by UPMC pharmacy via therapeutic interchange. OPTIMISE-C19 provides the therapeutic interchange via random allocation. Infusion center operations teams and pharmacists use a mAB assignment application embedded in the electronic medical record to determine the random allocation. Blinding (masking) This trial is open-label. However, outcome assessors conducting follow-up calls at day 28 are blinded to mAB assignment, and investigators are blinded to by-mAB aggregate outcome data until a statistical platform trial conclusion is reached. Numbers to be randomised (sample size) Sample size will be determined by case volume throughout the course of the pandemic, supply of FDA authorized mABs, and by that needed to reach a platform trial conclusion of inferiority, superiority, or futility of a given mAB. The trial will continue as long as more than one mAB type is available under EUA, and their comparative effectiveness is uncertain. Trial Status Protocol Version 1.0, February 24, 2021. Recruitment began March 10, 2021 and is ongoing at the time of manuscript submission. The estimated recruitment end date is February 22, 2022, though the final end date is dependent on how the pandemic evolves, mAB availability, and when final platform trial conclusions are reached. As noted above, due to U.S. Government decisions, UPMC Health System halted bamlanivimab monotherapy on March 31, 2021. Trial registration ClinicalTrials.gov Identifier: NCT04790786. Registered March 10, 2021 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated ‘omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease., The mechanisms driving metabolic dysfunction in obesity remain incompletely understood. Here, the authors show that the levels of Hippo pathway effector YAP are reduced in muscle from individuals with insulin resistance and obese-diabetic mice, and that YAP promotes skeletal muscle lipid metabolism and limits adiposity in obese mice.

The tongue is a heavily innervated and vascularized striated muscle that plays an important role in vocalization, swallowing and digestion. The surface of the tongue is lined with papillae which contain gustatory cells expressing various taste receptors. There is growing evidence to suggest that our perceptions of taste and food preference are remodelled following chronic consumption of Western diets rich in carbohydrate and fats. Our sensitivity to taste and also to metabolising Western diets may be a key factor in the rising prevalence of obesity, however, a systems-wide analysis of the tongue is lacking. Here, we defined the proteomic landscape of the mouse tongue and quantified changes following chronic consumption of a chow or Western diet enriched in lipid, fructose and cholesterol for 7 months. We observed a dramatic remodelling of the tongue proteome including proteins that regulate fatty acid and mitochondrial metabolism. Furthermore, the expressions of several receptors, metabolic enzymes and hormones were differentially regulated, and are likely to provide novel therapeutic targets to alter taste perception and food preference to combat obesity.

The presence of islet autoantibodies and islet reactive T cells (T+) in adults with established type 2 diabetes (T2D) have been shown to identify those patients with more severe β-cell dysfunction. However, at what stage in the progression toward clinical T2D does islet autoimmunity emerge as an important component influencing β-cell dysfunction? In this ancillary study to the Restoring Insulin SEcretion (RISE) Study, we investigated the prevalence of and association with β-cell dysfunction of T+ and autoantibodies to the 65 kDa glutamic acid decarboxylase antigen (GADA) in obese pre-diabetes adults with impaired glucose tolerance (IGT) and recently diagnosed treatment naïve (Ndx) T2D. We further investigated the effect of 12 months of RISE interventions (metformin or liraglutide plus metformin, or with 3 months of insulin glargine followed by 9 months of metformin or placebo) on islet autoimmune reactivity. We observed GADA(+) in 1.6% of NdxT2D and 4.6% of IGT at baseline, and in 1.6% of NdxT2D and 5.3% of IGT at 12 months, but no significant associations between GADA(+) and β-cell function. T(+) was observed in 50% of NdxT2D and 60.4% of IGT at baseline, and in 68.4% of NdxT2D and 83.9% of IGT at 12 months. T(+) NdxT2D were observed to have significantly higher fasting glucose (p = 0.004), and 2 h glucose (p = 0.0032), but significantly lower steady state C-peptide (sscpep, p = 0.007) compared to T(−) NdxT2D. T(+) IGT participants demonstrated lower but not significant (p = 0.025) acute (first phase) C-peptide response to glucose (ACPRg) compared to T(−) IGT. With metformin treatment, T(+) participants were observed to have a significantly lower Hemoglobin A1c (HbA1c, p = 0.002) and fasting C-peptide (p = 0.002) compared to T(−), whereas T(+) treated with liraglutide + metformin had significantly lower sscpep (p = 0.010) compared to T(−) participants. In the placebo group, T(+) participants demonstrated significantly lower ACPRg (p = 0.001) compared to T(−) participants. In summary, T(+) were found in a large percentage of obese pre-diabetes adults with IGT and in recently diagnosed T2D. Moreover, T(+) were significantly correlated with treatment effects and β-cell dysfunction. Our results demonstrate that T(+) are an important component in T2D.

The mobile south flank of Kīlauea Volcano hosts two normal fault systems, the Koa'e fault system (KFS) and the Hilina fault system (HFS). In historical time, at least three M>6.5 earthquakes have occurred on the basal detachment of the Kīlauea Volcano's south flank, with the most recent being the 4 May 2018 M6.9 earthquake. Here we analyze kinematic Global Positioning System data collected from 2001 to 2017 and interferometric synthetic aperture radar data before, during, and after the 2018 M6.9 earthquake to determine the crustal motion across the HFS and KFS faults. Our results indicate that the HFS faults did not significantly slip during the interseismic period from 2007 to 2011. Despite its substantial magnitude, interferometric synthetic aperture radar (InSAR) data show that the 2018 M6.9 earthquake triggered subcentimeter level slip along sections of the previously mapped HFS branches. Up to 20 cm of offset occurred on what appears to be a newly formed (or previously unknown) fault near the eastern end of the HFS. During the 3 months following the M6.9 earthquake, up to ~30 cm of slip occurred along the KFS, which helps accommodate rapid large‐scale subsidence of Kīlauea's summit region as large volumes of summit reservoir magma fed the lower East Rift Zone eruption. The HFS appears to activate only in concert with large earthquakes on the basal detachment. The KFS, on the other hand, moves both seismically during small local earthquakes and aseismically in response to nearby earthquakes and caldera subsidence.

Fatty acid receptors have been recognized as important players in glycaemic control. This study is the first to describe a role for the medium‐chain fatty acid (MCFA) receptor G‐protein‐coupled receptor (Gpr) 84 in skeletal muscle mitochondrial function and insulin secretion. We are able to show that Gpr84 is highly expressed in skeletal muscle and adipose tissue. Mice with global deletion of Gpr84 [Gpr84 knockout (KO)] exhibit a mild impairment in glucose tolerance when fed a MCFA‐enriched diet. Studies in mice and pancreatic islets suggest that glucose intolerance is accompanied by a defect in insulin secretion. MCFA‐fed KO mice also exhibit a significant impairment in the intrinsic respiratory capacity of their skeletal muscle mitochondria, but at the same time also exhibit a substantial increase in mitochondrial content. Changes in canonical pathways of mitochondrial biogenesis and turnover are unable to explain these mitochondrial differences. Our results show that Gpr84 plays a crucial role in regulating mitochondrial function and quality control.—Montgomery, M. K., Osborne, B., Brandon, A. E., O'Reilly, L., Fiveash, C. E., Brown, S. H. J., Wilkins, B. P., Samsudeen, A., Yu, J., Devanapalli, B., Hertzog, A., Tolun, A. A., Kavanagh, T., Cooper, A. A., Mitchell, T. W., Biden, T. J., Smith, N. J., Cooney, G. J., Turner, N. Regulation of mitochondrial metabolism in murine skeletal muscle by the medium‐chain fatty acid receptor Gpr84. FASEB J. 33, 12264‐12276 (2019). www.fasebj.org

Current limitations of platelet shelf life to 5 days have led to an increasingly greater demand for hemostatic agents with greater longevity. The objective of this study was to evaluate the function of a lyophilized platelet-derived hemostatic product (thrombosome [TS]) as a potential alternative to fresh platelets.Platelets were collected from whole blood from healthy donors. TSs were reconstituted with water and added to various configurations of reassembled whole blood (platelets, plasma, and RBCs); measures included rotational thromboelastometry (ROTEM), optical aggregometry, mitochondrial function, calibrated automated thrombogram, collagen adhesion under flow (shear flow assay), and flow cytometry.In ROTEM, no differences were observed between maximum clot formation values for contact pathway activation thromboelastometry tests with TSs or platelet samples. Significantly decreased aggregation was observed in the TSs versus platelets (p 0.001 for all agonists). Flow cytometry measures demonstrated significant decreases in glycoprotein Ib expression and increases in phosphatidylserine expression in the TS group (p 0.01). The calibrated automated thrombogram assay was suggestive (lag time and peak thrombin) that the TSs might have some thrombogenic properties. Measurements of mitochondrial function revealed that TSs had no functional mitochondria.In this study, TSs were shown to have nonfunctional mitochondria. ROTEM measures revealed that the TSs had no impact on clot strength. Likewise, compared to platelets, the TSs displayed minimal aggregation, had significantly more phosphatidylserine (measure of activation status), but had the ability to adhere to a collagen surface under flow conditions and contribute to clot formation and induced greater thrombin generation.

Myeloid-derived suppressor cells (MDSCs) have been identified in the burn wound, however their characterization is incomplete. To study this, mice were subjected to a major burn and skin cells were isolated 3 days thereafter for analysis. Significant infiltration of the burn wound with MDSCs was observed as compared with uninjured skin. The skin of naive mice did not contain MDSCs. Characterization of the cells showed that 33% of MDSCs in the wound were monocytic (M)-MDSCs, which was significantly less than that found in uninjured skin (52%). In contrast, polymorphonuclear (PMN)-MDSCs were greater in the burn wound as compared with uninjured skin. Burn wound TLR expression by both MDSCs subsets was decreased as compared with uninjured skin. Wound MDSCs produced pro- and anti-inflammatory cytokines and iNOS was present in both MDSC subsets, whereas ARG1 was only present in M-MDSCs. In conclusion, both M- and PMN-MDSCs infiltrate burn wound with after injury, however, they displayed decreased TLR expression, suggesting receptor down-regulation.

Summary: Background & aims: Dystrophic muscle fibres are fragile and prone to breakage, leading to impaired Ca2+ homeostasis and excessive inflammation, resulting in muscle wasting and weakness. Choline, an essential water-soluble nutrient, is involved in multiple biological processes, including modulation of inflammation and oxidative stress. We tested the hypothesis that choline supplementation would ameliorate the dystrophic pathology in mdx mice. Methods: Three-week old male mdx mice (n = 40) were fed control purified laboratory chow (CON; n = 20) or a choline-enriched diet (5 g/kg choline; CHL, n = 20) for four weeks. Rotarod performance, grip strength and running (wheel) distance were assessed during treatment. Markers of Ca2+-handling, inflammation, oxidative stress and fibrosis were measured in the diaphragm, quadriceps muscle and the liver. Results: Choline-treated mdx mice displayed less macrophage (CD68 -33%, P

Elevated whole blood serotonin (WB5-HT) is a well-replicated biomarker in autism spectrum disorder (ASD). Decreased platelet serotonin receptor 5-HT2A binding has been reported in ASD. WB5-HT levels and platelet 5-HT2A specific binding were obtained from 110 individuals with ASD and 18 controls. Individuals with ASD had significantly higher WB5-HT levels than controls. There was no difference in the platelet 5-HT2A specific binding between groups. Multiple regression analyses revealed that platelet 5-HT2A binding significantly predicted WB5-HT in the control sample but not in the ASD sample. These results indicate that the relationship between WB5-HT and platelet 5-HT2A binding differs depending on ASD diagnosis, suggesting differences in platelet 5-HT system regulation in ASD.

Regional networks of Global Navigation Satellite System (GNSS) stations cover seismically and volcanically active areas throughout the United States. Data from these networks have been used to produce high-precision, three-component velocity fields covering broad geographic regions as well as position time series that track time-varying crustal deformation. This information has contributed to assessing interseismic strain accumulation and related seismic hazard, revealed previously unknown occurrences of aseismic fault slip, constrained coseismic slip estimates, and enabled monitoring of volcanic unrest and postseismic deformation. In addition, real-time GNSS data are now widely available. Such observations proved invaluable for tracking the rapidly evolving eruption of Kīlauea in 2018. Real-time earthquake source modeling using GNSS data is being incorporated into tsunami warning systems, and a vigorous research effort is focused on quantifying the contribution that real-time GNSS can make to improve earthquake early warnings as part of the Advanced National Seismic System ShakeAlert system. Real-time GNSS data can also aid in the tracking of ionospheric disturbances and precipitable water vapor for weather forecasting. Although regional GNSS and seismic networks generally have been established independently, their spatial footprints often overlap, and in some cases the same institution operates both types of networks. Further integration of GNSS and seismic networks would promote joint use of the two data types to better characterize earthquake sources and ground motion as well as offer opportunities for more efficient network operations. Looking ahead, upgrading network stations to leverage new GNSS technology could enable more precise positioning and robust real-time operations. New computational approaches such as machine learning have the potential to enable full utilization of the large amounts of data generated by continuous GNSS networks. Development of seafloor Global Positioning System-acoustic networks would provide unique information for fundamental and applied research on subduction zone seismic hazard and, potentially, monitoring.

Obesity-associated comorbidities include non-alcoholic fatty liver disease, Type 2 diabetes, and cardiovascular disease. These diseases are associated with accumulation of lipids in non-adipose tissues, which can impact many intracellular cellular signaling pathways and functions that have been broadly defined as “lipotoxic.” This review moves beyond understanding intracellular lipotoxic outcomes and outlines the consequences of lipotoxicity on protein secretion and inter-tissue “cross talk,” and the impact this exerts on systemic metabolism.

Connecting caldera collapse The Kīlauea Volcano on the island of Hawai‘i erupted for 3 months in 2018. Neal et al. present a summary of the eruption sequence along with a variety of geophysical observations collected by the Hawaiian Volcano Observatory. The cyclic inflation, deflation, and eventual collapse of the summit was tied to lava eruption from lower East Rift Zone fissures. A total volume of 0.8 cubic kilometers of magma erupted, roughly the equivalent of 320,000 swimming pools, which matched the change in volume at the summit. Science , this issue p. 367

Defects in hepatic lipid metabolism cause nonalcoholic fatty liver disease and insulin resistance, and these pathologies are closely linked. Regulation of lipid droplet metabolism is central to the control of intracellular fatty acid fluxes, and perilipin 5 (PLIN5) is important in this process. We examined the role of PLIN5 on hepatic lipid metabolism and systemic glycemic control using liver-specific Pliny-deficient mice (Plin5(LKO)). Hepatocytes isolated from Plin5(LKO) mice exhibited marked changes in lipid metabolism characterized by decreased fatty acid uptake and storage, decreased fatty acid oxidation that was associated with reduced contact between lipid droplets and mitochondria, and reduced triglyceride secretion. With consumption of a high-fat diet, Plin5(LKO)) mice accumulated intrahepatic triglyceride, without significant changes in inflammation, ceramide or diglyceride contents, endoplasmic reticulum stress, or autophagy. Instead, livers of Plin5(LKO)) mice exhibited activation of c-Jun N-terminal kinase, impaired insulin signal transduction, and insulin resistance, which impaired systemic insulin action and glycemic control. Re-expression of Plin5 in the livers of Plin5(LKO)) mice reversed these effects. Together, we show that Plin5 is an important modulator of intrahepatic lipid metabolism and suggest that the increased Plin5 expression that occurs with overnutrition may play an important role in preventing hepatic insulin resistance.

Objective The serotonin (5-hydroxytryptamine [HT]) system has long been implicated in autism spectrum disorder (ASD). Whole-blood 5-HT level (WB5-HT) is a stable, heritable biomarker that is elevated in more than 25% of children with ASD. Recent findings indicate that the maternal 5-HT system may influence embryonic neurodevelopment, but maternal WB5-HT has not been examined in relation to ASD phenotypes. Method WB5-HT levels were obtained from 181 individuals (3–27 years of age) diagnosed with ASD, 99 of their fathers, and 119 of their mothers. Standardized assessments were used to evaluate cognitive, behavioral, and language phenotypes. Results Exploratory regression analyses found relationships between maternal WB5-HT and nonverbal IQ (NVIQ), Autism Diagnostic Interview-Revised (ADI-R) Nonverbal Communication Algorithm scores, and overall adaptive function on the Vineland Adaptive Behavior Scales−II. Latent class analysis identified a three-class structure in the assessment data, describing children with low, intermediate, and high severity across measures of behavior, cognition, and adaptive function. Mean maternal WB5-HT differed across classes, with the lowest maternal WB5-HT levels seen in the highest-severity group (Welch F2,46.048 = 17.394, p Conclusion Maternal WB5-HT is associated with neurodevelopmental outcomes in offspring with ASD. Prospective, longitudinal studies will be needed to better understand the relationship between the function of the maternal serotonin system during pregnancy and brain development. Further studies in animal models may be able to reveal the mechanisms underlying these findings.

BackgroundMonoclonal antibody (mAb) treatment may prevent complications of COVID-19. We sought to quantify the impact of bamlanivimab monotherapy on hospitalizations and mortality, as well as Emergency Department (ED) visits without hospitalization, among outpatients at high risk of COVID-19 complications.MethodsWe compared patients receiving mAb to patients who met criteria but did not receive mAb from December 2020 through March 2021. The study population selection used propensity scores to match 1:1 by likelihood to receive mAb. The primary outcome was hospitalization or all-cause mortality within 28 days; the secondary outcome was hospitalization or ED visit without hospitalization within 28 days. Odds ratios (OR) calculation used logistic regression modeling including propensity score and mAb receipt predictors.ResultsThe study population included 234 patients receiving mAb and 234 matched comparator patients not receiving mAb. Patients receiving mAb were less likely to experience hospitalization or mortality (OR 0.31, 95% confidence interval [95%CI] 0.17-0.56, p=0.00001) and hospitalization or ED visit without hospitalization (OR 0.50, 95%CI 0.43-0.83, p=0.007). The impact of mAb was more pronounced in prevention of hospitalization (among all age groups, OR 0.35, 95%CI 0.19-0.66, p=0.001) than mortality or ED visit without hospitalization, and most strongly associated with patients age 65 years and older (primary outcome OR 0.28, 95%CI 0.14-0.56, p=0.0003).ConclusionsBamlanivimab monotherapy was associated with reduction in the composite outcome of hospitalizations and mortality in patients with mild-moderate COVID-19. The benefit may be strongest in preventing hospitalization in patients ages 65 years or older.

Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, yet the pathophysiological mechanisms underpinning this bidirectional relationship remain unresolved. Using proteomic approaches, we interrogate hepatocyte protein secretion in two models of murine NASH to understand how liver-derived factors modulate lipid metabolism and insulin sensitivity in peripheral tissues. We reveal striking hepatokine remodelling that is associated with insulin resistance and maladaptive lipid metabolism, and identify arylsulfatase A (ARSA) as a hepatokine that is upregulated in NASH and type 2 diabetes. Mechanistically, hepatic ARSA reduces sulfatide content and increases lysophosphatidylcholine (LPC) accumulation within lipid rafts and suppresses LPC secretion from the liver, thereby lowering circulating LPC and lysophosphatidic acid (LPA) levels. Reduced LPA is linked to improvements in skeletal muscle insulin sensitivity and systemic glycemic control. Hepatic silencing of Arsa or inactivation of ARSA's enzymatic activity reverses these effects. Together, this study provides a unique resource describing global changes in hepatokine secretion in NASH, and identifies ARSA as a regulator of liver to muscle communication and as a potential therapeutic target for type 2 diabetes.

Simple Summary A key molecule, EGFRvIII has been shown to provide several growth advantages for brain tumors. However, we have found a new mechanism in which the EGFRvIII provides increased survival to brain cancer cells when under sub-optimal conditions. Specifically, we have found that the EGFRvIII drives the expression of a molecule called Reticulocalbin 1 (RCN1) and that RCN1 blocks cell stress and cell death, thereby allowing cells to survive and proliferate. Importantly, these findings will allow for the generation of drugs that block the function of EGFRvIII and RCN1 with the hope that these drugs will induce brain cancer cell death. Abstract Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.

The Long Valley Caldera, California (USA), has been restless over the past few decades, experiencing seismic swarms and ground deformation episodes. The last inflation began in late 2011, when a radially symmetric tumescence was detected coinciding with a large resurgent dome within the caldera. Since then, a continuous inflation with quasi-steady rate of ~1.5 cm/yr has been observed. Earthquakes mostly occur within the caldera along the South Moat Seismic Zone, to the south of the maximum deformation area. Although the area is tectonically active, increased seismic activity has been documented during periods of renewed inflation since the onset of this tumescence in 1978. In this study, we aim to investigate the nature and dynamics of the long-term unrest at Long Valley Caldera, as well as to provide new insights into the interaction between magmatic and tectonic processes. For this purpose, we consider a variety of datasets including geodetic and seismic records over the period spanning from late 2011 to the end of 2020. A complete seismic catalog supports our study, with more than 200 M2.5-4.5 earthquakes recorded since 2011, most with epicenters located within the caldera. Measurements from a dense network of continuous GPS stations collected in the last 10 years are analyzed in combination with high resolution Interferometric Synthetic Aperture Radar (InSAR) data. For full temporal coverage, we integrate InSAR velocities obtained from the acquisition of different satellite missions. We use, in particular, data from SAR systems operating with X and C-bands such as TerraSAR-X, COSMO-SkyMed and Sentinel-1. The multi-sensor dataset (i.e., GPS and multi-mission InSAR data) compensate the limitations of each technique, with reliable mapping of the deformation pattern evolving over several years. Data analysis highlights uplift velocities with peaks of ~2 cm/yr within the caldera and beyond its southern rim. Moreover, compared to the first half of the period of analysis (2011-2014), the area affected by high deformation rates is broader in the last several years (2017-2020). Models based on the geodetic data are developed to constrain the deformation source and to better interpret the observed signals. This study is motivated as a contribution to the understanding of this long-lived caldera unrest, for a more reliable hazard assessment.

Since 2012, we have supported 18 children with single ventricle (SV) physiology on ventricular assist devices (VADs) as a bridge to decision, transplantation, or recovery. We provide a detailed report of our cumulative surgical experience and lessons learned from these patients.We reviewed all SV-VADs between March 2012 and April 2020. Implanted SV-VADs intended for short-term support were excluded. Demographic and clinical data included palliation stage at the time of VAD implantation, cannulation configuration, device type, duration of support, circuit and device interventions, postoperative support, anticoagulation strategy, complications, mortality, and 1-year survival postdischarge.Five SV newborns without prior surgical palliation, 8 infants post-Norwood/hybrid procedure, 4 infants post-Glenn, and 1 infant post-Fontan were initially supported with either continuous-flow (n = 13 of 18, 72%) or pulsatile-flow (n = 5 of 18, 28%) devices. Three (17%) of 18 transitioned to another device during support. Before VAD conversion, 9 (50%) of 18 were supported by extracorporeal membrane oxygenation. Outcomes included 7 (39%) of 18 who transplanted, 2 (11%) of 18 who recovered, and 9 (50%) of 18 who died before discharge. Of these deaths, 2 occurred after transplantation and 2 after explantation, and 5 had redirection of care while on support secondary to previously undiagnosed pulmonary venoocclusive disease (n = 2) or severe neurologic events (n = 3). Overall, 6 (33%) of 18 experienced neurologic injury. At last follow-up, 9 (50%) of 18 children were alive (median 1.2 [interquartile range, 0.8-4.3] years postexplantation/transplantation).Our experience shows that SV children, including newborns, can be successfully bridged to desired endpoints with proper patient selection and using specific cannulation strategies. Continuing utilization of this strategy is warranted for future children requiring VAD support.

Perilipin 5 (PLIN5) is a lipid-droplet-associated protein that coordinates intracellular lipolysis in highly oxidative tissues and is thought to regulate lipid metabolism in response to phosphorylation by protein kinase A (PKA). We sought to identify PKA phosphorylation sites in PLIN5 and assess their functional relevance in cultured cells and the livers of mice. We detected phosphorylation on S155 and identified S155 as a functionally important site for lipid metabolism. Expression of phosphorylation-defective PLIN5 S155A in Plin5 null cells resulted in decreased rates of lipolysis and triglyceride-derived fatty acid oxidation. FLIM-FRET analysis of protein-protein interactions showed that PLIN5 S155 phosphorylation regulates PLIN5 interaction with adipose triglyceride lipase at the lipid droplet, but not with α-β hydrolase domain-containing 5. Re-expression of PLIN5 S155A in the liver of Plin5 liver-specific null mice reduced lipolysis compared with wild-type PLIN5 re-expression, but was not associated with other changes in hepatic lipid metabolism. Furthermore, glycemic control was impaired in mice with expression of PLIN5 S155A compared with mice expressing PLIN5. Together, these studies demonstrate that PLIN5 S155 is required for PKA-mediated lipolysis and builds on the body of evidence demonstrating a critical role for PLIN5 in coordinating lipid and glucose metabolism.

Ectodysplasin A (EDA) was recently identified as a liver-secreted protein that is increased in the liver and plasma of obese mice and causes skeletal muscle insulin resistance. We assessed if liver and plasma EDA is associated with worsening non-alcoholic fatty liver disease (NAFLD) in obese patients and evaluated plasma EDA as a biomarker for NAFLD. Using a cross-sectional study in a public hospital, patients with a body mass index >30 kg/m2 (n=152) underwent liver biopsy for histopathology assessment and fasting liver EDA mRNA. Fasting plasma EDA levels were also assessed. Non-alcoholic fatty liver (NAFL) was defined as >5% hepatic steatosis and nonalcoholic steatohepatitis (NASH) as NAFLD activity score ≥3. Patients were divided into three groups: No NAFLD (n=45); NAFL (n=65); and NASH (n=42). Liver EDA mRNA was increased in patients with NASH compared with No NAFLD (P=0.05), but not NAFL. Plasma EDA levels were increased in NAFL and NASH compared with No NAFLD (P=0.03). Plasma EDA was related to worsening steatosis (P=0.02) and fibrosis (P=0.04), but not inflammation or hepatocellular ballooning. ROC analysis indicates that plasma EDA is not a reliable biomarker for NAFL or NASH. Plasma EDA was not increased in patients with type 2 diabetes and did not correlate with insulin resistance. Together, we show that plasma EDA is increased in NAFL and NASH, is related to worsening steatosis and fibrosis but is not a reliable biomarker for NASH. Circulating EDA is not associated with insulin resistance in human obesity.Clinical Trial Registrationhttps://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12615000875505, identifier ACTRN12615000875505.

The East Rift Zone (ERZ) of Kīlauea Volcano, Hawai'i, represents one of the most volcanically active regions in the world. The 2007 Father's Day (FD) dike intrusion, eruption, and accompanying slow-slip event (SSE) has been previously modeled using geodetic data to constrain the geometry of the intrusion and the timing and magnitude of the SSE. Here, we perform inversions of three interferometric synthetic aperture radar (InSAR) datasets and a new intensity offset tracking dataset to assess the effect of integrating intensity cross-correlation offsets into inversion problems and explore additional potential models for the intrusion geometry of the FD event based on this additional data. The overall lowest misfit single Okada model for all datasets opens 2.3 m, strikes 73 degrees while dipping sub-vertically at 83 degrees, and extends approximately 2.9 km to the ENE and 2.4 km downdip. The differences are minor between complex en-echelon distributed Okada and decollement model of (Montgomery-Brown et al., 2010) or 3D-MBEM breaching models including multiple surface breaches and free-slipping decollement movement. Finally, we examine the static Coulomb stress changes for the proposed decollement fault created by our preferred model and a representative model of deep rift opening and find that deep rift zones dilation, not shallow ERZ intrusions, are likely modulating slip on the decollement.

Purpose There is a hesitancy to use older donor lungs in lung transplants, and to perform them in older patients. To invalidate the use of donor and recipient age as relative contraindications for lung transplantation, we examined both, and factored in transplant type, then analyzed their effects on survival outcomes using propensity matching. Methods Patients were stratified by recipient age ( Results Using 743 lung transplant patients at our single center over 8 years (Feb-2012 to Mar-2020) in the pre-propensity match, there was a significant difference in survival outcomes for the group: ≥50 donor age ≥70 recipient age group in survival when looking at single vs. double lung transplant (p = 0.038). There were no other statistically significant differences in survival based on donor and recipient age, or transplant type. Post-propensity matching, there was no difference in survival based on the interplay between donor and recipient age, for donor group ≥50 (p = 0.092), for donor group Conclusion While donor and recipient age are undoubtedly important factors to consider during lung transplantation, neither of these independently affects long-term survival. Upon matching, there was no differences in survival for lung transplant patients based on transplant type. Older lungs and older patients can result in reasonable post-transplant outcomes.

Purpose Currently the continuous suturing technique is used on the bronchial anastomosis during lung transplantation. This study investigated that technique vs. the interrupted suturing technique, comparing survival and occurrence of post-operative bronchial complications to examine if a switch in technique is merited. Methods Survival outcomes of 721 single-center lung transplant recipients over 8 years (Feb-2012 to Mar-2020) were compared. Continuous suturing technique was performed with 3/0 polypropylene suture on an SH needle. Interrupted used the same technique for the membranous portion of the anastomosis and multiple interrupted 2/0 polypropylene sutures for the cartilaginous portion. Clinical parameters and demographics were compared. The two groups were compared for post-operative morbidity and survival was compared using Kaplan-Meier curves. Log-rank tests were performed, as was Cox regression analysis, with p Results Of the 721 patients, 429 received the continuous suturing technique while 292 had interrupted suturing technique. Demographics and clinical parameters compared were: age (p=0.008), gender (p=0.643), race (p=0.268), etiology (p Conclusion Although both techniques showed reasonable post-transplant outcomes, our study indicated better survival and relatively fewer complications when using interrupted suturing technique vs continuous. Further long-term study of similar groups with similar long-term follow up in these two groups should be performed to validate this effect.

Purpose Donor after cardiac death (DCD) is an organ procurement method that is being increasingly used to expand the current lung donor pool. We hypothesize that in our single-center study, DCD and donor after brain death (DBD) groups would have similar survival rates as found in previous studies. Methods A retrospective analysis was performed at a single center which identified 801 lung transplants completed between March 2012 and September 2020. DCD LTx patients (n=18) were matched by propensity scores with donors after brain death DBD recipients. Propensity scores (PS) were determined using patient age, sex, race diagnosis, BMI, and donor age. PS matching was done by comparing 1:1, 1:2, and 1:3 pooled groups (DCD:DBD), and performing either chi-squared or t-tests analyses on each variable before and after matching. Survival outcomes were calculated using Kaplan-Meier curves and log-rank tests. Results Of the 801 LTx patients, mean donor age for DCD lungs was 27.59. The PS matched DBD group did not significantly differ from the DCD group in age (p=0.6339), sex (p=0.401), race (p=0.846), diagnosis (p=0.102), pump use (p=0.867), BMI (p=0.0467) or donor age (p=0.8275). Log-rank testing with Kaplan-Meier curves of pre-PS matching revealed no significant survival difference between DCD and DBD groups (p=0.38). The PS matched data similarly found no significant difference in patient survival (p=0.26) which was consistent across the 1:1, 1:2 and 1:3 matched groups. Conclusion Our study found both DBD and DCD donor lungs provide comparable short-term survival outcomes. This is in agreement with previous studies, which argue for the viability of DCD donor lungs and for their use to be expanded.

Intertissue communication is a fundamental feature of metabolic regulation, and the liver is central to this process. We have identified sparc-related modular calcium-binding protein 1 (SMOC1) as a glucose-responsive hepatokine and regulator of glucose homeostasis. Acute intraperitoneal administration of SMOC1 improved glycemic control and insulin sensitivity in mice without changes in insulin secretion. SMOC1 exerted its favorable glycemic effects by inhibiting adenosine 3',5'-cyclic monophosphate (cAMP)-cAMP-dependent protein kinase (PKA)-cAMP response element-binding protein (CREB) signaling in the liver, leading to decreased gluconeogenic gene expression and suppression of hepatic glucose output. Overexpression of SMOC1 in the liver or once-weekly intraperitoneal injections of a stabilized SMOC1-FC fusion protein induced durable improvements in glucose tolerance and insulin sensitivity in db/db mice, without adverse effects on adiposity, liver histopathology, or inflammation. Furthermore, circulating SMOC1 correlated with hepatic and systemic insulin sensitivity and was decreased in obese, insulin-resistant humans. Together, these findings identify SMOC1 as a potential pharmacological target for the management of glycemic control in type 2 diabetes.

Background There is broad interest in the use of cell therapies and cell products for treatment of a variety of diseases and problems. Of interest to the military, cellular therapies have the potential to confer tremendous benefit for treatment of both acute and chronic injuries. Although many different cell therapy products are currently under investigation, mesenchymal stromal cells (MSCs) are good candidates, based on their ability to respond to inflammation, limit vascular permeability, and modulate immune responses to injury. Although a large number of clinical trials utilize MSCs or their products, there is no firm consensus defining the characteristics and activities of a good MSC product. Here, we test multiple human MSCs in several assays designed to test potency, to determine if functionally relevant differences between MSCs can be defined using in vitro assays, allowing identification of superior MSC products for preclinical or clinical testing. Methods Human MSCs derived from several tissue sources (adipose, bone marrow, umbilical cord) were evaluated for their ability to respond to inflammatory signaling by upregulating indoleamine-2,3-dioxygenase and TSG6, suppress lymphocyte proliferation, alter the polarization of macrophages, and affect tube formation by endothelial cells. Results All MSCs tested displayed activity in the functional assays utilized, but differences in potency were observed in each assay. Conclusion The indoleamine-2,3-dioxygenase enzyme activity assay represents a simple way to screen multiple samples. The mixed lymphocyte reaction and monocyte assays used to test interactions between MSCs and immune cells are more involved but give direct information on immunomodulation potential. The endothelial cell tube formation assay is relatively simple to perform but a large number of images must be generated and analyzed. However, it tests a functional activity other than immunomodulation and, therefore, adds another facet to MSC evaluation.

Background This study evaluated blood components processed by the platelet rich plasma (PRP) method from fresh whole blood (FWB) treated with a pathogen reduction technology (PRT). The effects of storage temperature on PRT treated platelet concentrates (PCs) were also examined. Study design and methods PRT was performed using riboflavin and ultraviolet light on FWB in citrate phosphate dextrose anticoagulant. Following PRT, red blood cells (RBCs), PCs, and plasma for fresh frozen plasma (FFP), were isolated by sequential centrifugation. RBCs were stored at 4°C, FFP at -80°C, and PC at 22°C or at 4°C. Components were assayed throughout their storage times for blood gases, chemistry and CBC, hemostatic function as well as platelet (PLT) and RBC integrity. Results Component processing following PRT resulted in a significant drop in platelet recovery. Most PRT-PC bags fell below AABB guidelines for platelet count. PRT-PC also showed a decrease in clot strength and decreased aggregometry response. Platelet caspases were activated by PRT. Storage at 4°C improved platelet function. In PRT-FFP, prothrombin time and partial thromboplastin time (PT and aPTT) were prolonged; factors V, VII, VIII, and XI, protein C, and fibrinogen were significantly decreased. Free hemoglobin was elevated two-fold in PRT-RBC. Conclusion Blood components isolated by the PRP method from PRT-treated WB result in a high percentage of PC that fail to meet AABB guidelines. FFP also shows diminished coagulation capacity. However, PRT-RBC are comparable to control-RBC. PRT-WB retains acceptable hemostatic function but alternatives to the PRP method of component separation may be more suitable.

Vertical and horizontal components of GNSS displacements in the Long Valley Caldera and adjacent Sierra Nevada range show a clear correlation with hydrological trends at both multiyear and seasonal time scales. We observe a clear vertical and horizontal seasonal deformation pattern primarily attributable to the solid earth response to hydrological surface loading at large‐to‐regional (Sierra Nevada range) scales. Several GNSS sites, located at the eastern edge of the Sierra Nevada along the southwestern rim of Long Valley Caldera, also show significant horizontal deformation that cannot be explained by elastic deformation from surface loading. Due to the location of these sites and the strong correlation between their horizontal displacements and spring discharge, we hypothesize that this deformation reflects poroelastic processes related to snowmelt runoff water infiltrating into the Sierra Nevada slopes around Long Valley Caldera. Interestingly, this is also an area where water infiltrates to feed the local hydrothermal system, and where snowmelt‐induced earthquake swarms have been recently detected.

Pediatric fractures are a common injury, and treatment often includes cast immobilization. For pediatric patients being treated in a cast, cast damage is among the most common reasons patients return to the emergency room. The figure-of-eight wrapping technique interdigitates layers of fiberglass which may create a stronger cast. The aim of this study was to assess the strength of the figure-of-eight wrapping technique in comparison to the spiral wrapping technique. A total of 10 casts were wrapped with a three-inch fiberglass using the spiral technique and 10 casts were wrapped using the figure-of-eight technique. Each cast was then subjected to a three-point bending test and loaded until failure using an Instron machine. The figure-of-eight technique had an average load to failure of 278.2 + 27.6 N/mm which was similar to the spiral technique's load to failure of 281.2 + 25.4 N/mm (p=0.795). Prior to normalizing for thickness, the load to failure of the figure-of-eight technique was 949.8 + 109.5 N, which was significantly higher than the spiral technique of 868.2 + 65.1 N (p=0.038). The figure-of-eight casts were slightly thicker than the spiral casts (average 0.3 mm, p=0.004). This suggests that the thickness of the fiberglass cast may improve the strength. The figure-of-eight wrapping technique had similar biomechanical characteristics to spiral wrapping techniques. Providers should wrap in whichever technique they feel most comfortable performing as there is no difference in strength of the cast. If a stronger cast is desired, then thickness of the cast can be increased.

Impairments in mitochondrial function in patients with insulin resistance and type 2 diabetes have been disputed for decades. This review aims to briefly summarize the current knowledge on mitochondrial dysfunction in metabolic tissues and to particularly focus on addressing a new perspective of mitochondrial dysfunction, the altered capacity of mitochondria to communicate with other organelles within insulin-resistant tissues. Organelle interactions are temporally and spatially formed connections essential for normal cell function. Recent studies have shown that mitochondria interact with various cellular organelles, such as the endoplasmic reticulum, lysosomes and lipid droplets, forming inter-organelle junctions. We will discuss the current knowledge on alterations in these mitochondria-organelle interactions in insulin resistance and diabetes, with a focus on changes in mitochondria-lipid droplet communication as a major player in ectopic lipid accumulation, lipotoxicity and insulin resistance.

Student performance can be affected by internal and external stressors, so we explored the effects of an experiential psychiatric/mental health nursing class designed to present methods of stress reduction. Mixed methods to assess the effects of experiential learning about self-care in a baccalaureate psychiatric nursing class were used with 113 nursing students. Students were exposed in class each week to one of 6 techniques: deep breathing, progressive muscle relaxation, mindfulness & exercise, aromatherapy, guided imagery, and yoga. Students used the method at home and journaled about the experience weekly. Journals and free-text responses from a post-intervention assessment were examined with qualitative content analysis. The Beck Anxiety Inventory, the Ten-Item Personality Inventory, and the Skovholt Practitioner Professional Resiliency and Self-Care inventory were used. Moderate to strong negative correlations between emotional stability (Ten-Item) and anxiety scores (Beck) was seen. Themes included physical/emotional effects of stress, lack of control during nursing school, and fears about communicating with psychiatric patients. Preferred coping methods were easy to perform, portable, and low cost; students used them to alleviate anxiety and promote relaxation before sleep. Family/friend support and self-care promoted professional vitality. Lack of time for self-care, sleep problems, and financial problems were negatives for students.

Caldera collapse and flank eruption Real-time monitoring of volcanic eruptions involving caldera-forming events are rare (see the Perspective by Sigmundsson). Anderson et al. used several types of geophysical observations to track the caldera-forming collapse at the top of Kīlauea Volcano, Hawai'i, during the 2018 eruption. Gansecki et al. used near–real-time lava composition analysis to determine when magma shifted from highly viscous, slow-moving lava to low-viscosity, fast-moving lava. Patrick et al. used a range of geophysical tools to connect processes at the summit to lava rates coming out of far-away fissures. Together, the three studies improve caldera-collapse models and may help improve real-time hazard responses. Science , this issue p. eaaz0147 , p. eaay9070 ; p. eaaz1822 ; see also p. 1200

Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity., Ceramides are signalling molecules that regulate several physiological functions including insulin sensitivity. Here the authors report a selective ceramide synthase 1 inhibitor that counteracts lipid accumulation within the muscle and adiposity by increasing fatty acid oxidation but without affecting insulin sensitivity in mice fed with an obesogenic diet.