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Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Alcohol-associated liver disease (ALD) is a prevalent medical problem with limited effective treatment strategies. Although many biological processes contributing to ALD have been elucidated, a complete understanding of the underlying mechanisms is still lacking. The current study employed a proteomic approach to identify hepatic changes resulting from ethanol (EtOH) consumption and the genetic ablation of the formyl peptide receptor 2 (FPR2), a G-protein coupled receptor known to regulate multiple signaling pathways and biological processes, in a mouse model of ALD. Since previous research from our team demonstrated a notable reduction in hepatic FPR2 protein levels in patients with alcohol-associated hepatitis (AH), the proteomic changes in the livers of Fpr2-/- EtOH mice were compared to those observed in patients with AH in order to identify common hepatic proteomic alterations. Several pathways linked to exacerbated ALD in Fpr2-/- EtOH mice, as well as hepatic protein changes resembling those found in patients suffering from AH, were identified. These alterations included decreased levels of coagulation factors F2 and F9, as well as reduced hepatic levels of glutamate-cysteine ligase catalytic subunit (GCLC) and total glutathione in Fpr2-/- EtOH compared to WT EtOH mice. In conclusion, the data suggest that FPR2 may play a regulatory role in hepatic blood coagulation and the antioxidant system, both in a pre-clinical model of ALD and in human AH, however further experiments are required to validate these findings.

BackgroundAutism spectrum disorder (ASD) is a prevalent and heterogeneous neurodevelopmental disorder. Risk is attributed to genetic and prenatal environmental factors, though the environmental agents are incompletely characterized.MethodsIn Early Autism Risk Longitudinal Investigation (EARLI) and Markers of Autism Risk in Babies Learning Early Signs (MARBLES), two pregnancy cohorts of siblings of children with ASD, urinary metals concentrations during two pregnancy time periods (

BackgroundPrenatal exposure to metals is hypothesized to be associated with child autism. We aim to investigate the joint and individual effects of prenatal exposure to urine metals including lead (Pb), mercury (Hg), manganese (Mn), and selenium (Se) on child Social Responsiveness Scale (SRS) scores.MethodsWe used data from 2 cohorts enriched for likelihood of autism spectrum disorder (ASD): Early Autism Risk Longitudinal Investigation (EARLI) and the Markers of Autism Risk in Babies-Learning Early Signs (MARBLES) studies. Metal concentrations were measured in urine collected during pregnancy. We used Bayesian Kernel Machine Regression and linear regression models to investigate both joint and independent associations of metals with SRS Z-scores in each cohort. We adjusted for maternal age at delivery, interpregnancy interval, maternal education, child race/ethnicity, child sex, and/or study site.ResultsThe final analytic sample consisted of 251 mother-child pairs. When Pb, Hg, Se, and Mn were at their 75th percentiles, there was a 0.03 increase (95% credible interval [CI]: -0.11, 0.17) in EARLI and 0.07 decrease (95% CI: -0.29, 0.15) in MARBLES in childhood SRS Z-scores, compared to when all 4 metals were at their 50th percentiles. In both cohorts, increasing concentrations of Pb were associated with increasing values of SRS Z-scores, fixing the other metals to their 50th percentiles. However, all the 95% credible intervals contained the null.ConclusionsThere were no clear monotonic associations between the overall prenatal metal mixture in pregnancy and childhood SRS Z-scores at 36 months. There were also no clear associations between individual metals within this mixture and childhood SRS Z-scores at 36 months. The overall effects of the metal mixture and the individual effects of each metal within this mixture on offspring SRS Z-scores might be heterogeneous across child sex and cohort. Further studies with larger sample sizes are warranted.

Abstract Background Although telemental health can make suicide prevention treatments more scalable and accessible, limited evidence demonstrates successful reductions in suicidality when interventions are administered through telehealth platforms. To address this limitation, the current work investigated the effects of two suicide prevention treatments – a clinician-guided Crisis Response Plan and a self-guided Safety Planning approach. Methods After completing the screening process, 82 participants with high suicide ideation and/or a lifetime history of suicidal behavior were randomly assigned across the two groups. Trained research clinicians administered the interventions using a videoconferencing platform. After the intervention delivery was complete, participants reported the therapeutic alliance they experienced with their clinician using an online survey. Participants also reported their overall suicidality 45 days after receiving the intervention. In addition, participants’ perceived usefulness of the received intervention and actual use of the plan were recorded. Linear and logistic regression models predicted how suicidality, perceived utility, and actual use of their intervention protocols varied depending on the high (Crisis Response Plan) versus low (self-guided Safety Planning) level of clinician-led collaboration the two treatments entailed. Results Both Crisis Response Plan and self-guided Safety Planning were found to lower suicidality after receiving them via telehealth services. At the same time, those who received the Crisis Response Plan (the more collaborative form of therapy) reported experiencing a stronger therapeutic alliance with the clinician, utilizing the plan more often and perceiving it as more useful. These findings demonstrate the additional benefits of adopting a more collaborative approach because of its effectiveness and perceived utility, which has implications for suicide-related distress reduction in the short and long term. Conclusions Evidence from this randomized control trial suggests that Crisis Response Plan is a suitable candidate for delivering suicide prevention via telehealth platform because of its effectiveness in reducing suicidality and its collaborative approach to building a strong therapeutic alliance, perceived usefulness, and actual utility in everyday life. Trial registration This paper was part of a registered RCT: https://clinicaltrials.gov/study/NCT04888845 . Registration date: Date: 2021-04-22.

Abstract The teratogenic potential of valproate in pregnancy is well established; however, evidence regarding the long-term safety of other antiseizure medications (ASMs) during pregnancy remains limited. Using routinely collected primary care data from the UK and nationwide Swedish registries to create a cohort of 3,182,773 children, of which 17,495 were exposed to ASMs in pregnancy, we show that those exposed to valproate were more likely to receive a diagnosis of autism, intellectual disability, and ADHD, when compared to children not exposed to ASMs. Additionally, children exposed to topiramate were 2.5 times more likely to be diagnosed with intellectual disability (95% CI: 1.23–4.98), and those exposed to carbamazepine were 1.25 times more likely to be diagnosed with autism (95% CI: 1.05–1.48) and 1.30 times more likely to be diagnosed with intellectual disability (95% CI: 1.01–1.69). There was little evidence that children exposed to lamotrigine in pregnancy were more likely to receive neurodevelopmental diagnoses. While further research is needed, these findings may support considering safer treatment alternatives well before conception when clinically appropriate.

Abstract Background HIV risk perception is an important cognition for prevention, theoretically engendering service-seeking and risk-reduction behaviors, but its composition remains poorly understood. We examined country-specific correlates of self-appraised HIV exposure risk among sexually active adolescent girls and young women (AGYW, aged 15–24 years) without HIV in Kenya, Malawi, and Zambia. We also explored overlaps between self-appraised HIV exposure risk and pre-exposure prophylaxis (PrEP) eligibility to identify engagement opportunities. Methods We analyzed cross-sectional data (2016/2017) to estimate sexual-related correlates of self-appraised HIV exposure risk (likely vs. not, temporally framed as “ever”) using log-Poisson models with robust standard errors. For sexual-related factors with an unadjusted p ≤ 0.10, individual adjusted models were fitted, controlling for sociodemographic and cognitive factors with an unadjusted p ≤ 0.10. PrEP eligibility was defined using national guidelines; since conditional criteria are in Malawi’s (age-disparate sex + ever-pregnant) and Zambia’s (multiple partners + condomless sex) guidelines, we also assessed PrEP eligibility after decoupling these factors. Results Few AGYW reported likely HIV exposures (Kenya [N = 746]: 15.7%, Malawi [N = 1348]: 46.2%, Zambia [N = 349]: 9.5%) despite ubiquitous HIV risk (98.7%, 99.8%, and 98.9% of Kenyan, Malawian, and Zambian AGYW reported ≥ 1 sexual-related factor). However, the adjusted models found some actual-perceived risk concordance. Positive correlates of self-appraised likely HIV exposures included partner(s)’ likely HIV exposure (all countries); partner(s)’ unknown HIV status and other partners (Kenya, Malawi); STI symptoms and partner(s) living outside the community (Kenya); non-partner sexual violence (Zambia); and transactional sex, multiple partners, pre-coital alcohol use, and physical/sexual intimate partner violence (Malawi). Per national guidelines, PrEP eligibility criteria differentially identified HIV risk (Kenya: 93.6%, Malawi: 53.3%, Zambia: 44.6%), and self-appraised likely HIV exposures were low among PrEP-eligible AGYW (Kenya: 16.5%, Malawi: 48.5%, Zambia: 18.8%). Decoupling Malawi’s and Zambia’s conditional PrEP criteria could increase risk identification to > 85% and potential engagement by ~ 70% and ~ 30%, respectively. Conclusions AGYW's HIV risk perceptions were mostly influenced by factors beyond their locus of control. Conditional PrEP eligibility criteria may inhibit AGYW’s access and uptake in some settings: countries should consider decoupling these factors to minimize barriers. Intersections between autonomy, behaviors, and perceptions among AGYW in gender-inequitable settings warrants further investigation.

In this article, the authors share their favorite "Construct It!" activity, which focuses on rate of change and functions. The initial approach to instruction was procedural in nature and focused on making use of formulas. Specifically, after modeling how to find the slope of the line given two points and use it to solve for the y-intercept, the authors gave students time to practice. They recognized that their approach lacked an opportunity for students to engage in reasoning and sense making. According to Lithner (2008), imitative reasoning (i.e., a focus on memorizing) is ubiquitous in mathematics classrooms in the United States, whereas creative reasoning (i.e., reasoning that results in knowledge creation) is rare. To help students generalize the process of identifying a linear relationship that holds for two ordered pairs, explain the connection to the slope formula, and engage in creative reasoning, the authors designed the activity they call Turn A Into B. This activity focuses on reasoning about the relationship between two quantities and reflecting on how this is related to rate of change and functions.

Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, driven by activating mutation of GNAQ/GNA11; however, there are limited therapies against UM and metastatic UM (mUM). Here, we perform a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with BRAF-mutant cutaneous melanoma, defining the druggable landscape of these distinct melanoma subtypes. Across all compounds, darovasertib demonstrates the highest preferential activity against UM. Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.

BackgroundAtrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility.MethodsRight atrial appendage tissues were isolated from human patients with AF versus sinus rhythm controls. Western blots, coimmunoprecipitation, and phosphorylation studies were performed to examine how the PP1c (PP1 catalytic subunit)-PPP1R12C interaction causes MLC2a dephosphorylation. In vitro studies of pharmacological MRCK (myotonic dystrophy kinase-related Cdc42-binding kinase) inhibitor (BDP5290) in atrial HL-1 cells were performed to evaluate PP1 holoenzyme activity on MLC2a. Cardiac-specific lentiviral PPP1R12C overexpression was performed in mice to evaluate atrial remodeling with atrial cell shortening assays, echocardiography, and AF inducibility with electrophysiology studies.ResultsIn human patients with AF, PPP1R12C expression was increased 2-fold versus sinus rhythm controls (P=2.0×10-2; n=12 and 12 in each group) with >40% reduction in MLC2a phosphorylation (P=1.4×10-6; n=12 and 12 in each group). PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF (P=2.9×10-2 and 6.7×10-3, respectively; n=8 and 8 in each group). In vitro studies utilizing drug BDP5290, which inhibits T560-PPP1R12C phosphorylation, demonstrated increased PPP1R12C binding with both PP1c and MLC2a and dephosphorylation of MLC2a. Mice treated with lentiviral PPP1R12C vector demonstrated a 150% increase in left atrial size versus controls (P=5.0×10-6; n=12, 8, and 12), with reduced atrial strain and atrial ejection fraction. Pacing-induced AF in mice treated with lentiviral PPP1R12C vector was significantly higher than in controls (P=1.8×10-2 and 4.1×10-2, respectively; n=6, 6, and 5).ConclusionsPatients with AF exhibit increased levels of PPP1R12C protein compared with controls. PPP1R12C overexpression in mice increases PP1c targeting to MLC2a and causes MLC2a dephosphorylation, which reduces atrial contractility and increases AF inducibility. These findings suggest that PP1 regulation of sarcomere function at MLC2a is a key determinant of atrial contractility in AF.

Abstract Background Fatigue is a common complication of stroke that has a significant impact on quality of life. The biological mechanisms that underly post-stroke fatigue are currently unclear, however, reactivation of latent viruses and their impact on systemic immune function have been increasingly reported in other conditions where fatigue is a predominant symptom. Epstein-Barr virus (EBV) in particular has been associated with fatigue, including in long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome, but has not yet been explored within the context of stroke. Aims We performed an exploratory analysis to determine if there is evidence of a relationship between EBV reactivation and post-stroke fatigue. Methods In a chronic ischemic stroke cohort (> 5 months post-stroke), we assayed circulating EBV by qPCR and measured the titres of anti-EBV antibodies by ELISA in patients with high fatigue (FACIT-F 41). Statistical analysis between two-groups were performed by t-test when normally distributed according to the Shapiro-Wilk test, by Mann-Whitney test when the data was not normally distributed, and by Fisher’s exact test for categorical data. Results We observed a similar incidence of viral reactivation between people with low versus high levels of post-stroke fatigue (5 of 22 participants (24%) versus 6 of 22 participants (27%)). Although the amount of circulating EBV was similar, we observed an altered circulating anti-EBV antibody profile in participants with high fatigue, with reduced IgM against the Viral Capsid Antigen (2.244 ± 0.926 vs. 3.334 ± 2.68; P = 0.031). Total IgM levels were not different between groups indicating this effect was specific to anti-EBV antibodies (3.23 × 105 ± 4.44 × 104 high fatigue versus 4.60 × 105 ± 9.28 × 104 low fatigue; P = 0.288). Conclusions These data indicate that EBV is not more prone to reactivation during chronic stroke recovery in those with post-stroke fatigue. However, the dysregulated antibody response to EBV may be suggestive of viral reactivation at an earlier stage after stroke.

Abstract Background This study aimed to describe the prevalence of Duchenne muscular dystrophy (DMD) and associated healthcare resource utilisation and costs from an England perspective. Methods Patients with DMD were selected by recorded diagnoses from the Clinical Practice Research Datalink Aurum database and matched to non-DMD controls. The point prevalence of DMD (2020) was estimated. Primary care, inpatient, outpatient, and A&E department contacts and prescription items emanating from primary care were aggregated and their costs were compared between cases and controls. People with DMD were further classified by ambulatory phase and ventilation status and respective costs presented. Results The point prevalence of DMD in 2020 was 3.23 per 100,0000 (95% confidence interval [CI] 2.82–3.63). There was a significant increase in contacts in all healthcare sectors compared to controls: primary care (incidence rate ratios (IRR) = 3.19 (95% CI 3.11–3.28)), inpatient admissions (IRR = 9.24 (95% CI 8.19–10.46)), outpatient appointments (IRR = 11.44 (95% CI 10.95–11.96)) and accident and emergency (IRR = 1.65 (1.52–1.81)). Overall, healthcare costs were almost ten-fold higher (adjusted cost ratio (ACR = 9.33 (95% CI 6.75–12.91)). Healthcare costs increased with the progression of DMD: £2816, on average, in the ambulatory phase; £5700 in the non-ambulatory without-ventilation, and £7634 in the non-ambulatory with ventilation phase. Conclusion DMD was associated with almost a ten-fold increase in healthcare costs. Worsening DMD status, as characterized by non-ambulation and requirement for ventilation, was associated with increased costs. However, the use of standard tariffs may underestimate the true financial burden of the condition. This assessment excluded social care and carer costs some of which will encompass medical needs and may contribute significantly to the cost burden of DMD.