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For the potable reuse of municipal wastewater effluent, carbon based advanced treatment (CBAT) using coagulation, ozonation, biofiltration and/or granular activated carbon (GAC) adsorption is a promising approach for controlling disinfection byproduct (DBP) formation. However, CBAT can also favor a shift in DBP formation to more toxic brominated DBP species. To protect public health, treatment-specific DBP formation and speciation trends need to be identified and understood. First, this study systematically evaluated the treatment of six wastewater effluents with four CBAT process trains (experimental n was 55) and measured DBP formation and speciation trends. Overall, CBAT decreased DBP formation by >90% and GAC preferentially removed highly-reactive effluent organic matter as indicated by lower yields of both highly-forming and highly-toxic classes of carbonaceous and nitrogenous DBPs. Since GAC treatment also induced systematic speciation changes by increasing the ratio of bromide to dissolved organic matter, the second part of this study focused on understanding the health impacts of DBP speciation changes on calculated additive toxicity (CAT). Based on the evaluation of 20 DBPs, measured using established methods, the CAT values from cyto- and genotoxicity metrics decreased by as much as 85% due to high levels of precursor removal by GAC. Expanding the evaluation to include 52 DBPs, measured using more extensive analytical methods, resulted in the same conclusions. This study also developed a "speciation potency" metric, that re-scales class-by-class speciation trends using toxic potency factors (e.g., cytotoxicity [LC 50 ]). The observed shifts in DBP speciation after treatment increased the class-level toxic potency factors by up to a factor of 4; a greater amount of precursor removal is required for treatment to reduce toxicity, which was achieved with CBAT trains. This proposed approach of combining speciation potency with DBP yields enables evaluation of DBP-associated risk with easily measured surrogates (i.e., bromide and dissolved organic carbon [DOC]). By identifying and quantitatively comparing DBP formation and speciation trends over multiple wastewater effluents and treatment trains, this study demonstrates that CBAT can be a robust approach to DBP precursor removal for potable reuse., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: Despite years of research and the development of countless awareness campaigns, the number of deaths related to prescription opioid overdose is steadily rising. Often, naive patients undergoing trauma-related surgery are dispensed opioids while in the hospital, resulting in an escalation to long-term opioid misuses. We explored the impact of an educational intervention to modify perceptions of opioid needs at the bedside of trauma inpatients in post-surgery pain management., Materials and Methods: Twenty-eight inpatients with acute post-surgical pain completed this proof-of-concept study adopting an educational intervention related to opioids and non-pharmacological strategies in the context of acute post-surgical pain. An education assessment survey was developed to measure pre- and post-education perceptions of opioid needs to manage pain. The survey statements encompassed the patient's perceived needs for opioids and other pharmacological and non-pharmacological therapeutics to manage acute pain. The primary outcome was the change in the patient's perceived need for opioids. The secondary (explorative) outcome was the change in Morphine Milligram Equivalents (MME) used on the day of the educational intervention while inpatients and prescribed at the time of the hospital discharge., Results: After the educational intervention, patients reported less agreement with the statement, "I think a short course of opioids (less than 5 days) is safe." Moreover, less agreement on using opioids to manage trauma-related pain was positively associated with a significant reduction in opioids prescribed at discharge after the educational intervention. The educational intervention might have effectively helped to cope with acute trauma-related pain while adjusting potential unrealistic expectancies about pain management and, more in general, opioid-related needs., Conclusion: These findings suggest that trauma patients' expectations and understanding of the risks associated with the long-term use of opioids can be modified by a short educational intervention delivered by health providers during the hospitalization. Establishing realistic expectations in managing acute traumatic pain may empower patients with the necessary knowledge to minimize the potential of continuous long-term opioid use, opioid misuse, and the development of post-trauma opioid abuse and/or addiction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Colloca, Taj, Massalee, Haycock, Murray, Wang, McDaniel, Scalea, Fouche-Weber and Murthi.)

Cytochrome P450 reaction phenotyping to determine the fraction of metabolism values (f m ) for individual enzymes is a standard study in the evaluation of a new drug. However, there are technical challenges in these studies caused by shortcomings in the selectivity of P450 inhibitors and unreliable scaling procedures for recombinant P450 (rCYP) data. In this investigation, a two-step "qualitative-then-quantitative" approach to P450 reaction phenotyping is described. In the first step, each rCYP is tested qualitatively for potential to generate metabolites. In the second step, selective inhibitors for the P450s identified in step1 are tested for their effects on metabolism using full inhibition curves. Forty-eight drugs were evaluated in step 1 and there were no examples of missing an enzyme important to in vivo clearance. Five drugs (escitalopram, fluvastatin, pioglitazone, propranolol, and risperidone) were selected for full phenotyping in step2 to determine f m values, with findings compared to f m values estimated from single inhibitor concentration data and rCYP with intersystem-extrapolation-factor corrections. The two-step approach yielded f m values for major drug clearing enzymes that are close to those estimated from clinical data: escitalopram and CYP2C19 (0.42 vs 0.36-0.82), fluvastatin and CYP2C9 (0.76 vs 0.76), pioglitazone and CYP2C8 (0.72 vs 0.73), propranolol and CYP2D6 (0.68 vs 0.37-0.56) and risperidone and CYP2D6 (0.60 vs 0.66-0.88). Reaction phenotyping data generated in this fashion should offer better input to physiologically-based pharmacokinetic models for prediction of DDI and impact of genetic polymorphisms on drug clearance. The qualitative-then-quantitative approach is proposed as a replacement to standard reaction phenotyping strategies. Significance Statement P450 reaction phenotyping is important for projecting drug-drug interactions and interpatient variability in drug exposure. However, currently recommended practices can frequently fail to provide reliable estimates of the fractional contributions of specific P450 enzymes (f m ) to drug clearance. In this report, we describe a two-step qualitative-then-quantitative reaction phenotyping approach that yields more accurate estimates of f m .

Recovering endangered species is a difficult and often controversial task that challenges status quo land uses. Southern Mountain caribou are a threatened ecotype of caribou that historically ranged in southwestern Canada and northwestern USA and epitomize the tension between resource extraction, biodiversity conservation, and Indigenous Peoples' treaty rights. Human-induced habitat alteration is considered the ultimate cause of caribou population declines, whereby an increased abundance of primary prey-such as moose and deer-elevates predator populations and creates unsustainable caribou mortality. Here we focus on the Klinse-Za and Quintette subpopulations, part of the endangered Central Group of Southern Mountain caribou in British Columbia. These subpopulations were trending toward immediate extirpation until a collaborative group initiated recovery by implementing two short-term recovery actions. We test the effectiveness of these recovery actions-maternity penning of adult females and their calves, and the reduction of a primary predator, wolves-in increasing vital rates and population growth. Klinse-Za received both recovery actions, whereas Quintette only received wolf reductions, providing an opportunity to test efficacy between recovery actions. Between 1995 and 2021, we followed 162 collared female caribou for 414 animal-years to estimate survival and used aerial counts to estimate population abundance and calf recruitment. We combined these data in an integrated population model to estimate female population growth, total population abundance, and recovery action effectiveness. Results suggest that the subpopulations were declining rapidly (λ = 0.90-0.93) before interventions and would have been functionally extirpated (<10 animals) within 10-15 years. Wolf reduction increased population growth rates by ~0.12 for each subpopulation. Wolf reduction halted the decline of Quintette caribou and allowed them to increase (λ = 1.05), but alone would have only stabilized the Klinse-Za (λ = 1.02). However, maternity penning in the Klinse-Za increased population growth by a further ~0.06, which when combined with wolf reductions, allowed populations to grow (λ = 1.08). Taken together, the recovery actions in these subpopulations increased adult female survival, calf recruitment, and overall population growth, more than doubling abundance. Our results suggest that maternity penning and wolf reductions can be effective at increasing caribou numbers in the short term, while long-term commitments to habitat protection and restoration are made., (© 2022 The Authors. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

The utility of chemical inhibitors in cytochrome P450 (CYP) reaction phenotyping is highly dependent on their selectivity and potency for their target CYP isoforms. In the present study, seventeen inhibitors of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 commonly used in reaction phenotyping were evaluated for their cross-enzyme selectivity in pooled human liver microsomes. The data were evaluated using a statistical desirability analysis to identify (1) inhibitors of superior selectivity for reaction phenotyping and (2) optimal concentrations for each. Among the inhibitors evaluated, α-naphthoflavone, furafylline, sulfaphenazole, tienilic acid, N -benzylnirvanol, and quinidine were most selective, such that their respective target enzymes were inhibited by ~95% without inhibiting any other CYP enzyme by more than 10%. Other commonly employed inhibitors, such as ketoconazole and montelukast, among others, were of insufficient selectivity to yield a concentration that could adequately inhibit their target enzymes without affecting other CYP enzymes. To overcome these shortcomings, an experimental design was developed wherein dose response data from a densely sampled multi-concentration inhibition curve are analyzed by a six-parameter inhibition curve function, allowing accounting of the inhibition of off-target CYP isoforms inhibition and more reliable determination of maximum targeted enzyme inhibition. The approach was exemplified using rosiglitazone N -demethylation, catalyzed by both CYP2C8 and 3A4, and was able to discern the off-target inhibition by ketoconazole and montelukast from the inhibition of the targeted enzyme. This methodology yields more accurate estimates of CYP contributions in reaction phenotyping. Significance Statement Isoform-selective chemical inhibitors are important tools for identifying and quantifying enzyme contributions as part of a CYP reaction phenotyping assessment for projecting drug-drug interactions. However, currently employed practices fail to adequately compensate for shortcomings in inhibitor selectivity and the resulting confounding impact on estimates of the CYP enzyme contribution to drug clearance. In this report, we describe a detailed IC 50 study design with 6-parameter modeling approach that yields more accurate estimates of enzyme contribution.

Indigenous Peoples around the northern hemisphere have long relied on caribou for subsistence and for ceremonial and community purposes. Unfortunately, despite recovery efforts by federal and provincial agencies, caribou are currently in decline in many areas across Canada. In response to recent and dramatic declines of mountain caribou populations within their traditional territory, West Moberly First Nations and Saulteau First Nations (collectively, the "Nations") came together to create a new vision for caribou recovery on the lands they have long stewarded and shared. The Nations focused on the Klinse-Za subpopulation, which had once encompassed so many caribou that West Moberly Elders remarked that they were "like bugs on the landscape." The Klinse-Za caribou declined from ~250 in the 1990s to only 38 in 2013, rendering Indigenous harvest of caribou nonviable and infringing on treaty rights to a subsistence livelihood. In collaboration with many groups and governments, this Indigenous-led conservation initiative paired short-term population recovery actions, predator reduction and maternal penning, with long-term habitat protection in an effort to create a self-sustaining caribou population. Here, we review these recovery actions and the promising evidence that the abundance of Klinse-Za caribou has more than doubled from 38 animals in 2013 to 101 in 2021, representing rapid population growth in response to recovery actions. With looming extirpation averted, the Nations focused efforts on securing a landmark conservation agreement in 2020 that protects caribou habitat over a 7986-km 2 area. The Agreement provides habitat protection for >85% of the Klinse-Za subpopulation (up from only 1.8% protected pre-conservation agreement) and affords moderate protection for neighboring caribou subpopulations (29%-47% of subpopulation areas, up from 0%-20%). This Indigenous-led conservation initiative has set both the Indigenous and Canadian governments on the path to recover the Klinse-Za subpopulation and reinstate a culturally meaningful caribou hunt. This effort highlights how Indigenous governance and leadership can be the catalyst needed to establish meaningful conservation actions, enhance endangered species recovery, and honor cultural connections to now imperiled wildlife., (© 2022 The Authors. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

Background: Diabetes related foot ulcers can have physical, social, emotional, and financial impacts on the daily life and wellbeing of many people living with diabetes. Effective treatment of diabetes related foot ulcers requires a multi-faceted, multi-disciplinary approach involving a podiatrist, other healthcare professionals, and the person with diabetes however, limited research has been conducted on the lived experience of podiatric treatment for diabetes related foot ulcers to understand how people are engaged in their ulcer management. Therefore, this study aimed to explore the lived experience of receiving podiatric treatment for diabetes related foot ulcers in a tertiary care outpatient setting., Methods: Ten participants were interviewed. All were male, with mean age of 69 (SD 15) years and currently undergoing podiatric treatment for a diabetes related foot ulcer in a tertiary care setting. Participants with diabetes related foot ulcers were purposively recruited from the outpatient podiatry clinic at a tertiary hospital in a metropolitan region of South Australia. Semi-structured interviews were conducted to gain insight into the lived experience of people receiving podiatric treatment for their foot ulcer and understand how this experience impacts their regular lifestyle. Data were analysed using a thematic analysis method., Results: Four themes were identified that add an understanding of the lived experience of participants: 'Trusting the podiatrists with the right expertise', 'Personalised care', 'Happy with the service, but not always with prescribed care', and 'It's a long journey'. Participants described professional behaviour including high organisation and hygiene practices and demonstrated expertise as key factors influencing their trust of a podiatrist's care. Information tailored to individual needs was helpful for participants. Offloading devices and ulcer dressings were often burdensome. Podiatric treatment for foot ulcers was a lengthy and onerous experience for all participants., Conclusions: The findings of this study suggest podiatrists can use practical strategies of maintaining consistency in who provides podiatry care for the person, demonstration of high organisational and hygiene standards, and using innovation to adapt information and equipment to suit an individual's lifestyle to support positive experiences of podiatric ulcer care. There is a need for further research to understand how a person's experience of podiatric ulcer care differs amongst genders, cultural groups, and healthcare settings to facilitate positive care experiences and reduce treatment burden for all people with diabetes requiring podiatric ulcer treatment., (© 2022. The Author(s).)

Neurologic complications of the human immunodeficiency virus (HIV) are common in treated individuals, and toxicity of certain antiretroviral therapies (ART) may contribute to cognitive impairment. We investigated exposures to specific ART and cognition among women living with HIV (WLWH). Virologically suppressed (viral load <200 copies/mL during at least two semi-annual visits) WLWH and age/race matched HIV-seronegative controls enrolled in the Women's Interagency HIV Study who completed at least two biennial cognitive assessments were included. Analysis of WLWH was restricted to those with exposure to the drug class of interest and a nucleoside reverse transcriptase inhibitor (NRTI) backbone. Generalized estimating equations were used to evaluate repeated measures of cognition over time in association with ART class exposure. Among 1,242 eligible WLWH, 20% ( n  = 247) had isolated drug exposure to non-nucleoside reverse transcriptase inhibitors (NNRTI), 18% ( n  = 219) to protease inhibitors (PIs), and 6% ( n  = 79) to integrase inhibitors with a NRTI backbone. Cognitive assessments were performed at a median of 3 biennial visits {IQR 2-4 visits}. At the index assessment, 21% of WLWH demonstrated global cognitive impairment versus 29% at their last cognitive assessment. In multivariable analyses adjusted for hypertension, depression, diabetes mellitus, history of AIDS-defining illness, alcohol use, number of medications, and time on ART, WLWH exposed to NNRTIs demonstrated verbal learning improvements (mean T-score change 1.3, p  = .020) compared to other treated women. Compared to HIV-seronegative women, WLWH exposed to PIs had worse verbal learning (mean T-score difference -2.62, p  = .002) and verbal memory performance (mean T-score difference -1.74, p  = .032) at baseline. Compared to HIV-seronegative women, WLWH exposed to PIs had improvements in verbal learning (mean T-score slope difference 0.36, p  = .025) and verbal memory (mean T-score slope difference 0.32, p  = .042). The index T-score and slope of change in the T-score were similar among other treated groups and the HIV-seronegative group. We noted emerging trends in cognition in WLWH exposed to specific drug classes. Ongoing study of this relatively young group is important to characterize long-term cognitive outcomes and effect of antiretrovirals as treatment guidelines evolve.

Background: Two previous Phase 3 studies ("parent studies") showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study., Methods: This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651). The primary endpoint was safety and tolerability. Secondary endpoints were absolute change from baseline in lung clearance index 2.5 (LCI 2.5 ), sweat chloride (SwCl) concentration, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI)., Results: One-hundred thirty children enrolled and received ≥ 1 dose of tezacaftor/ivacaftor; 109 completed treatment. Most (n = 129) had ≥ 1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in severity and generally consistent with common manifestations of CF. Exposure-adjusted TEAE rates were similar to or lower than those in the parent studies. Five (3.8%) had TEAEs leading to treatment discontinuation. Efficacy results from the parent studies were maintained, with improvements in lung function, SwCl concentration, CFQ‑R respiratory domain score, and BMI observed from parent study baseline to Week 96., Conclusions: Tezacaftor/ivacaftor is generally safe and well tolerated, and treatment effects are maintained for up to 120 weeks. These results support long-term use of tezacaftor/ivacaftor in children ≥ 6 years of age with CF and F/F or F/RF genotypes., Competing Interests: Declaration of Competing Interest All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated. Additional disclosures are as follows: GSS reports consulting fees and serving on an advisory board for Vertex Pharmaceuticals. JM reports support for attending the NACFC meeting from the CF Foundation (care center award), outside the submitted work. LN reports grants from the German Center for Lung Research, Vertex Pharmaceuticals, and Boehringer Ingelheim, serving on a steering committee for CF STORM, serving as a medical lead for the German Cystic Fibrosis registry, and serving as a pharmacovigilance study manager for the European Cystic Fibrosis Society (ECFS), outside the submitted work. CS reports grants from the Cystic Fibrosis Foundation, Cystic Fibrosis Ireland, Cystic Fibrosis Trust, and Engineering and Physical Sciences Research Council (EPSRC), personal fees from Vertex Pharmaceuticals, outside the submitted work; in addition, CS is an employee of Royal Brompton Hospital, which received remuneration from Vertex Pharmaceuticals and Boehringer Ingelheim for services provided by the European Cystic Fibrosis Clinical Trials Network's Central Over-reading Centre during sponsored clinical trials. ISG reports grants, serving on advisory boards, and travel support from Vertex Pharmaceuticals, outside the submitted work. CEW reports grants, honorarium to support attending meetings, and serving on advisory boards and steering committees for Vertex Pharmaceuticals, outside the submitted work; in addition, CEW is Deputy Editor for Thorax and Associate Editor for Respirology. NA, RSH, HPD, and JLS are employees of Vertex Pharmaceuticals and may own stock or stock options in the company. DC was an employee of Vertex Pharmaceuticals at the time of the study and is a current employee of Biohaven Pharmaceuticals. JCD reports clinical trial leadership and/or advisory board and speaking roles for Vertex Pharmaceuticals, Boehringer Ingelheim, Eloxx, AlgiPharma, AbbVie, Arcturus, and Enterprise Therapeutics, grants from the Cystic Fibrosis Foundation, Cystic Fibrosis Ireland, Cystic Fibrosis Trust, EPSRC, and European Cystic Fibrosis Society; in addition, JCD is Deputy Editor for the Journal of Cystic Fibrosis. MC has nothing further to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Limited reports exist regarding adeno-associated virus (AAV) biodistribution in swine. This study assessed biodistribution following antegrade intracoronary and intravenous delivery of two self-complementary serotype 9 AAV (AAV9sc) biologics designed to target signaling in the cardiomyocyte considered important for the development of heart failure. Under the control of a cardiomyocyte-specific promoter, AAV9sc.shmAKAP and AAV9sc.RBD express a small hairpin RNA for the perinuclear scaffold protein muscle A-kinase anchoring protein β (mAKAPβ) and an anchoring disruptor peptide for p90 ribosomal S6 kinase type 3 (RSK3), respectively. Quantitative PCR was used to assess viral genome (vg) delivery and transcript expression in Ossabaw and Yorkshire swine tissues. Myocardial viral delivery was 2-5 × 10 5 vg/µg genomic DNA (gDNA) for both infusion techniques at a dose ∼10 13 vg/kg body wt, demonstrating delivery of ∼1-3 viral particles per cardiac diploid genome. Myocardial RNA levels for each expressed transgene were generally proportional to dose and genomic delivery, and comparable with levels for moderately expressed endogenous genes. Despite significant AAV9sc delivery to other tissues, including the liver, neither biologic induced toxic effects as assessed using functional, structural, and circulating cardiac and systemic markers. These results indicate successful targeted delivery of cardiomyocyte-selective viral vectors in swine without negative side effects, an important step in establishing efficacy in a preclinical experimental setting.

Online registries offer many advantages for research, including the ability to efficiently assess large numbers of individuals and identify potential participants for clinical trials and genetic studies. Of particular interest is the validity and utility of self-endorsement of psychiatric disorders in online registries, which, while increasingly more common, remain understudied. We thus assessed the comparability of prevalence estimated from self-endorsement of psychiatric disorders in one such registry, the Brain Health Registry (BHR) to prevalence computed from large US-based epidemiological studies and the degree to which BHR participants report psychiatric disorders consistently. We also examined the concordance between self-report and clinically determined diagnoses of various DSM-5 psychiatric disorders in a subset of participants who underwent direct assessments and identified possible reasons for discordance. Rates of self-reported psychiatric disorders were closest to previously reported population prevalence rates when endorsed at multiple timepoints, and accuracy was at least 70% for all except Hoarding Disorder as compared to the clinical diagnoses. Clinical data suggested that self-endorsement of a given psychiatric diagnosis was indicative of the presence of a closely related condition, although not necessarily for the specific disorder, with the exception of major depressive disorder, panic disorder, and hoarding disorder, which had high positive predictive values (85%, 73%, 100%, respectively). We conclude that self-reporting of psychiatric conditions in an online setting is a fair indicator of psychopathology, but should be accompanied by more in-depth interviews if using data from a participant for a specific disorder., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Glaucoma is the second leading cause of blindness worldwide and despite its prevalence, there are still many unanswered questions related to its pathogenesis. There is evidence that oxidative stress and inflammation play a major role in disease progression. Glaucoma patients from several studies showed altered gene expression in leukocytes, revealing the possibility of using peripheral biomarkers to diagnose or stage glaucoma. The fact that glaucoma is associated with gene expression changes in tissues distant from the retina underscores the possible involvement of systemic oxidative stress and inflammation as potential contributing or compounding factors in glaucoma., Methods: We assembled a list of oxidative stress and inflammatory markers related to glaucoma based on a review of the literature. In addition, we utilized publicly available data sets of gene expression values collected from peripheral blood mononuclear cells and macrophages from two patient groups: those chronically infected by the hepatitis C virus and those who have cleared it. Activation of the innate immune response can render cells or tissues more responsive to a second delayed proinflammatory stimulus. Additional gene expression data from these cells after subsequent polyinosinic:polycytidylic acid treatment, used to elicit an acute inflammatory response, allowed for the investigation of the acute inflammatory response in these groups. We used fold-change comparison values between the two patient groups to identify genes of interest., Results: A comparison analysis identified 17 glaucoma biomarkers that were differentially expressed in response to HCV-mediated inflammation. Of these 17, six had significant p-values in the baseline vs treated values. Expression data of these genes were compared between patients who had cleared the Hepatitis C virus versus those who had not and identified three genes of interest for further study., Discussion: These results support our hypothesis that inflammation secondary to Hepatitis C virus infection affects the expression of glaucoma biomarker genes related to the antioxidant response and inflammation. In addition, they provide several potential targets for further research into understanding the relationship between innate responses to viral infection and inflammatory aspects of glaucoma and for potential use as a predictive biomarker or pharmacological intervention in glaucoma., Competing Interests: The authors report no conflicts of interest in relation to this work and declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The research reported in this publication was supported in part by grants from the National Eye Institute (EY022774, EY031248) of the National Institutes of Health (PK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional support by the Felix and Carmen Sabates Missouri Endowed Chair in Vision Research, a Challenge Grant from Research to Prevent Blindness and the Vision Research Foundation of Kansas City, is gratefully acknowledged., (© 2022 Player et al.)

Stay-at-home restrictions such as closure of non-essential businesses were effective at reducing SARS-CoV-2 transmission in New York City (NYC) in the spring of 2020. Relaxation of these restrictions was desirable for resuming economic and social activities, but could only occur in conjunction with measures to mitigate the expected resurgence of new infections, in particular social distancing and mask-wearing. We projected the impact of individuals' adherence to social distancing and mask-wearing on the duration, frequency, and recurrence of stay-at-home restrictions in NYC. We applied a stochastic discrete time-series model to simulate community transmission and household secondary transmission in NYC. The model was calibrated to hospitalizations, ICU admissions, and COVID-attributable deaths over March-July 2020 after accounting for the distribution of age and chronic health conditions in NYC. We projected daily new infections and hospitalizations up to May 31, 2021 under the different levels of adherence to social distancing and mask-wearing after relaxation of stay-at-home restrictions. We assumed that the relaxation of stay-at-home policies would occur in the context of adaptive reopening, where a new hospitalization rate of ≥ 2 per 100,000 residents would trigger reinstatement of stay-at-home restrictions while a new hospitalization rate of ≤ 0.8 per 100,000 residents would trigger relaxation of stay-at-home restrictions. Without social distancing and mask-wearing, simulated relaxation of stay-at-home restrictions led to epidemic resurgence and necessary reinstatement of stay-at-home restrictions within 42 days. NYC would have stayed fully open for 26% of the time until May 31, 2021, alternating reinstatement and relaxation of stay-at-home restrictions in four cycles. At a low (50%) level of adherence to mask-wearing, NYC would have needed to implement stay-at-home restrictions between 8% and 32% of the time depending on individual adherence to social distancing. At moderate to high levels of adherence to mask-wearing without social distancing, NYC would have needed to implement stay-at-home restrictions. In threshold analyses, avoiding reinstatement of stay-at-home restrictions required a minimum of 60% adherence to mask-wearing at 50% adherence to social distancing. With low adherence to mask-wearing and social distancing, reinstatement of stay-at-home restrictions in NYC was inevitable. High levels of adherence to social distancing and mask-wearing could have attributed to avoiding recurrent surges without reinstatement of stay-at-home restrictions., (© 2022. The Author(s).)

Background: Women in Africa face disproportionate risk of human immunodeficiency virus (HIV) acquisition, accounting for more than half of new infections in Africa and similarly face a disproportionate burden of sexually transmitted infections (STIs). Very high STI prevalence is being observed globally, especially among people taking pre-exposure prophylaxis (PrEP) for HIV prevention. Doxycycline post-exposure prophylaxis (dPEP) has been proposed as an STI prevention strategy to reduce chlamydia, syphilis, and possibly gonorrhea, and trials are ongoing among cisgender men who have sex with men (MSM) and transgender women who are taking PrEP in high-income settings. We designed and describe here the first open-label trial to determine the effectiveness of dPEP to reduce STI incidence among cisgender women., Methods: We are conducting an open-label 1:1 randomized trial of dPEP versus standard of care (STI screening and treatment and risk-reduction counseling without dPEP) among 446 Kenyan women aged ≥ 18 and ≤ 30 years old women taking PrEP. Women are followed for 12 months, with quarterly STI testing, treatment, and adherence counseling. The primary trial outcome will be the combined incidence of Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum, compared between the randomized groups. We will also assess dPEP acceptability, tolerability, safety, impact on sexual behavior, adherence, and occurrence of antimicrobial resistance (AMR) in N. gonorrhoeae and C. trachomatis isolates. Finally, we will estimate cost per incident STI case and complications averted accounting for nonadherence and benefits relative AMR or side effects., Discussion: The results of this trial may have immediate implications for the global epidemic of STIs and sexual health. If effective, dPEP could put STI prevention into women's hands. While dPEP may be able to prevent STIs, it carries important risks that could counter its benefits; global debate about the balance of these potential risks and benefits requires data to inform policy and implementation and our study aims to fill this gap., Trial Registration: ClinicalTrials.gov NCT04050540 ., (© 2022. The Author(s).)

It is unknown which families are at risk for poor outcomes following a child's critical illness., Objectives: To evaluate if pediatric septic shock severity is associated with caregiver distress and family dysfunction throughout the year postadmission and if caregiver outcomes are associated with child health-related quality of life (HRQL)., Design Setting and Participants: Secondary analysis of the Life After Pediatric Sepsis Evaluation prospective cohort study among children less than 18 years old with community-acquired septic shock requiring vasoactive-inotropic support and invasive or noninvasive ventilation in 12 academic U.S. PICUs., Main Outcomes and Measures: Caregivers reported personal psychologic distress (Brief Symptom Inventory), family functioning (Family Assessment Device), and child HRQL (Pediatric Quality of Life Inventory, Functional Status II-Revised) at baseline and 1, 3, 6, and 12 months following PICU admission., Results: Among 276 caregivers, psychologic distress prevalence initially decreased then rose to 15.3%, whereas prevalence of family dysfunction increased steadily to 30.9% at 12 months. On multivariable logistic regression adjusting for patient age, medical complexity, and immunosuppression, higher Pediatric Risk of Mortality and vasoactive-inotropic scores and longer PICU and hospital stay were associated with greater caregiver distress at 1 month. Higher Pediatric Logistic Organ Dysfunction (PELOD) score, longer ventilation, and longer PICU stay were associated with lower odds of family dysfunction at 1, 3, and 6 months (average PELOD vs new 6-mo dysfunction: odds ratio [OR], 0.73 [95% CI, 0.55-0.96]). Caregiver distress was associated with child HRQL decline from baseline to 1 month (OR, 2.92 [1.27-6.75]), 3 months (OR, 2.34 [1.01-5.42]), and 12 months (OR, 3.94 [1.54-10.06])., Conclusions and Relevance: Family dysfunction becomes increasingly prevalent over the year following pediatric septic shock and is less likely following higher severity illness. Caregiver psychologic distress is associated with worse child HRQL. Both patients and families may benefit from ongoing psychosocial support following survival from pediatric septic shock., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Diabetes mellitus (pregestational (PDM) and gestational (GDM)) is associated with adverse pregnancy outcomes (APOs). However, studies exploring the association of APOs with maternal glycemia among women without PDM/GDM are limited. We utilized data from 4119 women (307-PDM; 582-GDM; 3230-non-PDM/GDM) in the Boston Birth Cohort (1998-2016). Women in the non-PDM/GDM group were subdivided by tertiles of 1 h, 50 g oral glucose load test at 24-32 weeks: T1: 50-95 mg/dL ( n = 1166), T2: 96-116 mg/dL ( n = 1151), T3: 117-201 mg/dL ( n = 913). Using multivariable logistic regression, we examined the association of maternal glycemia with APOs-preterm birth (PTB) and hypertensive disorders of pregnancy (HDP)-and adverse perinatal outcomes-high birth weight (HBW), cesarean section (CS), and sub-analyses by race-ethnicity. Compared to women in T1, women in T2 and T3 had a higher prevalence of pre-existing hypertension (T1: 2.8% vs. T2: 5.2% vs. T3: 6.3%) and obesity (T1: 13.3% vs. T2: 18.1% vs. T3: 22.9%). Women in T2 and T3 had higher odds of HBW (adjusted odds ratio aOR T2: 1.47 [1.01-2.19] T3: 1.68 [1.13-2.50]) compared to women in T1. Additionally, women in T2, compared to T1, had higher odds of HDP (aOR 1.44 [1.10-1.88]). Among non-Hispanic Black (NHB) women, those in T2 and T3 had higher odds of HDP compared to T1 (aOR T2 1.67 [1.13-2.51]; T3: 1.68 [1.07-2.62]). GDM and PDM were associated with higher odds of HBW, CS, PTB, and HDP, compared to women in T1. In this predominantly NHB and Hispanic cohort, moderate maternal glycemia without PDM/GDM was associated with higher odds of HBW and HDP, even more strongly among NHB women. If confirmed, a review of current guidelines of glucose screening and risk stratification in pregnancy may be warranted.

Aging of the vasculature is characterized by endothelial dysfunction and arterial stiffening, two key events in the pathogenesis of cardiovascular disease (CVD). Treatment with sodium glucose transporter 2 (SGLT2) inhibitors is now known to decrease cardiovascular morbidity and mortality in type 2 diabetes. However, whether SGLT2 inhibition attenuates vascular aging is unknown. We first confirmed in a cohort of adult subjects that aging is associated with impaired endothelial function and increased arterial stiffness and that these two variables are inversely correlated. Next, we investigated whether SGLT2 inhibition with empagliflozin (Empa) ameliorates endothelial dysfunction and reduces arterial stiffness in aged mice with confirmed vascular dysfunction. Specifically, we assessed mesenteric artery endothelial function and stiffness (via flow-mediated dilation and pressure myography mechanical responses, respectively) and aortic stiffness (in vivo via pulse wave velocity and ex vivo via atomic force microscopy) in Empa-treated (14 mg/kg/day for 6 weeks) and control 80-week-old C57BL/6 J male mice. We report that Empa-treated mice exhibited improved mesenteric endothelial function compared with control, in parallel with reduced mesenteric artery and aortic stiffness. Additionally, Empa-treated mice had greater vascular endothelial nitric oxide synthase activation, lower phosphorylated cofilin, and filamentous actin content, with downregulation of pathways involved in production of reactive oxygen species. Our findings demonstrate that Empa improves endothelial function and reduces arterial stiffness in a preclinical model of aging, making SGLT2 inhibition a potential therapeutic alternative to reduce the progression of CVD in older individuals., (© 2022. The Author(s).)

Background and Objectives: Definitions for pediatric sepsis were established in 2005 without data-driven criteria. It is unknown whether the more recent adult Sepsis-3 definitions meet the needs of providers caring for children. We aimed to explore the use and applicability of criteria to diagnose sepsis and septic shock in children across the world., Methods: This is an international electronic survey of clinicians distributed across international and national societies representing pediatric intensive care, emergency medicine, pediatrics, and pediatric infectious diseases. Respondents stated their preferences on a 5-point Likert scale., Results: There were 2835 survey responses analyzed, of which 48% originated from upper-middle income countries, followed by high income countries (38%) and low or lower-middle income countries (14%). Abnormal vital signs, laboratory evidence of inflammation, and microbiologic diagnoses were the criteria most used for the diagnosis of "sepsis." The 2005 consensus definitions were perceived to be the most useful for sepsis recognition, while Sepsis-3 definitions were stated as more useful for benchmarking, disease classification, enrollment into trials, and prognostication. The World Health Organization definitions were perceived as least useful across all domains. Seventy one percent of respondents agreed that the term sepsis should be restricted to children with infection-associated organ dysfunction., Conclusions: Clinicians around the world apply a myriad of signs, symptoms, laboratory studies, and treatment factors when diagnosing sepsis. The concept of sepsis as infection with associated organ dysfunction is broadly supported. Currently available sepsis definitions fall short of the perceived needs. Future diagnostic algorithms should be pragmatic and sensitive to the clinical settings., (Copyright © 2022 by the American Academy of Pediatrics.)

Introduction: Bosutinib, a dual Abelson/Src inhibitor, was investigated in individuals with dementia with Lewy bodies (DLB)., Methods: A single site, randomized, double-blind, placebo-controlled study of the effects of oral bosutinib, 100 mg once daily for 12 weeks on primary safety and pharmacokinetics and secondary biomarker outcomes., Results: Twenty-six participants were randomized and included male and female (12:1) in the bosutinib arm and all male (13) in the placebo arm. The average age was 72.9 ± 8.1 (year ± standard deviation). There were no serious adverse events and no dropouts. Bosutinib was measured in the cerebrospinal fluid (CSF) and inhibited Abelson. Bosutinib reduced CSF alpha-synuclein and dopamine catabolism., Discussion: Bosutinib is safe and well tolerated and penetrates the blood-brain barrier to inhibit Abelson and reduce CSF alpha-synuclein and dopamine catabolism, suggesting that bosutinib (100 mg) may be at or near the lowest effective dose in DLB. These results will guide adequately powered studies to determine the efficacy of a dose range of bosutinib and longer treatment in DLB., Highlights: Bosutinib is a dual Abl/Src inhibitor that penetrates the blood brain barrierBosutinib is safe and tolerated in individuals with dementia with Lewy bodiesBosutinib engages its target via inhibition of Abl and SrcBosutinib reduces CSF alpha-synuclein and attenuates breakdown of dopamineBosutinib improves activities of daily living in dementia with Lewy bodies., Competing Interests: Charbel Moussa is an inventor on a Georgetown University (GU) US and International Patent to use bosutinib in neurodegenerative diseases, including alpha‐synucleinopathies. GU exclusively licensed bosutinib use patent to KeifeRx LLC. Charbel Moussa and Fernando Pagan are founders and shareholders of KeiferX LLC, and Charbel Moussa and Jaeil Ahn are paid consultants to KeifeRX LLC. All other authors declare no conflict with this manuscript., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

BACKGROUND: Single-dose human papillomavirus (HPV) vaccination, if efficacious, would be tremendously advantageous, simplifying implementation and decreasing costs. METHODS: We performed a randomized, multicenter, double-blind, controlled trial of single-dose nonavalent (HPV 16/18/31/33/45/52/58/6/11 infection) or bivalent (HPV 16/18 infection) HPV vaccination compared with meningococcal vaccination among Kenyan women 15 to 20 years of age. Enrollment and 6-monthly cervical swabs and a month 3 vaginal swab were tested for HPV deoxyribonucleic acid (DNA). Enrollment sera were tested for HPV antibodies. The modified intent-to-treat (mITT) cohort comprised participants who had an HPV antibody-negative result at enrollment and an HPV DNA-negative result at enrollment and month 3. The primary outcome was incident persistent vaccine-type HPV infection by month 18. RESULTS: Between December 2018 and June 2021, 2275 women were randomly assigned and followed. A total of 758 participants received the nonavalent HPV vaccine, 760 received the bivalent HPV vaccine, and 757 received the meningococcal vaccine; retention was 98%. Thirty-eight incident persistent infections were detected in the HPV 16/18 mITT cohort: one each among participants assigned to the bivalent and nonavalent groups and 36 among those assigned to the meningococcal group. Nonavalent vaccine efficacy (VE) was 97.5% (95% confidence interval [CI], 81.7 to 99.7%; P≤0.0001), and bivalent VE was 97.5% (95% CI, 81.6 to 99.7%; P≤0.0001). Thirty-three incident persistent infections were detected in the HPV 16/18/31/33/45/52/58 mITT cohort: four in the nonavalent group and 29 in the meningococcal group. Nonavalent VE for HPV 16/18/31/33/45/52/58 was 88.9% (95% CI, 68.5 to 96.1; P<0.0001). The rate of serious adverse events was 4.5% to 5.2% by group. CONCLUSIONS: Over the 18-month timeframe we studied, single-dose bivalent and nonavalent HPV vaccines were each highly effective in preventing incident persistent oncogenic HPV infection, similar to multidose regimens. (Funded by the National Institutes of Health, the Bill and Melinda Gates Foundation, and the University of Washington; ClinicalTrials.gov number, NCT03675256.), (Copyright: © 2022 Author(s), Massachusetts Medical Society. All rights reserved.)

Objective: Our objective was to determine the extent surgical disciplines categorize, define, and study errors, then use this information to provide recommendations for both current practice and future study., Summary of Background Data: The report "To Err is Human" brought the ubiquity of medical errors to public attention. Variability in subsequent literature suggests the true prevalence of error remains unknown., Methods: In January 2020, PubMed, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched. Only studies with Oxford Level of Evidence Level 3 or higher were included., Results: Of 3064 studies, 92 met inclusion criteria: 6 randomized controlled trials, 4 systematic reviews, 24 cohort, 10 before-after, 35 outcome/audit, 5 cross sectional and 8 case-control studies. Over 15,933,430 patients and 162,113 errors were represented. There were 6 broad error categories, 13 different definitions of error, and 14 study methods., Conclusions: Reported prevalence of error varied widely due to a lack of standardized categorization, definitions, and study methods. Future research should focus on immediately recognizing errors to minimize harm., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Periodontitis has been associated with adverse pregnancy outcomes. Little is known about the burden and risk factors for periodontitis among reproductive age women in sub-Saharan Africa. This analysis aimed to determine the prevalence and correlates of periodontitis among Kenyan women planning to conceive., Methods: HIV-seronegative, reproductive-age women who were planning to conceive were enrolled and underwent a periodontal examination. Following the US Centers for Disease Control and Prevention clinical case definitions, the presence and severity of periodontitis was determined by establishing the level of clinical periodontal attachment loss and graded in three categories: no/mild, moderate, and severe. Secondary outcomes included the scores on the Gingival Index and Decayed, Missing, and Filled Teeth (DMFT) Index. Correlates of periodontitis were examined using univariable and multivariable logistic regression., Results: Of the 647 women in the study, 84% (n = 541) had no/mild periodontitis, 15% (n = 97) had moderate periodontitis, and 1% (n = 9) had severe periodontitis. Mild gingivitis was present in 61% (n = 396) of women, while 27% (n = 176) had moderate gingivitis, and 1% (n = 9) had severe gingivitis. The majority (75%, n = 487) of women had a DMFT index in the very low range (score < 5). Periodontitis was observed in 12% (12/101) of nulliparous women compared to 13% (36/286) of women with one prior delivery (prevalence ratio [PR] 1.03, 95% confidence interval [95% CI] 0.57-1.96), 21% (36/170) of women with two prior deliveries (PR 1.78, 95% CI 0.97-3.26), and 24% (22/90) of women with 3 or more prior deliveries (PR 2.06, 95% CI 1.08-3.92)., Conclusion: This study demonstrated a substantial prevalence of moderate-severe periodontitis among women planning to conceive in Kenya. These results highlight the need to address the oral care needs of reproductive age women, particularly those with multiple prior pregnancies., (© 2022. The Author(s).)

MAGE proteins are cancer testis antigens (CTAs) that are characterized by highly conserved MAGE homology domains (MHDs) and are increasingly being found to play pivotal roles in promoting aggressive cancer types. MAGE-A4, in particular, increases DNA damage tolerance and chemoresistance in a variety of cancers by stabilizing the E3-ligase RAD18 and promoting trans-lesion synthesis (TLS). Inhibition of the MAGE-A4:RAD18 axis could sensitize cancer cells to chemotherapeutics like platinating agents. We use an mRNA display of thioether cyclized peptides to identify a series of potent and highly selective macrocyclic inhibitors of the MAGE-A4:RAD18 interaction. Co-crystal structure indicates that these inhibitors bind in a pocket that is conserved across MHDs but take advantage of A4-specific residues to achieve high isoform selectivity. Cumulatively, our data represent the first reported inhibitor of the MAGE-A4:RAD18 interaction and establish biochemical tools and structural insights for the future development of MAGE-A4-targeted cellular probes.

The juvenile-to-adult transition in plants is known as vegetative phase change and is marked by changes in the expression of leaf traits in response to a decrease in the level of miR156 and miR157. To determine whether this is the only mechanism of vegetative phase change, we measured the appearance of phase-specific leaf traits in 70 natural accessions of Arabidopsis thaliana. We found that leaf shape was poorly correlated with abaxial trichome production (two adult traits), that variation in these traits was not necessarily correlated with the level of miR156, and that there was little to no correlation between the appearance of adult-specific vegetative traits and flowering time. We identified eight quantitative trait loci controlling phase-specific vegetative traits from a cross between the Columbia (Col-0) and Shakdara (Sha) accessions. Only one of these quantitative trait loci includes genes known to regulate vegetative phase change (MIR156A and TOE1), which were expressed at levels consistent with the precocious phenotype of Sha. Our results suggest that vegetative phase change is regulated both by the miR156/SPL module and by genes specific to different vegetative traits, and that natural variation in vegetative phase change can arise from either source., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2022. Published by The Company of Biologists Ltd.)

Sotatercept is an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that improves cardiopulmonary function in patients with pulmonary arterial hypertension (PAH) by selectively trapping activins and growth differentiation factors. However, the cellular and molecular mechanisms of ActRIIA-Fc action are incompletely understood. Here, we determined through genome-wide expression profiling that inflammatory and immune responses are prominently upregulated in the lungs of a Sugen-hypoxia rat model of severe angio-obliterative PAH, concordant with profiles observed in PAH patients. Therapeutic treatment with ActRIIA-Fc-but not with a vasodilator-strikingly reversed proinflammatory and proliferative gene expression profiles and normalized macrophage infiltration in diseased rodent lungs. Furthermore, ActRIIA-Fc normalized pulmonary macrophage infiltration and corrected cardiopulmonary structure and function in Bmpr2 haploinsufficient mice subjected to hypoxia, a model of heritable PAH. Three high-affinity ligands of ActRIIA-Fc each induced macrophage activation in vitro, and their combined immunoneutralization in PAH rats produced cardiopulmonary benefits comparable to those elicited by ActRIIA-Fc. Our results in complementary experimental and genetic models of PAH reveal therapeutic anti-inflammatory activities of ActRIIA-Fc that, together with its known anti-proliferative effects on vascular cell types, could underlie clinical activity of sotatercept as either monotherapy or add-on to current PAH therapies., (© 2022. The Author(s).)

Introduction: The emergence of the COVID-19 pandemic has had significant impact on human lives as well as economic and social stability. The United States has a complicated history with biosecurity as policy making, biodefense activities, and government transparency have historically been in contention. The terror attacks of September 11, 2001 uncovered various weaknesses in the national public health infrastructure that have persisted into the current pandemic., Methods: This study explores the biodefense and public health preparedness landscape for trends in federal support and capacity building. It also investigates the applicability of public health emergency management principles to the biodefense structure. A mixed method was utilized in this study to investigate the qualitative and quantitative factors of the research inquiry. Braun and Clarke's six phase framework for thematic analysis will assist with defining the important information from a review of the literature. The concurrent triangulation design permits that use of qualitative and quantitative data to more accurately define and analyze the relationship among the variables of interest., Results: The results included the identification of 8 common themes of failure during the COVID-19 response: (1) accountable leadership, (2) statutory authorities and policies, (3) inter-agency coordination, (4) coherent data system for situational awareness, (5) strategic national stockpile and supply chain, (6) testing and surveillance, (7) health care system surge capacity and resilience, and (8) federal funds and the role of public health emergency management in the evolving landscape of biothreats, both intentional and natural., Discussion: To counter the increasing biothreats, the United States must invest in revamping the biodefense infrastructure to mimic and support public health emergency preparedness initiatives which will increase our resilience to various biothreats.

The objective of the current study was to investigate the feasibility of quantitative 3D ultrashort echo time (UTE)-based biomarkers in detecting proteoglycan (PG) loss and collagen degradation in human cartilage. A total of 104 cartilage samples were harvested for a trypsin digestion study (n = 44), and a sequential trypsin and collagenase digestion study (n = 60), respectively. Forty-four cartilage samples were randomly divided into a trypsin digestion group (tryp group) and a control group (phosphate-buffered saline [PBS] group) (n = 22 for each group) for the trypsin digestion experiment. The remaining 60 cartilage samples were divided equally into four groups (n = 15 for each group) for sequential trypsin and collagenase digestion, including PBS + Tris (incubated in PBS, then Tris buffer solution), PBS + 30 U col (incubated in PBS, then 30 U/ml collagenase [30 U col] with Tris buffer solution), tryp + 30 U col (incubated in trypsin solution, then 30 U/ml collagenase with Tris buffer solution), and tryp + Tris (incubated in trypsin solution, then Tris buffer solution). The 3D UTE-based MRI biomarkers included T 1 , multiecho T 2 *, adiabatic T 1ρ (AdiabT 1ρ ), magnetization transfer ratio (MTR), and modeling of macromolecular proton fraction (MMF). For each cartilage sample, UTE-based biomarkers (T 1 , T 2 *, AdiabT 1ρ , MTR, and MMF) and sample weight were evaluated before and after treatment. PG and hydroxyproline assays were performed. Differences between groups and correlations were assessed. All the evaluated biomarkers were able to differentiate between healthy and degenerated cartilage in the trypsin digestion experiment, but only T 1 and AdiabT 1ρ were significantly correlated with the PG concentration in the digestion solution (p = 0.004 and p = 0.0001, respectively). In the sequential digestion experiment, no significant differences were found for T 1 and AdiabT 1ρ values between the PBS + Tris and PBS + 30 U col groups (p = 0.627 and p = 0.877, respectively), but T 1 and AdiabT 1ρ values increased significantly in the tryp + Tris (p = 0.031 and p = 0.024, respectively) and tryp + 30 U col groups (both p < 0.0001). Significant decreases in MMF and MTR were found in the tryp + 30 U col group compared with the PBS + Tris group (p = 0.002 and p = 0.001, respectively). It was concluded that AdiabT 1ρ and T 1 have the potential for detecting PG loss, while MMF and MTR are promising for the detection of collagen degradation in articular cartilage, which could facilitate earlier, noninvasive diagnosis of osteoarthritis., (© 2021 John Wiley & Sons, Ltd.)

Importance: Late-life depression (LLD) is characterized by considerable heterogeneity in clinical manifestation. Unraveling such heterogeneity might aid in elucidating etiological mechanisms and support precision and individualized medicine., Objective: To cross-sectionally and longitudinally delineate disease-related heterogeneity in LLD associated with neuroanatomy, cognitive functioning, clinical symptoms, and genetic profiles., Design, Setting, and Participants: The Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) study is an international multicenter consortium investigating brain aging in pooled and harmonized data from 13 studies with more than 35 000 participants, including a subset of individuals with major depressive disorder. Multimodal data from a multicenter sample (N = 996), including neuroimaging, neurocognitive assessments, and genetics, were analyzed in this study. A semisupervised clustering method (heterogeneity through discriminative analysis) was applied to regional gray matter (GM) brain volumes to derive dimensional representations. Data were collected from July 2017 to July 2020 and analyzed from July 2020 to December 2021., Main Outcomes and Measures: Two dimensions were identified to delineate LLD-associated heterogeneity in voxelwise GM maps, white matter (WM) fractional anisotropy, neurocognitive functioning, clinical phenotype, and genetics., Results: A total of 501 participants with LLD (mean [SD] age, 67.39 [5.56] years; 332 women) and 495 healthy control individuals (mean [SD] age, 66.53 [5.16] years; 333 women) were included. Patients in dimension 1 demonstrated relatively preserved brain anatomy without WM disruptions relative to healthy control individuals. In contrast, patients in dimension 2 showed widespread brain atrophy and WM integrity disruptions, along with cognitive impairment and higher depression severity. Moreover, 1 de novo independent genetic variant (rs13120336; chromosome: 4, 186387714; minor allele, G) was significantly associated with dimension 1 (odds ratio, 2.35; SE, 0.15; P = 3.14 ×108) but not with dimension 2. The 2 dimensions demonstrated significant single-nucleotide variant-based heritability of 18% to 27% within the general population (N = 12 518 in UK Biobank). In a subset of individuals having longitudinal measurements, those in dimension 2 experienced a more rapid longitudinal change in GM and brain age (Cohen f2 = 0.03; P = .02) and were more likely to progress to Alzheimer disease (Cohen f2 = 0.03; P = .03) compared with those in dimension 1 (N = 1431 participants and 7224 scans from the Alzheimer's Disease Neuroimaging Initiative [ADNI], Baltimore Longitudinal Study of Aging [BLSA], and Biomarkers for Older Controls at Risk for Dementia [BIOCARD] data sets)., Conclusions and Relevance: This study characterized heterogeneity in LLD into 2 dimensions with distinct neuroanatomical, cognitive, clinical, and genetic profiles. This dimensional approach provides a potential mechanism for investigating the heterogeneity of LLD and the relevance of the latent dimensions to possible disease mechanisms, clinical outcomes, and responses to interventions.

Objective: Endothelial nitric oxide synthase (eNOS) is a potential mediator of exercise-induced hepatic mitochondrial adaptations., Methods: Here, male and female hepatocyte-specific eNOS knockout (eNOS hep-/- ) and intact hepatic eNOS (eNOS fl/fl ) mice performed voluntary wheel-running exercise (EX) or remained in sedentary cage conditions for 10 weeks., Results: EX resolved the exacerbated hepatic steatosis in eNOS hep-/- male mice. Elevated hydrogen peroxide emission (~50% higher in eNOS hep-/- vs. eNOS fl/fl mice) was completely ablated with EX. Interestingly, EX increased [1- 14 C] palmitate oxidation in eNOS fl/fl male mice, but this was blunted in the eNOS hep-/- male mice. eNOS hep-/- mice had lower markers of the energy sensors AMP-activated protein kinase (AMPK)/phospho- (p)AMPK and mammalian target of rapamycin (mTOR) and p-mTOR, as well as the autophagy initiators serine/threonine-protein kinase ULK1 and pULK1, compared with eNOS fl/fl mice. Females showed elevated electron transport chain protein content and markers of mitochondrial biogenesis (transcription factor A, mitochondrial, peroxisome proliferator-activated receptor-gamma coactivator 1α)., Conclusions: Collectively, this study demonstrates for the first time, to the authors' knowledge, the requirement of eNOS in hepatocytes in the EX-induced increases in hepatic fatty acid oxidation in male mice. Deletion of eNOS in hepatocytes also appears to impair the energy-sensing ability of the cell and inhibit the activation of the autophagy initiating factor ULK1. These data uncover the important and novel role of hepatocyte eNOS in EX-induced hepatic mitochondrial adaptations., (© 2022 The Obesity Society.)

Hoarding disorder often results in debilitating functional impairment and may also compromise health-related quality of life (QoL). This study investigated the association between hoarding behavior and QoL relative to six highly impairing medical and psychiatric disorders in a sample of 20,722 participants enrolled in the internet-based Brain Health Registry. Nearly 1 in 8 participants (12.2%) endorsed clinically relevant hoarding symptoms (CHS). In separate multivariable linear regression models, hoarding was more strongly associated with mental QoL than diabetes (Standardizedβ = -0.21, 95% CI: [-0.22, -0.20] vs. -0.01 [-0.02, 0.0]), heart disease (-0.22 [-0.23, -0.20] vs. 0.00 [-0.02, 0.01]), chronic pain (-0.18 [-0.19, -0.16] vs. -0.12 [-0.13, -0.10]), post-traumatic stress disorder (PTSD; -0.20 [-0.22, -0.19] vs. -0.07 [-0.09, -0.06]), and substance use disorder (SUD; -0.21 [-0.23, -0.20] vs. -0.04 [-0.05, -0.03]). Similarly, CHS was more strongly negatively associated with physical QoL than diabetes (-0.11 [-0.10, -0.12] vs. -0.08 [-0.06, -0.09]), major depressive disorder (-0.09 [-0.10, -0.08] vs. -0.05 [-0.06, 0.03]), PTSD (-0.11 [-0.12, -0.10] vs. -0.08 [-0.09, -0.07]), and SUD (-0.12 [-0.13, -0.09] vs. -0.01 [-0.02, 0.00]). Higher hoarding severity was associated with reductions in both mental (Standardizedβ = -0.28, ΔR 2  = 0.08, p < 0.0001) and physical (β = -0.12, ΔR 2  = 0.02, p < 0.0001) QoL, though the strength of the relationship between hoarding symptoms and QoL varied with depression severity. Efforts to improve the overall QoL and well-being of those with CHS are needed., (Published by Elsevier Ltd.)

Optimizing energy acquisition and expenditure is a fundamental trade-off for consumers, strikingly reflected in how mobile organisms use space. Several studies have established that home range size decreases as resource density increases, but the balance of costs and benefits associated with exploiting a given resource density is unclear. We evaluate how the ability of consumers to exploit their resources through movement (termed "resource exploitation") interacts with resource density to influence home range size. We then contrast two hypotheses to evaluate how resource exploitation influences home range size across a vast gradient of productivity and density of human-created linear features (roads and seismic lines) that are known to facilitate animal movements. Under the Diffusion Facilitation Hypothesis, linear features are predicted to lead to more diffuse space use and larger home ranges. Under the Exploitation Efficiency Hypothesis, linear features are predicted to increase foraging efficiency, resulting in less space being required to meet energetic demands and therefore smaller home ranges. Using GPS telemetry data from 142 wolves (Canis lupus) distributed over more than 500,000 km 2 , we found that wolf home range size was influenced by the interaction between resource density and exploitation efficiency. Home range size decreased as linear feature density increased, supporting the Exploitation Efficiency Hypothesis. However, the effect of linear features on home range size diminished in more productive areas, suggesting that exploitation efficiency is of greater importance when resource density is low. These results suggest that smaller home ranges will occur where both linear feature density and primary productivity are higher, thereby increasing regional wolf density., (© 2022 The Ecological Society of America.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor PF-07321332 (nirmatrelvir), in combination with ritonavir (Paxlovid), was recently granted emergency use authorization by multiple regulatory agencies for the treatment of coronavirus disease 2019 (COVID-19) in adults and pediatric patients. Disposition studies on nirmatrelvir in animals and in human reagents, which were used to support clinical studies, are described herein. Plasma clearance was moderate in rats (27.2 ml/min per kg) and monkeys (17.1 ml/min per kg), resulting in half-lives of 5.1 and 0.8 hours, respectively. The corresponding oral bioavailability was moderate in rats (34%-50%) and low in monkeys (8.5%), primarily due to oxidative metabolism along the gastrointestinal tract in this species. Nirmatrelvir demonstrated moderate plasma protein binding in rats, monkeys, and humans with mean unbound fractions ranging from 0.310 to 0.478. The metabolism of nirmatrelvir was qualitatively similar in liver microsomes and hepatocytes from rats, monkeys, and humans; prominent metabolites arose via cytochrome P450 (CYP450)-mediated oxidations on the P1 pyrrolidinone ring, P2 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, and the tertiary-butyl group at the P3 position. Reaction phenotyping studies in human liver microsomes revealed that CYP3A4 was primarily responsible (fraction metabolized = 0.99) for the oxidative metabolism of nirmatrelvir. Minor clearance mechanisms involving renal and biliary excretion of unchanged nirmatrelvir were also noted in animals and in sandwich-cultured human hepatocytes. Nirmatrelvir was a reversible and time-dependent inhibitor as well as inducer of CYP3A activity in vitro. First-in-human pharmacokinetic studies have demonstrated a considerable boost in the oral systemic exposure of nirmatrelvir upon coadministration with the CYP3A4 inhibitor ritonavir, consistent with the predominant role of CYP3A4 in nirmatrelvir metabolism. SIGNIFICANCE STATEMENT: The manuscript describes the preclinical disposition, metabolism, and drug-drug interaction potential of PF-07321332 (nirmatrelvir), an orally active peptidomimetic-based inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease, which has been granted emergency use authorization by multiple regulatory agencies around the globe for the treatment of coronavirus disease 2019 (COVID-19) in COVID-19-positive adults and pediatric patients who are at high risk for progression to severe COVID-19, including hospitalization or death., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Use of 3D printing for microfluidics is a rapidly growing area, with applications involving cell culture in these devices also becoming of interest. 3D printing can be used to create custom-designed devices that have complex features and integrate different material types in one device; however, there are fewer studies studying the ability to culture cells on the various substrates that are available. This work describes the effect of PolyJet 3D-printing technology on cell culture of two cell lines, bovine pulmonary artery endothelial cells (BPAECs) and Madin-Darby Canine Kidney (MDCK) cells, on two different types of printed materials (VeroClear or MED610). It was found that untreated devices, when used for studies of 1 day or more, led to unsuccessful culture. A variety of device treatment methodologies were investigated, with the most success coming from the use of sodium hydroxide/sodium metasilicate solution. Devices treated with this cleaning step resulted in culture of BPAECs and MDCK cells that were more similar to what is obtained in traditional culture flasks (in terms of cell morphology, viability, and cell density). LC-MS/MS analysis (via Orbitrap MS) was used to determine potential leachates from untreated devices. Finally, the use of a fiber scaffold in the devices was utilized to further evaluate the treatment methodology and to also demonstrate the ability to perform 3D culture in such devices. This study will be of use for researchers wanting to utilize these or other cell types in PolyJet-based 3D-printed devices., (© 2022. Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction/background: Adrenal incidentalomas (AIs) are masses > 1 cm found incidentally during radiographic imaging. They are present in up to 4.4% of patients undergoing CT scan, and incidence is increasing with usage and sensitivity of cross-sectional imaging. Most result in diagnosis of adrenal cortical adenoma, questioning guidelines recommending removal of all AIs with negative functional workup. This retrospective study analyzes histological outcome based on size of non-functional adrenal masses., Material and Methods: 10 years of data was analyzed from two academic institutions. Exclusion criteria included patients with positive functional workups, those who underwent adrenalectomy during nephrectomy, < 18 years, and incomplete records. AI radiologic and histologic size, histologic outcome, laterality, imaging modality, gender, and age were collected. T-test was used for comparison of continuous variables, and the two-sided Fisher's exact or chi-square test were used to determine differences for categorical variables. Univariate analysis of each independent variable was performed using simple logistic regression., Results: 73 adrenalectomies met the above inclusion criteria. 60 were detected on CT scan, 12 on MRI, and one on ultrasound. Eight of 73 cases resulted in malignant pathology, 3 of which were adrenocortical carcinoma (ACC). Each ACC measured > 6 cm, with mean radiologic and pathologic sizes of 11.2 cm and 11.3 cm. Both radiologic and pathologic size were significant predictors of malignancy (p = 0.008 and 0.011)., Conclusions: Our results question the generally-accepted 4 cm cutoff for excision of metabolically-silent AIs. They suggest a 6 cm threshold would suffice to avoid removal of benign lesions while maintaining sensitivity for ACC., (© 2022. The Author(s).)

Background: This report describes an unusual meningioma with a large left frontal component and extensive growth within the sagittal sinus and its successful treatment with a staged approach: left frontal craniotomy followed by a sagittal craniotomy and intrinsic removal of the tumor from the sagittal sinus., Observations: A previously healthy 27-year-old presented with 6 months of progressively worsening bilateral headaches, visual changes, and nausea. On examination she had a left cranial nerve VI palsy and severe papilledema. Magnetic resonance imaging revealed a 5.1 × 3.8 × 4.1 cm homogenously enhancing left superior frontal parafalcine extra-axial mass with surrounding vasogenic edema and growth through the sagittal sinus extending just short of the torcula., Lessons: This case report describes a fast-growing meningioma with a unique pattern of spread, growing through the sagittal sinus as if it were a conduit and resulting in complete occlusion of flow in the sinus. An important recognition in this case was that a robust parasagittal venous plexus had developed on either side of the falx cerebri with drainage to the inferior sagittal sinus. This collateral drainage pattern allowed for an extradural opening of the sagittal sinus from front to back and intrinsic resection of the tumor from the sinus with preservation of the lateral walls of the sinus.

A relationship between an acidic pH in the joints, osteoarthritis (OA), and pain has been previously demonstrated. Acidosis Chemical Exchange Saturation Transfer (acidoCEST) indirectly measures the extracellular pH through the assessment of the exchange of protons between amide groups on iodinated contrast agents and bulk water. It is possible to estimate the extracellular pH in the osteoarthritic joint using acidoCEST MRI. However, conventional MR sequences cannot image deep layers of cartilage, meniscus, ligaments, and other musculoskeletal tissues that present with short echo time and fast signal decay. Ultrashort echo time (UTE) MRI, on the other hand, has been used successfully to image those joint tissues. Here, our goal is to compare the pH measured in the knee joints of volunteers without OA and patients with severe OA using acidoCEST-UTE MRI. Patients without knee OA and patients with severe OA were examined using acidoCEST-UTE MRI and the mean pH of cartilage, meniscus, and fluid was calculated. Additionally, the relationship between the pH measurements and the Knee Injury and Osteoarthritis Outcome Score (KOOS) was investigated. AcidoCEST-UTE MRI can detect significant differences in the pH of knee cartilage, meniscus, and fluid between joints without and with OA, with OA showing lower pH values. In addition, symptoms and knee-joint function become worse at lower pH measurements.

Background: Transgender and nonbinary (TNB) populations are disproportionately affected by HIV and few local health departments or HIV surveillance systems collect/report data on TNB identities. Our objective was to estimate the prevalence of HIV testing among TNB adults by US county and state, with a focus on the Ending the HIV Epidemic (EHE) geographies., Methods: We applied a Bayesian hierarchical spatial small area estimation model to data from the 2015 US Transgender Survey, a large national cross-sectional Internet-based survey. We estimated the county- and state-level proportion of TNB adults who ever tested or tested for HIV in the last year by gender identity, race/ethnicity, and age., Results: Our analysis included 26,100 TNB participants with valid zip codes who resided in 1688 counties (54% of all 3141 counties that cover 92% of the US population). The median county-level proportion of TNB adults who ever tested for HIV was 44% (range 10%-80%) and who tested in the last year was 17% (range 4%-44%). Within most counties, testing was highest among transgender women, black respondents, and people aged ≥25 years. HIV testing was lowest among nonbinary people and young adults aged <25 years. The proportion of TNB adults who tested within the last year was very low in most EHE counties and in all 7 rural states., Conclusions: HIV testing among TNB adults is likely below national recommendations in the majority of EHE geographies. Geographic variation in HIV testing patterns among TNB adults indicates that testing strategies need to be tailored to local settings., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

In this work, we demonstrate the ability to use micromolds along with a stacked three-dimensional (3D) printing process on a commercially available PolyJet printer to fabricate microchip electrophoresis devices that have a T-intersection, with channel cross sections as small as 48 × 12 μm 2 being possible. The fabrication process involves embedding removable materials or molds during the printing process, with various molds being possible (wires, brass molds, PDMS molds, or sacrificial materials). When the molds are delaminated/removed, recessed features complementary to the molds are left in the 3D prints. A thermal lab press is used to bond the microchannel layer that also contains printed reservoirs against another solid 3D-printed part to completely seal the microchannels. The devices exhibited cathodic electroosmotic flow (EOF), and mixtures of fluorescein isothiocyanate isomer I (FITC)-labeled amino acids were successfully separated on these 3D-printed devices using both gated and pinched electrokinetic injections. While this application is focused on microchip electrophoresis, the ability to 3D-print against molds that can subsequently be removed is a general methodology to decrease the channel size for other applications as well as to possibly integrate 3D printing with other production processes., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Infectious disease transmission is a nonlinear process with complex, sometimes unintuitive dynamics. Modeling can transform information about a disease process and its parameters into quantitative projections that help decision makers compare public health response options. However, modelers face methodologic challenges, data challenges, and communication challenges, which are exacerbated under the time constraints of a public health emergency. We review methods, applications, challenges and opportunities for real-time infectious disease modeling during public health emergencies, with examples drawn from the two deadliest pandemics in recent history: HIV/AIDS and coronavirus disease 2019 (COVID-19).

The oxazolidinone antibacterial linezolid has been in clinical use for over 20 years, yet knowledge of the contributions of specific cytochrome (CYP) 450 enzymes to the metabolic clearance of this drug were mostly unknown. In this investigation, it was revealed that three P450 enzymes that had not been previously explored in linezolid metabolism, CYP2J2, CYP4F2, and CYP1B1, catalyzed the 2-hydroxylation and de-ethyleneation of the morpholine moiety of linezolid. The intrinsic clearance for linezolid metabolism in pooled human liver microsomes was low at 0.51 μL/min/mg protein, consistent with its in vivo clearance in humans, and the K M was high (>200 μM). In recombinant human P450 enzymes, a rank order of intrinsic clearance values for linezolid 2-hydroxylation were CYP2J2 ≫ CYP4F2 > CYP2C8 > CYP1B1 ≈ CYP2D6 ≈ CYP3A4 > CYP1A1 > CYP3A5, with nine other P450 enzymes showing no linezolid metabolism. The effect of selective inhibitors for these eight P450 enzymes on linezolid metabolism in pooled human liver microsomes was evaluated to provide estimates of the relative fractional contributions of these enzymes to linezolid metabolism. These experiments suggest that CYP2J2 and CYP4F2 contribute about 50% each to linezolid hepatic metabolism. It is proposed that the oxidative metabolic clearance of linezolid is primarily catalyzed by these two unusual P450 enzymes and that this explains the lack of observation of meaningful effects of common perpetrators of drug interactions on linezolid pharmacokinetics. SIGNIFICANCE STATEMENT: Linezolid is an important antibacterial drug, but the enzymes involved in its oxidative metabolism were unknown. In this study, evidence is shown that supports an important role for two enzymes not frequently associated with the metabolism of drugs: cytochrome P450 2J2 and cytochrome P450 4F2. These observations offer insight to understand the results of clinical drug-drug interaction studies conducted on linezolid., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Medical errors were largely concealed prior to the landmark report "To Err Is Human". The purpose of this systematic scoping review was to determine the extent pediatric surgery defines and studies errors, and to explore themes among papers focused on errors in pediatric surgery., Methods: The methodological framework used to conduct this scoping study has been outlined by Arksey and O'Malley. In January 2020, PubMed, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials were searched. Oxford Level of Evidence was assigned to each study; only studies rated Level 3 or higher were included., Results: Of 3,064 initial studies, 12 were included in the final analysis: 4 cohort studies, and 8 outcome/audit studies. This data represented 5,442,000 aggregate patients and 8,893 errors. There were 6 different error definitions and 5 study methods. Common themes amongst the studies included a systems-focused approach, an increase in errors seen with increased complexity, and studies exploring the relationship between error and adverse events., Conclusions: This study revealed multiple error definitions, multiple error study methods, and common themes described in the pediatric surgical literature. Opportunities exist to improve the safety of surgical care of children by reducing errors. Original Scientific Research Type of Study: Systematic Scoping Review Level of Evidence Rating: 1., (Copyright © 2021. Published by Elsevier Inc.)

One-third of current pharmaceuticals target G protein-coupled receptors (GPCRs), the largest receptor superfamily in humans and mediators of diverse physiological processes. This review summarizes the recent progress in GPCR structural dynamics, focusing on class A receptors and insights derived from nuclear magnetic resonance (NMR) and other spectroscopic techniques. We describe the structural aspects of GPCR activation and the various pharmacological models that capture aspects of receptor signaling behavior. Spectroscopic studies revealed that receptors and their signaling complexes are dynamic allosteric systems that sample multiple functional states under basal conditions. The distribution of states within the conformational ensemble and the kinetics of transitions between states are regulated through the binding of ligands, allosteric modulators, and the membrane environment. This ensemble view of GPCRs provides a mechanistic framework for understanding many of the pharmacological phenomena associated with receptor signaling, such as basal activity, efficacy, and functional bias.

Purpose: Evaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors., Methods: A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability., Results: Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo., Conclusions: Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors., Trial Registration: NCT03276858, registered September 8, 2017, retrospectively registered., (© 2021. The Author(s).)

Objectives: To identify postdischarge outcome phenotypes and risk factors for poor outcomes using insurance claims data., Design: Retrospective cohort study., Setting: Single quaternary center., Patients: Children without preexisting tracheostomy who required greater than or equal to 3 days of invasive mechanical ventilation, survived the hospitalization, and had postdischarge insurance eligibility in Colorado's All Payer Claims Database., Interventions: None., Measurements and Main Results: We used unsupervised machine learning to identify functional outcome phenotypes based on claims data representative of postdischarge morbidities. We assessed health trajectory by comparing change in the number of insurance claims between quarters 1 and 4 of the postdischarge year. Regression analyses identified variables associated with unfavorable outcomes. The 381 subjects had median age 3.3 years (interquartile range, 0.9-12 yr), and 147 (39%) had a complex chronic condition. Primary diagnoses were respiratory (41%), injury (23%), and neurologic (11%). We identified three phenotypes: lower morbidity (n = 300), higher morbidity (n = 62), and 1-year nonsurvivors (n = 19). Complex chronic conditions most strongly predicted the nonsurvivor phenotype. Longer PICU stays and tracheostomy placement most strongly predicted the higher morbidity phenotype. Patients with high but improving postdischarge resource use were differentiated by high illness severity and long PICU stays. Patients with persistently high or increasing resource use were differentiated by complex chronic conditions and tracheostomy placement., Conclusions: New morbidities are common after prolonged mechanical ventilation. Identifying phenotypes at high risk of postdischarge morbidity may facilitate prognostic enrichment in clinical trials., Competing Interests: Dr. Maddux’s institution received funding from the Francis Family Foundation and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (K23HD096018). This project was also supported by the Health Data Compass Data Warehouse project (healthdatacompass.org). Virtual Pediatric Systems (VPS) data were provided by our site’s collection of data for the VPS, LLC. Dr. Miller’s institution received funding from the NICHD (K23HD096018). Dr. Mourani’s institution received funding from the National Institutes of Health. Dr. Bennett’s institution received funding from the NICHD, the National Center for Advancing Translational Sciences, and the National Institute of Allergy and Infectious Diseases. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Across plant species and biomes, a conserved set of leaf traits govern the economic strategy used to assimilate and invest carbon. As plants age, they face new challenges that may require shifts in this leaf economic strategy. In this study, we investigate the role of the developmental transition, vegetative phase change (VPC), in altering carbon economics as plants age. We used overexpression of microRNA 156 (miR156), the master regulator of VPC, to modulate the timing of VPC in Populus tremula x alba, Arabidopsis thaliana and Zea mays to understand the impact of this transition on leaf economic traits, including construction cost, payback time and return on investment. Here, we find that VPC causes a shift from a low-cost, quick return juvenile strategy to a high-cost, high-return adult strategy. The juvenile strategy is advantageous in light-limited conditions, whereas the adult strategy provides greater returns in high light. The transition between these strategies is correlated with the developmental decline in the level of miR156, suggesting that is regulated by the miR156/SPL pathway. Our results provide an ecophysiological explanation for the existence of juvenile and adult leaf types and suggest that natural selection for these alternative economic strategies could be an important factor in plant evolution., (© 2022 John Wiley & Sons Ltd.)

Background: Children who have been discharged from hospital in sub-Saharan Africa remain at substantial risk of mortality in the post-discharge period. Antimicrobial resistance (AMR) may be an important factor. We sought to determine the prevalence and risk factors associated with AMR in commensal Escherichia coli (E. coli) from Kenyan children at the time of discharge., Methodology/principle Findings: Fecal samples were collected from 406 children aged 1-59 months in western Kenya at the time of discharge from hospital and cultured for E. coli. Susceptibility to ampicillin, ceftriaxone, cefotaxime, ceftazidime, cefoxitin, imipenem, ciprofloxacin, gentamicin, combined amoxicillin/clavulanic acid, trimethoprim-sulfamethoxazole, azithromycin, and chloramphenicol was determined by disc diffusion according to guidelines from the Clinical and Laboratory Standards Institute (CLSI). Poisson regression was used to determine associations between participant characteristics and the presence of extended-spectrum beta-lactamases (ESBL) producing E. coli. Non-susceptibility to ampicillin (95%), gentamicin (44%), ceftriaxone (46%), and the presence of ESBL (44%) was high. Receipt of antibiotics during the hospitalization was associated with the presence of ESBL (aPR = 2.23; 95% CI: 1.29-3.83) as was being hospitalized within the prior year (aPR = 1.32 [1.07-1.69]). Open defecation (aPR = 2.02; 95% CI: 1.39-2.94), having a toilet shared with other households (aPR = 1.49; 95% CI: 1.17-1.89), and being female (aPR = 1.42; 95% CI: 1.15-1.76) were associated with carriage of ESBL E. coli., Conclusions/significance: AMR is common among isolates of E. coli from children at hospital discharge in Kenya, including nearly half having detectable ESBL., Competing Interests: The authors have declared that no competing interests exist.

Despite the notoriously poor membrane permeability of peptides, many cyclic peptide natural products show high passive membrane permeability and potently inhibit a variety of "undruggable" intracellular targets. A major impediment to the design of cyclic peptides with good permeability is the high desolvation energy associated with the peptide backbone amide NH groups. While several strategies have been proposed to mitigate this deleterious effect, only few studies have used polar side chains to sequester backbone NH groups. We investigated the ability of N , N -pyrrolidinylglutamine (Pye), whose side chain contains a powerful hydrogen-bond-accepting C═O amide group but no hydrogen-bond donors, to sequester exposed backbone NH groups in a series of cyclic hexapeptide diastereomers. Analyses revealed that specific Leu-to-Pye substitutions conferred dramatic improvements in aqueous solubility and permeability in a scaffold- and position-dependent manner. Therefore, this approach offers a complementary tool for improving membrane permeability and solubility in cyclic peptides.

Second-generation anti-amyloid monoclonal antibodies are emerging as a viable therapeutic option for individuals with prodromal and mild dementia due to Alzheimer's disease (AD). Passive immunotherapy with aducanumab (Aduhelm), lecanemab, donanemab, and gantenerumab all lower CNS amyloid (Aβ) burden but come with a significant risk of amyloid-related imaging abnormality (ARIA)-the most common side effect of this class of drugs. While usually asymptomatic and detected only on brain MRI, ARIA may lead to new signs and symptoms including headache, worsening confusion, dizziness, visual disturbances, nausea, and seizures. In addition, one fatality related to ARIA-E (edema) with aducanumab and one fatality due to ARIA-H (hemorrhage) with donanemab are reported to date. ARIA-E may be associated with excessive neuroinflammation and saturation of perivascular clearance pathways, while ARIA-H may be related to vascular amyloid clearance with weakening and rupture of small blood vessels. The risk of ARIA-E is higher at treatment initiation, in ApoE4 carriers, with higher dosage, and with >4 of microhemorrhages on a baseline MRI. The risk of ARIA-H increases with age and cerebrovascular disease. Dose titration mitigates the risk of ARIA, and contraindications include individuals with >4 microhemorrhages and those prescribed anti-platelet or anti-coagulant drugs. A brain MRI is required before aducanumab is initiated, before each scheduled dose escalation, and with any new neurologic sign or symptom. Management of ARIA ranges from continued antibody treatment with monthly MRI monitoring for asymptomatic individuals to temporary or permanent suspension for symptomatic individuals or those with moderate to severe ARIA on MRI. Controlled studies regarding prevention and treatment of ARIA are lacking, but anecdotal evidence suggests that a pulse of intravenous corticosteroids may be of benefit, as well as a course of anticonvulsant for seizures., Competing Interests: RT is a site PI for studies of all of the monoclonal antibodies under discussion, with research funding from Biogen, Eisai, Lilly, and Roche/Genentech to Georgetown University. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Withington and Turner.)