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This report describes the analytical models Lawrence Berkeley National Laboratory (LBNL) developed to estimate impacts of the U.S. Environmental Protection Agency’s (EPA’s) WaterSense® labeling program. The models assess national impacts for WaterSense labeled toilets, faucets, faucet aerators, showerheads, flushing urinals, commercial pre-rinse spray valves, and weather or soil moisture sensor-based irrigation controllers (WBICs) by analyzing national inputs for water use in residential and commercial/institutional (CI) markets. For irrigation controllers, LBNL’s methodology also incorporates a scenario that evaluates impacts in three key large states that are considered to be the principal market for “smart” irrigation controllers: California, Florida, and Texas. The models estimate impacts for the water savings attributable to the program and the net present value (NPV) of the lifetime water savings from more efficient products.

Market penetration of energy-efficient technologies can be estimated using energy optimization models that minimize cost; however, such models typically estimate the minimum cost of optimal pathways under a certain set of non-dynamic assumptions, so technology penetrations determined for the long-term do not fully respond to changing circumstances or costs. In this study, investment costs of energy-efficient technologies are modeled dynamically in the Industrial Sector Energy-Efficiency Model (ISEEM) using a technological learning formula. Results from 24 energy-efficient technologies – 14 existing, 10 emerging – selected from the United States (U.S.) iron and steel sector show that when technological learning is incorporated into the model, total energy consumption of this sector is expected to decrease by 13% (180 PJ) in 2050 compared to energy consumption in a non-learning scenario. Average energy intensity of the steel production improves from 12.3 GJ/t in the non-learning scenario to 10.7 GJ/t in the learning scenario in 2050. This decrease represents a cost savings of US$1.6 billion and a carbon dioxide emissions reduction potential of 14.9 billion tonnes. Results discussed in this paper focus on the U.S. iron and steel sector, but the proposed framework can be applied to study new technology development in any other industrial processes and regions.

The article presents a case study of a 47-year-old woman who presented with dermatomyositis symptoms in 2009. Steroids effected initial remission of symptoms, and the subsequent administration of hydroxychloroquine, azathioprine, and intravenous and subcutaneous immunoglobulin controlled skin symptoms and reduced adverse effects. The patient self-administered infusions, and her quality of life improved with no issues as of 2019. Also noted is the therapy's effectiveness in suitable patients.

Background: AIDS-related Kaposi sarcoma (AIDS-KS) remains a leading cause of morbidity and mortality among people living with HIV in Africa. Mortality among people with AIDS-KS on antiretroviral therapy remains high compared with people on antiretroviral therapy who do not have AIDS-KS., Setting: People living with HIV with Kaposi sarcoma (KS) who participated in 2 randomized trials (A5263/AMC066 [advanced stage] and A5264/AMC067 [mild-to-moderate stage]) conducted by AIDS Clinical Trials Group/AIDS Malignancy Consortium in low- and middle-income countries., Methods: We estimated mortality rates over the trial period. Cox proportional hazards regressions were used to identify baseline characteristics associated with mortality and compared mortality rates between participants who had KS progression within 12 weeks of treatment initiation (early progression of KS [KS-PD]) and those who did not., Results: Of the 329 and 189 eligible participants in A5263/AMC066 and A5264/AMC067, 71 (21.6%) and 24 (12.7%) died, respectively. In both trials, hypoalbuminemia was associated with increased hazards of death compared with normal albumin; A5263/AMC066: mild hypoalbuminemia (adjusted hazard ratio [aHR] = 3.01; 95% CI: 1.42 to 6.29), moderate hypoalbuminemia (aHR = 5.11; 95% CI: 2.54 to 10.29), and severe hypoalbuminemia (aHR = 14.58; 95% CI: 6.32 to 35.60), and A5264/AMC067: mild hypoalbuminemia (aHR = 5.66; 95% CI: 1.90 to 16.93) and moderate hypoalbuminemia (aHR = 7.02; 95% CI: 2.57 to 19.15). The rate of death was higher among participants who had early KS-PD than those without early KS-PD in A5263/AMC066 (HR = 5.09; 95% CI: 1.71 to 15.19) but not in A5264/AMC067 (HR = 1.74; 95% CI: 0.66 to 4.62)., Conclusions: Albumin measurements may be used to identify individuals at higher risk of death after initiating KS treatment and for evaluation of interventions that can reduce AIDS-KS mortality., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Puccinia coronata f. sp. avenae is the causal agent of the disease known as crown rust, which represents a bottleneck in oat production worldwide. Characterization of pathogen populations often involves race (pathotype) assignments using differential sets, which are not uniform across countries. This study compared the virulence profiles of 25 P. coronata f. sp. avenae isolates from Australia using two host differential sets, one from Australia and one from the United States. These differential sets were also genotyped using diversity arrays technology sequencing technology. Phenotypic and genotypic discrepancies were detected on 8 out of 29 common lines between the two sets, indicating that pathogen race assignments based on those lines are not comparable. To further investigate molecular markers that could assist in the stacking of rust resistance genes important for Australia, four published Pc91 -linked markers were validated across the differential sets and then screened across a collection of 150 oat cultivars. Drover, Aladdin, and Volta were identified as putative carriers of the Pc91 locus. This is the first report to confirm that the cultivar Volta carries Pc91 and demonstrates the value of implementing molecular markers to characterize materials in breeding pools of oat. Overall, our findings highlight the necessity of examining seed stocks using pedigree and molecular markers to ensure seed uniformity and bring robustness to surveillance methodologies. [Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license., Competing Interests: The author(s) declare no conflict of interest.

Problem: Physicians in training are responsible for leading clinical teams, coordinating interdisciplinary management, navigating conflict, and supervising and giving feedback to junior learners. Giving feedback and resolving conflict are key leadership skills for internal medicine (IM) residents, many of whom desire additional training. Although these skills are integral to successful leadership for physicians in training, residents receive little explicit education and existing curricula have not established best practices for skill acquisition., Approach: Study authors designed a pilot longitudinal, skills-based curriculum to teach first- through third-year IM residents at the University of Pittsburgh how to give formative feedback and engage in conflict resolution. From February to May 2021, authors delivered a series of interactive lectures utilizing frameworks, workplace-based scenarios, skills practice, and discussion. Skills transfer was evaluated with novel pre- and postcurriculum objective structured clinical examinations (OSCEs) wherein participants played the role of senior resident. Each OSCE involved 2 feedback and 2 conflict resolution stations. OSCE performances were evaluated using an author-created checklist with a 1-4 rating scale. The exposure group comprised post-OSCE participants who attended the curriculum. Data were analyzed using a mixed effects regression model., Outcomes: Thirty-six residents participated in curriculum evaluation, and 23 were included in postcurriculum data analysis. Within feedback, the skill "explores feedback content" significantly improved for exposure group participants (precurriculum median, 2.64; postcurriculum, 3.24; P < .05). For conflict resolution, among the exposure group, the skill "identifies a common goal, value, or purpose" significantly improved (pre, 3.10; post, 3.62; P < .05)., Next Steps: This curriculum and evaluation can serve as a stepping stone for further evidence-based leadership frameworks, curricula, and evaluations developed specifically for physicians within their unique leadership roles. The feedback and conflict resolution frameworks used in this curriculum can be applied to various medical specialties, with specialty-relevant scenario adaptations for interactive skills practice., (Copyright © 2023 the Association of American Medical Colleges.)

INTRODUCTION: Work-related stress is common in pilots, with broad implications, including the potential development of mental health symptoms and sometimes even psychiatric disease. This commentary argues for the use of narrative as a tool to promote preventive health behaviors in pilots and combat misinformation about aeromedical certification related to mental health. Hoffman WR, McNeil M, Tvaryanas A. The untapped potential of narrative as a tool in aviation mental health and certification . Aerosp Med Hum Perform. 2024; 95(3):165-166.

Tenofovir disoproxil fumarate (TDF), a potent and commonly used antiretroviral drug, is associated with renal tubular dysfunction and renal adverse events. We evaluated the frequency of, time to, and baseline risk factors for discontinuing TDF from initial antiretroviral therapy (ART) regimens because of renal adverse events from presumed tenofovir renal toxicity. We conducted an observational cohort study as a secondary analysis of data from four clinical trials conducted mainly in low- and middle-income countries. We included ART naïve participants living with HIV who started TDF-containing ART regimens in the trials. Participants had to have estimated creatinine clearance (eCrCl) equal to or greater than 60ml/min before starting ART. The primary outcome was the first instance of discontinuing TDF because of renal adverse events attributed to tenofovir renal toxicity during the first 48 weeks after starting ART. We evaluated the cumulative incidence of discontinuing TDF and associated risk factors using Fine and Gray competing risk regression models with a backward elimination variable selection strategy. There were 2802 ART-naïve participants who started TDF-containing ART from the four clinical trials were included in the analysis. Fifty-eight percent were female, the median age was 34 years, and 87% had CD4 cell counts less than 200 cells/μl. Sixty-four participants (2.4%, 95% CI 1.7%-2.8%) discontinued TDF due to renal adverse events. Among the 64 participants, the median time to discontinue TDF was 9.4 weeks (IQR: 3.4-20.7 weeks). From multivariable Fine and Gray regression models, risk factors for discontinuing TDF were older age, CD4 cell count <200 cells/μl, presence and severity of anemia, and eCrCl <90 ml/min. The risk of discontinuing TDF because of renal adverse events was low in participants initiating TDF-containing ART with advanced HIV and normal renal function, attesting to the tolerability of TDF in ART in low- and middle-income countries., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ngongondo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We report on the existence of two phosphatidic acid biosynthetic pathways in mycobacteria, a classical one wherein the acylation of the sn-1 position of glycerol-3-phosphate (G3P) precedes that of sn-2 and another wherein acylations proceed in the reverse order. Two unique acyltransferases, PlsM and PlsB2, participate in both pathways and hold the key to the unusual positional distribution of acyl chains typifying mycobacterial glycerolipids wherein unsaturated substituents principally esterify position sn-1 and palmitoyl principally occupies position sn-2. While PlsM selectively transfers a palmitoyl chain to the sn-2 position of G3P and sn-1-lysophosphatidic acid (LPA), PlsB2 preferentially transfers a stearoyl or oleoyl chain to the sn-1 position of G3P and an oleyl chain to sn-2-LPA. PlsM is the first example of an sn-2 G3P acyltransferase outside the plant kingdom and PlsB2 the first example of a 2-acyl-G3P acyltransferase. Both enzymes are unique in their ability to catalyze acyl transfer to both G3P and LPA., (© 2023. Springer Nature Limited.)

The covalent modification of bacterial (lipo)polysaccharides with discrete substituents may impact their biosynthesis, export and/or biological activity. Whether mycobacteria use a similar strategy to control the biogenesis of its cell envelope polysaccharides and modulate their interaction with the host during infection is unknown despite the report of a number of tailoring substituents modifying the structure of these glycans. Here, we show that discrete succinyl substituents strategically positioned on Mycobacterium tuberculosis (Mtb) lipoarabinomannan govern the mannose-capping of this lipoglycan and, thus, much of the biological activity of the entire molecule. We further show that the absence of succinyl substituents on the two main cell envelope glycans of Mtb, arabinogalactan and lipoarabinomannan, leads to a significant increase of pro-inflammatory cytokines and chemokines in infected murine and human macrophages. Collectively, our results validate polysaccharide succinylation as a critical mechanism by which Mtb controls inflammation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Palčeková et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: In this scoping review, we evaluated existing literature related to factors influencing treatment decision-making for patients diagnosed with cancer in low- and middle-income countries, noting factors that influence decisions to pursue treatment with curative versus non-curative intent. We identified an existing framework for adult cancer developed in a high-income country (HIC) context and described similar and novel factors relevant to low-and middle-income country settings., Methods: We used scoping review methodology to identify and synthesize existing literature on factors influencing decision-making for pediatric and adult cancer in these settings. Articles were identified through an advanced Boolean search across six databases, inclusive of all article types from inception through July 2022., Results: Seventy-nine articles were identified from 22 countries across six regions, primarily reporting the experiences of lower-middle and upper-middle-income countries. Included articles largely represented original research (54%), adult cancer populations (61%), and studied patients as the targeted population (51%). More than a quarter of articles focused exclusively on breast cancer (28%). Approximately 30% described factors that influenced decisions to choose between therapies with curative versus non-curative intent. Of 56 reported factors, 22 novel factors were identified. Socioeconomic status, reimbursement policies/cost of treatment, and treatment and supportive care were the most commonly described factors., Conclusions: This scoping review expanded upon previously described factors that influence cancer treatment decision-making in HICs, broadening knowledge to include perspectives of low- and middle-income countries. While global commonalities exist, certain variables influence treatment choices differently or uniquely in different settings. Treatment regimens should further be tailored to local environments with consideration of contextual factors and accessible resources that often impact decision-making., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The opioid epidemic in the US continues to worsen. Opioid-only and polysubstance-involved opioid overdose deaths are increasing among adolescents and young adults, who have limited knowledge of opioid overdose prevention, including recognition and response. College campuses have infrastructure to support national-level implementation of evidence-based public health strategies for providing opioid overdose prevention and naloxone training programs among this priority population. However, college campuses are an underutilized, understudied setting for this programming. To address this gap, we conducted research assessing barriers and facilitators to planning and implementing this programming on college campuses., Methods: We held 9 focus groups among purposively selected campus stakeholders whose perceptions were important to understand in planning for the dissemination and implementation of opioid overdose prevention and naloxone training. Focus group scripts were informed by The Consolidated Framework for Implementation Research (CFIR) to query about perceptions of opioid and other substance use, opioid and other substance use-related resources, and naloxone administration training. We used a deductive-inductive, iterative approach to thematic analysis., Results: Themes about implementation barriers included (1) the perception that problematic use of other (non-opioid) substances was more prevalent than opioid use on campus and focus on those substances would be a greater priority on college campuses; (2) student schedules were overwhelmed with academic commitments and extracurricular activities, making delivery of additional training challenging; (3) barriers related to the perceived complexity and decentralization of communication on campus, preventing students from knowing how to access substance use-related resources. Themes about implementation facilitators included (1) framing naloxone training as important in becoming a responsible leader on campus and in the broader community and (2) leveraging existing infrastructure, champions within existing campus groups, and tailored messaging to facilitate participation in naloxone training., Conclusions: This is the first study to provide in-depth insights into potential barriers and facilitators to widespread, routine implementation of naloxone/opioid education on undergraduate college campuses. The study captured diverse stakeholder perspectives and was theoretically grounded in CFIR, contributing to the growing literature on the application and refinement of CFIR across diverse community and school contexts., (© 2023. The Author(s).)

There is mounting evidence that the development of Alzheimer's disease (AD) interacts extensively with immunological processes in the brain and extends beyond the neuronal compartment. Accumulation of misfolded proteins can activate an innate immune response that releases inflammatory mediators and increases the severity and course of the disease. It is widely known that type-I interferon-driven neuroinflammation in the central nervous system (CNS) accelerates the development of numerous acute and chronic CNS diseases. It is becoming better understood how the cyclic GMP-AMP synthase (cGAS) and its adaptor protein Stimulator of Interferon Genes (STING) triggers type-I IFN-mediated neuroinflammation. We discuss the principal elements of the cGAS-STING signaling pathway and the mechanisms underlying the association between cGAS-STING activity and various AD pathologies. The current understanding of beneficial and harmful cGAS-STING activity in AD and the current treatment pathways being explored will be discussed in this review. The cGAS-STING regulation offers a novel therapeutic opportunity to modulate inflammation in the CNS because it is an upstream regulator of type-I IFNs.

Background: There has been an increase in the integration of qualitative studies in randomised controlled trials. The purpose of this article is to reflect on our experience of carrying out a rapid qualitative study during a feasibility trial of goal-directed fluid therapy (GDFT) in patients with acute pancreatitis, including our sharing of emerging findings and the use of these findings by the trial team., Methods: The study was designed as a rapid feedback evaluation and combined interviews with staff and patients who took part in the trial., Findings: The rapid qualitative study pointed to common problems in trial recruitment among multiple sites, where lack of engagement of clinical teams across sites might impact negatively on patient recruitment. The article describes how the use of rapid feedback loops can be used as the trial is ongoing to inform changes in implementation. It also covers the potential challenges of working rapidly and collaborative with the trial team., Conclusions: Rapid feedback evaluations can be used to generate findings across all stages of trial design and delivery. Additional research is required to explore the implementation of this research design in other settings and trial designs., (© 2023. The Author(s).)

Cardiovascular disease (CVD) is the leading cause of death for American women. CVD is preventable although risk reduction goals are not achieved for women compared with men. Considering a woman's cardiometabolic profile for prevention counseling and prescribing may help. Coronary artery calcium scores provide additional risk assessment and reproductive and menopause histories identify risk enhancers. Diagnosis of CVD is often delayed, and treatment is less optimal for women compared with men. Differences in presentation and underlying CVD etiology (Including spontaneous coronary artery dissection and microvascular disease) may partially account for these disparities. Improvements in CVD imaging to better diagnose these etiologies may benefit women's care., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Depression may influence treatment participation and outcomes of people with post-stroke aphasia, yet its prevalence and associated characteristics in aphasia are poorly understood. Using retrospective data from an overarching experimental study, we examined depressive symptoms and their relationship to demographic and language characteristics in people with chronic aphasia. As a secondary objective, we compared prevalence of depressive symptoms among the overarching study's included and excluded participants., Methods: We examined retrospective data from 121 individuals with chronic aphasia including depression scale scores, demographic information (sex, age, time post onset of stroke, education, race/ethnicity, and Veteran status), and scores on assessments of general and modality-specific language impairments., Results: Approximately 50% of participants reported symptoms indicative of depressive disorders: 23% indicative of major depression and 27% indicative of mild depression. Sex (males) and comparatively younger age emerged as statistically significant variables associated with depressive symptoms; naming ability was minimally associated with depressive symptoms. Time post onset of stroke, education level, race/ethnicity, Veteran status, and aphasia severity were not significantly associated with depressive symptoms. Depression-scale scores were significantly higher for individuals excluded from the overarching study compared to those who were included., Conclusions: The rate of depressive disorders in this sample was higher than rates of depression reported in the general stroke literature. Participant sex, age, and naming ability emerged as factors associated with depressive symptoms, though these links appear complex, especially given variable reports from prior research. Importantly, depressive symptoms do not appear to diminish over time for individuals with chronic aphasia. Given these results and the relatively limited documentation of depression in aphasia literature, depression remains a pressing concern for aphasia research and routine clinical care., (Copyright © 2022. Published by Elsevier Inc.)

We performed a high-throughput phenotypic whole cell screen of Mycobacterium tuberculosis against a diverse chemical library of approximately 100,000 compounds from the AbbVie corporate collection and identified 24 chemotypes with anti-tubercular activity. We selected two series for further exploration and conducted structure-activity relationship studies with new analogs for the 4-phenyl piperidines (4PP) and phenylcyclobutane carboxamides (PCB). Strains with mutations in MmpL3 demonstrated resistance to both compound series. We isolated resistant mutants for the two series and found mutations in MmpL3. These data suggest that MmpL3 is the target, or mechanism of resistance for both series., (© 2022. The Author(s).)

Background: Many primary care providers (PCPs) in the Veterans Health Administration need updated clinical training in women's health. The objective was to design, implement, and evaluate a training program to increase participants' comfort with and provision of care to women Veterans, and foster practice changes in women's health care at their local institutions. Methods: The Women's Health Mini-Residency was developed as a multi-day training program, based on principles of adult learning, wherein knowledge gleaned through didactic presentations was solidified during small-group case study discussions and further enhanced by hands-on training and creation of a facility-specific action plan to improve women Veterans' care. Pre, post, and 6-month surveys assessed attendees' comfort with and provision of care to women. The 6-month survey also queried changes in practice, promulgation of program content, and action plan progress. Results: From 2008 to 2019, 2912 PCPs attended 26 programs. A total of 2423 (83.2%) completed pretraining and 2324 (79.3%) completed post-training surveys. The 6-month survey was sent to the 645 attendees from the first 14 programs; 297 (46.1%) responded. Comparison of pre-post responses indicated significant gains in comfort managing all 19 content areas. Six-month data showed some degradation, but comfort remained significantly improved from baseline. At 6 months, participants also reported increases in providing care to women, including performing more breast and pelvic examinations, dissemination of program content to colleagues, and progress on action plans. Conclusions: This interactive program appears to have been successful in improving PCPs' comfort in providing care for women Veterans and empowering them to implement institutional change.

Background: Most children needing palliative care (PC) live in low- and middle-income countries. In Colombia, pediatric palliative care (PPC) knowledge among healthcare professionals (HCPs) is lacking as PPC is not included in the educational curricula of healthcare programs. Therefore, specific training that improves knowledge of HCPs and access to PC for children and their families is needed. To address this gap, we organized and conducted the Essential Messages in Palliative Care and Pain Management in Children (EmPalPed), an educational toolkit to increase awareness and promote essential knowledge in PPC for low- and middle-income countries. Methodology: The EmPalPed toolkit consisted of a 5-h virtual workshop with small working groups of HCPs caring for children with life-threatening conditions such as cancer. The toolkit was organized along five key domains: (1) PC as it relates to the concept of quality of life (QoL), (2) effective communication, (3) addressing pain management as a top priority, (4) providing end-of-life care, and (5) access to high-quality PC as a fundamental human right. The workshop activities included different educational strategies and tools (e.g., a pocket guide for pain assessment and management, a PPC booklet, a quick guide for communicating bad news, role playing, and discussions of clinical cases). Results: A total of 145 HCPs from 22 centers were trained. The post-test analysis for HCPs showed that attitude and knowledge about communication (p < 0.001), pain assessment (p < 0.001), first-line opioid of choice in children (p < 0.001), and palliative sedation (p < 0.001) had positive and statistically significant changes from the pre-test analysis. Discussion: This study supported the notion that the EmPalPed educational toolkit is an effective mechanism for raising awareness regarding PPC as well as providing training in many of the key aspects of PPC. The EmPalPed training approach should be studied beyond this setting, and the impact should be measured longitudinally.

We previously identified a series of triazolopyrimidines with antitubercular activity. We determined that Mycobacterium tuberculosis strains with mutations in QcrB, a subunit of the cytochrome bcc-aa3 supercomplex, were resistant. A cytochrome bd oxidase deletion strain was more sensitive to this series. We isolated resistant mutants with mutations in Rv1339. Compounds led to the depletion of intracellular ATP levels and were active against intracellular bacteria, but they did not inhibit human mitochondrial respiration. These data are consistent with triazolopyrimidines acting via inhibition of QcrB.

Background: Northern England has been experiencing a persistent rise in the number of primary liver cancers, largely driven by an increasing incidence of hepatocellular carcinoma (HCC) secondary to alcohol-related liver disease and non-alcoholic fatty liver disease. Here we review the effect of the COVID-19 pandemic on primary liver cancer services and patients in our region., Objective: To assess the impact of the COVID-19 pandemic on patients with newly diagnosed liver cancer in our region., Design: We prospectively audited our service for the first year of the pandemic (March 2020-February 2021), comparing mode of presentation, disease stage, treatments and outcomes to a retrospective observational consecutive cohort immediately prepandemic (March 2019-February 2020)., Results: We observed a marked decrease in HCC referrals compared with previous years, falling from 190 confirmed new cases to 120 (37%). Symptomatic became the the most common mode of presentation, with fewer tumours detected by surveillance or incidentally (% surveillance/incidental/symptomatic; 34/42/24 prepandemic vs 27/33/40 in the pandemic, p=0.013). HCC tumour size was larger in the pandemic year (60±4.6 mm vs 48±2.6 mm, p=0.017), with a higher incidence of spontaneous tumour haemorrhage. The number of new cases of intrahepatic cholangiocarcinoma (ICC) fell only slightly, with symptomatic presentation typical. Patients received treatment appropriate for their cancer stage, with waiting times shorter for patients with HCC and unchanged for patients with ICC. Survival was associated with stage both before and during the pandemic. 9% acquired COVID-19 infection., Conclusion: The pandemic-associated reduction in referred patients in our region was attributed to the disruption of routine healthcare. For those referred, treatments and survival were appropriate for their stage at presentation. Non-referred or missing patients are expected to present with more advanced disease, with poorer outcomes. While protective measures are necessary during the pandemic, we recommend routine healthcare services continue, with patients encouraged to engage., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Alcohol use disorder (AUD) is commonly undertreated. Physicians cite discomfort with AUD medication as a barrier to treatment. While several curricula teach and assess screening and brief interventions, few teach and assess learner knowledge of treatment options., Methods: We created a video- and case-based curriculum for internal medicine residents delivered by 16 internal medicine faculty in three 30-minute sessions at four clinic sites. Learner knowledge, attitudes, and confidence were assessed before and after the curriculum. We used qualitative methods to evaluate learner reflections. We also assessed faculty satisfaction with the curriculum., Results: Of 153 residents receiving the curriculum, 35 (23%) completed both pre- and postsurveys. Median percent correct on knowledge questions improved from 67% pre- to 80% postcurriculum ( p < .001). Confidence increased for all three items assessing it, with a notable increase in confidence with pharmacotherapy (2.9 pre- vs. 4.5 postcurriculum on a 7-point Likert scale with high scores indicating greater confidence, p < .001). Positive attitudes toward people with AUD increased from 3.4 pre- to 3.9 postcurriculum ( p < .001) on a 7-point Likert scale. Learners continued to express concerns about prescribing logistics, the role of primary care, and management of ongoing use. Thirteen of 16 faculty (83%) completed the postcurricular survey; all said they would be happy to facilitate again., Discussion: Implementation of this curriculum for the management of AUD improved resident knowledge, attitudes, and confidence in AUD treatment. The curriculum was acceptable to faculty and is ideal for programs looking to expand teaching about AUD., (© 2022 Spinella et al.)

Background: Goal-directed fluid therapy (GDFT) has been shown to reduce the complications following a variety of major surgical procedures, possibly mediated by improved organ perfusion and function. We have shown that it is feasible to randomise patients to GDFT or standard fluid management following liver transplant in the cardiac-output optimisation following liver transplantation (COLT) trial. The current study compares end organ function in patients from the COLT trial who received GDFT in comparison to those receiving standard care (SC) following liver transplant., Methods: Adult patients with liver cirrhosis undergoing liver transplantation were randomised to GDFT or SC for the first 12 h following surgery as detailed in a published trial protocol. GDFT protocol was based on stroke volume (SV) optimisation using 250 ml crystalloid boluses. Total fluid administration and time to extubation were recorded. Hourly SV and cardiac output (CO) readings were recorded from the non-invasive cardiac output monitoring (NICOM) device in both groups. Pulmonary function was assessed by arterial blood gas (ABG) and ventilatory parameters. Lung injury was assessed using PaO 2 :FiO 2 ratios and calculated pulmonary compliance. The KDIGO score was used for determining acute kidney injury. Renal and liver graft function were assessed during the post-operative period and at 3 months and 1-year., Results: 60 patients were randomised to GDFT (n = 30) or SC (n = 30). All patients completed the 12 h intervention period. GDFT group received a significantly higher total volume of fluid during the 12 h trial intervention period (GDFT 5317 (2335) vs. SC 3807 (1345) ml, p = 0.003); in particular crystalloids (GDFT 3968 (2073) vs. SC 2510 (1027) ml, p = 0.002). There was no evidence of significant difference between the groups in SV or CO during the assessment periods. Time to extubation, PaO2: FIO 2 ratios, pulmonary compliance, ventilatory or blood gas measurements were similar in both groups. There was a significant rise in serum creatinine from baseline (77 μmol/L) compared to first (87 μmol/L, p = 0.039) and second (107 μmol/L, p = 0.001) post-operative days. There was no difference between GDFT and SC in the highest KDIGO scores for the first 7 days post-LT. At 1-year follow-up, there was no difference in need for renal replacement therapy or graft function., Conclusions: In this randomised trial of fluid therapy post liver transplant, GDFT was associated with an increased volume of crystalloids administered but did not alter early post-operative pulmonary or renal function when compared with standard care., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

The Mammary gland undergoes complicated epithelial remodeling to form lobuloalveoli during pregnancy, in which basal epithelial cells remarkably increase to form a basket-like architecture. However, it remains largely unknown how dormant mammary basal stem/progenitor cells involve in lobuloalveolar development. Here, we show that Nfatc1 expression marks a rare population of mammary epithelial cells with the majority being basal epithelial cells. Nfatc1 reporter-marked basal epithelial cells are relatively dormant mammary stem/progenitor cells. Although Nfatc1 reporter-marked basal epithelial cells have limited contribution to the homeostasis of mammary epithelium, they divide rapidly during pregnancy and contribute to lobuloalveolar development. Furthermore, Nfatc1 reporter-marked basal epithelial cells are preferentially used for multiple pregnancies. Using single-cell RNA-seq analysis, we identify multiple functionally distinct clusters within the Nfatc1 reporter-marked cell-derived progeny cells during pregnancy. Taken together, our findings underscore Nfatc1 reporter-marked basal cells as dormant stem/progenitor cells that contribute to mammary lobuloalveolar development during pregnancy., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, affect several million individuals worldwide. These diseases are heterogeneous at the clinical, immunological and genetic levels and result from complex host and environmental interactions. Investigating drug efficacy for IBD can improve our understanding of why treatment response can vary between patients. We propose an explainable machine learning (ML) approach that combines bioinformatics and domain insight, to integrate multi-modal data and predict inter-patient variation in drug response. Using explanation of our models, we interpret the ML models' predictions to infer unique combinations of important features associated with pharmacological responses obtained during preclinical testing of drug candidates in ex vivo patient-derived fresh tissues. Our inferred multi-modal features that are predictive of drug efficacy include multi-omic data (genomic and transcriptomic), demographic, medicinal and pharmacological data. Our aim is to understand variation in patient responses before a drug candidate moves forward to clinical trials. As a pharmacological measure of drug efficacy, we measured the reduction in the release of the inflammatory cytokine TNFα from the fresh IBD tissues in the presence/absence of test drugs. We initially explored the effects of a mitogen-activated protein kinase (MAPK) inhibitor; however, we later showed our approach can be applied to other targets, test drugs or mechanisms of interest. Our best model predicted TNFα levels from demographic, medicinal and genomic features with an error of only 4.98% on unseen patients. We incorporated transcriptomic data to validate insights from genomic features. Our results showed variations in drug effectiveness (measured by ex vivo assays) between patients that differed in gender, age or condition and linked new genetic polymorphisms to patient response variation to the anti-inflammatory treatment BIRB796 (Doramapimod). Our approach models IBD drug response while also identifying its most predictive features as part of a transparent ML precision medicine strategy., Competing Interests: The authors APC, LJG, EPK, MM declare that they have no competing interests. REPROCELL Europe Ltd is a commercial provider of laboratory-based tests for preclinical research. GM, KB and DCB are all paid employees of REPROCELL Europe. These commercial affiliations do not alter adherence of the authors to the journal policies on sharing data and materials.

Mammary gland is an outstanding system to study the regulatory mechanisms governing adult epithelial stem cell activity. Stem cells in the basal layer of the mammary gland fuel the morphogenesis and regeneration of a complex epithelial network during development and upon transplantation. The self-renewal of basal stem/progenitor cells is subjected to regulation by both cell-intrinsic and extrinsic mechanisms. Nfatc1 is a transcription factor that regulates breast tumorigenesis and metastasis, but its role in mammary epithelial development and stem cell function has not been investigated. Here we show that Nfatc1 is expressed in a small subset of mammary basal epithelial cells and its epithelial-specific deletion results in mild defects in side branching and basal-luminal cell balance. Moreover, Nfatc1-deficient basal cells exhibit reduced colony forming ability in vitro and somewhat compromised regenerative potential upon transplantation. Thus, our study provides evidence for a detectable yet non-essential role of Nfatc1 in mammary epithelial morphogenesis and basal stem/progenitor cell self-renewal., (© 2021. The Author(s).)

Autophagy is an important degradative pathway that eliminates misfolded proteins and damaged organelles from cells. Autophagy is crucial for neuronal homeostasis and function. A lack of or deficiency in autophagy leads to the accumulation of protein aggregates, which are associated with several neurodegenerative diseases. Compared with non-neuronal cells, neurons exhibit rapid autophagic flux because damaged organelles or protein aggregates cannot be diluted in post-mitotic cells; because of this, these cells exhibit characteristic features of autophagy, such as compartment-specific autophagy, which depends on polarized structures and rapid autophagy flux. In addition, neurons exhibit compartment-specific autophagy, which depends on polarized structures. Neuronal autophagy may have additional physiological roles other than amino acid recycling. In this review, we focus on the characteristics and regulatory factors of neuronal autophagy. We also describe intracellular selective autophagy in neurons and its association with neurodegenerative diseases.

Background: Despite oxygen being the commonest drug administered to critically ill patients we do not know which oxygen saturation (SpO 2 ) target results in optimal survival outcomes in those receiving mechanical ventilation. We therefore conducted a feasibility randomised controlled trial in the United Kingdom (UK) to assess whether it would be possible to host a larger national multi-centre trial to evaluate oxygenation targets in mechanically ventilated patients., Methods: We set out to recruit 60 participants across two sites into a trial in which they were randomised to receive conservative oxygenation (SpO 2 88-92%) or usual care (control - SpO 2 ≥96%). The primary outcome was feasibility; factors related to safety and clinical outcomes were also assessed., Results: A total of 34 patients were recruited into the study until it was stopped due to time constraints. A number of key barriers to success were identified during the course of the study. The conservative oxygenation intervention was feasible and appeared to be safe in this small patient cohort and it achieved wide separation of the median time-weighted average (IQR) SpO 2 at 91% (90-92%) in conservative oxygenation group versus 97% (96-97%) in control group., Conclusion: Whilst conservative oxygenation was a feasible and safe intervention which achieved clear group separation in oxygenation levels, the model used in this trial will require alterations to improve future participant recruitment rates in the UK., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DSM and MGM are in part funded by the UCLH/UCL NIHR Biomedical Research Centre. MPWG is in part funded by the Southampton NIHR Biomedical Research Centre., (© The Intensive Care Society 2021.)

LppX is an important virulence factor essential for surface localization of phthiocerol dimycocerosates (DIM) in Mycobacterium tuberculosis. Based on Concanavalin A recognition, M. tuberculosis LppX (LppX-tb) was initially proposed to be glycosylated in M. tuberculosis and more recently this glycosylation was characterized by mass spectrometry analysis on LppX-tb expressed and purified from Corynebacterium glutamicum. Here, using this model organism and Mycobacterium smegmatis, we show that S16 and T18 residues of LppX-tb are indeed glycosylated with several hexoses units. Interestingly this glycosylation is strictly dependent on the mannosyl transferase PMT which, in M. tuberculosis, has been reported to be crucial for virulence. Using a site directed mutagenesis approach, we were able to show that the absence of S16 and T18 glycosylation does not alter phthiocerol dimycocerosates (DIM) localization in M. tuberculosis., Competing Interests: Declaration of competing interest None declared., (Copyright © 2021 Institut Pasteur. All rights reserved.)

Resistance of sugarcane (Saccharum officinarum L.) to smut disease (caused by Sporisorium scitamineum) is driven by two separate mechanisms, external and internal resistance. Two progenies generated from an introgression cross, with contrasting responses to smut infection were used to investigate this interaction. Histopathological screening at different stages of the plant growth was used to determine the extent of mycelium growth within sugarcane tissues. Ten disease resistance-related genes were selected, and the relative expression determined using quantitative real-time reverse transcription PCR (real-time RT-qPCR). The results revealed that PR10, HCT1 and ScChi were down-regulated in the susceptible progeny and up-regulated in the resistant progeny early infection process. This may reflect an early attempt to halt pathogen development by increasing the lignin deposition at the infection site. At 8 weeks post-inoculation, they were highly up-regulated in the susceptible progeny coincided with whip development. This reveals a major role for these genes to whip development in the susceptible progeny and indicates that while PR10 is involved in the resistance mechanism of resistant progeny early infection process it also has a role in susceptibility. These results on genetically related progeny with different responses to smut infection reveal a complex interaction of genes and gene networks being induced in response to fungal invasion.

Background: The urine lipoarabinomannan (LAM) antigen test is a tuberculosis (TB) diagnostic test with highest sensitivity in individuals with advanced human immunodeficiency virus (HIV). Its role in TB diagnostic algorithms for HIV-positive outpatients remains unclear., Methods: The AIDS Clinical Trials Group (ACTG) A5274 trial demonstrated that empiric TB therapy did not improve 24-week survival compared to isoniazid preventive therapy (IPT) in TB screen-negative HIV-positive adults initiating antiretroviral therapy with CD4 counts <50 cells/µL. Retrospective LAM testing was performed on stored urine obtained at baseline. We determined the proportion of LAM-positive participants and conducted modified intent-to-treat analysis excluding LAM-positive participants to determine the effect on 24-week survival, TB incidence, and time to TB using Kaplan-Meier method., Results: A5274 enrolled 850 participants; 53% were male and the median CD4 count was 18 (interquartile range, 9-32) cells/µL. Of the 850, 566 (67%) had LAM testing (283 per arm); 28 (5%) were positive (21 [7%] and 7 [2%] in the empiric and IPT arms, respectively). Of those LAM-positive, 1 participant in each arm died and 5 of 21 and 0 of 7 in empiric and IPT arms, respectively, developed TB. After excluding these 28 cases, there were 19 and 21 deaths in the empiric and IPT arms, respectively (P = .88). TB incidence remained higher (4.6% vs 2%, P = .04) and time to TB remained faster in the empiric arm (P = .04)., Conclusions: Among outpatients with advanced HIV who screened negative for TB by clinical symptoms, microscopy, and Xpert testing, LAM testing identified an additional 5% of individuals with TB. Positive LAM results did not change mortality or TB incidence., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Racism in the United States has been cited as a key driver of racial health inequities. Racism as a public health crisis has been in the forefront, particularly with respect to state and municipal governments that have developed legislation, resolutions, and declarations. This policy brief includes a review of resolutions and declarations across the US related to Racism as a Public Health Crisis through the end of September 2020. There were 125 resolutions reviewed for content related to the history of racism, reference to racial health equity data, content related to action steps or implementation, and any accompanying funding or resources. We found that the majority of policies name racism as critical in addressing racial inequities in health with limited details about specific actions, funding, or resources., 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 © 2021 Mendez, Scott, Adodoadji, Toval, McNeil and Sindhu.)

Bovine tuberculosis is an important animal and zoonotic disease caused by Mycobacterium bovis . The innate immune response is the first line of defense against pathogens and is also crucial for the development of an efficient adaptive immune response. In this study we used an in vitro co-culture model of antigen presenting cells (APC) and autologous lymphocytes derived from peripheral blood mononuclear cells to identify the cell populations and immune mediators that participate in the development of an efficient innate response capable of controlling the intracellular replication of M. bovis . After M. bovis infection, bovine immune cell cultures displayed upregulated levels of iNOS, IL-22 and IFN-γ and the induction of the innate immune response was dependent on the presence of differentiated APC. Among the analyzed M. bovis isolates, only a live virulent M. bovis isolate induced an efficient innate immune response, which was increased upon stimulation of cell co-cultures with the M. bovis culture supernatant. Moreover, we demonstrated that an allelic variation of the early secreted protein ESAT-6 (ESAT6 T63A) expressed in the virulent strain is involved in this increased innate immune response. These results highlight the relevance of the compounds secreted by live M. bovis as well as the variability among the assessed M. bovis strains to induce an efficient innate immune response., 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 © 2021 Blanco, Gravisaco, Bigi, García, Marquez, McNeil, Jackson and Bigi.)

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) hospitalizations and deaths disportionally affect males and older ages. Here we investigated the impact of male sex and age comparing sex-matched or age-matched ferrets infected with SARS-CoV-2. Differences in temperature regulation was identified for male ferrets which was accompanied by prolonged viral replication in the upper respiratory tract after infection. Gene expression analysis of the nasal turbinates indicated that 1-year-old female ferrets had significant increases in interferon response genes post infection which were delayed in males. These results provide insight into COVID-19 and suggests that older males may play a role in viral transmission due to decreased antiviral responses., (© 2021. The Author(s).)

Background: The SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2) has led to more than 165 million COVID-19 cases and >3.4 million deaths worldwide. Epidemiological analysis has revealed that the risk of developing severe COVID-19 increases with age. Despite a disproportionate number of older individuals and long-term care facilities being affected by SARS-CoV-2 and COVID-19, very little is understood about the immune responses and development of humoral immunity in the extremely old person after SARS-CoV-2 infection. Here we conducted a serological study to investigate the development of humoral immunity in centenarians following a SARS-CoV-2 outbreak in a long-term care facility., Methods: Extreme aged individuals and centenarians who were residents in a long-term care facility and infected with or exposed to SARS-CoV-2 were investigated between April and June 2020 for the development of antibodies to SARS-CoV-2. Blood samples were collected from positive and bystander individuals 30 and 60 days after original diagnosis of SARS-CoV-2 infection. Plasma was used to quantify IgG, IgA, and IgM isotypes and subsequent subclasses of antibodies specific for SARS-CoV-2 spike protein. The function of anti-spike was then assessed by virus neutralization assays against the native SARS-CoV-2 virus., Findings: Fifteen long-term care residents were investigated for SARS-CoV-2 infection. All individuals had a Clinical Frailty scale score ≥5 and were of extreme older age or were centenarians. Six women with a median age of 98.8 years tested positive for SARS-CoV-2. Anti-spike IgG antibody titers were the highest titers observed in our cohort with all IgG positive individuals having virus neutralization ability. Additionally, 5 out of the 6 positive participants had a robust IgA anti-SARS-CoV-2 response. In all 5, antibodies were detected after 60 days from initial diagnosis., Competing Interests: Mary K. Foley – Ms. Foley has nothing to disclose. Samuel D. Searle - Dr. Searle received PhD and fellowship funding from the Canadian Frailty Network, Dalhousie Medical Research Foundation, Dalhousie University Internal Medicine Research Foundation and the QE II Innovation Fund. Ali Toloue – Toloue has nothing to disclose. Ryan Booth -Ryan Booth has nothing to disclose. Alec Falkenham – Dr. Falkenham has nothing to disclose. Darryl Falzarano – Dr. Falzarano has nothing to disclose. Salvatore Rubino – Dr. Rubino has nothing to disclose. Magen E. Francis – Ms. Francis has nothing to disclose. Mara McNeil – Ms. McNeil has nothing to disclose. Christopher Richardson – Dr. Richardson has nothing to disclose. Jason LeBlanc – Dr. LeBlanc has nothing to disclose. Sharon Oldford – Dr. Oldford has nothing to disclose. Volker Gerdts – Dr. Gerdts has nothing to disclose. Melissa K. Andrew – Dr. Andrew reports grants from Sanofi, grants from GSK, grants from Pfizer, grants from Canadian Frailty Network, grants from CIHR, grans from Public Health Agency of Canada, personal fees from Sanofi, from Pfizer, personal fees from Seqirus, outside the submitted work. Shelly A. McNeil – Dr. McNeil reports grants, personal fees and other from Pfizer, other from Medicago, personal fees and other from Sanofi, grants, personal fees and other from GlaxoSmithKline, grants personal fees and other from Merck, other from CanSino, other from IMV, other from Janssen, outside the submitted work. Barry Clarke – Dr. Clarke has nothing to disclose. Kenneth Rockwood – Dr. Rockwood reports personal fees from Clinical Cardio Day – Cape Breton University, personal fees from CRUIGM-Montreal, from Speaker at Jackson Lab, Bar Harbor MA, personal fees from Speaker at MouseAge Rome Italy, personal fees from Frontemporal Dementia Study Group, personal fees from SunLife Insurance Japan, outside the submitted work and Kenneth Rockwood is President and Co-founder of Ardea Outcomes, which in the last three years (as DGI Clinical) has contracts with pharma and device manufacturers (Shire, Hollister, Nutricia, Roche, Otsuka) on individualized outcome measurement. Otherwise any personal fees are for invited guest lectures and academic symposia, received directly from event organizers, chiefly for presentations on frailty. He is Associate Director of the Canadian Consortium on Neurodegeneration in Aging, which is funded by the Canadian Institutes of Health Research, and with additional funding from the Alzheimer Society of Canada and several other charities. He receives career support from the Dalhousie Medical Research Foundation as the Kathryn Allen Weldon Professor of Alzheimer Research, and research support from the Canadian Institutes of Health Research, The Canadian Frailty Network, the QEII Health Science centre Foundation, the Nova Scotia Health Research Fund and the Fountain Family Innovation Fund of the QEII Health Science centre Foundation. David J. Kelvin – Dr. Kelvin has nothing to disclose. Alyson A. Kelvin – Dr. A. Kelvin has nothing to disclose., (© 2021 The Authors.)