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Background: Malaria remains a public health concern and the leading cause of mortality in children aged under five years in South Sudan. Understanding the burden of malaria in children may assist in developing a strategy for mitigating and eliminating malaria. This would contribute to attaining the Sustainable Development Goals. We planned to determine the prevalence and outcome of malaria among hospitalized children in Al Sabah Children Hospital, South Sudan. Methods: We carried out a retrospective analysis of hospitalized children in Al Sabah Children Hospital between January to June 2020. The data for this study were analysed using Stata version 11 to calculate the prevalence and outcome of malaria among these children during the study period. Results: A total 781 children were recruited, of whom 777 contributed to the analysis (the others were excluded because of missing data). Overall prevalence of malaria was 78% among hospitalized children. Severe malaria alone affected 28%, while 50% had severe malaria in combination with other diseases. The highest death rate was amongst children from Munuki Block (11%, p= 0.001). Severe malaria alone and in combination was the diagnosis for 58% of the children who died. Severe malaria alone contributed to 14% of deaths. Conclusion: Malaria remains the number one cause of mortality in hospitalized children in this paediatric hospital. It predominantly affects young children, who are also at the highest risk of dying. Measures envisaged to protect children during their first five years of life are likely to have the greatest impact.

Background: Patients receiving oral anticoagulation therapy should be tested often enough to optimize control, but excessive testing increases burden and cost. We examined the relationship between follow-up intervals after obtaining an in-range (2.0-3.0) international normalized ratio (INR) and anticoagulation control.Methods: We studied 104,451 patients who were receiving anticoagulation therapy from 100 anticoagulation clinics in the US Veterans Health Administration. Most patients (98,877) had at least one in-range INR followed by another INR within 56 days. For each such patient, we selected the last in-range INR and characterized the interval between this index value and the next INR. The independent variable was the site mean follow-up interval after obtaining an in-range INR. The dependent variable was the site mean risk-adjusted percentage of time in the therapeutic range (TTR).Results: The site mean follow-up interval varied from 25 to 38 days. As the site mean follow-up interval became longer, the risk-adjusted TTR was worse (-0.51% per day, P = .004). This relationship persisted when the index value was the first consecutive in-range INR (-0.63%, P < .001) or the second (-0.58%, P < .001), but not the third or greater (-0.12%, P = .46).Conclusions: Sites varied widely regarding follow-up intervals after obtaining an in-range INR (25-38 days). Shorter intervals were generally associated with better anticoagulation control, but after obtaining a third consecutive in-range value, this relationship was greatly attenuated and no longer statistically significant. Our results suggest that a maximum interval of 28 days after obtaining the first or second in-range value and consideration of a longer interval after obtaining the third or greater consecutive in-range value may be appropriate. [ABSTRACT FROM AUTHOR]

Background: The potential to save money within a short time frame provides a more compelling "business case" for quality improvement than merely demonstrating cost-effectiveness. Our objective was to demonstrate the potential for cost savings from improved control in patients anticoagulated for atrial fibrillation.Methods and Results: Our population consisted of 67 077 Veterans Health Administration patients anticoagulated for atrial fibrillation between October 1, 2006, and September 30, 2008. We simulated the number of adverse events and their associated costs and utilities, both before and after various degrees of improvement in percent time in therapeutic range (TTR). The simulation had a 2-year time horizon, and costs were calculated from the perspective of the payer. In the base-case analysis, improving TTR by 5% prevented 1114 adverse events, including 662 deaths; it gained 863 quality-adjusted life-years and saved $15.9 million compared with the status quo, not accounting for the cost of the quality improvement program. Improving TTR by 10% prevented 2087 events, gained 1606 quality-adjusted life-years, and saved $29.7 million. In sensitivity analyses, costs were most sensitive to the estimated risk of stroke and the expected stroke reduction from improved TTR. Utilities were most sensitive to the estimated risk of death and the expected mortality benefit from improved TTR.Conclusions: A quality improvement program to improve anticoagulation control probably would be cost-saving for the payer, even if it were only modestly effective in improving control and even without considering the value of improved health. This study demonstrates how to make a business case for a quality improvement initiative. [ABSTRACT FROM AUTHOR]

The current study examined co-rumination (i.e., extensively discussing, rehashing, and speculating about problems) in the context of mother-adolescent relationships. Fifth-, eighth-, and eleventh-graders (N=516) reported on co-rumination and more normative self-disclosure with mothers, their relationships with mothers, and their own internalizing symptoms. A subset of mothers (N=200) reported on mother-adolescent co-rumination and self-disclosure. Results from the adolescent-report data indicated greater mother-adolescent co-rumination with daughters than sons and also adjustment trade-offs of mother-adolescent co-rumination. Mother-adolescent co-rumination was related to positive relationship quality but also to enmeshment in the relationship. Whereas the relation with positive relationship quality appeared to be due in part to normative self-disclosure, the relation with enmeshment was unique to co-rumination. Mother-adolescent co-rumination also was related to youth anxiety/depression. The relations with enmeshment and internalizing symptoms were strongest when co-rumination focused on the mothers' problems. Implications of mother-adolescent co-rumination for promoting appropriate relationship boundaries and youth well-being are discussed. [ABSTRACT FROM AUTHOR]

Some evidence suggests that close friends may be knowledgeable of youth's psychological adjustment. However, friends are understudied as reporters of adjustment. The current study examines associations between self- and friend-reports of internalizing and externalizing adjustment in a community sample of fifth-, eighth-, and eleventh-grade youth. The study extends prior work by considering the degree to which friends' reports of youth adjustment are accurate (i.e., predicted by youths' actual adjustment) versus biased (i.e., predicted by the friend reporters' own adjustment). Findings indicated stronger bias effects than accuracy effects, but the accuracy effects were significant for both internalizing and externalizing adjustment. Additionally, friends who perceived their relationships as high in positive quality, friends in relationships high in disclosure, and girls perceived youths' internalizing symptoms most accurately. Knowledge of externalizing adjustment was not influenced by gender, grade, relationship quality, or self-disclosure. Findings suggest that friends could play an important role in prevention efforts. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the mechanisms explaining improved insulin-stimulated glucose uptake after exercise training in human skeletal muscle. Eight healthy men performed 3 weeks of one-legged knee extensor endurance exercise training. Fifteen hours after the last exercise bout, insulin-stimulated glucose uptake was approximately 60% higher (P < 0.01) in the trained compared with the untrained leg during a hyperinsulinemic-euglycemic clamp. Muscle biopsies were obtained before and after training as well as after 10 and 120 min of insulin stimulation in both legs. Protein content of Akt1/2 (55 +/- 17%, P < 0.05), AS160 (25 +/- 8%, P = 0.08), GLUT4 (52 +/- 19%, P < 0.001), hexokinase 2 (HK2) (197 +/- 40%, P < 0.001), and insulin-responsive aminopeptidase (65 +/- 15%, P < 0.001) increased in muscle in response to training. During hyperinsulinemia, activities of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-K) (P < 0.005), Akt1 (P < 0.05), Akt2 (P < 0.005), and glycogen synthase (GS) (percent I-form, P < 0.05) increased similarly in both trained and untrained muscle, consistent with increased phosphorylation of Akt Thr(308), Akt Ser(473), AS160, glycogen synthase kinase (GSK)-3alpha Ser(21), and GSK-3beta Ser(9) and decreased phosphorylation of GS site 3a+b (all P < 0.005). Interestingly, training improved insulin action on thigh blood flow, and, furthermore, in both basal and insulin-stimulated muscle tissue, activities of Akt1 and GS and phosphorylation of AS160 increased with training (all P < 0.05). In contrast, training reduced IRS-1-associated PI3-K activity (P < 0.05) in both basal and insulin-stimulated muscle tissue. Our findings do not support generally improved insulin signaling after endurance training; rather it seems that improved insulin-stimulated glucose uptake may result from hemodynamic adaptations as well as increased cellular protein content of individual insulin signaling components and molecules involved in glucose transport and metabolism. [ABSTRACT FROM AUTHOR]

Objective: The study aimed to investigate the effects of glucagon on metabolic pathways in mouse models of obesity, fatty liver disease, and type 2 diabetes (T2D) to determine the extent and variability of hepatic glucagon resistance in these conditions., Methods: We investigated glucagon's effects in mouse models of fatty liver disease, obesity, and type 2 diabetes (T2D), including male BKS-db/db, high-fat diet-fed, and western diet-fed C57Bl/6 mice. Glucagon tolerance tests were performed using the selective glucagon receptor agonist acyl-glucagon (IUB288). Blood glucose, serum and liver metabolites include lipids and amino acids were measured. Additionally, liver protein expression related to glucagon signalling and a comprehensive liver metabolomics were performed., Results: Western diet-fed mice displayed impaired glucagon response, with reduced blood glucose and PKA activation. In contrast, high-fat diet-fed and db/db mice maintained normal glucagon sensitivity, showing significant elevations in blood glucose and phospho-PKA motif protein expression. Acyl-glucagon treatment also lowered liver alanine and histidine levels in high-fat diet-fed mice, but not in western diet-fed mice. Additionally, some amino acids, such as methionine, were increased by acyl-glucagon only in chow diet control mice. Despite normal glucagon sensitivity in PKA signalling, db/db mice had a distinct metabolomic response, with acyl-glucagon significantly altering 90 metabolites in db/+ mice but only 42 in db/db mice, and classic glucagon-regulated metabolites, such as cyclic adenosine monophosphate (cAMP), being less responsive in db/db mice., Conclusions: The study reveals that hepatic glucagon resistance in obesity and T2D is complex and not uniform across metabolic pathways, underscoring the complexity of glucagon action in these conditions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Adam Rose reports financial support was provided by Diabetes Australia. Adam Rose reports financial support was provided by National Health and Medical Research Council. Yuqin Wu reports financial support was provided by Australian Physiological Society. Adam Rose reports a relationship with Boehringer Ingelheim Pharma GmbH & Co KG that includes: funding grants. Patricia Rusu reports a relationship with Boehringer Ingelheim Pharma GmbH & Co KG that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Objective: This study examines the way healthcare staff describe challenging patients and perceive responsibility for follow-up of patients with chronic conditions., Methods: Interviews were conducted with 46 healthcare staff (15 primary care physicians/12 nurses/15 administrative staff/4 pharmacists) at 12 clinics in Israel. They were audiotaped, transcribed, and thematically analyzed using Atlas qualitative data analysis software., Results: Participants defined patients as "challenging" either because they are less likely to follow medical recommendations or are felt to overconsume care. Staff believed that patients did not follow medical recommendations because they were indifferent, unaware, in denial about deteriorating medical condition, or fear of the unknown. Participants generally perceived a shared responsibility for follow-up between the staff and the patient. Staff who endorsed closer relationships with staff members expressed empathy toward challenging patients and felt responsible for follow-up., Conclusions: Healthcare staff perceive themselves as partially responsible for helping patients follow up with medical recommendations. Cohesive staff relationships may promote higher levels of empathy toward challenging patients and may contribute to helping patients follow up with recommended care. Practice implications To improve follow-up with medical recommendations, there is a need to develop and test interventions to promote more cohesive ties among clinic staff., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The peptide hormone glucagon is a fundamental metabolic regulator that is also being considered as a pharmacotherapeutic option for obesity and type 2 diabetes. Despite this, we know very little regarding how glucagon exerts its pleiotropic metabolic actions. Given that the liver is a chief site of action, we performed in situ time-resolved liver phosphoproteomics to reveal glucagon signaling nodes. Through pathway analysis of the thousands of phosphopeptides identified, we reveal "membrane trafficking" as a dominant signature with the vesicle trafficking protein SEC22 Homolog B (SEC22B) S137 phosphorylation being a top hit. Hepatocyte-specific loss- and gain-of-function experiments reveal that SEC22B was a key regulator of glycogen, lipid and amino acid metabolism, with SEC22B-S137 phosphorylation playing a major role in glucagon action. Mechanistically, we identify several protein binding partners of SEC22B affected by glucagon, some of which were differentially enriched with SEC22B-S137 phosphorylation. In summary, we demonstrate that phosphorylation of SEC22B is a hepatocellular signaling node mediating the metabolic actions of glucagon and provide a rich resource for future investigations on the biology of glucagon action., (© 2024. The Author(s).)

SUMMARYThe ability to overcome metabolic stress is a major determinant of outcomes during infections. Pathogens face nutrient and oxygen deprivation in host niches and during their encounter with immune cells. Immune cells require metabolic adaptations for producing antimicrobial compounds and mounting antifungal inflammation. Infection also triggers systemic changes in organ metabolism and energy expenditure that range from an enhanced metabolism to produce energy for a robust immune response to reduced metabolism as infection progresses, which coincides with immune and organ dysfunction. Competition for energy and nutrients between hosts and pathogens means that successful survival and recovery from an infection require a balance between elimination of the pathogen by the immune systems (resistance), and doing so with minimal damage to host tissues and organs (tolerance). Here, we discuss our current knowledge of pathogen, immune cell and systemic metabolism in fungal infections, and the impact of metabolic disorders, such as obesity and diabetes. We put forward the idea that, while our knowledge of the use of metabolic regulation for fungal proliferation and antifungal immune responses (i.e., resistance) has been growing over the years, we also need to study the metabolic mechanisms that control tolerance of fungal pathogens. A comprehensive understanding of how to balance resistance and tolerance by metabolic interventions may provide insights into therapeutic strategies that could be used adjunctly with antifungal drugs to improve patient outcomes., Competing Interests: A.R. receives funding from Boehringer-Ingelheim, a pharmaceutical company, for an unrelated research project.

Metabolic diseases such as obesity and type 2 diabetes are marked by insulin resistance 1,2 . Cells within the arcuate nucleus of the hypothalamus (ARC), which are crucial for regulating metabolism, become insulin resistant during the progression of metabolic disease 3-8 , but these mechanisms are not fully understood. Here we investigated the role of a specialized chondroitin sulfate proteoglycan extracellular matrix, termed a perineuronal net, which surrounds ARC neurons. In metabolic disease, the perineuronal net of the ARC becomes augmented and remodelled, driving insulin resistance and metabolic dysfunction. Disruption of the perineuronal net in obese mice, either enzymatically or with small molecules, improves insulin access to the brain, reversing neuronal insulin resistance and enhancing metabolic health. Our findings identify ARC extracellular matrix remodelling as a fundamental mechanism driving metabolic diseases., (© 2024. The Author(s).)

In October 2023, Israel sustained a massive terror attack, with 1,300 people murdered, over 240 kidnapped, and millions exposed to the horrors. This study's aim is to examine the profile of patients arriving to the emergency department (ED) for psychiatric services during the month following the attack, compared to a similar period the year prior. In this cohort study, we compared patients arriving to the ED of a large general hospital in the center of Tel Aviv for psychiatric services during the month post-attack with the previous year using t-tests and chi-square exams. In 2023, 256 patients arrived in the ED for psychiatric evaluation and/or treatment, 46 % more than in 2022. Of these, 64 % were examined due to symptoms related to the terror attack. In 2023, significantly fewer patients had a prior psychiatric diagnosis (68% vs. 89 %). Significantly more patients were diagnosed with acute stress reaction or acute stress disorder in the ED, compared to almost no such diagnoses in 2022 (14 % and 43% vs. 0 % and 1 %). Major terror incidents profoundly influence psychiatric ED visits. Planning efforts for major emergencies should be adapted accordingly., Competing Interests: Declaration of competing interest The authors declare they have no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Background: Telepsychiatry (TP), a live video meeting, has been implemented in many contexts and settings. It has a distinct advantage in the psychiatric emergency department (ED) setting, as it expedites expert assessments for psychiatric patients. However, limited knowledge exits for TP's effectiveness in the ED setting, as well as the process of implementing TP in this setting., Objective: This scoping review aimed to review the existing evidence for the administrative and clinical outcomes for TP in the ED setting and to identify the barriers and facilitators to implementing TP in this setting., Methods: The scoping review was conducted according to the guidelines for the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews). Three electronic databases were examined: PubMed, Embase, and Web of Science. The databases were searched from January 2013 to April 2023 for papers and their bibliography. A total of 2816 potentially relevant papers were retrieved from the initial search. Studies were screened and selected independently by 2 authors., Results: A total of 11 articles were included. Ten papers reported on administrative and clinical outcomes of TP use in the ED setting and 1 on the barriers and facilitators of its implementation. TP is used in urban and rural areas and for settings with and with no on-site psychiatric services. Evidence shows that TP reduced waiting time for psychiatric evaluation, but in some studies, it was associated with prolonged total length of stay in the ED compared with in-person evaluation. Findings indicate lower admission rates in patients assessed with TP in the ED. Limited data were reported for TP costs, its use for involuntary commitment evaluations, and its use for particular subgroups of patients (eg, those with a particular diagnosis). A single paper examined TP implementation process in the ED, which explored the barriers and facilitators for implementation among patients and staff in a rural setting., Conclusions: Based on the extant studies, TP seems to be generally feasible and acceptable to key stakeholders. However, this review detected a gap in the literature regarding TP's effectiveness and implementation process in the ED setting. Specific attention should be paid to the examination of this service for specific groups of patients, as well as its use to enable assessments for possible involuntary commitment., (©Ligat Shalev, Renana Eitan, Adam J Rose. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 15.07.2024.)

Despite its implications for adjustment, little is known about factors that support co-rumination in friendships. The current multi-method, longitudinal study addressed this question with 554 adolescents (M age  = 14.50; 52% girls; 62% White; 31% Black; 7% Asian American) from the Midwestern United States in 2007-2010. Adolescents were observed talking about problems with a friend and reported on their outcome expectations for problem disclosures, relationship provisions during problem talk, and problem perceptions after problem talk. Participants reported on outcome expectations again 9 months later. Results indicate that the positive relationship provisions associated with co-rumination may outweigh negative problem perceptions in predicting adolescents' outcome expectations for problem disclosures over time. Implications for the potentially reinforcing nature of co-rumination are discussed., (© 2024 The Authors. Child Development published by Wiley Periodicals LLC on behalf of Society for Research in Child Development.)

New studies (Tang et al. 2024. J. Exp. Med.https://doi.org/10.1084/jem.20231395) describe a liver stress pathway that is activated by certain chemotherapeutic drugs, which in turn induces a peptide hormone which partially mediates the lower food intake and body weight loss during chemotherapy treatment., (© 2024 Rose and Lockie.)

Project INTERprofessional Autism Collaborative Training (INTERACT) is an interprofessional education program designed to prepare graduate students in psychology, special education, and speech-language pathology to work with autistic children with moderate to severe intellectual disabilities. The rising prevalence of autism, coupled with increased appreciation for interprofessional approaches to service delivery, indicates the need for university training programs to prepare graduate students to work interprofessionally with this population; yet descriptions of such programs and their effectiveness are not reported in the literature. In this article, we explain the process through which an interprofessional faculty team developed Project INTERACT, describe the sequence of coursework and team-based clinical experiences that comprise the program, and present preliminary data regarding its effectiveness. Twenty-four graduate students in psychology, special education, and speech-language pathology participated in this quantitative study. We report results from three rating scales that participants completed at program entry, midpoint, and program exit. Participants endorsed positive attitudes toward interprofessional practice and demonstrated high levels of knowledge about autism. Self-rated knowledge and abilities in interprofessional practice increased significantly by program exit. Project INTERACT scholars developed knowledge and skills related to understanding, assessing, and treating autistic children with intellectual disabilities, through the lens of team-based interprofessional collaboration. We discuss implications for practice with Project INTERACT. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

The role and molecular mechanisms of intermittent fasting (IF) in non-alcoholic steatohepatitis (NASH) and its transition to hepatocellular carcinoma (HCC) are unknown. Here, we identified that an IF 5:2 regimen prevents NASH development as well as ameliorates established NASH and fibrosis without affecting total calorie intake. Furthermore, the IF 5:2 regimen blunted NASH-HCC transition when applied therapeutically. The timing, length, and number of fasting cycles as well as the type of NASH diet were critical parameters determining the benefits of fasting. Combined proteome, transcriptome, and metabolome analyses identified that peroxisome-proliferator-activated receptor alpha (PPARα) and glucocorticoid-signaling-induced PCK1 act co-operatively as hepatic executors of the fasting response. In line with this, PPARα targets and PCK1 were reduced in human NASH. Notably, only fasting initiated during the active phase of mice robustly induced glucocorticoid signaling and free-fatty-acid-induced PPARα signaling. However, hepatocyte-specific glucocorticoid receptor deletion only partially abrogated the hepatic fasting response. In contrast, the combined knockdown of Ppara and Pck1 in vivo abolished the beneficial outcomes of fasting against inflammation and fibrosis. Moreover, overexpression of Pck1 alone or together with Ppara in vivo lowered hepatic triglycerides and steatosis. Our data support the notion that the IF 5:2 regimen is a promising intervention against NASH and subsequent liver cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest Not applicable.

The present study examined how friends' responses to each other during problem talk predicted depressive symptoms over time. Participants included 271 adolescent friend dyads (69 female and 69 male early adolescent dyads; 72 female and 61 male middle adolescent dyads; 66.4% White and 26.6% Black). The adolescents were observed discussing a problem with the friend and reported on depressive symptoms at the time of observation and 9 months later. Friends' responses were coded into one of nine response type categories (i.e., four positive/engaged response types, one neutral response type, and four negative/disengaged response types). Actor-partner interdependence models revealed significant actor and partner effects for both positive and negative responses. Notably, receiving and/or producing positive/engaged responses, including saying something supportive, sharing related experiences, and asking questions, were associated with lower depressive symptoms over time. Receiving and/or producing negative/disengaged responses, including sharing one's own experience in a distracting way, changing the subject, saying something unsupportive or minimizing the problem, and saying nothing at all heightened risk for depressive symptoms. Additionally, significant Actor × Partner interactions revealed that greater differences between the friends in the degree to which they produced supportive responses were associated with increased depressive symptoms and that both friends saying nothing at all was associated with increased depressive symptoms. When gender and grade differences were found, the associations typically were particularly strong for middle-adolescent girls. These results highlight the importance of attending to friends' specific behaviors in social support contexts. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Diabetes Mellitus (DM) is more common among individuals with severe mental illness (SMI). We aimed to assess quality-of-care-indicators in individuals with SMI following the 2015 Israel's Mental-Health-reform. We analyzed yearly changes in 2015-2019 of quality-of-care-measures and intermediate-DM-outcomes, with adjustment for gender, age-group, and socioeconomic status (SES) and compared individuals with SMI to the general adult population. Adults with SMI had higher prevalences of DM (odds ratio (OR) = 1.64; 95% confidence intervals (CI): 1.61-1.67) and obesity (OR = 2.11; 95% CI: 2.08-2.13), compared to the general population. DM prevalence, DM control, and obesity rates increased over the years in this population. In 2019, HbA1c testing was marginally lower (OR = 0.88; 95% CI: 0.83-0.94) and uncontrolled DM (HbA1c > 9%) slightly more common among patients with SMI (OR = 1.22; 95% CI: 1.14-1.30), control worsened by decreasing SES. After adjustment, uncontrolled DM (adj. OR = 1.02; 95% CI: 0.96-1.09) was not associated with SMI. Cardio-metabolic morbidity among patients with SMI may be related to high prevalences of obesity and DM rather than poor DM control. Effective screening for metabolic diseases in this population and social reforms are required., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy with limited treatment options. The development of novel therapies is hindered by a lack of preclinical models. We have generated ACC patient-derived xenograft (PDX) lines that retain the physical and genetic properties of the original tumours, including the presence of the common MYB::NFIB or MYBL1::NFIB translocations. We have developed the conditions for the generation of both 2D and 3D tumour organoid patient-derived ACC models that retain MYB expression and can be used for drug studies. Using these models, we show in vitro and in vivo sensitivity of ACC cells to the bromodomain degrader, dBET6. Molecular studies show a decrease in BRD4 and MYB protein levels and target gene expression with treatment. The most prominent effect of dBET6 on tumours in vivo was a change in the relative composition of ACC cell types expressing either myoepithelial or ductal markers. We show that dBET6 inhibits the progenitor function of ACC cells, particularly in the myoepithelial marker-expressing population, revealing a cell-type-specific sensitivity. These studies uncover a novel mechanistic effect of bromodomain inhibitors on tumours and highlight the need to impact both cell-type populations for more effective treatments in ACC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)

Fibroblast growth factor 21 (FGF21), an endocrine signal robustly increased by protein restriction independently of an animal's energy status, exerts profound effects on feeding behavior and metabolism. Here, we demonstrate that considering the nutritional contexts within which FGF21 is elevated can help reconcile current controversies over its roles in mediating macronutrient preference, food intake, and energy expenditure. We show that FGF21 is primarily a driver of increased protein intake in mice and that the effect of FGF21 on sweet preference depends on the carbohydrate balance of the animal. Under no-choice feeding, FGF21 infusion either increased or decreased energy expenditure depending on whether the animal was fed a high- or low-energy diet, respectively. We show that while the role of FGF21 in mediating feeding behavior is complex, its role in promoting protein appetite is robust and that the effects on sweet preference and energy expenditure are macronutrient-state-dependent effects of FGF21., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Friendships are a primary source of social support during young adulthood; however, little is known about the factors associated with young adults feeling greater support during interactions with friends. We examined how micro-level verbal responses and macro-level judgments of friendship quality were associated with perceptions of support following an interaction between friends. Same-gender friend dyads ( N = 132; 66.2% female; 18-24 years, M age = 19.63) took turns speaking about a problem, then participants rated their perceptions of support given and received following the task. We coded each participant's verbal responses while in the listening role. Actor Partner Interdependence Models (APIMs) revealed significant partner effects for negative engagement responses, such that greater negative engagement responses were linked with the partner perceiving poorer support both given and received. Models revealed significant actor effects for supportive responses, such that greater supportive responses predicted the actor perceiving better support both given and received. Additionally, models revealed significant actor effects of friendship quality predicting actors' perceiving better support both given and received. Finally, exploratory models revealed minimal interactions between a few types of verbal responses and positive friendship quality. Taken together, results suggest that (a) negative verbal responding styles may be more meaningfully associated with partners' perceptions of support in the moment than are supportive behaviours, whereas (b) supportive verbal responding styles may be more meaningfully associated with actors' perceptions of support in the moment, and (c) actors' judgments of friendship quality are strongly associated with their overall perceptions of support, and a critical factor to consider in future research., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Objective: To identify key research gaps regarding medication therapy to prevent osteoporotic fractures in men., Data Sources: Articles from the peer-reviewed literature containing empirical studies of the use of medication therapy for fracture prevention in men, either in clinical trials or observational studies., Study Selection and Data Extraction: We searched PubMed with search terms including "osteoporosis AND medication therapy management". We read all articles to ensure that they were indeed empirical studies of our topic. For each included study, we searched for all articles in the bibliography, all articles that cited the article, and all related articles, using these functions in PubMed., Data Synthesis: We have identified six research gaps that could inform the more rational, evidence-based treatment of male osteoporosis. Specifically, among men, we lack key information about: (1) whether treatment can prevent clinical fractures, (2) rates of side effects and complications of therapy, (3) the role of testosterone in treatment, (4) the comparative effectiveness of different therapeutic regimens, (5) role of drug holidays for those receiving bisphosphonates and sequential therapies, and (6) effectiveness of therapy for secondary prevention., Relevance to Patient Care and Clinical Practice: Addressing these six topics should be key goal for the next decade of research on male osteoporosis.

Background: The use of research tools developed and validated in one cultural and linguistic context to another often faces challenges. One major challenge is poor performance of the tool in the new context. This potentially impact the legitimacy of health policy research conducted with informal adaptations of existing tools which have not been subjected to formal validation. Best practices exist to guide researchers in adapting and validating research tools effectively. We present here, as an extended example, our validation of the SHEMESH questionnaire ('Organizational Readiness to Change Assessment'; In Hebrew: 'SHE'elon Muchanut Ergunit le'SHinuy'), a Hebrew-language version of the Organizational Readiness to Change Assessment (ORCA). SHEMESH is tailored to support implementation science projects, whose aim is to promote a more rapid and complete adoption of evidence-based health policies and practices., Methods: The SHEMESH included originally eleven questions from the Evidence (item 1-4) and Context (items 5-11) domains. We validated SHEMESH through the following steps: 1. Professional translation to Hebrew and discussion of the translation by multidisciplinary committee; 2. Back-translation into English by a different translator to detect discrepancies; 3. Eleven cognitive interviews with psychiatric emergency department physicians and nurses; and 4. Pilot testing and psychometric analyses, including Cronbach's alpha for subscales and factor analyses., Results: Following translation and cognitive interviews, SHEMESH was administered to 222 psychiatrists and nurses. Pearson correlation showed significant and strong correlations of items 1-4 to the Evidence construct and items 6-11 to the Context construct. Item 5 did not correlate with the other items, and therefore was removed from the other psychometric procedures and eventually from the SHEMESH. Factor analysis with the remaining 10 items yielded two factors, which together explained a total of 69.7% of variance. Cronbach's Alpha scores for the two subscales were high (Evidence, 0.887, and Context, 0.852)., Conclusions: This multi-step validation process of the SHEMESH questionnaire may serve as a comprehensive guideline for others who are willing to adapt research tools that were developed in other languages. Practically, SHEMESH has been validated for use in implementation science research projects in Israel., (© 2023. The Author(s).)

Background: In Israel, internal medicine admissions are currently reimbursed without accounting for patient complexity. This is at odds with most other developed countries and has the potential to lead to market distortions such as avoiding sicker patients. Our objective was to apply a well-known, freely available risk adjustment model, the Elixhauser model, to predict relevant outcomes among patients hospitalized on the internal medicine service of a large, Israeli tertiary-care hospital., Methods: We used data from the Shaare Zedek Medical Center, a large tertiary referral hospital in Jerusalem. The study included 55,946 hospitalizations between 01.01.2016 and 31.12.2019. We modeled four patient outcomes: in-hospital mortality, escalation of care (intensive care unit (ICU) transfer, mechanical ventilation, daytime bi-level positive pressure ventilation, or vasopressors), 30-day readmission, and length of stay (LOS). We log-transformed LOS to address right skew. As is usual with the Elixhauser model, we identified 29 comorbid conditions using international classification of diseases codes, clinical modification, version 9. We derived and validated the coefficients for these 29 variables using split-sample derivation and validation. We checked model fit using c-statistics and R 2 , and model calibration using a Hosmer-Lemeshow test., Results: The Elixhauser model achieved acceptable prediction of the three binary outcomes, with c-statistics of 0.712, 0.681, and 0.605 to predict in-hospital mortality, escalation of care, and 30-day readmission respectively. The c-statistic did not decrease in the validation set (0.707, 0.687, and 0.603, respectively), suggesting that the models are not overfitted. The model to predict log length of stay achieved an R 2 of 0.102 in the derivation set and 0.101 in the validation set. The Hosmer-Lemeshow test did not suggest issues with model calibration., Conclusion: We demonstrated that a freely-available risk adjustment model can achieve acceptable prediction of important clinical outcomes in a dataset of patients admitted to a large, Israeli tertiary-care hospital. This model could potentially be used as a basis for differential payment by patient complexity., (© 2023. The Author(s).)

Background: Telepsychiatry is the use of virtual communication, such as a video link, to deliver mental health assessment, treatment, and follow-up. Previous studies have shown telepsychiatry to be feasible, accurate compared with in-person practice, and satisfying for psychiatrists and patients. Telepsychiatry has also been associated with reduced waiting times for evaluation and, in some studies, lower admission rates. However, most previous studies focused on using telepsychiatry in community settings and not on involuntary admission., Objective: The aim of this study is to examine the effectiveness and implementation process of patient assessment for involuntary admissions in the psychiatric emergency department (ED) using a video link., Methods: This type 1 hybrid implementation study will examine telepsychiatry effectiveness and the implementation process, by comparing telepsychiatry (n=240) with historical controls who had a face-to-face evaluation (n=240) during the previous, usual care period in 5 psychiatric EDs in Israel. A temporary waiver of the standing policy requiring in-person evaluations only, for the purpose of research, was obtained from the Israeli Ministry of Health. During the telepsychiatry phase, clinical staff and patients will join a video call from the ED, while the attending physician will log in elsewhere. The Promoting Action on Research Implementation in Health Services (PARIHS) framework will guide the evaluation of the telepsychiatry implementation process in the ED. PARIHS has the following 3 constructs: (1) evidence: staff's opinions regarding the innovation's viability and practicality, their satisfaction levels with its use, and patients' perceptions of the change; (2) context: level of approval of new strategies in the ED, decision-making processes, and the manner in which clinical teams converse and work together; (3) facilitation: adequacy of the facilitation efforts using champions reports. Primary clinical outcomes include ED length of stay and violent incidents obtained from medical records., Results: This study received Helsinki approval from the Ethics Committee of Abarbanel Mental Health Center (174; March 13, 2023), Jerusalem Mental Health Center (22-21; November 6, 2022), Lev-Hasharon Mental Health Medical Center (LH12023; February 12, 2023), Tel-Aviv Medical Center (TLV-22-0656; January 3, 2023), and Sha'ar Menashe (1-4-23; April 18, 2023). Data collection began in July 2023 in 2 study sites and will begin soon at the others., Conclusions: Telepsychiatry could have significant benefits for patients in the psychiatric ED. Examining telepsychiatry effectiveness in the ED, in addition to identifying the facilitators and barriers of implementing it in different emergency settings, will facilitate better policy decisions regarding its implementation., Trial Registration: ClinicalTrials.gov NCT05771545; https://clinicaltrials.gov/study/NCT05771545., International Registered Report Identifier (irrid): DERR1-10.2196/49405., (©Ligat Shalev, Moises Bistre, Gadi Lubin, Keren Avirame, Sergey Raskin, Omer Linkovski, Renana Eitan, Adam J Rose. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 17.10.2023.)

It is known that dietary factors within the gestational and nursing period affect early life and stably affect later life traits in animals. However, there is very little understanding of whether dietary factors within the early life period from post-nursing to adulthood affect traits in adulthood. To address this, we conducted studies on male C57Bl/6J mice fed from 3 weeks (immediately post-nursing) until 12 weeks (full maturity) using nine different diets varying in all three major macronutrients to parse out the effects of individual macronutrients. Early life macronutrient balance affected body composition and glucose homeostasis in early adulthood, with dietary protein and fat showing major effects. Despite this, mice showed rapid reversal of the effects on body composition and glucose homeostasis of early life diet feeding, upon standard diet feeding in adulthood. However, some traits were persistent, with early life low dietary protein levels stably affecting lean and muscle mass, and early life dietary fat levels stably affecting serum and liver triglyceride levels. In summary, macronutrient balance in the post-nursing early life period does not stably affect adiposity or glucose homeostasis but does impact muscle mass and lipid homeostasis in adulthood, with prominent effects of both protein and fat levels. KEY POINTS: Early life dietary low protein and high fat levels lowered and heightened body mass, respectively. These effects did not substantially persist into adulthood with rapid catch-up growth on a normal diet. Early life protein (negative) and fat (positive) levels affected fat mass. Early life low protein levels negatively affected lean mass. Low protein effects on lower lean and muscle mass persisted into adulthood. Early life macronutrient balance effects did not affect later life glucose homeostasis but early life high fat level affected later life dyslipidaemia. Effects of dietary carbohydrate levels in early and later life were minor., (© 2023 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The COVID-19 pandemic and subsequent stay-at-home orders limited adolescents' ability to connect with friends in person, leading adolescents to rely on digital forms of communication to interact with friends. The present study ( N = 168 adolescents ages 11-20, 51.40% female) examined the types of digital communication adolescents used to connect with friends during the pandemic stay-at-home orders and how each form of digital communication related to adolescents' emotional adjustment. The results showed texting to be the most common way adolescents connected with friends. Boys were more likely than girls to talk with friends through social gaming. Synchronous forms of communication (i.e., texting, video calls, and social gaming) were associated with reduced loneliness and depressive symptoms and higher flourishing. Connecting with friends by posting or responding on social media was not associated with adolescent well-being. These results suggest that forms of digital communication that allowed adolescents to talk with friends in real time were particularly important for adolescents' emotional well-being during the COVID-19 pandemic.

Background: Previous studies have shown that more temporally regular primary care visits are associated with improved patient outcomes., Objective: To examine the association of temporal regularity (TR) of primary care with hospitalizations and mortality in patients with chronic illnesses. Also, to identify threshold values for TR for predicting outcomes., Design: Retrospective cohort study., Participants: We used data from the electronic health record of a health maintenance organization in Israel to study primary care visits of 70,095 patients age 40 + with one of three chronic conditions (diabetes mellitus, heart failure, chronic obstructive pulmonary disease)., Main Measures: We calculated TR for each patient during a two-year period (2016-2017), and divided patients into quintiles based on TR. Outcomes (hospitalization, death) were observed in 2018-2019. Covariates included the Bice-Boxerman continuity of care score, demographics, and comorbidities. We used multivariable logistic regression to examine TR's association with hospitalization and death, controlling for covariates., Key Results: Compared to patients receiving the most regular care, patients receiving less regular care had increased odds of hospitalization and mortality, with a dose-response curve observed across quintiles (p for linear trend < 0.001). For example, patients with the least regular care had an adjusted odds ratio of 1.40 for all-cause mortality, compared to patients with the most regular care. Analyses stratified by age, sex, ethnic group, area-level SES, and certain comorbid conditions did not show strong differential associations of TR across groups., Conclusions: We found an association between more temporally regular care in antecedent years and reduced hospitalization and mortality of patients with chronic illness in subsequent years, after controlling for covariates. There was no clear threshold value for temporal regularity; rather, more regular primary care appeared to be better across the entire range of the variable., (© 2023. The Author(s).)

Background: Patients admitted to internal medicine may be moved to more advanced-care settings when their condition deteriorates. In these advanced care settings, there may be higher levels of monitoring and greater ability to deliver Intensive Medical Treatments (IMTs). To the best of our knowledge, no previous study has examined the proportion of patients at different levels of care who receive different types of IMTs., Methods: In this retrospective observational cohort study, we examined data from 56,002 internal medicine hospitalizations at Shaare Zedek Medical Center, between 01.01.2016 and 31.12.2019. Patients were divided according to where they received care: general-ward, Intermediate-Care Unit, Intensive Care Unit (ICU), or both (Intermediate-Care and ICU). We examined the rates at which these different groups of patients received one or more of the following IMTs: mechanical ventilation, daytime bi-level positive airway pressure (BiPAP), or vasopressor therapy., Results: Most IMTs were delivered in a general-ward setting - ranging from 45.9% of IMT-treated hospitalizations involving combined mechanical ventilation and vasopressor therapy to as high as 87.4% of IMT-treated hospitalizations involving daytime BiPAP. Compared to ICU patients, Intermediate-Care Unit patients were older (mean age 75.1 vs 69.1, p < 0.001 for this and all other comparisons presented here), had longer hospitalizations (21.3 vs 14.5 days), and were more likely to die in-hospital (22% vs 12%). They were also more likely to receive most of the IMTs compared to ICU patients. For example, 9.7% of Intermediate-Care Unit patients received vasopressors, compared to 5.5% of ICU patients., Conclusion: In this study, most of the patients who received IMTs actually received them in a general-bed and not in a dedicated unit. These results imply that IMTs are predominantly delivered in unmonitored settings, and suggest an opportunity to re-examine where and how IMTs are given. In terms of health policy, these findings suggest a need to further examine the setting and patterns of intensive interventions, as well as a need to increase the number of beds dedicated to delivering intensive interventions., (© 2023. The Author(s).)

Health-care professionals (HCPs) are key trusted figures in addressing coronavirus disease 2019 (COVID-19) challenges. They are thought to influence others' health decisions by personal example. However, during the COVID-19 crisis, some HCPs hesitated to be vaccinated. We examined factors contributing to that decision. We performed 12 semi-structured interviews, between February and May 2021, with Israeli HCPs who had declined or delayed COVID-19 vaccination. Three coders conducted a combined top-down and bottom-up analysis. We identified four main themes shaping vaccine decision-making: (i) sources of information, (ii) perceptions of necessity and risks of the vaccine, (iii) individual versus collective responsibility and (iv) political climate and media influence. Participants were worried about long-term effectiveness and safety, and while many agreed that high-risk populations should be vaccinated, all considered themselves to be at low risk for serious disease. Some felt they should avoid taking a perceived risk (accepting a new vaccine) to protect society, although they felt pressured to do so. Vaccination campaign politization and the way the media approached the subject also contributed to mistrust and hesitancy to be vaccinated. These findings help us understand HCP beliefs and uncertainties about COVID-19 vaccinations. This study can help inform future campaigns targeted at HCPs to promote the acceptance of vaccines., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Patients with chronic diseases should meet with their primary care doctor regularly to facilitate proactive care. Little is known about what factors are associated with more regular follow-up., Methods: We studied 70,095 patients age 40 + with one of three chronic conditions (diabetes mellitus, heart failure, chronic obstructive pulmonary disease), cared for by Leumit Health Services, an Israeli health maintenance organization. Patients were divided into the quintile with the least temporally regular care (i.e., the most irregular intervals between visits) vs. the other four quintiles. We examined patient-level predictors of being in the least-temporally-regular quintile. We calculated the risk-adjusted regularity of care at 239 LHS clinics with at least 30 patients. For each clinic, compared the number of patients with the least temporally regular care with the number predicted to be in this group based on patient characteristics., Results: Compared to older patients, younger patients (age 40-49), were more likely to be in the least-temporally-regular group. For example, age 70-79 had an adjusted odds ratio (AOR) of 0.82 compared to age 40-49 (p < 0.001 for all findings discussed here). Males were more likely to be in the least-regular group (AOR 1.18). Patients with previous myocardial infarction (AOR 1.07), atrial fibrillation (AOR 1.08), and current smokers (AOR 1.12) were more likely to have an irregular pattern of care. In contrast, patients with diabetes (AOR 0.79) or osteoporosis (AOR 0.86) were less likely to have an irregular pattern of care. Clinic-level number of patients with irregular care, compared with the predicted number, ranged from 0.36 (fewer patients with temporally irregular care) to 1.71 (more patients)., Conclusions: Some patient characteristics are associated with more or less temporally regular patterns of primary care visits. Clinics vary widely on the number of patients with a temporally irregular pattern of care, after adjusting for patient characteristics. Health systems can use the patient-level model to identify patients at high risk for temporally irregular patterns of primary care. The next step is to examine which strategies are employed by clinics that achieve the most temporally regular care, since these strategies may be possible to emulate elsewhere., (© 2023. The Author(s).)

Background: Medical residents work long, continuous hours. Working in conditions of extreme fatigue has adverse effects on the quality and safety of care, and on residents' quality of life. Many countries have attempted to regulate residents' work hours., Objectives: We aimed to review residents' work hours regulations in different countries with an emphasis on night shifts., Methods: Standardized qualitative data on residents' working hours were collected with the assistance of experts from 14 high-income countries through a questionnaire. An international comparative analysis was performed., Results: All countries reviewed limit the weekly working hours; North-American countries limit to 60-80 h, European countries limit to 48 h. In most countries, residents work 24 or 26 consecutive hours, but the number of long overnight shifts varies, ranging from two to ten. Many European countries face difficulties in complying with the weekly hour limit and allow opt-out contracts to exceed it., Conclusions: In the countries analyzed, residents still work long hours. Attempts to limit the shift length or the weekly working hours resulted in modest improvements in residents' quality of life with mixed effects on quality of care and residents' education., (Copyright © 2023. Published by Elsevier B.V.)

Combination therapy with estrogen and spironolactone may help some transgender women achieve desired results. We used two databases, OptumLabs ® Data Warehouse (OLDW) and Veterans Health Administration (VHA), to examine trends in feminizing therapy. We included 3368 transgender patients from OLDW and 3527 from VHA, all of whom received estrogen, spironolactone, or both between 2006 and 2017. In OLDW, the proportion receiving combination therapy increased from 47% to 75% during this period. Similarly, in VHA, the proportion increased from 39% to 69% during this period. We conclude that the use of combination hormone therapy has become much more common over the past decade., Competing Interests: No competing financial interests exist., (Copyright 2023, Mary Ann Liebert, Inc., publishers.)

This study aimed to examine changes in depression and anxiety symptoms from before to during the first 6 months of the COVID-19 pandemic in a sample of 1,339 adolescents (9-18 years old, 59% female) from three countries. We also examined if age, race/ethnicity, disease burden, or strictness of government restrictions moderated change in symptoms. Data from 12 longitudinal studies (10 U.S., 1 Netherlands, 1 Peru) were combined. Linear mixed effect models showed that depression, but not anxiety, symptoms increased significantly (median increase = 28%). The most negative mental health impacts were reported by multiracial adolescents and those under 'lockdown' restrictions. Policy makers need to consider these impacts by investing in ways to support adolescents' mental health during the pandemic., (© 2022 Society for Research on Adolescence.)

Friendships are central relationships during adolescence. Given the increased experience of stress during adolescence, friends are especially critical sources of support at this time. Although experiencing social support is related to well-being, adolescents' experiences sharing problems with friends is not always positive. In this chapter, we consider two forms of problematic talk, co-rumination and conversational self-focus. Co-rumination refers to conversations about problems that is excessive, repetitive, speculative, and focused on negative affect. Conversational self-focus refers to adolescents re-directing conversations about friends' problems to oneself. Both co-rumination and conversational self-focus are associated with depressive symptoms. However, whereas co-rumination draws friends together and is associated with positive friendship quality, adolescents who engage in conversational self-focus are increasingly rejected by friends. Directions for future research and applied implications of studying social support processes between friends are discussed., (Copyright © 2023. Published by Elsevier Inc.)

Objective: We examined patient attitudes and beliefs and provider perspectives on patients' attitudes and beliefs towards testosterone therapy in Veterans Affairs (VA)., Methods: We used a thematic analysis approach to understand variation in patient attitudes and beliefs towards testosterone at six VA sites with high and low levels of testosterone prescribing in VA. Semi-structured phone interviews with 18 patients and 22 providers at these sites were transcribed and coded using a priori theoretical constructs and emergent themes. A cross-case matrix of coded data was used to evaluate themes related to patient-level factors., Results: Patients' beliefs toward testosterone did not differ across sites. Patients, not providers, generally initiated conversations about testosterone. We identified five key domains related to patient beliefs and provider perceived patient beliefs towards testosterone: reasons for initiating testosterone, patient information sources and expectations about testosterone, receptivity towards discontinuation of testosterone, patient/provider engagement in information sharing, and self-advocacy by the patients in decision-making., Conclusions: Patient factors play an important role in testosterone prescribing decisions., Practice Implications: By considering these patient factors, providers can potentially help create a partnership with patients and foster shared decision-making for testosterone and other, similar medications., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Guneet Jasuja reports financial support was provided by US Department of Veterans Affairs. Ryann Engle (corresponding author) received salary support from Dr. Guneet Jasuja’s US Department of Veterans Affairs grant., (Published by Elsevier B.V.)