Mechanisms of Regeneration and Fibrosis in the Endometrium.

The uterine lining (endometrium) regenerates repeatedly over the life span as part of its normal physiology. Substantial portions of the endometrium are shed during childbirth (parturition) and, in some species, menstruation, but the tissue is rapidly rebuilt without scarring, rendering it a powerful model of regeneration in mammals. Nonetheless, following some assaults, including medical procedures and infections, the endometrium fails to regenerate and instead forms scars that may interfere with normal endometrial function and contribute to infertility. Thus, the endometrium provides an exceptional platform to answer a central question of regenerative medicine: Why do some systems regenerate while others scar? Here, we review our current understanding of diverse endometrial disruption events in humans, nonhuman primates, and rodents, and the associated mechanisms of regenerative success and failure. Elucidating the determinants of these disparate repair processes promises insights into fundamental mechanisms of mammalian regeneration with substantial implications for reproductive health.

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis.

Genetic studies have identified ≥240 loci associated with the risk of type 2 diabetes (T2D), yet most of these loci lie in non-coding regions, masking the underlying molecular mechanisms. Recent studies investigating mRNA expression in human pancreatic islets have yielded important insights into the molecular drivers of normal islet function and T2D pathophysiology. However, similar studies investigating microRNA (miRNA) expression remain limited. Here, we present data from 63 individuals, the largest sequencing-based analysis of miRNA expression in human islets to date. We characterized the genetic regulation of miRNA expression by decomposing the expression of highly heritable miRNAs into cis- and trans-acting genetic components and mapping cis-acting loci associated with miRNA expression [miRNA-expression quantitative trait loci (eQTLs)]. We found i) 84 heritable miRNAs, primarily regulated by trans-acting genetic effects, and ii) 5 miRNA-eQTLs. We also used several different strategies to identify T2D-associated miRNAs. First, we colocalized miRNA-eQTLs with genetic loci associated with T2D and multiple glycemic traits, identifying one miRNA, miR-1908, that shares genetic signals for blood glucose and glycated hemoglobin (HbA1c). Next, we intersected miRNA seed regions and predicted target sites with credible set SNPs associated with T2D and glycemic traits and found 32 miRNAs that may have altered binding and function due to disrupted seed regions. Finally, we performed differential expression analysis and identified 14 miRNAs associated with T2D status-including miR-187-3p, miR-21-5p, miR-668, and miR-199b-5p-and 4 miRNAs associated with a polygenic score for HbA1c levels-miR-216a, miR-25, miR-30a-3p, and miR-30a-5p.

Modeling islet enhancers using deep learning identifies candidate causal variants at loci associated with T2D and glycemic traits.

Genetic association studies have identified hundreds of independent signals associated with type 2 diabetes (T2D) and related traits. Despite these successes, the identification of specific causal variants underlying a genetic association signal remains challenging. In this study, we describe a deep learning (DL) method to analyze the impact of sequence variants on enhancers. Focusing on pancreatic islets, a T2D relevant tissue, we show that our model learns islet-specific transcription factor (TF) regulatory patterns and can be used to prioritize candidate causal variants. At 101 genetic signals associated with T2D and related glycemic traits where multiple variants occur in linkage disequilibrium, our method nominates a single causal variant for each association signal, including three variants previously shown to alter reporter activity in islet-relevant cell types. For another signal associated with blood glucose levels, we biochemically test all candidate causal variants from statistical fine-mapping using a pancreatic islet beta cell line and show biochemical evidence of allelic effects on TF binding for the model-prioritized variant. To aid in future research, we publicly distribute our model and islet enhancer perturbation scores across ~67 million genetic variants. We anticipate that DL methods like the one presented in this study will enhance the prioritization of candidate causal variants for functional studies.

Father's care uniquely influences male neurodevelopment.

Mammalian infants depend on parental care for survival, with numerous consequences for their behavioral development. We investigated the epigenetic and neurodevelopmental mechanisms mediating the impact of early biparental care on development of alloparenting behavior, or caring for offspring that are not one's own. We find that receiving high parental care early in life leads to slower epigenetic aging of both sexes and widespread male-specific differential expression of genes related to synaptic transmission and autism in the nucleus accumbens. Examination of parental care composition indicates that high-care fathers promote a male-specific increase in excitatory synapses and increases in pup retrieval behavior as juveniles. Interestingly, females raised by high-care fathers have the opposite behavioral response and display fewer pup retrievals. These results support the concept that neurodevelopmental trajectories are programmed by different features of early-life parental care and reveal that male neurodevelopmental processes are uniquely sensitive to care by fathers.

Single-cell transcriptomic profiling of human pancreatic islets reveals genes responsive to glucose exposure over 24 h.

AIMS/HYPOTHESIS: Disruption of pancreatic islet function and glucose homeostasis can lead to the development of sustained hyperglycaemia, beta cell glucotoxicity and subsequently type 2 diabetes. In this study, we explored the effects of in vitro hyperglycaemic conditions on human pancreatic islet gene expression across 24 h in six pancreatic cell types: alpha; beta; gamma; delta; ductal; and acinar. We hypothesised that genes associated with hyperglycaemic conditions may be relevant to the onset and progression of diabetes. METHODS: We exposed human pancreatic islets from two donors to low (2.8 mmol/l) and high (15.0 mmol/l) glucose concentrations over 24 h in vitro. To assess the transcriptome, we performed single-cell RNA-seq (scRNA-seq) at seven time points. We modelled time as both a discrete and continuous variable to determine momentary and longitudinal changes in transcription associated with islet time in culture or glucose exposure. Additionally, we integrated genomic features and genetic summary statistics to nominate candidate effector genes. For three of these genes, we functionally characterised the effect on insulin production and secretion using CRISPR interference to knock down gene expression in EndoC-ßH1 cells, followed by a glucose-stimulated insulin secretion assay. RESULTS: In the discrete time models, we identified 1344 genes associated with time and 668 genes associated with glucose exposure across all cell types and time points. In the continuous time models, we identified 1311 genes associated with time, 345 genes associated with glucose exposure and 418 genes associated with interaction effects between time and glucose across all cell types. By integrating these expression profiles with summary statistics from genetic association studies, we identified 2449 candidate effector genes for type 2 diabetes, HbA1c, random blood glucose and fasting blood glucose. Of these candidate effector genes, we showed that three (ERO1B, HNRNPA2B1 and RHOBTB3) exhibited an effect on glucose-stimulated insulin production and secretion in EndoC-ßH1 cells. CONCLUSIONS/INTERPRETATION: The findings of our study provide an in-depth characterisation of the 24 h transcriptomic response of human pancreatic islets to glucose exposure at a single-cell resolution. By integrating differentially expressed genes with genetic signals for type 2 diabetes and glucose-related traits, we provide insights into the molecular mechanisms underlying glucose homeostasis. Finally, we provide functional evidence to support the role of three candidate effector genes in insulin secretion and production. DATA AVAILABILITY: The scRNA-seq data from the 24 h glucose exposure experiment performed in this study are available in the database of Genotypes and Phenotypes (dbGap; https://www.ncbi.nlm.nih.gov/gap/ ) with accession no. phs001188.v3.p1. Study metadata and summary statistics for the differential expression, gene set enrichment and candidate effector gene prediction analyses are available in the Zenodo data repository ( https://zenodo.org/ ) under accession number 11123248. The code used in this study is publicly available at https://github.com/CollinsLabBioComp/publication-islet_glucose_timecourse .

ß-importin Tnpo-SR promotes germline stem cell maintenance and oocyte differentiation in female Drosophila.

Germ cell development requires interplay between factors that balance cell fate and division. Early in their development, germ cells in many organisms divide mitotically with incomplete cytokinesis. Key regulatory events then lead to the specification of mature gametes, marked by the switch to a meiotic cell cycle program. Though the regulation of germ cell proliferation and meiosis are well understood, how these events are coordinated during development remains incompletely described. Originally characterized in their role as nucleo-cytoplasmic shuttling proteins, ß-importins exhibit diverse functions during male and female gametogenesis. Here, we describe novel, distinct roles for the ß-importin, Transportin-Serine/Arginine rich (Tnpo-SR), as a regulator of the mitosis to meiosis transition in the Drosophila ovary. We find that Tnpo-SR is necessary for germline stem cell (GSC) establishment and self-renewal, likely by controlling the response of GSCs to bone morphogenetic proteins. Depletion of Tnpo-SR results in germ cell counting defects and loss of oocyte identity. We show that in the absence of Tnpo-SR, proteins typically suppressed in germ cells when they exit mitosis fail to be down-regulated, and oocyte-specific factors fail to accumulate. Together, these findings provide new insight into the balance between germ cell division and differentiation and identify novel roles for ß-importins in germ cell development.

Systematic Review: Clinical Features, Antimicrobial Treatment, and Outcomes of Human Tularemia, 1993-2023.

BACKGROUND: Francisella tularensis, the causative agent of tularemia, is endemic throughout the Northern Hemisphere and requires as few as 10 organisms to cause disease, making this potential bioterrorism agent one of the most infectious bacterial pathogens known. Aminoglycosides, tetracyclines, and, more recently, fluoroquinolones are used for treatment of tularemia; however, data on the relative effectiveness of these and other antimicrobial classes are limited. METHODS: Nine databases, including Medline, Global Health, and Embase, were systematically searched for articles containing terms related to tularemia. Articles with case-level data on tularemia diagnosis, antimicrobial treatment, and patient outcome were included. Patient demographics, clinical findings, antimicrobial administration, and outcome (eg, intubation, fatality) were abstracted using a standardized form. RESULTS: Of the 8878 publications identified and screened, 410 articles describing 870 cases from 1993 to 2023 met inclusion criteria. Cases were reported from 35 countries; more than half were from the United States, Turkey, or Spain. The most common clinical forms were ulceroglandular, oropharyngeal, glandular, and pneumonic disease. Among patients treated with aminoglycosides (n = 452 [52%]), fluoroquinolones (n = 339 [39%]), or tetracyclines (n = 419 [48%]), the fatality rate was 0.7%, 0.9%, and 1.2%, respectively. Patients with pneumonic disease who received ciprofloxacin had no fatalities and the lowest rates of thoracentesis/pleural effusion drainage and intubation compared to those who received aminoglycosides and tetracyclines. CONCLUSIONS: Aminoglycosides, fluoroquinolones, and tetracyclines are effective antimicrobials for treatment of tularemia, regardless of clinical manifestation. For pneumonic disease specifically, ciprofloxacin may have slight advantages compared to other antimicrobials.

Tularemia Clinical Manifestations, Antimicrobial Treatment, and Outcomes: An Analysis of US Surveillance Data, 2006-2021.

BACKGROUND: Tularemia, a potentially fatal zoonosis caused by Francisella tularensis, has been reported from nearly all US states. Information on relative effectiveness of various antimicrobials for treatment of tularemia is limited, particularly for newer classes such as fluoroquinolones. METHODS: Data on clinical manifestations, antimicrobial treatment, and illness outcome of patients with tularemia are provided voluntarily through case report forms to the US Centers for Disease Control and Prevention by state and local health departments. We summarized available demographic and clinical information submitted during 2006-2021 and evaluated survival according to antimicrobial treatment. We grouped administered antimicrobials into those considered effective for treatment of tularemia (aminoglycosides, fluoroquinolones, and tetracyclines) and those with limited efficacy. Logistic regression models with a bias-reduced estimation method were used to evaluate associations between antimicrobial treatment and survival. RESULTS: Case report forms were available for 1163 US patients with tularemia. Francisella tularensis was cultured from a clinical specimen (eg, blood, pleural fluid) in approximately half of patients (592; 50.9%). Nearly three-quarters (853; 73.3%) of patients were treated with a high-efficacy antimicrobial. A total of 27 patients (2.3%) died. After controlling for positive culture as a proxy for illness severity, use of aminoglycosides, fluoroquinolones, and tetracyclines was independently associated with increased odds of survival. CONCLUSIONS: Most US patients with tularemia received high-efficacy antimicrobials; their use was associated with improved odds of survival regardless of antimicrobial class. Our findings provide supportive evidence that fluoroquinolones are an effective option for treatment of tularemia.

Root-associated fungi and acquisitive root traits facilitate permafrost nitrogen uptake from long-term experimentally warmed tundra.

Root-associated fungi (RAF) and root traits regulate plant acquisition of nitrogen (N), which is limiting to growth in Arctic ecosystems. With anthropogenic warming, a new N source from thawing permafrost has the potential to change vegetation composition and increase productivity, influencing climate feedbacks. Yet, the impact of warming on tundra plant root traits, RAF, and access to permafrost N is uncertain. We investigated the relationships between RAF, species-specific root traits, and uptake of N from the permafrost boundary by tundra plants experimentally warmed for nearly three decades at Toolik Lake, Alaska. Warming increased acquisitive root traits of nonmycorrhizal and mycorrhizal plants. RAF community composition of ericoid (ERM) but not ectomycorrhizal (ECM) shrubs was impacted by warming and correlated with root traits. RAF taxa in the dark septate endophyte, ERM, and ECM guilds strongly correlated with permafrost N uptake for ECM and ERM shrubs. Overall, a greater proportion of variation in permafrost N uptake was related to root traits than RAF. Our findings suggest that warming Arctic ecosystems will result in interactions between roots, RAF, and newly thawed permafrost that may strongly impact feedbacks to the climate system through mechanisms of carbon and N cycling.

Social evaluative stress enhances central detail memory, reduces false memory, and results in intrusive memories that last for days.

Few studies have quantified what an individual remembers about a laboratory-controlled stressor. Here, we aimed to replicate previous work by using a modified version of the Trier Social Stress Test (TSST) to quantify participant memory for a stressful experience. We also aimed to extend this work by quantifying false and intrusive memories that ensued. One hundred and seven participants were exposed to the TSST (stress) or the friendly TSST (f-TSST; no stress). The TSST required participants to deliver a ten-minute speech in front of two laboratory panel members as part of a mock job interview; the f-TSST required participants to casually converse with the panel members about their interests. In both conditions, the panel members interacted with (central) or did not interact with (peripheral) several objects sitting on a desk in front of them. The next day, participants' memory for the objects was assessed with recall and recognition tests. We also quantified participants' intrusive memories on Days 2, 4, 6, and 8. Stressed participants recalled more central objects and exhibited greater recognition memory, particularly for central objects, than controls. Stress also led to less false recall and more intrusive memories on Days 2 and 4. Consistent with previous work, these findings suggest that participants exhibit enhanced memory for the central details of a stressful experience; they also extend prior work by showing that participants exposed to a stressor have less false memories and experience intrusive memories for several days following the event. The modified TSST paradigm used here may be useful for researchers studying not only what participants remember about a stressful event but also their susceptibility to intrusive memory formation.

Dosing and Administration Strategies of Tocilizumab in Patients With COVID-19: A Retrospective Cohort Analysis.

BACKGROUND: Tocilizumab may reduce the risk of death, length of stay, and time of mechanical ventilation in patients hospitalized with COVID-19. Limited data are available evaluating low-dose subcutaneous administration of tocilizumab in this setting. OBJECTIVE: To compare outcomes of 2 tocilizumab dosing and administration strategies in patients hospitalized with COVID-19. METHODS: A retrospective, observational cohort study was conducted to compare clinical outcomes in patients hospitalized with COVID-19 receiving tocilizumab 400 mg intravenously (400 mg IV) or 162 mg subcutaneously (162 mg SC). Hospitalized patients receiving a single dose of tocilizumab were eligible for inclusion and grouped by dosing and administration strategy. The primary endpoint was ventilator-free days at day 28. Secondary endpoints included length of stay (LOS), intensive care unit (ICU) LOS, mechanical ventilation required after dose, 28-day readmission, 28-day mortality, and change in inflammatory markers. RESULTS: A total of 303 patients were included, with 147 who received tocilizumab 400 mg IV and 156 who received 162 mg SC. There was no significant difference in average ventilator-free days at day 28 in patients receiving 400 mg IV compared with 162 mg SC (26.4 ± 5.3 vs 25.6 ± 6.8 days, respectively; P = 0.812). There was also no difference in LOS (10.4 ± 12.6 vs 10.5 ± 14.0 days; P = 0.637), ICU LOS (3.9 ± 9.0 vs 3.5 ± 8.3 days; P = 0.679), mechanical ventilation after dose (15.6% vs 19.2%; P = 0.412), 28-day readmission (6.1% vs 9.6%; P = 0.268), or 28-day mortality (23.1% vs 25.6%; P = 0.611). Finally, there was no difference regarding change in inflammatory markers at 48 hours (P > 0.05 for all interactions). CONCLUSION AND RELEVANCE: In this retrospective study involving hospitalized patients with COVID-19, there was no difference between tocilizumab 162 mg SC and 400 mg IV in terms of efficacy. The 162 mg SC dose may be a reasonable alternative to traditional doses.

Local translation in nuclear condensate amyloid bodies.

Biomolecular condensates concentrate molecules to facilitate basic biochemical processes, including transcription and DNA replication. While liquid-like condensates have been ascribed various functions, solid-like condensates are generally thought of as amorphous sites of protein storage. Here, we show that solid-like amyloid bodies coordinate local nuclear protein synthesis (LNPS) during stress. On stimulus, translationally active ribosomes accumulate along fiber-like assemblies that characterize amyloid bodies. Mass spectrometry analysis identified regulatory ribosomal proteins and translation factors that relocalize from the cytoplasm to amyloid bodies to sustain LNPS. These amyloidogenic compartments are enriched in newly transcribed messenger RNA by Heat Shock Factor 1 (HSF1). Depletion of stress-induced ribosomal intergenic spacer noncoding RNA (rIGSRNA) that constructs amyloid bodies prevents recruitment of the nuclear protein synthesis machinery, abolishes LNPS, and impairs the nuclear HSF1 response. We propose that amyloid bodies support local nuclear translation during stress and that solid-like condensates can facilitate complex biochemical reactions as their liquid counterparts can.

Rotator Cuff Repair With Patch Augmentation Is Associated With Lower Retear Rates for Large Tears: A Systematic Review of Randomized Controlled Trials.

PURPOSE: To perform a systematic review of randomized controlled trials comparing clinical outcomes of rotator cuff repair with and without patch augmentation. METHODS: A systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines by searching PubMed, the Cochrane Library, and Embase to identify randomized controlled trials that directly compared outcomes between rotator cuff repair (RCR) with versus without patch augmentation. Patients were evaluated based on retear rate, histological outcomes, radiological outcomes, and patient-reported outcomes (Constant score; American Shoulder and Elbow Surgeons [ASES] score; University of California-Los Angeles shoulder scale; Simple Shoulder Test; EuroQol-visual analog scale; Disabilities of the Arm, Shoulder and Hand score; and PENN shoulder score questionnaire). RESULTS: Six studies (1 level I, 5 level II) met inclusion criteria, including 188 patients undergoing RCR alone (Control) and 193 patients undergoing RCR with patch augmentation (Patch). Patient age ranged from 56.0 to 68.0 years. The mean follow-up time ranged from 14.0 to 68.4 months. The average body mass index ranged from 24.4 to 29.4, and the overall percentage of males ranged from 32.5% to 82.3%. Three studies found significantly decreased retear rates with patch augmentation. The retear rate ranged from 34.0% to 65.4% in the Control group and 9.1% to 52.9% in the Patch group. One study found a significant difference for the Constant score favoring the Patch group. Two studies found a significant difference for the ASES score favoring the Patch group. One study found significantly better results with patch augmentation in terms of repaired tendon thickness and footprint coverage, based on magnetic resonance imaging. CONCLUSIONS: Patch augmentation of rotator cuff repairs may be associated with lower retear rates for large tears. There is limited evidence to suggest that patch augmentation is associated with improved patient-reported outcomes. LEVEL OF EVIDENCE: Level II, systematic review of level I and II studies.

Validity of submaximal aerobic capacity and strength tests in firefighters.

BACKGROUND: Typically, the fitness of UK firefighters is assessed via submaximal estimate methods due to the low demands on time, money, expertise and equipment. However, the firefighter-specific validity of such testing in relation to maximum aerobic capacity (V˙O2max) and particularly muscular strength is not well established. AIMS: To examine the validity of submaximal methods to estimate V˙O2max and maximal strength in operational firefighters. METHODS: Twenty-two full-time operational firefighters (3 female) completed same-day submaximal (Chester Step Test; CST) and maximal (treadmill) assessments of V˙O2max, with a sub-sample of 10 firefighters (1 female) also completing submaximal and maximal back-squat (i.e. one repetition maximum; 1RM) assessments. All participants then completed the Firefighter Simulation Test (FFST) within 2-4 days. RESULTS: CST underestimated actual V˙O2max by 1.4 ml·kg-1·min-1 (~3%), although V˙O2max values were positively correlated (r = 0.61, P < 0.01) and not significantly different. Estimated V˙O2max values negatively correlated with FFST performance (r = -0.42). Predicted 1RM underestimated actual 1RM by ~2%, although these values were significantly correlated (r = 0.99, P < 0.001) and did not significantly differ. The strongest predictive model of FFST performance included age, body mass index, and direct maximal measures of 1RM and V˙O2max. CONCLUSIONS: Submaximal back-squat testing offers good validity in estimating maximum firefighter strength without exposure to the fatigue associated with maximal methods. The CST provides a reasonably valid and cost-effective V˙O2max estimate which translates to firefighting task performance, although the error observed means it should be used cautiously when making operational decisions related to V˙O2max benchmarks.

Mental Robustness May Be Associated With Improved Physical Function in Bilateral Total Knee Arthroplasty Patients.

BACKGROUND: In accordance with the high incidence of bilateral knee osteoarthritis, many patients have undergone bilateral total knee arthroplasty (BTKA). Whether patients undergo bilateral procedures in a staged or simultaneous fashion, the physical and mental burden of undergoing 2 major orthopedic procedures is considerable. The aims of this study were to (1) investigate differences between minimal clinically important difference (MCID) achievement between staged versus simultaneous BTKA, and (2) identify the patient variables, specifically mental scores, that were associated with MCID achievement in patients undergoing BTKA. METHODS: Simultaneous and staged BTKA patients within a single health care network from 2016 to 2021 were retrospectively reviewed. Patient demographics, surgery details, and Patient-Reported Outcome Measurement Information System Physical Function Short Forms 10a (PROMIS PF10a), PROMIS Mental scores, and Knee Disability Osteoarthritis Outcome Scores (KOOS) were reviewed. Preoperative and postoperative patient-reported outcome measures were collected before the first total knee arthroplasty (TKA) and after the second TKA, respectively, in staged BTKA patients. The final cohort consisted of 249 patients, with an average age of 66 years (range, 21 to 87), 63% women, and an average body mass index of 32 (range, 20 to 52), at a mean follow-up of 1.1 years (range, 0.5 to 2.4). Multivariate regressions were performed on MCID PF10a and KOOS achievement, as well as whether the BTKA was performed simultaneously versus staged. RESULTS: A preoperative PROMIS Mental score in the upper 2 quartiles was associated with MCID PF10a achievement in BTKA. Men and surgeries performed at an Academic Medical Center were negatively associated with the achievement of MCID KOOS. Interestingly, those who underwent simultaneous BTKA were less likely to achieve MCID KOOS than those who underwent a staged BTKA. CONCLUSIONS: Preoperative mental robustness may be positively associated with improved physical function outcome in BTKA patients.

Pedicled chimeric superficial circumflex iliac artery perforator (SCIP) flap with external oblique fascia for vesicocutaneous bladder fistula repair: A case report and literature review on the utility of pedicled chimeric SCIP.

Following its initial description by Koshima in 2004, the superficial circumflex iliac artery perforator (SCIP) flap has become a ubiquitous and extremely useful flap in coverage of defects whereby bulkiness must be avoided. It also allows direct closure and concealment of the donor site. Its use as a free tissue transfer has been demonstrated by various surgeons globally. Nevertheless, there are few cases illustrating the utility of the pedicled SCIP flap in the reconstruction of lower abdominal defects. We present a case of a pedicled SCIP flap utilized as a chimeric flap incorporating external oblique muscle fascia on a deep branch along with the typical fasciocutaneous component based on the superficial branch to cover the suprapubic defect after vesicocutaneous fistula repair. We thereafter report on the literature of pedicled chimeric SCIP flap for locoregional reconstruction. A 26-year-old female was referred to the Plastic and Reconstructive Surgery unit after suffering a functional bladder outlet obstruction necessitating the creation of a urinary stoma. Subsequently, stoma obstruction occurred, and a suprapubic catheter was performed that was complicated by infection and resulted in the development of a vesicocutaneous fistula. Accordingly, the urological surgeons were planning surgical closure of the suprapubic vesicocutaneous defect, measuring 5 × 4 cm. A pedicled SCIP flap was designed to match the defect size; and raised as a chimeric flap with external oblique muscle fascia based on the deep branch, along with the fasciocutaneous component based on the superficial branch. The external oblique fascial component was used to secure the suture line of fistula repair, over which the fasciocutaneous component was inset, effectively double breasting the fistula repair and full thickness lower abdominal defect. The patient had an unremarkable postoperative recovery and has since been followed up in the outpatient setting without complication for the past 24 months. Robust coverage of the suprapubic defect was reliably achieved and no further fistulation has occurred. This case illustrates that a pedicled SCIP flap can be harvested as a chimeric flap and used to reliably cover defects in the infra-umbilical region.

Can MRI Replace Nasopharyngoscopy in the Evaluation of Velopharyngeal Insufficiency?

OBJECTIVE: To investigate whether flexible nasopharyngoscopy, when performed in addition to magnetic resonance imaging (MRI), influences the type of surgery selected or success of surgery in patients with velopharyngeal insufficiency (VPI). DESIGN: Cohort study. SETTING: A metropolitan children's hospital. PATIENTS: Patients with non-syndromic, repaired cleft palate presenting for management of VPI. INTERVENTIONS: MRI and nasopharyngoscopy or MRI alone for preoperative imaging of the velopharyngeal mechanism. MAIN OUTCOME MEASURES: (1) Surgical selection and (2) resolution of hypernasality. All speech, MRI, and nasopharyngoscopy measurements were performed by raters blinded to patients' medical and surgical history. RESULTS: Of the 25 patients referred for nasopharyngoscopy, 76% completed the exam. Of the 41 patients referred for MRI, the scan was successfully completed by 98% of patients. Completion of nasopharyngoscopy was significantly (p=0.01) lower than MRI. Surgical selection did not significantly differ (p=0.73) between the group receiving MRI and nasopharyngoscopy and the group receiving MRI alone, nor was there a significant difference between these groups in the proportion of patients achieving resolution of hypernasality postoperatively (p=0.63). Percent total velopharyngeal closure assessments on nasopharyngoscopy and MRI were strongly correlated (r=0.73). CONCLUSIONS: In patients receiving MRI as part of their preoperative VPI evaluation, the addition of nasopharyngoscopy did not result in a difference in surgical selection or resolution of hypernasality. Routine inclusion of nasopharyngoscopy may not be necessary for the evaluation of velopharyngeal anatomy when MRI is available.

Trends in breast cancer mortality by race/ethnicity, age, and US census region, United States─1999-2020.

BACKGROUND: Breast cancer remains a leading cause of morbidity and mortality among women in the United States. Previous analyses show that breast cancer incidence increased from 1999 to 2018. The purpose of this article is to examine trends in breast cancer mortality. METHODS: Analysis of 1999 to 2020 mortality data from the Centers for Disease Control and Prevention, National Center for Health Statistics, among women by race/ethnicity, age, and US Census region. RESULTS: It was found that overall breast cancer mortality is decreasing but varies by race/ethnicity, age group, and US Census region. The largest decrease in mortality was observed among non-Hispanic White women, women aged 45 to 64 years of age, and women living in the Northeast; whereas the smallest decrease in mortality was observed among non-Hispanic Asian or Pacific Islander women, women aged 65 years or older, and women living in the South. CONCLUSION: This report provides national estimates of breast cancer mortality from 1999 to 2020 by race/ethnicity, age group, and US Census region. The decline in breast cancer mortality varies by demographic group. Disparities in breast cancer mortality have remained consistent over the past two decades. Using high-quality cancer surveillance data to estimate trends in breast cancer mortality may help health care professionals and public health prevention programs tailor screening and diagnostic interventions to address these disparities.

Prediction of Mortality and Major Adverse Kidney Events in Critically Ill Patients With Acute Kidney Injury.

RATIONALE & OBJECTIVE: Risk prediction tools for assisting acute kidney injury (AKI) management have focused on AKI onset but have infrequently addressed kidney recovery. We developed clinical models for risk stratification of mortality and major adverse kidney events (MAKE) in critically ill patients with incident AKI. STUDY DESIGN: Multicenter cohort study. SETTING & PARTICIPANTS: 9,587 adult patients admitted to heterogeneous intensive care units (ICUs; March 2009 to February 2017) who experienced AKI within the first 3 days of their ICU stays. PREDICTORS: Multimodal clinical data consisting of 71 features collected in the first 3 days of ICU stay. OUTCOMES: (1) Hospital mortality and (2) MAKE, defined as the composite of death during hospitalization or within 120 days of discharge, receipt of kidney replacement therapy in the last 48 hours of hospital stay, initiation of maintenance kidney replacement therapy within 120 days, or a ≥50% decrease in estimated glomerular filtration rate from baseline to 120 days from hospital discharge. ANALYTICAL APPROACH: Four machine-learning algorithms (logistic regression, random forest, support vector machine, and extreme gradient boosting) and the SHAP (Shapley Additive Explanations) framework were used for feature selection and interpretation. Model performance was evaluated by 10-fold cross-validation and external validation. RESULTS: One developed model including 15 features outperformed the SOFA (Sequential Organ Failure Assessment) score for the prediction of hospital mortality, with areas under the curve of 0.79 (95% CI, 0.79-0.80) and 0.71 (95% CI, 0.71-0.71) in the development cohort and 0.74 (95% CI, 0.73-0.74) and 0.71 (95% CI, 0.71-0.71) in the validation cohort (P < 0.001 for both). A second developed model including 14 features outperformed KDIGO (Kidney Disease: Improving Global Outcomes) AKI severity staging for the prediction of MAKE: 0.78 (95% CI, 0.78-0.78) versus 0.66 (95% CI, 0.66-0.66) in the development cohort and 0.73 (95% CI, 0.72-0.74) versus 0.67 (95% CI, 0.67-0.67) in the validation cohort (P < 0.001 for both). LIMITATIONS: The models are applicable only to critically ill adult patients with incident AKI within the first 3 days of an ICU stay. CONCLUSIONS: The reported clinical models exhibited better performance for mortality and kidney recovery prediction than standard scoring tools commonly used in critically ill patients with AKI in the ICU. Additional validation is needed to support the utility and implementation of these models. PLAIN-LANGUAGE SUMMARY: Acute kidney injury (AKI) occurs commonly in critically ill patients admitted to the intensive care unit (ICU) and is associated with high morbidity and mortality rates. Prediction of mortality and recovery after an episode of AKI may assist bedside decision making. In this report, we describe the development and validation of a clinical model using data from the first 3 days of an ICU stay to predict hospital mortality and major adverse kidney events occurring as long as 120 days after hospital discharge among critically ill adult patients who experienced AKI within the first 3 days of an ICU stay. The proposed clinical models exhibited good performance for outcome prediction and, if further validated, could enable risk stratification for timely interventions that promote kidney recovery.

Evidence of Electron Heating by Alpha Particles in JET Deuterium-Tritium Plasmas.

The fusion-born alpha particle heating in magnetically confined fusion machines is a high priority subject for studies. The self-heating of thermonuclear fusion plasma by alpha particles was observed in recent deuterium-tritium (D-T) experiments on the joint European torus. This observation was possible by conducting so-called "afterglow" experiments where transient high fusion yield was achieved with neutral beam injection as the only external heating source, and then termination of the heating at peak performance. This allowed the first direct evidence for electron heating of plasmas by fusion-born alphas to be obtained. Interpretive transport modeling of the relevant D-T and reference deuterium discharges is consistent with the alpha particle heating observation.