Molecular glues that inhibit specific Zn2+-dependent DUB activity and inflammation.

Deubiquitylases (DUBs) play a pivotal role in cell signalling and are often regulated by homo- or hetero-interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signalling by selectively cleaving K63-linked polyubiquitin chains on Type I interferon receptors (IFNAR1). BRCC36 is a Zn2+-dependent JAMM/MPN DUB, a challenging ubiquitin protease class for the design of selective inhibitors. We identified first-in-class DUB inhibitors that act as BRISC molecular glues (BLUEs). BLUEs inhibit DUB activity by stabilising a BRISC dimer consisting of 16 subunits. The BLUE-stabilised BRISC dimer is an autoinhibited conformation, whereby the active sites and interactions with the recruiting subunit SHMT2 are blocked. This unique mode of action leads to highly selective inhibitors for BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs. Structure-guided inhibitor resistant mutants confirm BLUEs on-target activity in cells, and BLUE treatment results in reduced interferon-stimulated gene (ISG) expression in human peripheral blood mononuclear cells from Scleroderma patients, a disease linked with aberrant IFNAR1 activation. BLUEs represent a new class of molecules with potential utility in Type I interferon-mediated diseases and a template for designing selective inhibitors of large protein complexes by promoting protein-protein interactions instead of blocking them.

Antibiotic Prophylaxis for Genitourinary Procedures in Patients with Artificial Joint Replacement and Artificial Heart Valves.

Prosthetic joint infection (PJI) and prosthetic valve endocarditis (PVE) are uncommon but serious complications. According to current best practice statements, prior to a genitourinary procedure, patients with prosthetic joints should receive antibiotic prophylaxis if they are within 2 years of arthroplasty, if they are high risk for infection due to their individual comorbidities, or if the procedure poses a high risk for bacteremia. Patients with prosthetic valves should not receive antibiotic prophylaxis for the sole purpose of prevention of endocarditis. Enterococcus species are the uropathogens most often associated with PJI and PVE. Antibiotic selection should take into account local resistance patterns.

Differential Impact of Virtual Family-Centered Rounds in the Neonatal Intensive Care Unit by Social Factors: A Post Hoc Subgroup Analysis.

Background: Barriers to attending family-centered rounds (FCR) exist for socially disadvantaged families. Using telehealth to conduct virtual FCR could potentially promote equitable parent/guardian FCR access. The objective of this work was to assess whether the effects of a virtual FCR intervention on parent FCR attendance varied by subgroups defined by social factors. Methods: We conducted a post hoc analysis of a randomized controlled trial of virtual FCR in the neonatal intensive care unit. Parents of intervention arm infants were invited to participate in virtual FCR plus usual care; control arm infants received usual care. Participants were analyzed according to the assigned group and by race/ethnicity, insurance, mother's education, and neighborhood health conditions. We used Poisson regression to estimate and compare FCR parent attendance rates. Heterogeneity of intervention effects was assessed using interaction terms to evaluate the relative benefit of the intervention in increasing parent FCR attendance. Results: We included all enrolled trial subjects (74 intervention, 36 control). Intervention arm infants had 3.36 (95% confidence interval [CI]: 2.66-4.23) times the FCR parent attendance rate of subjects in the control arm. Compared with the corresponding reference subgroup, intervention benefits were 2.15 times (95% CI: 1.30-3.56) better for racial/ethnic minorities, 3.08 times (95% CI: 1.59-5.95) better for those with private insurance, 2.68 times (95% CI: 1.12-6.40) better for those whose mother reported no college education, and 4.14 times (95% CI: 2.07-8.25) better for those from a neighborhood with worse health conditions. Conclusions: Virtual FCR improved parent FCR attendance overall, with even greater benefits for certain subgroups. Further research is needed to mitigate the differential benefit demonstrated for privately insured subjects.

Predictive Factors of Non-Inflammatory Small Bowel Obstruction After Bowel Resection in Crohn's Patients.

Background: The aim of the study was to investigate the risk factors associated with the development of small bowel obstruction (SBO) in Crohn's disease (CD) after small bowel resection (SBR) that are not due to active/recurrent inflammation. Methods: We conducted a retrospective cohort study of patients who had SBR for active or complicated CD. Abstracted data included demographics, phenotype, therapies for CD, endoscopic disease recurrence, and several surgical variables. The primary outcome was the development of non-inflammatory SBO (NI-SBO) within 5 years after SBR. Results: A total of 335 patients were included. The cumulative rates of NI-SBO at 6 months, 1 year, and 5 years were 5 (1.5%), 8 (2.4%), and 29 (8.9%), respectively. Variables associated with the development of NI-SBO were active macroscopic or microscopic inflammation in the surgical margins (13 (56%) vs. 65 (27%), P = 0.004), open resection (vs. laparoscopic resection) (12 (41.4%) vs. 60 (19.5%), P = 0.0006) and a higher median number of previous resections (2 (interquartile range (IQR) 2 - 3) vs. 1 (IQR 1 - 2), P = 0.0002). Only 21% of patients who developed NI-SBO required surgical intervention. Conclusions: The incidence of NI-SBO after SBR in CD is low and associated with inflammation at the margins of the resected bowel, previous bowel resections, and an open laparotomy approach. Most NI-SBOs resolve with medical management.

Rethinking the consultation paradigm: Validity evidence for a new framework, a multimethods study.

BACKGROUND: In-hospital consultation is essential for patient care. We previously proposed a framework of seven specific consultation types to classify consult requests to improve communication, workflow, and provider satisfaction. METHODS: This multimethods study's aim was to evaluate the applicability of the consult classification framework to real internal medicine (IM) consults. We sought validity evidence using Kane's validity model with focus groups and classifying consult requests from five IM specialties. Participants attended five 1 h semi-structured focus groups that were recorded, transcribed, and coded for thematic saturation. For each specialty, three specialists and three hospitalists categorized 100 (total 500) random anonymized consult requests. The primary outcome was concordance in the classification of consult requests, defined as the sum of partial concordance and perfect concordance, where respectively 4-5/6 and 6/6 participants classified a consult in the same category. We used χ2 tests to compare concordance rates across specialties and between specialists and hospitalists. RESULTS: Five major themes were identified in the qualitative analysis of the focus groups: (1) consult question, (2) interpersonal interactions, (3) value, (4) miscommunication, (5) consult framework application, barriers, and iterative development. In the quantitative analysis, the overall concordance rate was 88.8% (95% confidence interval [CI]: 85.7-91.4), and perfect concordance was 46.6% (95% CI: 42.2-51.1). Concordance differed significantly between hospitalists and specialists overall (p = .01), with a higher proportion of hospitalists having perfect concordance compared to specialists (67.2% vs. 57.8%, p = .002). CONCLUSIONS: The consult classification framework was found to be applicable to consults from five different IM specialties, and could improve communication and education.

Diagnosis of Occult and Obscure Gastrointestinal Bleeding.

Occult and obscure bleeding are challenging conditions to manage; however, recent advances in gastroenterology and endoscopy have improved our diagnostic and therapeutic capabilities. Obscure gastrointestinal (GI) bleeding is an umbrella category of bleeding of unknown origin that persists or recurs after endoscopic evaluation of the entire bowel fails to reveal a bleeding source. This review details the evaluation of patients with occult and obscure GI bleeding and offers diagnostic algorithms. The treatment of GI bleeding depends on the type and location of the bleeding lesion and an overview of how to manage these conditions is presented.

Insulin Pump Therapy vs Multiple Daily Insulin Injections for Glycemic Control in Children With Type 1 Diabetes: A Systematic Review and Meta-Analysis.

Type 1 diabetes mellitus (T1DM), characterized by the autoimmune destruction of pancreatic beta cells and consequent insulin deficiency, leads to various complications. Management primarily focuses on optimal glycemic control through intensive insulin therapy, either via multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) using insulin pumps, which offer flexibility and improved basal insulin delivery. Despite the benefits of insulin pumps, such as reduced hypoglycemia risk and better mealtime insulin management, they pose challenges such as complexity in site changes and potential ketoacidosis due to tubing issues. This systematic review adheres to PRISMA guidelines and compares CSII with MDI in children and adolescents with T1DM, concentrating on outcomes such as glycemic control measured with HbA1c and glucose levels. The review includes studies meeting stringent criteria, encompassing a broad range of methodologies and geographies. The findings of this meta-analysis indicate the differences in glycemic control with CSII compared to MDI. However, significant heterogeneity in results and methodological variations across studies necessitate cautious interpretation. The study underscores the potential of CSII in offering better control for some patients, supporting a more personalized approach to T1DM management. It highlights the need for further research to understand the long-term effects and to refine treatment protocols, considering the variations in healthcare systems, treatment approaches, and patient demographics globally.

Traumatic injury of an ectopic kidney with iatrogenic ureteral injury and endovascular control of aberrant renal vessel.

The management of traumatic injuries in patients with ectopic kidneys presents special challenges. There is a paucity of literature regarding optimal strategies for renal salvage. We describe a case of a patient who presented in hemorrhagic shock after a motor vehicle collision. On initial operative exploration, he was found to have a large retroperitoneal mass. Subsequent imaging demonstrated a large retroperitoneal hematoma and an ectopic kidney. The patient was successfully treated with a combination of open renorrhaphy and endovascular angioembolization. This case demonstrates the importance of a multidisciplinary approach to treating these complex injuries.

Does survey mode matter? Comparing in-person and phone agricultural surveys in India.

Ubiquitous mobile phone ownership makes phone surveying an attractive method of low-cost data collection. We explore differences between in-person and phone survey measures of agricultural production collected for an impact evaluation in India. Phone responses have greater mean and variance, a difference that persists even within a subset of respondents that answered the same question over both modes. Treatment effect estimation remains stable across survey mode, but estimates are less precise when using phone data. These patterns are informative for cost and sample size considerations in study design and for aggregating evidence across study sites or time periods.

Differences in the Factor Structure of the Eating Attitude Test-26 (EAT-26) among Clinical vs. Non-Clinical Adolescent Israeli Females.

In recent years, the diagnostic definitions of eating disorders (EDs) have undergone dramatic changes. The Eating Attitudes Test-26 (EAT-26), which is considered an accepted instrument for community ED studies, has shown in its factorial structure to be inconsistent in different cultures and populations. The aim of the present study was to compare the factor structure of the EAT-26 among clinical and non-clinical populations. The clinical group included 207 female adolescents who were hospitalized with an ED (mean age 16.1). The non-clinical group included 155 female adolescents (mean age 16.1). Both groups completed the EAT-26. A series of factorial invariance models was conducted on the EAT-26. The results indicate that significant differences were found between the two groups regarding the original EAT-26 dimensions: dieting, bulimia and food preoccupation, and oral control. Additionally, the factorial structure of the EAT-26 was found to be significantly different in both groups compared to the original version. In the clinical group, the factorial structure of the EAT-26 consisted of four factors, whereas in the non-clinical sample, five factors were identified. Additionally, a 19-item version of the EAT-26 was found to be considerably more stable and well suited to capture ED symptoms in both groups, and a cutoff point of 22 (not 20) better differentiated clinical samples from non-clinical samples. The proposed shortening of the EAT from 40 to 26 and now to 19 items should be examined in future studies. That said, the shortened scale seems more suited for use among both clinical and non-clinical populations. These results reflect changes that have taken place in ED psychopathology over recent decades.

The association between deficiencies in paternal and maternal reflective functioning and anorexia nervosa symptomatology.

BACKGROUND: A large theoretical body of knowledge exists emphasizing the importance of parental mentalizing in the context of anorexia-nervosa (AN). However, the empirical support to these assumptions is still scarce. The aim of the present study was to examine whether parents of patients with AN are characterized by a lower mentalizing ability, and whether it is associated with impaired mentalizing, AN symptomatology and eating disorder (ED) related psychological traits in the daughters. METHODS: Thirty-two family triads (fathers, mothers, and daughters) of female adolescent and young adult inpatients with AN were compared with thirty-three non-clinical family triads (N = 195). The mentalizing ability of all the participants was assessed using semi-structured interviews and coded using the Reflective Functioning Scale (RFS). Self-report questionnaires were administered to the daughters to evaluate ED symptomatology and ED related psychological traits (e.g., low self-esteem, interpersonal insecurity, emotional dysregulation). RESULTS: Decreased reflective functioning (RF) levels were found among mothers and fathers of patients with AN compared to their control peers. Examining the entire sample, clinical and non-clinical groups together, showed that both paternal and maternal RF were associated with the daughters' RF and each were found to have a significant and distinct contribution to the daughters' RF. Significant associations were found between lower levels of maternal and paternal RF and increased ED symptoms and ED related psychological traits. The use of a mediation model suggested a serial relationship in which low maternal and paternal RF contributes to the daughters' low RF, which in turn is associated with higher levels of psychological maladjustment, and ultimately contributes to the increased severity of ED symptoms. CONCLUSIONS: The present results provide strong empirical support for theoretical models that suggest that deficits in parental mentalizing may represent important correlates of the presence and severity of ED symptoms in AN. Furthermore, the results highlight the relevance of fathers' mentalizing ability in the context of AN. Finally, clinical and research implications are discussed.

The goal of the study was to examine the relationship between deficits in parents' ability to reflect on their own and others' emotional experience and the severity of their daughter's eating disorder and psychological maladjustment. A clinical group of young female inpatients diagnosed with anorexia-nervosa and both their biological parents was compared to a control group of young females without eating disorder and their parents. Personal interviews assessed the participants' reflective ability and self-report questionnaires assessed the daughters' eating disorder severity and psychological difficulties. The results show that patients with anorexia nervosa and their parents are less able to reflect on their emotional experiences compared to the control group. The parents' reflective ability was found to be related to their daughter's reflective ability. For both fathers and mothers, the less able the parent is to reflect on his or her emotional experiences the higher the severity of the daughter's eating disorder symptoms and psychological maladjustment are. The results imply that deficits in the parents' ability to process their own and others' emotional experiences are related to the severity of eating disorders symptoms and psychological maladjustment among daughters.. The study results highlight the importance of assessing reflective abilities of fathers.

Differences in Telomere Length between Adolescent Females with Anorexia Nervosa Restricting Type and Anorexia Nervosa Binge-Purge Type.

Physiological and psychological distress may accelerate cellular aging, manifested by shortening of telomere length (TL). The present study focused on TL shortening in anorexia nervosa (AN), an illness combining physiological and psychological distress. For that purpose, we measured TL in 44 female adolescents with AN at admission to inpatient treatment, in a subset of 18 patients also at discharge, and in 22 controls. No differences in TL were found between patients with AN and controls. At admission, patients with AN-binge/purge type (AN-B/P; n = 18) showed shorter TL compared with patients with AN-restricting type (AN-R; n = 26). No change in TL was found from admission to discharge, despite an improvement in body mass index standard deviation score (BMI-SDS) following inpatient treatment. Older age was the only parameter assessed to be correlated with greater TL shortening. Several methodological changes have to be undertaken to better understand the putative association of shorter TL with B/P behaviors, including increasing the sample size and the assessment of the relevant pathological eating disorder (ED) and non-ED psychological correlates in the two AN subtypes.

Case report: Anorexia nervosa and unspecified restricting-type eating disorder in Jewish ultra-orthodox religious males, leading to severe physical and psychological morbidity.

Background: Young Jewish Ultra-Orthodox women usually show less disturbances in body image and eating in comparison to less religious communities. By contrast, problems with eating are highly unknown and unrecognized in Jewish Ultra-Orthodox males. Aim: To investigate whether in Ultra-Orthodox males, restricting-type AN (AN-R) with highly obsessional physical activity and unspecified restricting eating disorder (ED) in the context of obsessive-compulsive disorder (OCD) would lead to severe physical and emotional morbidity. Results: The study included two groups: the first, 3 adolescents with AN-R developing severely increased ritualized obsessional physical activity in addition to restricting eating, requiring inpatient treatment because of severe bradycardia. These youngsters ignored the severity of their obsessional physical activity, continuing with it in hospital despite their grave medical condition. One student began extensive training for triathlon, whereas another student, upon remitting from AN, developed severe muscle dysmorphia. These findings suggest that young Ultra-Orthodox males with AN may develop obsessional physical activity to increase their muscle mass rather than to lose weight Another four Jewish Ultra-Orthodox males developed malnutrition in the context of severe OCD, with no evidence of dieting or body-image disturbances. These individuals developed highly obsessional adherence to different Jewish religious rules, including prolonged praying, asceticism, and overvalued strict adherence to Jewish Kashrut rules of eating, leading in all cases to severe food restriction. They were highly unaware of their severe weight loss and required hospitalization because of severe physical disturbances associated with malnutrition. Moreover, most did not cooperate with their treatment, and their ED-related obsessionality was mostly resistant to psychopharmacotherapy. Conclusion: Owing to their highly ritualistic rigid way of life, combined with the need for excellency in studying, Jewish Ultra-Orthodox adolescent males with AN might be at a specific risk of developing severe physical disturbances if their illness is associated with highly perfectionistic obsessional physical activity. Second, Jewish Ultra-Orthodox religious males with OCD might be at a specific risk for severe undernutrition, as their rigid relentless observance of Jewish everyday laws might highly interfere with their eating.

Assessing the clinical viability of micro 3 pronuclei zygotes.

PURPOSE: What is the rate of euploidy and clinical viability of embryos resulting from micro 3 pronuclei zygotes? METHODS: Retrospective cohort analysis in a single, academic in vitro fertilization (IVF) center from March 2018 to June 2021. Cohorts were separated by fertilization as either a 2 pronuclear zygote (2PN) or micro 3 pronuclear zygote (micro 3PN). PGT-A was performed to identify embryonic ploidy rates in embryos created from micro 3PN zygotes. The clinical outcomes of all transferred euploid micro 3PN zygotes were evaluated from frozen embryo transfer (FET) cycles. RESULTS: During the designated study period, 75,903 mature oocytes were retrieved and underwent ICSI. Of these, 60,161 were fertilized as 2PN zygotes (79.3%) and 183 fertilized as micro 3PN zygotes (0.24%). Of the micro 3PN-derived embryos that underwent biopsy, 27.5% (n=11/42) were deemed euploid by PGT-A, compared to 51.4% (n=12,301/23,923) of 2PN-derived embryos, p=0.06. Four micro 3PN-derived embryos were transferred in subsequent single euploid FET cycles, which includes one live birth and one ongoing pregnancy. CONCLUSION: Micro 3PN zygotes that develop to the blastocyst stage and meet the criteria for embryo biopsy have the potential to be euploid by preimplantation genetic testing for aneuploidy (PGT-A) and if selected for transfer can achieve a live birth. Although there are a significantly lower number of micro 3PN embryos that make it to blastocyst biopsy, the potential to continue to culture abnormally fertilized oocytes may give these patients a chance at pregnancy that they previously did not have.

Mentalizing ability, mentalizing impairments, and anorexia nervosa: Validation of the Hebrew version of the Movie for the Assessment of Social Cognition (MASC).

The goal of this study was to validate the Hebrew version of the Movie for the Assessment of Social Cognition (MASC)-an ecological measure for assessing mentalizing ability-among patients with anorexia nervosa (AN) and healthy individuals. We examined the validity of the MASC's general mentalizing ability scale and of its mentalizing impairments subscales using validated measures of mentalizing ability (Reading the Mind in the Eyes test, Cambridge Mindreading Face-Voice Battery, and Reflective Function questionnaire) among female patients with AN (N = 35) and control participants (N = 42). ED symptoms were assessed via self-report questionnaires. The MASCHeb correlated with measures of mentalizing ability and was found to significantly differentiate patients with AN from controls. In addition to differing on general mental ability, the groups differed on hypomentalizing (but not hypermentalizing). Based on our findings, the MASCHeb proved to be an ecologically valid tool for assessing mentalizing ability and impairments among patients with AN. Moreover, our findings demonstrated the role played by general mentalizing ability in EDs and specifically pointed to the importance of hypomentalization in EDs. These findings have therapeutic implications, as outlined in the Discussion section.

Beyond collective intelligence: Collective adaptation.

We develop a conceptual framework for studying collective adaptation in complex socio-cognitive systems, driven by dynamic interactions of social integration strategies, social environments and problem structures. Going beyond searching for 'intelligent' collectives, we integrate research from different disciplines and outline modelling approaches that can be used to begin answering questions such as why collectives sometimes fail to reach seemingly obvious solutions, how they change their strategies and network structures in response to different problems and how we can anticipate and perhaps change future harmful societal trajectories. We discuss the importance of considering path dependence, lack of optimization and collective myopia to understand the sometimes counterintuitive outcomes of collective adaptation. We call for a transdisciplinary, quantitative and societally useful social science that can help us to understand our rapidly changing and ever more complex societies, avoid collective disasters and reach the full potential of our ability to organize in adaptive collectives.

Evaluating methods to create protein functionalized catanionic vesicles.

Catanionic surfactant vesicles (SVs) composed of sodium dodecylbenzenesulfonate (SDBS) and cetyltrimethylammonium tosylate (CTAT) have potential applications as targeted drug delivery systems, vaccine platforms, and diagnostic tools. To facilitate these applications, we evaluated various methods to attach proteins to the surface of SDBS/CTAT vesicles. Acid phosphatase from wheat germ was used as a model protein. Acid phosphatase was successfully conjugated to vesicles enriched with a Triton-X 100 derivative containing an unsaturated ester. Enzymatic activity of acid phosphatase attached to vesicles was assessed using an acid phosphatase assay. Results from the acid phosphatase assay indicated that 15 ± 3% of the attached protein remained functional but the presence of vesicles interferes with the assay. DLS and zeta potential results correlated with the protein functionalization studies. Acid phosphatase functionalized vesicles had an average diameter of 175 ± 85 nm and an average zeta potential of -61 ± 5 mV in PBS. As a control, vesicles enriched with Triton-X 100 were prepared and analyzed by DLS and zeta potential measurements. Triton X-100 enriched vesicles had an average diameter of 140 ± 67 nm and an average zeta potential of -49 ± 2 mV in PBS. Functionalizing the surface of SVs with proteins may be a key step in developing vesicle-based technologies. For drug delivery, antibodies could be used as targeting molecules; for vaccine formulation, functionalizing the surface with spike proteins may produce novel vaccine platforms.

SIRT6 is a key regulator of mitochondrial function in the brain.

The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mouse brains. Our analysis reveals that SIRT6 is a central regulator of mitochondrial activity in the brain. SIRT6 deficiency in the brain leads to mitochondrial deficiency with a global downregulation of mitochondria-related genes and pronounced changes in metabolite content. We suggest that SIRT6 affects mitochondrial functions through its interaction with the transcription factor YY1 that, together, regulate mitochondrial gene expression. Moreover, SIRT6 target genes include SIRT3 and SIRT4, which are significantly downregulated in SIRT6-deficient brains. Our results demonstrate that the lack of SIRT6 leads to decreased mitochondrial gene expression and metabolomic changes of TCA cycle byproducts, including increased ROS production, reduced mitochondrial number, and impaired membrane potential that can be partially rescued by restoring SIRT3 and SIRT4 levels. Importantly, the changes we observed in SIRT6-deficient brains are also occurring in aging human brains and particularly in patients with Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis disease. Overall, our results suggest that the reduced levels of SIRT6 in the aging brain and neurodegeneration initiate mitochondrial dysfunction by altering gene expression, ROS production, and mitochondrial decay.