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Objective Penetrating atherosclerotic ulcers (PAUs) in aortic branch vessels are rare. There is a paucity of data regarding their long-term natural history and associated management. This study aimed to determine the prevalence and natural history of aortic branch PAUs. Methods Institutional data on all patients with an aortic branch PAU from 2005 to 2020 were retrospectively reviewed. Branch PAUs were defined as any PAU in the iliac, mesenteric, or arch vessels. End points included symptoms, end-organ events, and interventions. All computed tomography angiographies (CTAs) for each patient were reviewed, and total diameter, ulcer width, and ulcer depth were recorded on each computed tomography scan for the branch PAUs. Rate of change was compared between groups (iliac vs arch and visceral vessels) using a linear mixed-effects model. Results Among 58,800 patients who underwent a CTA, 367 patients had an aortic PAU (prevalence: 0.6%) and 58 patients had a branch PAU (prevalence: 0.1%). Among those 58 patients, there were 66 ulcerated branches. There were 50 iliac (42 common iliac, 7 internal, and 1 external), 11 arch (8 left subclavian, 3 innominate), and 5 visceral ulcers (3 superior mesenteric artery, 1 celiac, and 1 renal). Mean age was 74.0 ± 8.8 years, and 86% of patients were male; 74% had hypertension, 79% had hyperlipidemia, and 59% had a concomitant aortic aneurysm. There were 45 PAU vessels with >1 CTA (total of 167 CTAs) with a median follow-up of 4.0 years (interquartile range: 2.0-6.2 years). Total vessel diameter increased in size by 0.27 mm/y but did not differ between groups (iliac vs visceral/arch vessels). PAU width and depth also did not significantly change over time, nor did it differ between groups. No branch PAUs caused symptoms, end-organ events, or rupture, nor required intervention due to symptoms and/or progression. Four PAUs spontaneously resolved (2 iliac, 2 other), and 1 iliac PAU progressed to a saccular aneurysm. Conclusions This is one of the largest studies evaluating the natural history of branched PAUs objectively via CTA. Branch PAUs are rare—the prevalence was one-sixth that of aortic PAUs. There was minimal growth noted in a median follow-up of 4 years, and no PAUs required intervention for symptoms or progression. Asymptomatic branch PAUs may be safely observed.

HIV service providers are the primary implementers of HIV care services, but rural HIV service providers are under researched. We used an interpretative phenomenological analysis to explore rural HIV service providers' lived experiences of working in HIV care, who work in a rural region of a Midwestern state in the United States. From July to August 2019, 15 HIV service providers participated in a one-hour semi-structured telephone interview that elicited their experiences working in the rural HIV care continuum. Participants were tired of constantly educating and working to reduce HIV stigma; however, they received support from family and friends once they educated them about HIV. Participants felt they lacked control over systems and they developed emotional-based coping to address constant occupational stressors. Findings highlight the importance of resiliency and advocacy research and practice across ecological levels.

BACKGROUND: Social support reciprocity (the extent to which people exchange mutual support) is associated with long-term health. METHODS: We examined whether overall social support and reciprocity of support between people living with HIV and their treatment partners (informal caregivers selected from patients’ social networks to support adherence) is associated with HIV viral suppression. A total of 130 patients living with HIV and their treatment partners were recruited from a clinic in Gaborone, Botswana from May 2016 to April 2017. Participants completed surveys assessing socio-demographic and social network characteristics. Patients and treatment partners rated their emotional closeness to each other (not at all close=0, somewhat close=1, very close=2). RESULTS: Multivariable logistic regressions indicated a significantly higher likelihood of viral suppression among patients who reported greater average emotional closeness to social network members. The likelihood of viral suppression was lower in asymmetric relationships in which patients felt closer to treatment partners than treatment partners felt to them (compared to when treatment partners felt closer to patients); this negative effect was strongest in dyads with female treatment partners and male patients. Follow-up analyses additionally indicated that asymmetric relationships in which treatment partners felt closer to patients were as protective as symmetric relationships, in which patients and treatment partners felt equally close. CONCLUSIONS: Perceptions around reciprocity may matter as much as overall relationship closeness in patients’ health outcomes. Interventions to improve the support of informal caregivers could help to improve relationship quality and health outcomes among people with HIV.

Black and Latina women are disproportionately impacted by HIV/AIDS. Despite existing research linking social networks and HIV risk among men who have sex with men (MSM) and other high-risk populations, little research has examined how ethnic/racial minority women's social networks shape HIV prevention and intervention targets. Using interviews with a sample of 165 predominantly Black and Latina-identifying women from a small city in the Western U.S., this research examines the relationship between egocentric network characteristics and HIV knowledge, attitudes, and testing history. Results reveal that network characteristics play a significant role in shaping HIV-related knowledge, prejudice, and testing intention but not HIV testing history. Individual-level factors like homelessness and perceptions of testing barriers are more salient for explaining testing behaviors than network characteristics. Intervention efforts to improve knowledge and reduce prejudice among Black and Latina women may benefit from mobilizing network ties.

BACKGROUND AND AIMS Alcohol intoxication among spectators and related problems are common at sporting events. This study estimated the impact a multi-component community-based alcohol prevention intervention, implemented at Swedish Premier Football (soccer) League matches, had on intoxication levels among spectators and refusal rates of alcohol service to, and arena entry of, obviously intoxicated spectators. DESIGN A quasi-experimental controlled study using a repeated cross-sectional design. SETTING AND PARTICIPANTS Spectators and sport arenas in Stockholm and Gothenburg, Sweden. INTERVENTION AND COMPARATOR The intervention was implemented in Stockholm and consisted of community mobilisation and collaboration, training of staff and improved enforcement and policy work. Gothenburg was the comparison area and received usual care. MEASUREMENTS Primary outcomes were spectators' mean breath alcohol concentration (BrAC), proportion of spectators with high intoxication levels, (defined as BrAC ≥0.1%), overserving at licensed premises inside arenas and refused arena entry of obviously intoxicated spectators. Baseline data were collected during 2015 and follow-up during 2016 and 2017. FINDINGS BrAC assessments (n = 10 188), arena entry attempts (n = 201) and alcohol purchase attempts at premises inside arenas (n = 495) were collected. There was evidence that the refusal rates of alcohol purchase at premises inside arenas improved differently between study areas and over time (adjusted odds ratio [aOR] = 0.28, 95% CI = 0.07, 1.06, P = 0.060, Bayes factor [BF] = 8.60). In both study areas, the arena entry refusal rates improved over time (aOR = 5.87, 95% CI = 1.16, 29.83, P = 0.033, BF = 17.7), but evidence that the rates improved differently between study areas and over time was equivocal (aOR = 0.57, 95% CI = 0.09, 3.56, P = 0.543, BF = 1.2). Mean BrAC levels decreased over time in both study areas (β = -0.032, 95% CI = -0.050, -0.015, P

This community-based study explored the lived experiences of being in and going through the rural HIV care continuum among 15 gay and bisexual men (GBM) with HIV who live in a rural area of a Midwe...

OBJECTIVE This research evaluated the South Carolina Alcohol Enforcement Team impact for reducing retail alcohol access to underage persons to decrease drinking and driving crashes among that population. METHODS The natural research experiment used interrupted time-series (ITS) analyses of drinking and driving crashes involving under 21-year-old drivers from July 2006 through December 2016 (126-month period = 4,782 Driving Under Influence [DUI] crashes for under 21-year-old drivers, µ = 38 crashes per month). Additional data analyzed included the monthly total number of retail compliance checks (total during 126-month period = 64,954 compliance checks completed, µ = 515.5 checks per month), the average percentage of underage alcohol purchases (total completed during 126-month period = 8,814 purchases, µ = 70 purchases per month), and a calculated measure of the percent of the population under 21 years old exposed to compliance checks each month. We used drinking and driving crashes for 21-year-old and over drivers as a control time series (total number over a 126-month period = 52,180 DUI crashes for 21 and older drivers, µ = 414.1 crashes per month). RESULTS The results show a decline in drinking and driving crashes for drivers under 21 when compliance checks increase, and when compliance checks decline, traffic crashes increase. Stable Alcohol Enforcement Team implementation over 78 months produced an overall 18 to 29% decline in such crashes. A visual examination of the crash time series demonstrated that under-21-age-driver crashes declined during the first wave of implementation and increased following a lag when enforcement declined, which provided additional empirical support for a South Carolina Alcohol Enforcement Team impact on retail alcohol availability. An ITS analysis of the prestable period compared to the stable period was statistically significant (T = -3.78, p

It has become increasingly appreciated that autoimmune responses against neuronal components play an important role in type 1 diabetes (T1D) pathogenesis. In fact, a large proportion of islet-infiltrating B lymphocytes in the NOD mouse model of T1D produce Abs directed against the neuronal type III intermediate filament protein peripherin. NOD-PerIg mice are a previously developed BCR-transgenic model in which virtually all B lymphocytes express the H and L chain Ig molecules from the intra-islet–derived anti-peripherin–reactive hybridoma H280. NOD-PerIg mice have accelerated T1D development, and PerIg B lymphocytes actively proliferate within islets and expand cognitively interactive pathogenic T cells from a pool of naive precursors. We now report adoptively transferred T cells or whole splenocytes from NOD-PerIg mice expectedly induce T1D in NOD.scid recipients but, depending on the kinetics of disease development, can also elicit a peripheral neuritis (with secondary myositis). This neuritis was predominantly composed of CD4+ and CD8+ T cells. Ab depletion studies showed neuritis still developed in the absence of NOD-PerIg CD8+ T cells but required CD4+ T cells. Surprisingly, sciatic nerve–infiltrating CD4+ cells had an expansion of IFN-γ− and TNF-α− double-negative cells compared with those within both islets and spleen. Nerve and islet-infiltrating CD4+ T cells also differed by expression patterns of CD95, PD-1, and Tim-3. Further studies found transitory early B lymphocyte depletion delayed T1D onset in a portion of NOD-PerIg mice, allowing them to survive long enough to develop neuritis outside of the transfer setting. Together, this study presents a new model of peripherin-reactive B lymphocyte–dependent autoimmune neuritis.

Patient-oriented applications of cell culture include cell therapy of organ failure like chronic renal failure. Clinical deployment of a cell-based device for artificial renal replacement requires ...

At postsynaptic sites of neurons, a prominent clathrin-coated structure, the endocytic zone (EZ), controls the trafficking of glutamate receptors and is essential for synaptic plasticity. Despite its importance, little is known about how this clathrin structure is organized to mediate endocytosis. We used live-cell and super-resolution microscopy to reveal the dynamic organization of this poorly understood clathrin structure in rat hippocampal neurons. We found that a subset of endocytic proteins only transiently appeared at postsynaptic sites. In contrast, other proteins were persistently enriched and partitioned at the edge of the EZ. We found that uncoupling the EZ from the synapse led to the loss of most of these components, while disrupting interactions with the actin cytoskeleton or membrane did not alter EZ positioning. Finally, we found that plasticity-inducing stimuli promoted the reorganization of the EZ. We conclude that the EZ is a stable, highly organized molecular platform where components are differentially recruited and positioned to orchestrate the endocytosis of synaptic receptors.

Sensitive quantification of RNA transcripts via fluorescence in situ hybridization (FISH) is a ubiquitous part of understanding quantitative gene expression in single cells. Many techniques exist to identify and localize transcripts inside the cell, but often they are costly and labor intensive. Here we present a method to use a singly labeled short DNA oligo probe to perform FISH in yeast cells. This method is effective for highly constrained FISH applications where the target length is limited (

We evaluated the effects of a culturally adapted evidence-based HIV prevention intervention (Mpowerment), named “Tayf”, on condom use and HIV testing among young men who have sex with men (YMSM) in Beirut. A 2-year implementation of Tayf was carried out independently and in parallel with a research cohort of 226 YMSM who were surveyed at baseline and months 6, 12, 18 and 24 after Tayf initiation. Primary outcomes were (1) any condomless anal sex with HIV-positive or unknown status partners in the past 3 months, and (2) HIV testing in the past six months. Hierarchical logistic regression models examined the association of Tayf participation with the outcomes averaged across all assessments, and the moderating effect of Tayf participation on change in the outcomes over the follow-up period. A total of 331 YMSM attended at least one event, including 33% of the cohort. Tayf participation was associated with a higher rate of any condomless sex with HIV-positive or unknown status partners averaged across the five assessments, but there was no moderating effect of Tayf participation on change in this outcome over time. Tayf participation was associated with higher HIV testing when averaged across all assessments, but its interaction with time showed that the strength of this association diminished over time. In conclusion, Tayf proved feasible and acceptable in Beirut, but with limited effects. Further work is needed, including innovative publicity and marketing strategies, to bolster effects in high stigma settings where security and legal risks are prominent.

Changed synapse density has been suggested to be involved in the altered brain connectivity underlying schizophrenia (SCZ) pathology. However, postmortem studies addressing this topic are heterogeneous and it is not known whether changes are restricted to specific brain regions. Using meta-analysis, we systematically and quantitatively reviewed literature on the density of postsynaptic elements in postmortem brain tissue of patients with SCZ compared to healthy controls. We included 3 outcome measurements for postsynaptic elements: dendritic spine density (DSD), postsynaptic density (PSD) number, and PSD protein expression levels. Random-effects meta-analysis (31 studies) revealed an overall decrease in density of postsynaptic elements in SCZ (Hedges’s g: −0.33; 95% CI: −0.60 to −0.05; P = .020). Subgroup analyses showed reduction of postsynaptic elements in cortical but not subcortical tissues (Hedges’s g: −0.44; 95% CI: −0.76 to −0.12; P = .008, Hedges’s g: −0.11; 95% CI: −0.54 to 0.35; P = .671) and specifically a decrease for the outcome measure DSD (Hedges’s g: −0.81; 95% CI: −1.37 to −0.26; P = .004). Further exploratory analyses showed a significant decrease of postsynaptic elements in the prefrontal cortex and cortical layer 3. In all analyses, substantial heterogeneity was present. Meta-regression analyses showed no influence of age, sex, postmortem interval, or brain bank on the effect size. This meta-analysis shows a region-specific decrease in the density of postsynaptic elements in SCZ. This phenotype provides an important cellular hallmark for future preclinical and neuropathological research in order to increase our understanding of brain dysconnectivity in SCZ.

A combined approach involving microbial bioaugmentation and enhanced sorption was demonstrated to be effective for in situ treatment of polychlorinated biphenyls (PCBs). A pilot study was conducted for 409 days on PCB impacted sediments in four 400 m2 plots located in a watershed drainage pond in Quantico, VA. Treatments with activated carbon (AC) agglomerate bioamended with PCB dechlorinating and oxidizing bacteria decreased the PCB concentration in the top 7.5 cm by up to 52% and the aqueous concentrations of tri- to nonachlorobiphenyl PCB congeners by as much as 95%. Coplanar congeners decreased by up to 80% in sediment and were undetectable in the porewater. There was no significant decrease in PCB concentrations in non-bioamended plots with or without AC. All homologue groups decreased in bioamended sediment and porewater, indicating that both anaerobic dechlorination and aerobic degradation occurred concurrently. The titer of the bioamendments based on quantitative PCR of functional marker genes dec...

This study tested a three-component community prevention intervention with alcohol businesses to reduce alcohol overservice and to reduce drinking and driving crashes using a longitudinal design. The intervention involved a responsible beverage serving practices toolkit, a series of on-site visits from law enforcement, and a supporting media campaign. The effort achieved a reduction in the monthly percentage of drivers arrested for driving under the influence who cited the alcohol-licensed establishments as the place of last drink, and the number of establishments mentioned 2+ times as well as a decline in alcohol-involved crashes in the 12-month postintervention period. Results supported a conclusion that the intensive intervention media can achieve a reduction in the frequency with which drinking drivers utilized bars and restaurants and overall impaired driving-related crashes.

Spinal cord ischemia (SCI) is one of the most devastating complications after descending thoracic aortic (DTA) and thoracoabdominal aortic (TAA) repairs. Patients who develop SCI have a poor prognosis, with mortality rates reaching 75% within the first year after surgery. Many factors have been shown to increase the risk of this complication, including the extent of TAA repair, length of aortic and collateral network coverage, embolization, and reduced spinal cord perfusion pressure. As a result, a variety of treatment strategies have been developed. We aimed to provide an up-to-date review of SCI rates with associated treatment algorithms from open and endovascular DTA and TAA repair.Using PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines, a literature review with the MeSH (medical subject headings) terms "spinal cord ischemia," "spinal cord ischemia prevention and mitigation strategies," "spinal cord ischemia rates," and "spinal cord infarction" was performed in the Cochrane and PubMed databases to find all peer-reviewed studies of DTA and TAA repair with SCI complications reported. The search was limited to 2012 to 2021 and English-language reports. MeSH subheadings, including diagnosis, complications, physiopathology, surgery, mortality, and therapy, were used to further restrict the included studies. Studies were excluded if they were not of humans, had not pertained to SCI after DTA or TAA operative repair, and if the study had primarily discussed neuromonitoring techniques. Additionally, studies with 40 patients or limited information regarding SCI protection strategies were excluded. Each study was individually reviewed by two of us (S.L. and A.D.) to assess the type and extent of aortic pathology, operative technique, SCI protection or mitigation strategies, rates of overall and permanent SCI symptoms, associations with SCI on multivariate analysis, and mortality.Of the 450 studies returned by the MeSH search strategy, 41 met the inclusion criteria and were included in the final analysis. For the endovascular DTA repair patients, the overall SCI rates ranged from 0% to 10.6%, with permanent SCI symptoms ranging from 0% to 5.1%. The rate of overall SCI after endovascular and open TAA repair was 0% to 35%. The permanent SCI symptom rate was reported by only one study of open repair at 1.1%. The permanent SCI symptom rate after endovascular TAA repair was 2% to 20.5%.The present review has provided an up-to-date review of the current rates of SCI and the prevention and mitigation strategies used during DTA and TAA repair. We found that a multimodal approach, including a bundled institutional protocol, staging of multiple repairs, preservation of the collateral blood flow network, augmented spinal cord perfusion, selective cerebrospinal fluid drainage, and distal aortic perfusion during open TAA repairs, appears to be important in reducing the risk of SCI.

Axon formation critically relies on local microtubule remodeling and marks the first step in establishing neuronal polarity. However, the function of the microtubule‐organizing centrosomes during the onset of axon formation is still under debate. Here, we demonstrate that centrosomes play an essential role in controlling axon formation in human‐induced pluripotent stem cell (iPSC)‐derived neurons. Depleting centrioles, the core components of centrosomes, in unpolarized human neuronal stem cells results in various axon developmental defects at later stages, including immature action potential firing, mislocalization of axonal microtubule‐associated Trim46 proteins, suppressed expression of growth cone proteins, and affected growth cone morphologies. Live‐cell imaging of microtubules reveals that centriole loss impairs axonal microtubule reorganization toward the unique parallel plus‐end out microtubule bundles during early development. We propose that centrosomes mediate microtubule remodeling during early axon development in human iPSC‐derived neurons, thereby laying the foundation for further axon development and function., Live‐cell imaging of centriole‐depleted cultured neurons demonstrates the essential role of human centrosomes in regulating various aspects of axon maturation and function via microtubule network reorganization.

Presynaptic metabotropic glutamate receptors (mGluRs) are essential for activity-dependent modulation of synaptic transmission. However, the mechanisms that control the subsynaptic dynamics of these receptors and their contribution to synaptic signaling are poorly understood. Here, using complementary super-resolution microscopy and single-molecule tracking techniques, we provide novel insights into the molecular mechanisms that control the nanoscale distribution and mobility of presynaptic mGluRs in hippocampal neurons. We demonstrate that the group II receptor mGluR2 localizes diffusely along the axon and boutons, and is highly mobile, while the group III receptor mGluR7 is stably anchored at the active zone, indicating that distinct mechanisms underlie the dynamic distribution of these receptor types. Surprisingly, using domain swapping experiments we found that intracellular interactions modulate surface diffusion of mGluR2, but not mGluR7. Instead, we found that immobilization of mGluR7 at the active zone relies on its extracellular domain. Importantly, receptor activation or increase in synaptic activity did not alter the surface mobility of presynaptic mGluRs. Finally, computational modeling of presynaptic mGluR activity revealed that the precise subsynaptic distribution of mGluRs controls their activation probability and thus directly impacts their ability to modulate neurotransmitter release. Altogether, this study demonstrates that distinct mechanisms control surface mobility of presynaptic mGluRs to differentially contribute to the regulation of glutamatergic synaptic transmission.

Objective To gain an in-depth understanding of parents’ experiences telling children conceived by gamete and embryo donation about their genetic origins. Design Qualitative, descriptive. Setting Families’ homes. Patient(s) Gamete or embryo donation recipient parents living in the United States and who told their children, from birth to 16 years, about their genetic origins. Intervention(s) Individual semistructured (n = 12) or dyadic (n = 2) parent interviews. Main Outcome Measure(s) Directed qualitative content analysis. Result(s) Fourteen families that comprised 16 gamete or embryo donation recipient parents and represented 24 donor-conceived children between the ages of 4 months and 16 years participated in the study. Single parents (n = 3) and both parents in most two-parent families (n = 9) led the initial telling conversations. Parents recounted personal short stories using language that was both developmentally and medically appropriate. Multiple strategies, including children’s books, were used by parents to aid them in their telling. The oldest donor-conceived children in each family were first informed of their genetic origins at birth (n = 10 families) or at 6 months (n = 1 family; “practice runs”) or from 3.5 to 12 years (n = 3 families). The telling conversations took place during routine family activities that naturally brought parents and children in close proximity, usually in the home. Conclusion(s) Awareness of the nuances of parents’ telling conversations with their children through the age of 16 years can help guide clinical counseling and the development of tools to aid parents in their telling conversations.

Cu/Zn superoxide dismutase (Sod1) is a highly conserved and abundant antioxidant enzyme that detoxifies superoxide (O2⸱-) by catalyzing its conversion to dioxygen (O2) and hydrogen peroxide (H2O2). Using Saccharomyces cerevisiae and mammalian cells, we discovered that a major new aspect of the antioxidant function of Sod1 is to integrate O2 availability to promote NADPH production. The mechanism involves Sod1-derived H2O2 oxidatively inactivating the glycolytic enzyme, glyceraldehyde phosphate dehydrogenase (GAPDH), which in turn re-routes carbohydrate flux to the oxidative phase of the pentose phosphate pathway (oxPPP) to generate NADPH. The aerobic oxidation of GAPDH is exclusively dependent on and rate-limited by Sod1. Thus, Sod1 senses O2 via O2⸱- to balance glycolytic and oxPPP flux, through control of GAPDH activity, for adaptation to life in air. Importantly, this new mechanism for Sod1 antioxidant activity requires the bulk of cellular Sod1, unlike for its role in protection against O2⸱- toxicity, which only requires < 1% of total Sod1. Using mass spectrometry, we identified proteome-wide targets of Sod1-dependent redox signaling, including numerous metabolic enzymes. Altogether, Sod1-derived H2O2 is important for antioxidant defense and a master regulator of metabolism and the thiol redoxome.Significance StatementCu/Zn superoxide dismutase (Sod1) is a key antioxidant enzyme and its importance is underscored by the fact that its ablation in cell and animal models results in oxidative stress, metabolic defects, and reductions in cell proliferation, viability, and lifespan. Curiously, Sod1 detoxifies superoxide radicals (O2⸱-) in a manner that produces an oxidant as a byproduct, hydrogen peroxide (H2O2). While much is known about the necessity of scavenging O2⸱-, it is less clear what the physiological roles of Sod1-derived H2O2 are. Herein, we discovered that Sod1-derived H2O2 plays a very important role in antioxidant defense by stimulating the production of NADPH, a vital cellular reductant required for ROS scavenging enzymes, as well as redox regulating a large network of enzymes.

This survey study examines individual-level changes in alcohol use in US adults and associated negative consequences, from before to during the coronavirus disease 2019 (COVID-19) pandemic.

Key points Nrf2 is a master regulator of endogenous cellular defences, governing the expression of more than 200 cytoprotective proteins, including a panel of antioxidant enzymes. Nrf2 plays an important role in redox haemostasis of skeletal muscle in response to the increased generation of reactive oxygen species during contraction. Employing skeletal muscle-specific transgenic mouse models with unbiased-omic approaches, we uncovered new target proteins, downstream pathways and molecular networks of Nrf2 in skeletal muscle following Nrf2 or Keap1 deletion. Based on the findings, we proposed a two-way model to understand Nrf2 function: a tonic effect through a Keap1-independent mechanism under basal conditions and an induced effect through a Keap1-dependent mechanism in response to oxidative and other stresses. Abstract Although Nrf2 has been recognized as a master regulator of cytoprotection, its functional significance remains to be completely defined. We hypothesized that proteomic/bioinformatic analyses from Nrf2-deficient or overexpressed skeletal muscle tissues will provide a broader spectrum of Nrf2 targets and downstream pathways than are currently known. To this end, we created two transgenic mouse models; the iMS-Nrf2flox/flox and iMS-Keap1flox/flox , employing which we demonstrated that selective deletion of skeletal muscle Nrf2 or Keap1 separately impaired or improved skeletal muscle function. Mass spectrometry revealed that Nrf2-KO changed expression of 114 proteins while Keap1-KO changed expression of 117 proteins with 10 proteins in common between the groups. Gene ontology analysis suggested that Nrf2 KO-changed proteins are involved in metabolism of oxidoreduction coenzymes, purine ribonucleoside triphosphate, ATP and propanoate, which are considered as the basal function of Nrf2, while Keap1 KO-changed proteins are involved in cellular detoxification, NADP metabolism, glutathione metabolism and the electron transport chain, which belong to the induced effect of Nrf2. Canonical pathway analysis suggested that Keap1-KO activated four pathways, whereas Nrf2-KO did not. Ingenuity pathway analysis further revealed that Nrf2-KO and Keap1-KO impacted different signal proteins and functions. Finally, we validated the proteomic and bioinformatics data by analysing glutathione metabolism and mitochondrial function. In conclusion, we found that Nrf2-targeted proteins are assigned to two groups: one mediates the tonic effects evoked by a low level of Nrf2 at basal condition; the other is responsible for the inducible effects evoked by a surge of Nrf2 that is dependent on a Keap1 mechanism.

We conducted a pilot randomized controlled trial of Game Changers, a 6-session group intervention that empowers people with HIV to be HIV prevention advocates in their social networks. Ninety-nine people with HIV (51 intervention, 48 wait-list control) and 58 of their social network members (alters) completed baseline and 5- and 8-month post-baseline assessments. Results indicated high acceptability, demonstrated by participants’ and facilitators’ positive attitudes qualitatively and favorable ratings of intervention sessions quantitatively, and high feasibility (76% attended all intervention sessions). Intention-to-treat analyses indicated significantly increased HIV prevention advocacy among HIV-positive participants and alters [b (SE) = 0.4 (0.2), p = .017; b (SE) = 0.4 (0.2), p = .035]; reduced internalized HIV stigma [b (SE) = − 0.3 (0.1), p = .012], increased HIV-serostatus disclosure [b (SE) = 0.1 (0.1), p = .051], and increased social network density among HIV-positive participants [b (SE) = 0.1 (0.03), p = .004]; and marginally reduced condomless sex among alters [OR (95% CI) = 0.3 (0.1–1.2), p = .08]. Positioning people with HIV as central to prevention has the potential to reduce stigma and improve prevention outcomes throughout social networks.

The differentiation of neuronal stem cells into polarized neurons is a well-coordinated process which has mostly been studied in classical non-human model systems, but to what extent these findings are recapitulated in human neurons remains unclear. To study neuronal polarization in human neurons, we cultured hiPSC-derived neurons, characterized early developmental stages, measured electrophysiological responses, and systematically profiled transcriptomic and proteomic dynamics during these steps. The neuron transcriptome and proteome shows extensive remodeling, with differential expression profiles of ~1100 transcripts and ~2200 proteins during neuronal differentiation and polarization. We also identified a distinct axon developmental stage marked by the relocation of axon initial segment proteins and increased microtubule remodeling from the distal (stage 3a) to the proximal (stage 3b) axon. This developmental transition coincides with action potential maturation. Our comprehensive characterization and quantitative map of transcriptome and proteome dynamics provides a solid framework for studying polarization in human neurons.

Alcohol's impact on global health is substantial and of a similar order of magnitude to that from COVID-19. Alcohol now also poses specific concerns, such as increased risk of severe lung infections, domestic violence, child abuse, depression and suicide. Its use is unlikely to aid physical distancing or other preventative behavioural measures. Globally, alcohol contributes to 20% of injury and 11.5% of non-injury emergency room presentations. We provide some broad comparisons between alcohol-attributable and COVID-19-related hospitalisations and deaths in North America using most recent data. For example, for Canada in 2017 it was recently estimated there were 105 065 alcohol-attributable hospitalisations which represent a substantially higher rate over time than the 10 521 COVID-19 hospitalisations reported during the first 5 months of the pandemic. Despite the current importance of protecting health-care services, most governments have deemed alcohol sales to be as essential as food, fuel and pharmaceuticals. In many countries, alcohol is now more readily available and affordable than ever before, a situation global alcohol producers benefit from and have helped engineer. We argue that to protect frontline health-care services and public health more generally, it is essential that modest, evidence-based restrictions on alcohol prices, availability and marketing are introduced. In particular, we recommend increases in excise taxation coupled with minimum unit pricing to both reduce impacts on health-care services and provide much-needed revenues for governments at this critical time.

International audience; Single-molecule FRET (smFRET) has become a mainstream technique for studying biomolecular structural dynamics. The rapid and wide adoption of smFRET experiments by an ever- increasing number of groups has generated significant progress in sample preparation, measurement procedures, data analysis, algorithms and documentation. Several labs that employ smFRET approaches have joined forces to inform the smFRET community about streamlining how to perform experiments and analyze results for obtaining quantitative information on biomolecular structure and dynamics. The recent efforts include blind tests to assess the accuracy and the precision of smFRET experiments among different labs using various procedures. These multi-lab studies have led to the development of smFRET procedures and documentation, which are important when submitting entries into the archiving system for integrative structure models, PDB- Dev. This position paper describes the current ‘state of the art’ from different perspectives, points to unresolved methodological issues for quantitative structural studies, provides a set of ‘soft recommendations’ about which an emerging consensus exists, and lists openly available resources for newcomers and seasoned practitioners. To make further progress, we strongly encourage‘open science’ practices.

The current Society for Vascular Surgery practice guidelines recommend carotid revascularization for asymptomatic disease in patients with at least a 3-year life expectancy and stenosis60% when the expected perioperative stroke and death rate is 3%. Based on this recommendation, it was previously determined that asymptomatic patients who require dialysis would not meet the perioperative stroke and death thresholds nor the long-term survival benchmarks to justify carotid surgery. To determine whether carotid surgery for patients requiring dialysis is appropriate, the present study compared the perioperative outcomes after carotid revascularization for dialysis-dependent patients relative to nondialysis patients in a contemporary, national cohort.The targeted vascular module from the American College of Surgeons National Surgical Quality Improvement Program was queried to identify patients who undergone carotid endarterectomy or carotid artery stenting for asymptomatic carotid disease from 2011 to 2018. The cohort was categorized as requiring or not requiring dialysis. The primary 30-day outcomes included mortality and the composite of stroke/death and stroke/death/myocardial infarction (MI). Univariate analyses were performed using the Fisher exact test and Wilcoxon rank sum test. Multivariable analyses were used to assess the independent associations of the estimated glomerular filtration rate and dialysis dependence with the stroke/death rate.A total of 17,579 patients met the inclusion criteria. Of these patients, 226 (1.3%) required dialysis at revascularization. No difference was found in the degree of severe stenosis (80%-99%) demonstrated by 69% of the dialysis cohort and 72% of the nondialysis cohort (P = .9). Of the dialysis and nondialysis cohorts, 5% and 3.6% underwent carotid artery stenting (P = .3). The dialysis-dependent patients were younger (68 vs 71 years; P .001) and were more likely to have insulin-dependent diabetes (47% vs 12%; P .001), congestive heart failure (8.4% vs 1.4%; P .001), and severe chronic obstructive pulmonary disease (15% vs 10%; P = .03). In the dialysis and nondialysis cohort, 2 (0.9%) and 88 (0.5%) patients died (P = .3); 4 (1.8%) and 247 (1.4%) experienced strokes (P = .6); and 3 (1.3%) and 185 (1.1%) patients experienced MI (P = .5), respectively. The composite outcomes of stroke/death and stroke/death/MI was 2.2% (n = 5) and 1.8% (n = 319; P = .6) and 3.5% (n = 8) and 2.8% (n = 479; P = .4) in the dialysis and nondialysis cohorts, respectively. After multivariable analysis, neither the estimated glomerular filtration rate (adjusted odds ratio, 1.0; 95% confidence interval, 1.00-1.01; P = .26) nor dialysis dependence (adjusted odds ratio, 0.21; 95% confidence interval, 0.03-1.57; P = .13) was independently associated with the composite outcome of stroke/death.The 30-day carotid revascularization outcomes for asymptomatic disease in dialysis-dependent patients met the Society for Vascular Surgery guidelines in this national cohort and might be better than previously surmised. Hence, vascular surgeons could consider carotid revascularization for select dialysis-dependent patients with the appropriate expected longevity and perioperative risk.

Background: In Australia’s Northern Territory, 33% of babies are born to Indigenous mothers, who experience high rates of hyperglycemia in pregnancy. We aimed to determine the extent to which pregnancy outcomes for Indigenous Australian women are explained by relative frequencies of diabetes type [type 2 diabetes (T2DM) and gestational diabetes (GDM)]. Methods: This prospective birth cohort study examined participants recruited from a hyperglycemia in pregnancy register. Baseline data collected were antenatal and perinatal clinical information, cord blood and neonatal anthropometry. Of 1135 women (48%Indigenous), 900 had diabetes: 175 T2DM, 86 newly diagnosed diabetes in pregnancy(DIP) and 639 had GDM. A group of 235 women without hyperglycemia in pregnancywas also recruited. Results: Diabetes type differed for Indigenous and non-Indigenous women (T2DM, 36 vs5%; DIP, 15 vs 7%; GDM, 49 vs 88%, p < 0.001). Within each diabetes type, Indigenous women were younger and had higher smoking rates. Among women with GDM/DIP,Indigenous women demonstrated poorer birth outcomes than non-Indigenous women:large for gestational age, 19 vs 11%, p ¼ 0002; neonatal fat 11.3 vs 10.2%, p < 0.001. Inthe full cohort, on multivariate regression, T2DM and DIP were independently associated(and Indigenous ethnicity was not) with pregnancy outcomes Conclusions: Higher rates of T2DM among Indigenous women predominantly contribute to absolute poorer pregnancy outcomes among Indigenous women with hyperglycemia.As with Indigenous and minority populations globally, prevention or delay of type 2 diabetes in younger women is vital to improve pregnancy outcomes and possibly to improve the long-term health of their offspring. Refereed/Peer-reviewed

The sociocultural model of eating disorders asserts that societies which emphasize the thin-ideal have higher rates of body dissatisfaction and disordered eating. Recent research questions the related presumption that non-White cultures value a larger ideal female and thus have lower rates of body dissatisfaction and disordered eating. The limited research on these constructs in racial/ethnic minorities primarily has used non-validated instruments. The current study investigated rates of body dissatisfaction and disordered eating with validated, widely used measures. Measures of body dissatisfaction and disordered eating were completed by 896 college women in the United States: 473 Hispanics, 341 non-Hispanic whites, and 82 Native Americans. Although Native Americans and Hispanics had higher body mass indices (and larger ideal shapes) than White women, the groups had similar body dissatisfaction scores. Native Americans reported somewhat less restricted eating compared to White women. When controlling for body mass index and age, group differences on body dissatisfaction emerged and the group differences in eating disorder symptoms became more pronounced, with White women showing more pathology. Reliability and validity across groups were good. This study offers some support for the sociocultural model of eating disorders and provides mean scores for Native American and Hispanic females on widely-used eating disorder measures. Level V, cross-sectional descriptive study.

Objectives The aim of the present research was to evaluate the current caries experience of schoolchildren in the Republic of Moldova. Methods A pathfinder study was planned and executed according to the World Health Organization (WHO) recommendations. Caries experience was recorded in three large cities (the capital city and two other large cities) and four villages throughout the country. Within each site and age group, school clusters were randomly chosen. Three different age groups (6, 12 and 15 years) of schoolchildren were assessed. Results Overall, 1,100 children were examined: 724 from cities and 376 from the villages. Among the study population, 408 (37.1%) were female and 692 (62.9%) were male, 380 were 6 years of age, 365 were 12 years and 355 were 15 years. The prevalence of caries experience [decayed, missing and filled scores of > 1 for primary (dmft) and secondary (DMFT) teeth] was 87.4% (dmft score = 3.9 ± 3.0) for 6-year-old participants, 77.53% (DMFT score = 2.7 ± 2.3) for 12-year-old participants and 86.2% (DMFT score = 3.7 ± 2.9) for 15-year-old participants. For the 12-year group, a higher proportion of caries-free children were detected in urban areas than in rural areas (25.5% vs. 15.5%, P = 0.003). We found more caries-free participants among 12-year-olds than among 15-year-olds (22.5% vs. 13.8%, P = 0.004). Conclusions These WHO key index age groups may be inserted into the global oral health databank and provide a 'pathfinder' baseline for formulating and conducting future public oral health programmes in the Republic of Moldova, with an emphasis on children in rural locations.

BackgroundDifferences between an individual’s estimated epigenetic gestational age (EGA) and their actual gestational age (GA) are defined as gestational age acceleration (GAA). GAA is associated with increased birthweight and birth length. Whether these associations persist through childhood is yet to be investigated.MethodsWe examined the association between GAA and trajectories of height and weight from birth to 10 years (n=785) in a British birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). EGA of participants was estimated using DNA methylation data from cord blood using a recently-developed prediction model. GA of participants was gathered in ALSPAC from clinical records and was measured from last menstrual period (LMP) for most participants. GAA of participants, measured in weeks, was calculated as the residuals from a regression model of EGA on actual GA. Height and weight were obtained from several sources including birth records, research clinics, routine child health clinics, links to health visitor records and parent-reported measures from questionnaires. Analyses were performed using linear spline multilevel models and adjusted for maternal age, maternal pre-pregnancy BMI, maternal smoking during pregnancy and maternal education.ResultsIn adjusted analyses, offspring with a one-week greater GAA were born on average 0.14 kg heavier (95% Confidence Interval (CI) 0.09, 0.19) and 0.55 cm taller (95% CI 0.33, 0.78) at birth. These differences in weight persisted up to approximately age 9 months but thereafter began to attenuate and reduce in magnitude. From age 5 years onwards, the association between GAA and weight reversed such that GAA was associated with lower weight and this association strengthened with age (mean difference at age 10 years −0.60 kg (95% CI, −1.19, −0.01)). Differences in height persisted only up to age 9 months (mean difference at 9 months 0.15 cm, (95% CI −0.09, 0.39)). From age 9 months to age 10 years, offspring with a one-week greater GAA were of comparable height to those with no GAA (mean difference at age 10 years −0.07 cm, (95% CI −0.64, 0.50)).ConclusionsGestational age acceleration is associated with increased birth weight and length and these differences persist to age 9 months. From 5 years onwards, the association of GAA and weight reverses such that by age 10 years greater GAA is associated with lower childhood weight. Further work is required to examine whether the weight effects of GAA strengthen further through adolescence and into early adulthood.

Type 1 diabetes (T1D) is characterized by T cell–mediated destruction of the insulin-producing β cells of the pancreatic islets. Among the loci associated with T1D risk, those most predisposing are found in the MHC region. HLA-B*39:06 is the most predisposing class I MHC allele and is associated with an early age of onset. To establish an NOD mouse model for the study of HLA-B*39:06, we expressed it in the absence of murine class I MHC. HLA-B*39:06 was able to mediate the development of CD8 T cells, support lymphocytic infiltration of the islets, and confer T1D susceptibility. Because reduced thymic insulin expression is associated with impaired immunological tolerance to insulin and increased T1D risk in patients, we incorporated this in our model as well, finding that HLA-B*39:06–transgenic NOD mice with reduced thymic insulin expression have an earlier age of disease onset and a higher overall prevalence as compared with littermates with typical thymic insulin expression. This was despite virtually indistinguishable blood insulin levels, T cell subset percentages, and TCR Vβ family usage, confirming that reduced thymic insulin expression does not impact T cell development on a global scale. Rather, it will facilitate the thymic escape of insulin-reactive HLA-B*39:06–restricted T cells, which participate in β cell destruction. We also found that in mice expressing either HLA-B*39:06 or HLA-A*02:01 in the absence of murine class I MHC, HLA transgene identity alters TCR Vβ usage by CD8 T cells, demonstrating that some TCR Vβ families have a preference for particular class I MHC alleles.

Heart failure (HF) is a global public health problem that, independent of its etiology [reduced (HFrEF) or preserved ejection fraction (HFpEF)], is characterized by functional impairments of cardiac function, chemoreflex hypersensitivity, baroreflex sensitivity (BRS) impairment, and abnormal autonomic regulation, all of which contribute to increased morbidity and mortality. Exercise training (ExT) has been identified as a nonpharmacological therapy capable of restoring normal autonomic function and improving survival in patients with HFrEF. Improvements in autonomic function after ExT are correlated with restoration of normal peripheral chemoreflex sensitivity and BRS in HFrEF. To date, few studies have addressed the effects of ExT on chemoreflex control, BRS, and cardiac autonomic control in HFpEF; however, there are some studies that have suggested that ExT has a beneficial effect on cardiac autonomic control. The beneficial effects of ExT on cardiac function and autonomic control in HF may have important implications for functional capacity in addition to their obvious importance to survival. Recent studies have suggested that the peripheral chemoreflex may also play an important role in attenuating exercise intolerance in HFrEF patients. The role of the central/peripheral chemoreflex, if any, in mediating exercise intolerance in HFpEF has not been investigated. The present review focuses on recent studies that address primary pathophysiological mechanisms of HF (HFrEF and HFpEF) and the potential avenues by which ExT exerts its beneficial effects.

We tested the generalizability of a science-based community prevention design to reduce DUI crashes. Previous researcher-led studies have confirmed the effects of an intervention design of visible enforcement coupled with heightened public awareness of enforcement to increase driver perception of likely detection for drinking and driving. A community coalition based the project on a prevention intervention model that included two key intermediate variables: levels of visible enforcement and of public awareness of enforcement. We evaluated the project using community-specific monthly time-series measures of DUI crashes and state level trends in DUI crashes, indicators of enforcement, and public attention to enforcement. We devised the evaluation design to determine if an observed trend in DUI crashes declined and to verify if key intermediate variables increased, as stimulated by local efforts. DUI crash analysis documented an upward trend during a pre-trial period from July 2010-December 2011, which matched the upward trend in state DUI crashes. After the local intervention began in January 2012, local DUI crashes began a clear downward trend (average 2013 crashes were 23% lower than in 2012 and a 5-month post-intervention average from 2013 was lower than the equivalent 5-month pre-intervention average). This contrasted with the continued upward state DUI crash trend, with a 2-year increase of 16%. The downward trend in local crashes was associated with an increase in DUI enforcement as well as news stories concerning DUI enforcement that were stimulated by the efforts of the community prevention project. These results confirm the generalizability of two previous community research trials that were conducted with limited or no research resources or leadership. We discuss the importance of controlling for external factors in attributing causation in a local prevention evaluation by confirming both sufficient local prevention efforts and a decline in DUI crashes.