The synergistic impact of type 2 diabetes and MASLD on cardiovascular, liver, diabetes-related and cancer outcomes.

BACKGROUND AND AIMS: We examined the impact of a co-diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) on patient outcomes. METHODS: Using TriNetX, a global federated research network (n = 114 million), we undertook two retrospective cohort studies, using time-to-event analysis. Analysis 1 compared MASLD with T2D to MASLD alone; analysis 2 compared T2D with MASLD to T2D alone. Propensity score matching using greedy nearest neighbour (calliper .1) balanced the cohorts (1:1) for significant covariates. Primary outcomes were cardiovascular, liver, diabetes-related, and cancer events over 5 years. RESULTS: Analysis 1 (n = 95 275): a co-diagnosis of T2D significantly increased the risk of ischaemic heart disease (IHD) (HR 1.39; CI: 1.34, 1.44), ischaemic stroke (HR 1.45; CI: 1.35, 1.56), heart failure (HR 1.42; CI: 1.36, 1.49), atrial fibrillation (HR 1.09; CI: 1.03, 1.16), hepatocellular carcinoma (HR 1.96; CI: 1.69, 2.27), pancreatic cancer (HR 1.25; CI: 1.06, 1.48) and liver-related complications over 5 years from MASLD diagnosis. Analysis 2 (n = 15 208): a co-diagnosis of MASLD significantly increased risk of all-cause mortality (HR 1.11; CI: 1.02, 1.22), IHD (HR 1.181; CI: 1.08, 1.29), hepatocellular (HR 50.31; CI: 6.94, 364.72), pancreatic (HR 1.78; CI: 1.12, 2.84), breast (HR 1.43; CI: 1.09, 1.88) and renal cancer (HR 2.01; CI: 1.24, 3.26), and diabetic neuropathy (HR 1.17; CI: 1.09, 1.27) over 5 years from metformin initiation. CONCLUSIONS: T2D significantly potentiates the risk of cardiovascular, malignancy and liver-related outcomes in people with MASLD. The effect of MASLD on people with T2D, although less dramatic, still potentiated risk of death, IHD, malignancy and peripheral neuropathy.

Systematic analysis of the Candida albicans kinome reveals environmentally contingent protein kinase-mediated regulation of filamentation and biofilm formation in vitro and in vivo.

Protein kinases are critical regulatory proteins in both prokaryotes and eukaryotes. Accordingly, protein kinases represent a common drug target for a wide range of human diseases. Therefore, understanding protein kinase function in human pathogens such as the fungus Candida albicans is likely to extend our knowledge of its pathobiology and identify new potential therapies. To facilitate the study of C. albicans protein kinases, we constructed a library of 99 non-essential protein kinase homozygous deletion mutants marked with barcodes in the widely used SN genetic background. Here, we describe the construction of this library and the characterization of the competitive fitness of the protein kinase mutants under 11 different growth and stress conditions. We also screened the library for protein kinase mutants with altered filamentation and biofilm formation, two critical virulence traits of C. albicans. An extensive network of protein kinases governs these virulence traits in a manner highly dependent on the specific environmental conditions. Studies on specific protein kinases revealed that (i) the cell wall integrity MAPK pathway plays a condition-dependent role in filament initiation and elongation; (ii) the hyper-osmolar glycerol MAPK pathway is required for both filamentation and biofilm formation, particularly in the setting of in vivo catheter infection; and (iii) Sok1 is dispensable for filamentation in hypoxic environments at the basal level of a biofilm but is required for filamentation in normoxia. In addition to providing a new genetic resource for the community, these observations emphasize the environmentally contingent function of C. albicans protein kinases.IMPORTANCECandida albicans is one of the most common causes of fungal disease in humans for which new therapies are needed. Protein kinases are key regulatory proteins and are increasingly targeted by drugs for the treatment of a wide range of diseases. Understanding protein kinase function in C. albicans pathogenesis may facilitate the development of new antifungal drugs. Here, we describe a new library of 99 protein kinase deletion mutants to facilitate the study of protein kinases. Furthermore, we show that the function of protein kinases in two virulence-related processes, filamentation and biofilm formation, is dependent on the specific environmental conditions.

Exploring crystal structure-physical property relationships with pressure.

From its conception, X-ray crystallography has provided a unique understanding of the structure, bonding and electronic state of materials, which, in turn, unlocks a means of examining the properties and function of crystalline systems. Using state-of-the-art single-crystal X-ray diffraction, along with UV-Vis spectroscopy and DFT calculations, Zwolenik et al. [(2024). IUCrJ, 11, 519-527] have provided a comprehensive study of the structure-optical property relationship of 1,3-diacetylpyrene with methodologies that are increasingly accessible to non-specialist laboratories.

Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by increasing fibrosis, which can enhance tumor progression and spread. Here, we undertook an unbiased temporal assessment of the matrisome of the highly metastatic KPC (Pdx1-Cre, LSL-KrasG12D/+, LSL-Trp53R172H/+) and poorly metastatic KPflC (Pdx1-Cre, LSL-KrasG12D/+, Trp53fl/+) genetically engineered mouse models of pancreatic cancer using mass spectrometry proteomics. Our assessment at early-, mid-, and late-stage disease reveals an increased abundance of nidogen-2 (NID2) in the KPC model compared to KPflC, with further validation showing that NID2 is primarily expressed by cancer-associated fibroblasts (CAFs). Using biomechanical assessments, second harmonic generation imaging, and birefringence analysis, we show that NID2 reduction by CRISPR interference (CRISPRi) in CAFs reduces stiffness and matrix remodeling in three-dimensional models, leading to impaired cancer cell invasion. Intravital imaging revealed improved vascular patency in live NID2-depleted tumors, with enhanced response to gemcitabine/Abraxane. In orthotopic models, NID2 CRISPRi tumors had less liver metastasis and increased survival, highlighting NID2 as a potential PDAC cotarget.

New pathways to neurogenesis: Insights from injury-induced retinal regeneration.

The vertebrate retina is a tractable system for studying control of cell neurogenesis and cell fate specification. During embryonic development, retinal neurogenesis is under strict temporal regulation, with cell types generated in fixed but overlapping temporal intervals. The temporal sequence and relative numbers of retinal cell types generated during development are robust and show minimal experience-dependent variation. In many cold-blooded vertebrates, acute retinal injury induces a different form of neurogenesis, where Müller glia reprogram into retinal progenitor-like cells that selectively regenerate retinal neurons lost to injury. The extent to which the molecular mechanisms controlling developmental and injury-induced neurogenesis resemble one another has long been unclear. However, a recent study in zebrafish has shed new light on this question, using single-cell multiomic analysis to show that selective loss of different retinal cell types induces the formation of fate-restricted Müller glia-derived progenitors that differ both from one another and from progenitors in developing retina. Here, we discuss the broader implications of these findings, and their possible therapeutic relevance.

Long-Term Outcomes of Self-Fit vs Audiologist-Fit Hearing Aids.

Importance: With rising interest in over-the-counter (OTC) hearing aids as an alternative to traditional audiologist-fit devices, understanding their long-term efficacy is crucial. However, given the novelty of the US Food and Drug Administration category of OTC hearing aids, minimal evidence currently supports their long-term efficacy. Objective: To compare the long-term self-reported outcomes at 8 months of self-fit OTC hearing aids to the same hearing aids fit by audiologists. Design, Setting, and Participants: Building on a previous randomized clinical trial, this follow-up comparative effectiveness research study reassessed a number of the original participants that were not lost to follow-up. Participants were initially divided into those with self-fit OTC hearing aids and those with audiologist-fit devices. Approximately 8 months after fitting, participants completed self-reported questionnaires. Missing data were addressed through multiple imputation. The original noninferiority trial was conducted at the University of Pretoria in South Africa from April 2022 to August 2022. The current analysis took place between July 7, 2023, to November 20, 2023. Interventions: In the original trial, participants in the self-fit device group received a pair of OTC hearing aids and independently fit them with remote support as needed. The audiologist-fit device group received the same hearing aids fit by a certified audiologist using best practices. Main Outcomes and Measures: The main outcomes were self-reported hearing aid benefit, measured using the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the International Outcome Inventory for Hearing Aids (IOI-HA). Results: Of 64 participants in the trial, 44 participants were included in the extension study (21 [47.7%] in the audiologist-fit group; 23 [52.3%] in the self-fit group). The mean (SD) age of these participants was 63.0 (13.2) years, and 21 (47.7%) were male. At the long-term follow-up, self-fit and audiologist-fit groups showed no significant differences in the APHAB global score (mean difference, 0.02 [95% CI, -7.1 to 7.1]; Cohen d, 0.01 [95% CI, -0.5 to 0.5]) or the IOI-HA total score (mean difference, 1.5 [95% CI, -1.4 to 4.4]; Cohen d, 0.3 [95% CI, -0.2 to 0.8]). From 6 weeks to 8 months, no clinically meaningful group-time interaction was found between groups for the APHAB global score (Cohen d, 0.1 [95% CI, -0.2 to 0.3]), but a significant interaction for the IOI-HA total score was found (Cohen d, -0.6 [95% CI, -0.8 to -0.3]), with the self-fit group generally performing better. Conclusion: This comparative effectiveness research study demonstrated that self-fit OTC hearing aids can offer comparable long-term benefits to audiologist-fit hearing aids for individuals with mild to moderate hearing loss.

An HSF1-JMJD6-HSP feedback circuit promotes cell adaptation to proteotoxic stress.

Heat Shock Factor 1 (HSF1) is best known as the master transcriptional regulator of the heat-shock response (HSR), a conserved adaptive mechanism critical for protein homeostasis (proteostasis). Combining a genome-wide RNAi library with an HSR reporter, we identified Jumonji domain-containing protein 6 (JMJD6) as an essential mediator of HSF1 activity. In follow-up studies, we found that JMJD6 is itself a noncanonical transcriptional target of HSF1 which acts as a critical regulator of proteostasis. In a positive feedback circuit, HSF1 binds and promotes JMJD6 expression, which in turn reduces heat shock protein 70 (HSP70) R469 monomethylation to disrupt HSP70-HSF1 repressive complexes resulting in enhanced HSF1 activation. Thus, JMJD6 is intricately wired into the proteostasis network where it plays a critical role in cellular adaptation to proteotoxic stress.

Phase II Trial of Afatinib in Patients With EGFR-Mutated Solid Tumors Excluding Lung Cancer: Results From NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol A.

PURPOSE: National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) was a multicohort phase 2 trial that assigned patients with advanced pretreated cancers to molecularly targeted therapies on the basis of tumor genomic testing. NCI-MATCH Arm A evaluated afatinib, an EGFR tyrosine kinase inhibitor (TKI) approved for advanced non-small cell lung cancer, in patients with tumors other than lung cancer harboring EGFR mutations. METHODS: Patients with advanced pretreated cancers other than lung cancer found to have selected actionable EGFR mutations were offered participation in Arm A. Previous therapy with an EGFR TKI was not allowed. Patients received afatinib 40 mg once daily continuously until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), 6-month PFS, and overall survival (OS). RESULTS: Seventeen patients received protocol therapy. Tumor types included glioblastoma multiforme (GBM) (13), gliosarcoma (1), adenocarcinoma not otherwise specified (NOS) (2), and adenosquamous carcinoma of the breast (1). Fifty-nine percent of patients received ≥2 lines of previous therapy. The ORR was 11.8% (90% CI, 2.1 to 32.6), with one complete response lasting 16.4 months (GBM harboring a rare exon 18 EGFR-SEPT14 fusion) and one partial response lasting 12.8 months (adenocarcinoma NOS with the classic EGFR mutation, p.Glu746_Ala750del). Three patients had stable disease. The 6-month PFS was 15% (90% CI, 0 to 30.7); the median OS was 9 months (90% CI, 4.6 to 14.0). Rash and diarrhea were the most common toxicities. CONCLUSION: Afatinib had modest activity in a cohort of patients with heavily pretreated cancer with advanced nonlung, EGFR-mutated tumors, but the trial's primary end point was not met. Further evaluation of afatinib in GBM with EGFR exon 18 fusions may be of interest.

Health and economic impacts of Lassa vaccination campaigns in West Africa.

Lassa fever is a zoonotic disease identified by the World Health Organization (WHO) as having pandemic potential. This study estimates the health-economic burden of Lassa fever throughout West Africa and projects impacts of a series of vaccination campaigns. We also model the emergence of "Lassa-X" - a hypothetical pandemic Lassa virus variant - and project impacts of achieving 100 Days Mission vaccination targets. Our model predicted 2.7M (95% uncertainty interval: 2.1M-3.4M) Lassa virus infections annually, resulting over ten years in 2.0M (793.8K-3.9M) disability-adjusted life years (DALYs). The most effective vaccination strategy was a population-wide preventive campaign primarily targeting WHO-classified "endemic" districts. Under conservative vaccine efficacy assumptions, this campaign averted $20.1M ($8.2M-$39.0M) in lost DALY value and $128.2M ($67.2M-$231.9M) in societal costs (International dollars 2021). Reactive vaccination in response to local outbreaks averted just one-tenth the health-economic burden of preventive campaigns. In the event of Lassa-X emerging, spreading throughout West Africa and causing approximately 1.2M DALYs within two years, 100 Days Mission vaccination averted 22% of DALYs given a vaccine 70% effective against disease, and 74% of DALYs given a vaccine 70% effective against both infection and disease. These findings suggest how vaccination could alleviate Lassa fever's burden and assist in pandemic preparedness.

An RNA interference approach for functional studies in the sea urchin and its use in analysis of Nodal signaling gradients.

We report the first RNAi-based gene knockdowns in a sea urchin. Dicer-Substrate interfering RNAs (DsiRNAs) successfully disrupted expression of multiple transcripts in embryos of the sea urchin Lytechinus variagatus, phenocopying known morpholino and inhibitor knockdowns. We describe our approach for the design of DsiRNAs most likely to target mRNAs of interest. An examination of DsiRNAs directed against pks1 , an enzyme necessary for pigment production, reveal destruction of the pks1 mRNA without destroying the now-albino pigment cells. Application of DsiRNA on Nodal-Lefty signaling in this species confirms well-known functional studies. DsiRNA-based knockdowns of nodal and lefty phenocopy morpholino- and drug-based inhibition of expression of these genes. A dilution series of DsiRNAs directed against nodal and lefty reveals new diffusion properties of these signals in specifying dorsal vs ventral mesoderm. Highlights: DsiRNA provides an RNAi approach for perturbation of sea urchin embryos. A dilution series of DsiRNA oligos reveals properties of the Nodal gradient in establishing the Dorsal-Ventral axis.

Spironolactone Reduces the Risk of Death in Veterans With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome increasing in prevalence and affecting millions worldwide but with limited evidence-based therapies. Results from explanatory clinical trials suggest that spironolactone may help to improve outcomes in patients with HFpEF. We sought to investigate the effectiveness of spironolactone in reducing death and hospitalization outcomes for patients with HFpEF in a real-world setting. METHODS AND RESULTS: We used electronic health records from the US Veterans Affairs (VA) health care system between 2002 and 2012 to identify patients with HFpEF who were followed longitudinally through 2014 using a validated algorithm. Among our HFpEF cohort that is 96% men, 85% White individuals, and aged 74±11 years, 3690 spironolactone users and 49 191 nonusers were identified and followed for a median of 2.9 (interquartile range [IQR], 1.5-2.4) and 3.3 (IQR, 1.6-5.9) years, respectively. We evaluated the effect of spironolactone use on all-cause death and number of days hospitalized per year for heart failure or for any cause by fitting generalized estimating equation-based Poisson and negative binomial models. Crude rates of 10.3 versus 13.5 deaths and 394.0 versus 485.9 days hospitalized were observed per 100 person-years for spironolactone users versus nonusers, respectively. After multivariable adjustment, there was a 21% reduction (95% CI, 13-29; P<0.0001) in rate of all-cause death among spironolactone users compared with nonusers and no statistically significant difference in days hospitalized for all causes or heart failure. CONCLUSIONS: In a real-world national cohort of patients with HFpEF, spironolactone use reduced all-cause death and demonstrated a favorable trend in reducing the burden of hospitalizations.

Directed Evolution of Acoustic Reporter Genes Using High-Throughput Acoustic Screening.

A major challenge in the fields of biological imaging and synthetic biology is noninvasively visualizing the functions of natural and engineered cells inside opaque samples such as living animals. One promising technology that addresses this limitation is ultrasound (US), with its penetration depth of several cm and spatial resolution on the order of 100 µm. Within the past decade, reporter genes for US have been introduced and engineered to link cellular functions to US signals via heterologous expression in commensal bacteria and mammalian cells. These acoustic reporter genes (ARGs) represent a novel class of genetically encoded US contrast agent, and are based on air-filled protein nanostructures called gas vesicles (GVs). Just as the discovery of fluorescent proteins was followed by the improvement and diversification of their optical properties through directed evolution, here we describe the evolution of GVs as acoustic reporters. To accomplish this task, we establish high-throughput, semiautomated acoustic screening of ARGs in bacterial cultures and use it to screen mutant libraries for variants with increased nonlinear US scattering. Starting with scanning site saturation libraries for two homologues of the primary GV structural protein, GvpA/B, two rounds of evolution resulted in GV variants with 5- and 14-fold stronger acoustic signals than the parent proteins. We anticipate that this and similar approaches will help high-throughput protein engineering play as large a role in the development of acoustic biomolecules as it has for their fluorescent counterparts.

Systematic optimization of prime editing for the efficient functional correction of CFTR F508del in human airway epithelial cells.

Prime editing (PE) enables precise and versatile genome editing without requiring double-stranded DNA breaks. Here we describe the systematic optimization of PE systems to efficiently correct human cystic fibrosis (CF) transmembrane conductance regulator (CFTR) F508del, a three-nucleotide deletion that is the predominant cause of CF. By combining six efficiency optimizations for PE-engineered PE guide RNAs, the PEmax architecture, the transient expression of a dominant-negative mismatch repair protein, strategic silent edits, PE6 variants and proximal 'dead' single-guide RNAs-we increased correction efficiencies for CFTR F508del from less than 0.5% in HEK293T cells to 58% in immortalized bronchial epithelial cells (a 140-fold improvement) and to 25% in patient-derived airway epithelial cells. The optimizations also resulted in minimal off-target editing, in edit-to-indel ratios 3.5-fold greater than those achieved by nuclease-mediated homology-directed repair, and in the functional restoration of CFTR ion channels to over 50% of wild-type levels (similar to those achieved via combination treatment with elexacaftor, tezacaftor and ivacaftor) in primary airway cells. Our findings support the feasibility of a durable one-time treatment for CF.

Biomechanical properties of the capsule and extracellular matrix play a major role during the Wolffian/epididymal duct development.

BACKGROUND: The epididymis is important for sperm maturation and without its proper development, male infertility will result. Biomechanical properties of tissues/organs play key roles during their morphogenesis, including the Wolffian duct. It is hypothesized that structural/bulk stiffness of the capsule and mesenchyme/extracellular matrix that surround the duct is a major biomechanical property that regulates Wolffian duct morphogenesis. These data will provide key information as to the mechanisms that regulate the development of this important organ. OBJECTIVES: To measure the structural/bulk stiffness in Pascals (force/area) of the capsule and the capsule and mesenchyme together that surrounds the Wolffian duct during the development. To examine the relative membrane tension of mesenchymal cells during the Wolffian duct development. Since Ptk7 was previously shown to regulate ECM integrity and Wolffian duct elongation and coiling, the hypothesis that Ptk7 regulates structural/bulk stiffness and mesenchymal cell membrane tension was tested. MATERIALS AND METHODS: Atomic force microscopy and a microsquisher compression apparatus were used to measure the structural stiffness. Biomechanical properties within the membranes of cells within the capsule and mesenchyme were examined using a membrane-tension fluorescent probe. RESULTS AND DISCUSSION: The structural stiffness (Pascals) of the capsule and underlying mesenchyme was relatively constant during development, with a significant increase in the capsule at the later stages. However, this increase may reflect the ECM and associated mesenchyme being close to the capsule because the coiling of the duct pushed or compressed them into that space. Keeping the capsule and mesenchyme/ECM at constant stiffness would ensure that the duct will continue to coil under similar biomechanical forces throughout the development. Cells within the capsule and mesenchyme at different Wolffian duct regions during the development had varying degrees of membrane lipid tension. It is hypothesized that the dynamic changes ensure the duct is kept at a constant stiffness regardless of any external forces. Loss of Ptk7 resulted in an increase in stiffness at E18.5, which was presumable due to the loss of integrity of the ECM within the mesenchyme. CONCLUSION: Biomechanical properties of the capsule and the mesenchyme/extracellular matrix that surround the Wolffian duct play an important role toward Wolffian duct morphogenesis, thereby allowing for the proper development of the epididymis and subsequent male fertility.

Microbiota signature of oral chronic graft-versus-host disease 6+ years after transplantation.

Not available.

Complications Associated with AMBU™ Scope Use: An FDA MAUDE Analysis.

Ambu® aScope™ is a disposable flexible videoscope used for a wide range of medical procedures. However, adverse events associated with this device can occur. The Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database was explored for patient-related adverse events associated with Ambu® aScope™ use between January 1, 2000 and December 15, 2023. Search terms included "Ambu" and "Ascope." Thirty unique adverse events were identified. Twenty-one of the events were associated with patient injury, and 9 with device malfunction. Eight patient-reported problems were documented as foreign bodies, 3 events as airway obstruction, desaturation, or hypoxic events, and 1 event as anxiety/cardiac arrest. The remaining 18 reported insufficient information other than associated with patient injury. We found that Ambu® aScope™ flexible nasolaryngoscopes and bronchoscopes are a common and effective tool for airway evaluations that may infrequently serve as a rare form of foreign body with potentially life-threatening consequences.

Safety of treating acute pulmonary embolism at home: an individual patient data meta-analysis.

BACKGROUND AND AIMS: Home treatment is considered safe in acute pulmonary embolism (PE) patients selected by a validated triage tool (e.g. simplified PE severity index score or Hestia rule), but there is uncertainty regarding the applicability in underrepresented subgroups. The aim was to evaluate the safety of home treatment by performing an individual patient-level data meta-analysis. METHODS: Ten prospective cohort studies or randomized controlled trials were identified in a systematic search, totalling 2694 PE patients treated at home (discharged within 24 h) and identified by a predefined triage tool. The 14- and 30-day incidences of all-cause mortality and adverse events (combined endpoint of recurrent venous thromboembolism, major bleeding, and/or all-cause mortality) were evaluated. The relative risk (RR) for 14- and 30-day mortalities and adverse events is calculated in subgroups using a random effects model. RESULTS: The 14- and 30-day mortalities were 0.11% [95% confidence interval (CI) 0.0-0.24, I2 = 0) and 0.30% (95% CI 0.09-0.51, I2 = 0). The 14- and 30-day incidences of adverse events were 0.56% (95% CI 0.28-0.84, I2 = 0) and 1.2% (95% CI 0.79-1.6, I2 = 0). Cancer was associated with increased 30-day mortality [RR 4.9; 95% prediction interval (PI) 2.7-9.1; I2 = 0]. Pre-existing cardiopulmonary disease, abnormal troponin, and abnormal (N-terminal pro-)B-type natriuretic peptide [(NT-pro)BNP] at presentation were associated with an increased incidence of 14-day adverse events [RR 3.5 (95% PI 1.5-7.9, I2 = 0), 2.5 (95% PI 1.3-4.9, I2 = 0), and 3.9 (95% PI 1.6-9.8, I2 = 0), respectively], but not mortality. At 30 days, cancer, abnormal troponin, and abnormal (NT-pro)BNP were associated with an increased incidence of adverse events [RR 2.7 (95% PI 1.4-5.2, I2 = 0), 2.9 (95% PI 1.5-5.7, I2 = 0), and 3.3 (95% PI 1.6-7.1, I2 = 0), respectively]. CONCLUSIONS: The incidence of adverse events in home-treated PE patients, selected by a validated triage tool, was very low. Patients with cancer had a three- to five-fold higher incidence of adverse events and death. Patients with increased troponin or (NT-pro)BNP had a three-fold higher risk of adverse events, driven by recurrent venous thromboembolism and bleeding.

Increasing Screening Rates for Comorbidities in Adolescents with Elevated Body Mass Index in Pediatric Primary Care.

Introduction: Adolescents with elevated body mass index are at increased risk for comorbidities such as dyslipidemia, diabetes mellitus, and metabolic dysfunction-associated steatotic liver disease. Guideline-based screening can identify impacted patients early, allowing for lifestyle modifications and other treatments to improve long-term health. Unfortunately, only 20% of pediatric patients with obesity receive recommended screening. Methods: A multidisciplinary quality improvement team designed and implemented a project to improve comorbidity screening utilizing the Model for Improvement. Provider education and incentive, clinical decision support, and regular performance feedback were chosen as interventions. Screening rates were tracked on a statistical process control chart. Results: From March through December of 2022, 9547 pediatric patients aged 10 years and up with body mass index greater than or equal to the 95th percentile were seen for preventive care visits. Screening rates for comorbidities increased from a baseline of 19.5%-58% and were sustained for over 3 months. Numerous patients at risk for chronic disease were identified. Conclusions: Evidence-based clinical decision support, along with provider education and engagement, can effectively increase screening rates for comorbidities in pediatric patients with obesity.

The lived experiences of transgender and gender-diverse people in accessing publicly funded penile-inversion vaginoplasty in Canada.

BACKGROUND: Canada's health care systems underserve people who are transgender and gender diverse (TGD), leading to unique disparities not experienced by other patient groups, such as in accessing gender-affirmation surgery. We sought to explore the experiences of TGD people seeking and accessing gender-affirmation surgery at a publicly funded hospital in Canada to identify opportunities to improve the current system. METHODS: We used hermeneutic phenomenology according to Max van Manen to conduct this qualitative study. Between January and August 2022, we conducted interviews with TGD people who had undergone penile-inversion vaginoplasty at Women's College Hospital, Toronto, Ontario, since June 2019. We conducted interviews via Microsoft Teams and transcribed them verbatim. We coded the transcripts using NVivo version 12. Using inductive analysis, we constructed themes, which we mapped onto van Manen's framework of lived body, lived time, lived space, and lived human relations. RESULTS: We interviewed 15 participants who had undergone penile-inversion vaginoplasty; they predominantly self-identified as transgender women (n = 13) and White (n = 14). Participants lived in rural (n = 4), suburban (n = 5), or urban (n = 6) locations. Their median age was 32 (range 27-67) years. We identified 11 themes that demonstrated the interconnected nature of TGD peoples' lived experiences over many years leading up to accessing gender-affirmation surgery. These themes emphasized the role of the body in experiencing the world and shaping identity, the lived experience of the body in shaping human connectedness, and participants' intersecting identities and emotional pain (lived body); participants' experiences of the passage of time and progression of events (lived time); environments inducing existential anxiety or fostering affirmation, the role of technology in shaping participants' understanding of the body, and the effect of liminal spaces (lived space); and finally, the role of communication and language, empathy and compassion, and participants' experiences of loss of trust and connection (lived human relations). INTERPRETATION: Our findings reveal TGD patients' lived experiences as they navigated a lengthy and often difficult journey to penile-inversion vaginoplasty. They suggest a need for improved access to gender-affirmation surgery by reducing wait times, increasing capacity, and improving care experiences.