Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma.

PURPOSE: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents. METHODS: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284). RESULTS: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response. CONCLUSIONS: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.

Explainable Risk Prediction of Post-Stroke Adverse Mental Outcomes Using Machine Learning Techniques in a Population of 1780 Patients.

Post-stroke depression and anxiety, collectively known as post-stroke adverse mental outcome (PSAMO) are common sequelae of stroke. About 30% of stroke survivors develop depression and about 20% develop anxiety. Stroke survivors with PSAMO have poorer health outcomes with higher mortality and greater functional disability. In this study, we aimed to develop a machine learning (ML) model to predict the risk of PSAMO. We retrospectively studied 1780 patients with stroke who were divided into PSAMO vs. no PSAMO groups based on results of validated depression and anxiety questionnaires. The features collected included demographic and sociological data, quality of life scores, stroke-related information, medical and medication history, and comorbidities. Recursive feature elimination was used to select features to input in parallel to eight ML algorithms to train and test the model. Bayesian optimization was used for hyperparameter tuning. Shapley additive explanations (SHAP), an explainable AI (XAI) method, was applied to interpret the model. The best performing ML algorithm was gradient-boosted tree, which attained 74.7% binary classification accuracy. Feature importance calculated by SHAP produced a list of ranked important features that contributed to the prediction, which were consistent with findings of prior clinical studies. Some of these factors were modifiable, and potentially amenable to intervention at early stages of stroke to reduce the incidence of PSAMO.

Qualitative systematic review: The lived experiences of males in the nursing profession on gender discrimination encounters.

AIMS: This review aims to synthesise the best available evidence exploring the lived experiences of males in the nursing profession on gender discrimination encounters. BACKGROUND: The underrepresentation of males within the nursing profession could potentially cause discrimination and stereotypes against them, causing barriers to entry into, and retention within, the profession. With a shortage in manpower, the deterrence of males to nursing might exacerbate the existing manpower shortage. This review consolidates and highlights the lived experiences of males in the profession. METHODS: The review was synthesised according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. Employing the meta-synthesis approach, two independent reviewers conducted critical appraisal and data extraction of included studies, using the standard Joanna Briggs Institute (JBI) Critical Appraisal Instrument for Qualitative Research and a standardised data extraction form, respectively. RESULTS: Twenty-three studies were included. Extracted findings were aggregated into 14 categories and synthesised into three themes: stereotypes, discrimination and challenges faced by males. DISCUSSION: The synthesised findings showed that male nurses faced gender discrimination in multiple facets. These caused them to have difficulty in carrying out their nursing duties, missing out of clinical opportunities and causing them multiple social and mental stressors. CONCLUSION: This review informed the discriminatory experiences faced by males within the nursing profession. With males already underrepresented within this profession, it is imperative for interventions, policies and research to be made to address this issue to improve experiences of male nurses, thereby limiting the deterrence of males into the profession. IMPLICATIONS: Findings of this study showed that males are being stereotyped and discriminated, resulting in challenges faced solely because of their gender. Effective interventions and policies could be implemented to alleviate the negative experiences.

A phase 1b study of OXIRI in pancreatic adenocarcinoma patients and its immunomodulatory effects.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and debilitating disease with limited therapeutic options. The aim of this clinical study was to evaluate the safety, efficacy and pharmacokinetics of a novel regimen comprised of metronomic oxaliplatin (O), chronomodulated capecitabine (X) and UGT1A1 genotype-guided dosing of irinotecan (IRI) [OXIRI] as well as its immunomodulatory effects. Thirty-six patients were enrolled into either dose-escalation or expansion cohorts. In the dose escalation phase, capecitabine doses (2000, 2650, 3500 and 4500 mg/day) were administered at midnight on days 1 to 14 while oxaliplatin and irinotecan were intravenously infused at fixed doses of 50 and 75 mg/m2 respectively on days 1, 8 in a 21-day cycle. The maximum tolerated dose of capecitabine was 2650 mg/day and the most common grade 3 adverse events were neutropenia (30.6%) and diarrhea (13.9%). No grade 4 toxicity was observed. UGT1A1-genotype directed dosing resulted in similar exposure levels of irinotecan, SN-38 and SN-38G in all patients. Objective response rate was 22.2%. Median overall survival and progression-free survival were 8.1 and 5.2 months, respectively. Exploratory immunoprofiling by flow cytometry and quantitative spatial localization analysis of infiltrated immune cells performed on biopsy and plasma samples revealed significant declines in CCL22, CCL2 and TNFα levels at end of first cycle and an active host immune response. Our study showed that OXIRI was well-tolerated and exhibited good efficacy, with immunomodulatory effects. It may be considered as an alternative to FOLFIRINOX in patients intolerant to the latter.

A nutritional screening threshold for optimal outcomes after Hartmann's reversal.

PURPOSE: Determining is nutritionally replete enough for Hartmann's reversal (HR) can be controversial and multifactorial. While there are many preoperative nutritional screening tools, the impact of malnourishment on HR has not been evaluated. The study aims to clarify how often patients undergoing HR are high risk for malnourishment at the time of surgery and how this impacts postoperative outcomes. METHODS: From 2012-2019, all elective HRs were identified in ACS-NSQIP. Patients were categorized in a malnourished group if they met one of the following criteria: (1) BMI < 18.5 kg/m2, (2) albumin < 3.5 g/dL, or (3) > 10% body weight loss in the last 6 months. Bivariate associations of preoperative demographics and postoperative outcomes were analyzed. Multivariable logistic regression was performed to identify independent predictors for 30-day mortality and organ space wound infection. RESULTS: 8878 procedures were evaluated (well-nourished = 7116 and malnourished = 1762). The malnourished group had higher mortality (p < 0.001), shorter operating time (p < .001), longer length of stay (p = 0.016), and higher rates of infection (p = 0.011), reintubation (p = 0.002), bleeding (p < 0.001), sepsis (p = 0.001), and reoperation (p = 0.018). In multivariate regression models, malnourishment was an independent predictor for mortality (OR = 2.72, p < 0.001) and wound infection (OR = 1.19, p = 0.028). CONCLUSION: A large percentage of patients undergoing HR were classified as being high-risk for malnutrition. Malnourishment was associated with some worse postoperative compilations including death and wound infection. Surgeons should routinely use preoperative screening for malnutrition to identify and attempt to optimize nutritional status prior to undergoing Hartmann's Reversal.

Short-term outcomes following resection of right colon diverticulitis: a comparison of open and minimally invasive approaches using the NSQIP database.

BACKGROUND: Right colon diverticulitis is a rare disease process for which there are no established treatment guidelines, and outcomes following surgical management are underreported in the literature. We sought to describe the demographics of patients undergoing ileocecectomy for right colon diverticulitis and compare short-term postoperative outcomes between open and minimally invasive approaches. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) was queried for patients with diverticulitis of the colon who underwent ileocecectomy between 2012 and 2019. Patients with ascites, disseminated cancer, ASA class 5, and patients requiring mechanical ventilation were excluded. Preoperative, intraoperative, and 30-day postoperative outcomes were compared between the groups using both univariable chi-square or t-tests and multivariable logistical regression models. RESULTS: 484 patients met inclusion criteria, 150 (31%) of whom underwent open surgery and 334 (69%) who underwent minimally invasive surgery with an 18% conversion rate. 71% of patients were White, 11% of were Black, 7% were Hispanic, and 5% were Asian. The indication for surgery differed significantly by approach with acute diverticulitis representing 47% of indications for open cases and 25% for MIS cases (p < 0.0001). After adjusting for possible confounders, patients undergoing the open approach had a significantly higher chance of post-operative sepsis (p = 0.009) and ileus (p = 0.04) compared with MIS. Hospital length of stay was also significantly shorter after MIS compared to open (5.9 days vs. 11.5 days; p < 0.0001). Mean operative time was significantly longer in MIS than open (173 min vs. 198 min; p = 0.001). CONCLUSION: Our analysis demonstrates that minimally invasive surgery is associated with equivalent or improved short-term morbidity and shorter hospital stay despite longer mean operative time. Interestingly, unlike other countries where the prevalence of right colon diverticulitis is higher, a minority of patients requiring operative therapy in our study of patients in the Western hemisphere were of Asian descent.

The impact of surgical approach on short- and long-term outcomes after rectal cancer resection in elderly patients: a national cancer database propensity score matched comparison of robotic, laparoscopic, and open approaches.

BACKGROUND: Elderly patients are underrepresented in studies demonstrating the advantages of laparoscopy for the management of colorectal diseases. Moreover, few studies have examined the robotic approach in this population. In this retrospective analysis, we compare outcomes for open, laparoscopic, and robotic approaches in elderly patients with nonmetastatic rectal cancer. METHODS: The U.S. National Cancer Database was queried for patients aged ≥ 65 with nonmetastatic adenocarcinoma of the rectum who underwent surgical resection from 2010 to 2016. Groups were separated based on approach (open, laparoscopic, robotic). One-to-one nearest neighbor propensity score matching (PSM) ± 1% caliper was performed across surgical approach cohorts to balance potential confounding covariates. Kaplan-Meier estimation and Cox-proportional hazards regression were used to analyze the primary outcome of survival. Secondary outcomes were analyzed by way of logistic regression. RESULTS: Inclusion criteria and PSM identified 1891 patients per approach (n = 5673). PSM provided adequate discrimination between cohorts (0.6 < AUC < 0.8), and potential confounding covariates did not significantly differ (respective P > 0.05). After PSM, robotic and laparoscopic approaches were associated with decreased odds of 90 day mortality compared to the open approach (P < 0.05). Compared to laparoscopy, a robotic approach was associated with increased odds of ≥ 12 regional lymph nodes examined and negative circumferential resection margin (P < 0.05). No differences were seen in 30 day or 90 day mortality between robotic and laparoscopic approaches. Cox proportional hazards regression showed that both robotic and laparoscopic approaches were significantly associated with decreased mortality hazards relative to open. CONCLUSION: Our study demonstrates that in elderly patients, minimally invasive surgery for rectal adenocarcinoma was associated with equivalent or improved short- and long-term mortality over open surgery. Compared to laparoscopy, the robotic approach showed no survival disadvantage and greater odds of an appropriate oncological resection. Our study adds evidence to the conclusion that robotic rectal surgery can be safely performed in patients regardless of age.

Open versus minimally invasive small bowel resection for Crohn's disease: a NSQIP retrospective review and analysis.

INTRODUCTION: Many patients with Crohn's Disease will require surgical resection. While many studies have described outcomes following ileocecectomy, few have evaluated surgical resection of other portions of small bowel. We sought to compare open and minimally invasive surgery (MIS) approaches for small bowel resection excluding ileocecectomy of patients with Crohn's Disease using the National Surgical Quality Improvement Program (NSQIP) database. METHODS: The NSQIP database was queried for patients with Crohn's disease or complications related to Crohn's disease who underwent segmental small bowel resection utilizing open or minimally invasive approaches between 2012 and 2018. Patients requiring ileocecectomy or diagnosed with ascites, disseminated cancer, pre-operative sepsis, ASA class 5, and patients requiring mechanical ventilation were excluded. The association of pre-operative variables including patient demographic information and comorbidities with surgical approach were examined using Fishers exact test. Intraoperative, and 30-day post-operative outcomes were compared between the groups using both univariate and multivariate logistical regression models. SAS was used for data analysis with p < 0.05 considered significant. RESULTS: After exclusions, we found 1697 patients with Crohn's disease who underwent segmental small bowel resection, 1252 of whom underwent open surgery and 445 of whom underwent MIS. After adjusting for possible confounders with multivariable analysis, patients who underwent MIS had a lower incidence of wound events (surgical site, organ space, or deep wound infection, or dehiscence), post-operative bleeding, need for return to the operating room, and shorter total hospital length of stay despite longer operative times compared with open surgery. CONCLUSIONS: This retrospective review of NSQIP shows that minimally invasive small bowel resection is associated with equivalent or improved morbidity over open surgery in select patients with small bowel Crohn's Disease. We show that in select patients minimally invasive small bowel resection can be safe and performed for patients with isolated small bowel Crohn's disease.

Demographic and clinical factors associated with psychiatric inpatient admissions during the COVID-19 pandemic.

OBJECTIVE: The COVID-19 pandemic may cause a major mental health impact. We aimed to identify demographic or clinical factors associated with psychiatric admissions where COVID-19 was attributed to contribute to mental state, compared to admissions which did not. METHODS: A retrospective cohort study was undertaken of inpatients admitted to Northern Psychiatric Unit 1, Northern Hospital in Melbourne, Victoria, Australia during 27/02/2020 to 08/07/2020. Data were extracted for participants who identified COVID-19 as a stressor compared to participants who did not. Fisher's exact test and Mann-Whitley rank sum test were used. RESULTS: Thirty six of 242 inpatients reported the COVID-19 pandemic contributed to mental ill health and subsequent admission. Reasons given included social isolation, generalized distress about the pandemic, barriers to support services, disruption to daily routine, impact on employment, media coverage, re-traumatization, cancelled ECT sessions, loss of loved ones, and increased drug use during the lockdown. Chronic medical conditions or psychiatric multimorbidity were positively associated and smoking status was negatively associated with reporting the COVID-19 pandemic as a contributor to mental ill health. CONCLUSION: Screening and identifying vulnerable populations during and after the global disaster is vital for timely and appropriate interventions to reduce the impact of the pandemic worldwide.

Surgical management of splenic flexure colon cancer: a retrospective propensity-matched study comparing open and minimally invasive approaches using the national cancer database.

PURPOSE: Minimally invasive resection of colon cancer at the splenic flexure can be technically challenging with concerns for a suboptimal oncologic outcome. We aimed to compare open and minimally invasive approaches following curative resection. METHODS: The National Cancer Database was queried for patients with non-metastatic colon adenocarcinoma at the splenic flexure who underwent resection from 2010 to 2016. Cohorts were separated into open and minimally invasive approaches, and demographic and clinicopathologic variables were compared. Propensity-score matching (PSM) was utilized to balance potential confounding covariates between cohorts to elucidate the independent association between surgical approach and outcomes. Kaplan-Meier estimation and Cox-proportional hazards regression were used to analyze survival. Secondary outcomes were analyzed by way of logistic regression or Mann-Whitney U test. RESULTS: After matching, 842 patients were compared between approaches. Patients who underwent minimally invasive surgery had no significant difference in regional nodes ≥ 12 examined, positive margins, negative circumferential margins, unplanned 30-day readmission, or time from surgery to initiation of chemotherapy when compared to patients who underwent open surgery. Minimally invasive surgery was significantly associated with decreased odds of 30-day mortality, 90-day mortality, and decreased mortality hazard for 5-year overall survival compared to open surgery. CONCLUSION: The optimal approach for surgical management of splenic flexure colon cancer has not been standardized given its rarity and exclusion from randomized controlled trials. Our retrospective review suggests that minimally invasive resection of splenic flexure colon cancers in carefully selected patients is associated with equivalent oncologic outcomes as well as improved short and long-term survival compared to an open approach.

A systematic scoping review of approaches to teaching and assessing empathy in medicine.

BACKGROUND: Empathy is pivotal to effective clinical care. Yet, the art of nurturing and assessing empathy in medical schools is rarely consistent and poorly studied. To inform future design of programs aimed at nurturing empathy in medical students and doctors, a review is proposed. METHODS: This systematic scoping review (SSR) employs a novel approach called the Systematic Evidence Based Approach (SEBA) to enhance the reproducibility and transparency of the process. This 6-stage SSR in SEBA involved three teams of independent researchers who reviewed eight bibliographic and grey literature databases and performed concurrent thematic and content analysis to evaluate the data. RESULTS: In total, 24429 abstracts were identified, 1188 reviewed, and 136 included for analysis. Thematic and content analysis revealed five similar themes/categories. These comprised the 1) definition of empathy, 2) approaches to nurturing empathy, 3) methods to assessing empathy, 4) outcome measures, and 5) enablers/barriers to a successful curriculum. CONCLUSIONS: Nurturing empathy in medicine occurs in stages, thus underlining the need for it to be integrated into a formal program built around a spiralled curriculum. We forward a framework built upon these stages and focus attention on effective assessments at each stage of the program. Tellingly, there is also a clear need to consider the link between nurturing empathy and one's professional identity formation. This foregrounds the need for more effective tools to assess empathy and to better understand their role in longitudinal and portfolio based learning programs.

Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial.

BACKGROUND: Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma. METHODS: CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing. FINDINGS: Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7-23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15-27·93) of 92 evaluable patients. INTERPRETATION: These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab). FUNDING: MacroGenics.

L-leucyl-L-leucine methyl ester does not release cysteine cathepsins to the cytosol but inactivates them in transiently permeabilized lysosomes.

L-leucyl-L-leucine methyl ester (LLOMe) induces apoptosis, which is thought to be mediated by release of lysosomal cysteine cathepsins from permeabilized lysosomes into the cytosol. Here, we demonstrated in HeLa cells that apoptotic as well as sub-apoptotic concentrations of LLOMe caused rapid and complete lysosomal membrane permeabilization (LMP), as evidenced by loss of the proton gradient and release into the cytosol of internalized lysosomal markers below a relative molecular mass of 10,000. However, there was no evidence for the release of cysteine cathepsins B and L into the cytosol; rather they remained within lysosomes, where they were rapidly inactivated and degraded. LLOMe-induced adverse effects, including LMP, loss of cysteine cathepsin activity, caspase activation and cell death could be reduced by inhibition of cathepsin C, but not by inhibiting cathepsins B and L. When incubated with sub-apoptotic LLOMe concentrations, lysosomes transiently lost protons but annealed and re-acidified within hours. Full lysosomal function required new protein synthesis of cysteine cathepsins and other hydrolyses. Our data argue against the release of lysosomal enzymes into the cytosol and their proposed proteolytic signaling during LLOMe-induced apoptosis.

Positive reappraisal coping mediates the relationship between parental abuse and lack of affection on adulthood generalized anxiety severity.

Exposure to parental abuse and lack of parental affection during childhood are risk factors for adulthood psychopathology. Tendency to engage in positive reappraisal may be a plausible mechanism underlying this relationship. The current study examined if positive reappraisal coping mediated the relationship between maternal/paternal abuse/affection and adulthood generalized anxiety disorder (GAD) symptoms. Participant data (N = 3294) from the Midlife Development in the United States study was collected in three waves, spaced nine years apart. Longitudinal structural equation mediation modeling examined whether positive reappraisal coping at Time 2 mediated the relationship between maternal/paternal abuse/affection at Time 1 and GAD symptoms at Time 3, controlling for GAD symptoms at Time 1. Positive reappraisal coping mediated maternal/paternal childhood abuse - GAD symptom severity and maternal/paternal childhood affection - GAD severity relations. Maternal and paternal abuse was associated with lower positive reappraisal tendencies, predicting increased GAD symptom severity. Conversely, higher maternal/paternal affection was associated with increased positive reappraisal, predicting lower GAD severity. Incremental prediction revealed that childhood abuse to GAD severity via positive reappraisal path was significant for maternal but not paternal abuse, whereas affection from both parents remained significant. Positive reappraisal coping may be a possible mechanism linking childhood experiences to adulthood GAD severity.

Characterization of a Novel Mouse Model for Fuchs Endothelial Corneal Dystrophy.

Purpose: Fuchs endothelial corneal dystrophy (FECD) is a progressive blinding disorder, characterized by increased corneal endothelial excrescences (guttae), corneal endothelial cell loss, and edema. These symptoms are hypothesized to be caused by changes in the extracellular matrix (ECM) and mitochondrial dysfunction in the corneal endothelium. Despite this clinical and biological relevance, a comprehensive animal model that recapitulates all the major disease characteristics is currently unavailable. In this study, we develop such a model to improve our understanding of the signaling pathways involved in the FECD progression and develop strategies for early intervention. Method: To generate a comprehensive FECD model, we generated a double mutant mouse bearing tamoxifen-inducible knockdown of Slc4a11 and the Col8a2 (Q455K) mutation. We performed optical coherence tomography (OCT) and in vivo confocal microscopy using the Heidelberg Retinal Tomography 3 - Rostock Cornea module (HRT3-RCM) on the mice at 5 weeks of age before tamoxifen feeding to establish baseline values for corneal thickness, endothelial cell density, and test for the presence of guttae. We measured these parameters again post-tamoxifen treatment at 16 weeks of age. We collected corneas at 16 weeks to perform histopathology, immunofluorescence staining for tight junctions, adherens junctions, and oxidative stress. We evaluated endothelial pump function using a lactate assay. Results: The double mutant tamoxifen-fed animals showed the presence of guttae, and displayed increased corneal thickness and decreased endothelial cell density. Endothelial cells showed altered morphology with disrupted adherens junctions and elevated reactive oxygen species (ROS). Finally, we found that stromal lactate concentrations were elevated in the double mutant mice, indicative of compromised endothelial pump function. Conclusions: Overall, this mouse model recapitulates all the important phenotypic features associated with FECD.

Machine Learning and Bayesian Network Analyses Identifies Psychiatric Disorders and Symptom Associations with Insomnia in a national sample of 31,285 Treatment-Seeking College Students.

Background: A better understanding of the structure of relations among insomnia and anxiety, mood, eating, and alcohol-use disorders is needed, given its prevalence among young adults. Supervised machine learning provides the ability to evaluate the discriminative accuracy of psychiatric disorders associated with insomnia. Combined with Bayesian network analysis, the directionality between symptoms and their associations may be illuminated. Methods: The current exploratory analyses utilized a national sample of college students across 26 U.S. colleges and universities collected during population-level screening before entering a randomized controlled trial. Firstly, an elastic net regularization model was trained to predict, via repeated 10-fold cross-validation, which psychiatric disorders were associated with insomnia severity. Seven disorders were included: major depressive disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, anorexia nervosa, and alcohol use disorder. Secondly, using a Bayesian network approach, completed partially directed acyclic graphs (CPDAG) built on training and holdout samples were computed via a Bayesian hill-climbing algorithm to determine symptom-level interactions of disorders most associated with insomnia [based on SHAP (SHapley Additive exPlanations) values)] and were evaluated for stability across networks. Results: Of 31,285 participants, 20,597 were women (65.8%); mean (standard deviation) age was 22.96 (4.52) years. The elastic net model demonstrated clinical significance in predicting insomnia severity in the training sample [R2 = .449 (.016); RMSE = 5.00 [.081]), with comparable performance in accounting for variance explained in the holdout sample [R2 = .33; RMSE = 5.47). SHAP indicated the presence of any psychiatric disorder was associated with higher insomnia severity, with major depressive disorder demonstrated to be the most associated disorder. CPDAGs showed excellent fit in the holdout sample and suggested that depressed mood, fatigue, and self-esteem were the most important depression symptoms that presupposed insomnia. Conclusion: These findings offer insights into associations between psychiatric disorders and insomnia among college students and encourage future investigation into the potential direction of causality between insomnia and major depressive disorder. Trial registration: Trial may be found on the National Institute of Health RePORTER website: Project Number: R01MH115128-05.

A novel practical method to predict anterior cruciate ligament hamstring graft size using preoperative MRI.

BACKGROUND: Predicting hamstring graft size preoperatively for anterior cruciate ligament (ACL) reconstruction is important for preempting an insufficient diameter in graft size intraoperatively, possibly leading to graft failure. While there are multiple published methods using magnetic resonance imaging (MRI) picture archiving and communication systems (PACS), most are not feasible and practical. Our study aims to (1) practically predict the ACL hamstring graft size in a numerically continuous manner using the preoperative MRI from any native MRI PACS system, (2) determine the degree of correlation between the predicted and actual graft size, and (3) determine the performance of our prediction method if we define an adequate actual graft size as ≥ 8 mm. METHODS: A retrospective review of 112 patients who underwent primary ACL reconstruction with quadrupled hamstring semitendinosus-gracilis grafts at a tertiary institution was conducted between January 2018 and December 2018. Graft diameter can be predicted in a numerically continuous manner as √[2*(AB + CD)], where A and B are the semitendinosus cross-sectional length and breath, respectively, and C and D are the gracilis cross-sectional length and breath, respectively. RESULTS: A moderately positive correlation exists between the predicted and actual graft diameter (r = 0.661 and p < .001). Our method yields a high specificity of 92.6% and a moderate sensitivity of 67.2% if we define an adequate actual graft size as ≥ 8 mm. An area under receiver-operating characteristic curve shows good discrimination (AUC = 0.856). CONCLUSIONS: We present a practical method to predict the ACL hamstring graft size with high specificity using preoperative MRI measurements.

Evaluating global research trends in special needs dentistry: A systematic bibliometrix analysis.

OBJECTIVES: Special needs dentistry (SND) is a vast and fragmented field of study. This comprehensive bibliometric analysis aimed to evaluate the scope of SND, including the existing knowledge base, distribution structure, quantitative relationships, and research trends. MATERIAL AND METHODS: A systematic search was conducted on March 10, 2022, using the Web of Science Core Collection database, covering the period from 1985 to 2021, focusing on studies reporting on special needs populations in a dentally relevant context. Records were title-screened and analyzed for key bibliometric indicators. RESULTS: Among 48,374 articles, 13,869 underwent bibliometric analysis. Peak SND research occurred during 1985-1997. United States led in productivity, trailed by Brazil and Japan. University of Sao Paulo excelled in Brazil, University of Washington and University of North Carolina in the United States. The Journal of Dental Research was the most productive source of research and also had the highest number of citations, followed by Community Dentistry and Oral Epidemiology. Keyword analysis revealed that "elderly", "caries", and "epidemiology" were the most commonly used author keywords. CONCLUSIONS: This study represents the first bibliometric analysis of SND literature. It emphasizes the need for increased collaboration between institutions and authors. Furthermore, it suggests focusing on research input from non-dental disciplines and populations with rarer intellectual or developmental conditions.