Simultaneous Global Drug Development and Multiregional Clinical Trials (MRCT): 5 Years After Implementation of ICH E17 Guidelines.

The ICH E17 guidelines (2014-2017) on Multiregional Clinical Trials (MRCT) was a joint effort by the regulators and industry to facilitate simultaneous global drug development and registration through taking a strategic approach for clinical trials. In other words, the objective was to reduce the time it takes to bringing medications to patients around the world through minimizing unnecessary duplication of local or regional studies, which may add the regulatory burden to cost and time of bringing new therapies to patients. Under the auspices of ICH, training materials were created and provided to various stakeholders. Despite the successful promotion of the benefits of ICH E17 MRCT guidelines across the different regions, the uptake of some concepts (e.g., pooling strategy) in the ICH E17 guidelines has been slow. This paper describes various factors which could affect the conduct of MRCT at a global level, including ambiguity in definition of "region" (in MRCT), new regulatory requirements to enroll a diverse patient population, the use of decentralized clinical trials, use of data sources other than randomized clinical trials (e.g., use of Real Word Data), and the impact of the COVID-19 pandemic on the conduct of MRCT.

Macrophage PET imaging in mouse models of cardiovascular disease and cancer with an apolipoprotein-inspired radiotracer.

Macrophages are key inflammatory mediators in many pathological conditions, including cardiovascular disease (CVD) and cancer, the leading causes of morbidity and mortality worldwide. This makes macrophage burden a valuable diagnostic marker and several strategies to monitor these cells have been reported. However, such strategies are often high-priced, non-specific, invasive, and/or not quantitative. Here, we developed a positron emission tomography (PET) radiotracer based on apolipoprotein A1 (ApoA1), the main protein component of high-density lipoprotein (HDL), which has an inherent affinity for macrophages. We radiolabeled an ApoA1-mimetic peptide (mA1) with zirconium-89 (89Zr) to generate a lipoprotein-avid PET probe (89Zr-mA1). We first characterized 89Zr-mA1's affinity for lipoproteins in vitro by size exclusion chromatography. To study 89Zr-mA1's in vivo behavior and interaction with endogenous lipoproteins, we performed extensive studies in wildtype C57BL/6 and Apoe-/- hypercholesterolemic mice. Subsequently, we used in vivo PET imaging to study macrophages in melanoma and myocardial infarction using mouse models. The tracer's cell specificity was assessed by histology and mass cytometry (CyTOF). Our data show that 89Zr-mA1 associates with lipoproteins in vitro. This is in line with our in vivo experiments, in which we observed longer 89Zr-mA1 circulation times in hypercholesterolemic mice compared to C57BL/6 controls. 89Zr-mA1 displayed a tissue distribution profile similar to ApoA1 and HDL, with high kidney and liver uptake as well as substantial signal in the bone marrow and spleen. The tracer also accumulated in tumors of melanoma-bearing mice and in the ischemic myocardium of infarcted animals. In these sites, CyTOF analyses revealed that natZr-mA1 was predominantly taken up by macrophages. Our results demonstrate that 89Zr-mA1 associates with lipoproteins and hence accumulates in macrophages in vivo. 89Zr-mA1's high uptake in these cells makes it a promising radiotracer for non-invasively and quantitatively studying conditions characterized by marked changes in macrophage burden.

Staged Versus Concomitant TAVI and PCI for the Treatment of Coexisting Aortic Stenosis and Coronary Artery Disease.

Aortic stenosis (AS) is one of the most common valvular pathologies. Severe coronary artery disease (CAD) often coexists with AS. Transcatheter aortic valve implantation (TAVI) and percutaneous coronary intervention (PCI) have been established as alternatives to open surgical interventions. The data on the timing for the treatment of the 2 conditions are scarce and depend on multiple factors. This review compares the clinical outcomes of the concomitant versus staged PCI and TAVI for the treatment of AS and CAD. A systematic, electronic search was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines to identify relevant articles that compared outcomes of the staged versus concomitant approaches for the TAVI and PCI. Seven studies were included involving 3745 patients. We found no statistically significant difference in primary outcomes such as 30-day mortality [odds ratio (OR) = 0.78; 95% confidence interval (CI): 0.39-1.57] and secondary outcomes including length of hospital stay (mean difference = -4.74, 95% CI: -10.96 to 1.48), new-onset renal failure (OR = 0.83, 95% CI: 0.22-3.13), cerebrovascular accidents (OR = 1.28, 95% CI: 0.64-2.57), and intraoperative blood loss (OR = 0.83, 95% CI: 0.32-2.12). New pacemaker insertion was statistically significant in favor of the concomitant approach (OR = 0.78, 95% CI: 0.63-0.96). This analysis suggests that while the 2 approaches are largely comparable in terms of most outcomes, patients at risk of requiring a pacemaker postprocedure may benefit from a concomitant approach. In conclusion, concomitant TAVI + PCI approach is nonsuperior to the staged approach for the treatment of CAD and AS. This review calls for robust trials in the field to further strengthen the evidence.

Health systems challenges, mitigation strategies and adaptations to maintain essential health services during the COVID-19 pandemic: learnings from the six geopolitical regions in Nigeria.

BACKGROUND: The COVID-19 pandemic control strategies disrupted the smooth delivery of essential health services (EHS) globally. Limited evidence exists on the health systems lens approach to analyzing the challenges encountered in maintaining EHS during the COVID-19 pandemic. This study aimed to identify the health system challenges encountered and document the mitigation strategies and adaptations made across geopolitical zones (GPZs) in Nigeria. METHODS: The national qualitative survey of key actors across the six GPZs in Nigeria involved ten states and the Federal Capital Territory (FCT) which were selected based on resilience, COVID-19 burden and security considerations. A pre-tested key informant guide was used to collect data on service utilization, changes in service utilization, reasons for changes in primary health centres' (PHCs) service volumes, challenges experienced by health facilities in maintaining EHS, mitigation strategies implemented and adaptations to service delivery. Emerging sub-themes were categorized under the appropriate pillars of the health system. RESULTS: A total of 22 respondents were interviewed. The challenges experienced in maintaining EHS cut across the pillars of the health systems including: Human resources shortage, shortages in the supply of personal protective equipments, fear of contracting COVID-19 among health workers misconception, ignorance, socio-cultural issues, lockdown/transportation and lack of equipment/waiting area (. The mitigation strategies included improved political will to fund health service projects, leading to improved accessibility, affordability, and supply of consumables. The health workforce was motivated by employing, redeploying, training, and incentivizing. Service delivery was reorganized by rescheduling appointments and prioritizing some EHS such as maternal and childcare. Sustainable systems adaptations included IPC and telehealth infrastructure, training and capacity building, virtual meetings and community groups set up for sensitization and engagement. CONCLUSION: The mitigation strategies and adaptations implemented were important contributors to EHS recovery especially in the high resilience LGAs and have implications for future epidemic preparedness plans.

Integrating predictive coding and a user-centric interface for enhanced auditing and quality in cancer registry data.

Data curation for a hospital-based cancer registry heavily relies on the labor-intensive manual abstraction process by cancer registrars to identify cancer-related information from free-text electronic health records. To streamline this process, a natural language processing system incorporating a hybrid of deep learning-based and rule-based approaches for identifying lung cancer registry-related concepts, along with a symbolic expert system that generates registry coding based on weighted rules, was developed. The system is integrated with the hospital information system at a medical center to provide cancer registrars with a patient journey visualization platform. The embedded system offers a comprehensive view of patient reports annotated with significant registry concepts to facilitate the manual coding process and elevate overall quality. Extensive evaluations, including comparisons with state-of-the-art methods, were conducted using a lung cancer dataset comprising 1428 patients from the medical center. The experimental results illustrate the effectiveness of the developed system, consistently achieving F1-scores of 0.85 and 1.00 across 30 coding items. Registrar feedback highlights the system's reliability as a tool for assisting and auditing the abstraction. By presenting key registry items along the timeline of a patient's reports with accurate code predictions, the system improves the quality of registrar outcomes and reduces the labor resources and time required for data abstraction. Our study highlights advancements in cancer registry coding practices, demonstrating that the proposed hybrid weighted neural-symbolic cancer registry system is reliable and efficient for assisting cancer registrars in the coding workflow and contributing to clinical outcomes.

Unplanned rehospitalisation due to medication harm following an Acute Myocardial Infarction.

Introduction The contribution of medication harm to rehospitalisation and adverse patient outcomes after an acute myocardial infarction (AMI) needs exploration. Rehospitalisation is costly to both patients and the healthcare facility. Following an AMI, patients are at risk of medication harm as they are often older, have multiple comorbidities and polypharmacy. This study aimed to quantify and evaluate medication harm causing unplanned rehospitalisation after an AMI. Methods This was a retrospective cohort study of patients discharged from a quaternary hospital post-AMI. All rehospitalisations within 18 months were identified using medical record review and coding data. The primary outcome measure was medication harm rehospitalisation. Preventability, causality and severity assessments of medication harm were conducted. Results A total of 1564 patients experienced an AMI and 415 (26.5%) were rehospitalised. Eighty-nine patients (5.7% of total population; 6.0% of those discharged) experienced a total of 101 medication harm events. Those with medication harm were older (p=0.007) and had higher rates of heart failure (p=0.005), chronic kidney disease (CKD) (p=0.046), chronic obstructive pulmonary disease (COPD) (p=0.037) and a prior history of ischaemic heart disease (p=0.005). Gastrointestinal (GI) bleeding, acute kidney injury (AKI) and hypotension were the most common medication harm events. Forty percent of events were avoidable and 84% were classed as 'serious'. Furosemide, antiplatelets and angiotensin-converting enzyme inhibitors (ACEi) were the most commonly implicated medications. The median time to medication harm rehospitalisation was 79 days (interquartile range [IQR]: 16-200 days). Conclusion Medication harm causes unplanned rehospitalisation in 5.7% of all AMI patients (1 in 17 patients; 6.0% of those discharged). The majority of harm was serious and occurred within the first 200 days of discharge. This study highlights that measures to attenuate the risk of medication harm rehospitalisation are essential, including post-discharge medication management.

Association of semaglutide with reduced incidence and relapse of cannabis use disorder in real-world populations: a retrospective cohort study.

Cannabis is the most frequently used illicit drug in the United States with more than 45 million users of whom one-third suffer from a cannabis use disorder (CUD). Despite its high prevalence, there are currently no FDA-approved medications for CUD. Patients treated with semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for treating type 2 diabetes (T2D) and for weight management have reported reduced desire to drink and smoke. Preclinical studies have shown that semaglutide decreased nicotine and alcohol consumption. Preclinical and preliminary clinical evidence of semaglutide's potential beneficial effects on various substance use disorders led us to evaluate if it pertained to CUD. In this retrospective cohort study of electronic health records (EHRs) from the TriNetX Analytics Network, a global federated health research network of approximately 105.3 million patients from 61 large healthcare organizations in the US, we aimed to assess the associations of semaglutide with both incident and recurrent CUD diagnosis compared to non-GLP-1RA anti-obesity or anti-diabetes medications. Hazard ratio (HR) and 95% confidence intervals (CI) of incident and recurrent CUD were calculated for 12-month follow-up by comparing propensity-score matched patient cohorts. The study population included 85,223 patients with obesity who were prescribed semaglutide or non-GLP-1RA anti-obesity medications, with the findings replicated in 596,045 patients with T2D. In patients with obesity (mean age 51.3 years, 65.6% women), semaglutide compared with non-GLP-1RA anti-obesity medications was associated with lower risk for incident CUD in patients with no prior history CUD (HR: 0.56, 95% CI: 0.42-0.75), and recurrent CUD diagnosis in patients with a prior history CUD (HR: 0.62, 95% CI: 0.46-0.84). Consistent reductions were seen for patients stratified by gender, age group, race and in patients with and without T2D. Similar findings were replicated in the study population with T2D when comparing semaglutide with non-GLP-1RA anti-diabetes medications for incident CUD (HR: 0.40, 95% CI: 0.29-0.56) and recurrent CUD (HR: 0.66, 95% CI: 0.42-1.03). While these findings provide preliminary evidence of the potential benefit of semaglutide in CUD in real-world populations, further preclinical studies are warranted to understand the underlying mechanism and randomized clinical trials are needed to support its use clinically for CUD.

Effects of a culturally informed model of care for Aboriginal and Torres Strait Islander patients with acute coronary syndrome in a tertiary hospital in Australia: a pre-post, quasi-experimental, interventional study.

BACKGROUND: Aboriginal and Torres Strait Islander (Indigenous) peoples with cardiac disease in Australia have worse outcomes than non-Indigenous people with cardiac disease. We hypothesised that the implementation of a culturally informed model of care for Indigenous patients hospitalised with acute coronary syndrome (ACS) would improve their clinical outcomes. METHODS: For this pre-post, quasi-experimental, interventional study, cohorts of Indigenous patients before and after the implementation of a model of care were compared. The novel, culturally informed, multidisciplinary-team model of care was a local programme of care developed to reduce morbidity and mortality from cardiac conditions among Indigenous Australians. All index admissions in the 24-month pre-implementation period (Jan 1 2013, to Dec 31, 2014) were analysed, as were all index admissions in the 12-month post-implementation period (Oct 1, 2015, to Sept 30, 2016). Comparisons were also made with non-Indigenous cohorts in the same timeframes. Admissions were excluded if the patient did not survive to hospital discharge. The study was conducted at Princess Alexandra Hospital, a tertiary hospital in metropolitan Brisbane (QLD, Australia). Data on presentation, comorbidities, investigations, treatment, and for outcomes were manually collected from a consolidated clinical information application. Mortality data were obtained from the Queensland Registry of Births, Deaths, and Marriages. The primary outcome was a composite of death, acute myocardial infarction, unplanned revascularisation, and cardiac readmission at 90 days after index admission, assessed in all patients. FINDINGS: The Indigenous cohorts included 199 patients admitted with ACS before the model of care was implemented (85 [43%] were female and 114 [57%] were male) and 119 admitted post-implementation (62 [52%] were female and 57 [48%] were male). The non-Indigenous cohorts included 440 patients with ACS before the model of care was implemented (140 [32%] were female and 300 [68%] were male) and 467 admitted post-implementation (143 [31%] were female and 324 [69%] were male). Compared with the pre-implementation group, Indigenous patients admitted post-implementation had a significant reduction in the primary outcome (67 [34%] of 199 vs 24 [20%] of 119; hazard ratio 0·60, 95% CI 0·40-0·90; p=0·012), which was driven by a reduction in unplanned cardiac readmissions (64 [32%] of 199 vs 21 [18%] of 119; 0·55, 0·35-0·85; p=0·0060). There was no significant change in non-Indigenous patients between the pre-implementation and post-implementation timeframes in the composite endpoint at 90 days (81 [18%] of 440 vs 93 [20%] of 467; 1·08, 0·83-1·41; p=0·54). Pre-implementation, there was significantly more incidence of the primary outcome in Indigenous patients than non-Indigenous patients (p<0·0001), with no significant difference in the post-implementation period (p=0·92). INTERPRETATION: Clinical outcomes for Indigenous patients admitted to a tertiary hospital in Australia improved after implementation of a culturally informed model of care, with a reduction in the disparity in incidence of primary endpoints that existed between Indigenous and non-Indigenous patients before implementation. FUNDING: Queensland Department of Health Aboriginal and Torres Strait Islander Health Division (now First Nations Health Office).

A web-based tool for real-time adequacy assessment of kidney biopsies.

The escalating incidence of kidney biopsies providing insufficient tissue for diagnosis poses a dual challenge, straining the healthcare system and jeopardizing patients who may require rebiopsy or face the prospect of an inaccurate diagnosis due to an unsampled disease. Here, we introduce a web-based tool that can provide real-time, quantitative assessment of kidney biopsy adequacy directly from photographs taken with a smartphone camera. The software tool was developed using a deep learning-driven automated segmentation technique, trained on a dataset comprising nephropathologist-confirmed annotations of the kidney cortex on digital biopsy images. Our framework demonstrated favorable performance in segmenting the cortex via 5-fold cross-validation (Dice coefficient: 0.788±0.130) (n=100). Offering a bedside tool for kidney biopsy adequacy assessment has the potential to provide real-time guidance to the physicians performing medical kidney biopsies, reducing the necessity for re-biopsies. Our tool can be accessed through our web-based platform: http://www.biopsyadequacy.org.

Lisocabtagene maraleucel for treatment of relapsed and refractory primary mediastinal large B-cell lymphoma in an adolescent patient.

The safety and efficacy of CAR T-cell therapy are unknown in pediatric and adolescent patients with relapsed or refractory primary mediastinal large B-cell lymphoma (R/R PMBCL) which is associated with dismal prognosis. Here, we present a case report of a 16-year-old patient with R/R PMBCL treated with lisocabtagene maraleucel including correlative studies. Patient achieved complete response at 6 months without cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. She only experienced mild cytopenias, requiring filgrastim once. This report highlights the safety and efficacy of lisocabtagene maraleucel in this population, warranting prospective studies to improve clinical outcomes.

Association of semaglutide with risk of suicidal ideation in a real-world cohort.

Concerns over reports of suicidal ideation associated with semaglutide treatment, a glucagon-like peptide 1 receptor (GLP1R) agonist medication for type 2 diabetes (T2DM) and obesity, has led to investigations by European regulatory agencies. In this retrospective cohort study of electronic health records from the TriNetX Analytics Network, we aimed to assess the associations of semaglutide with suicidal ideation compared to non-GLP1R agonist anti-obesity or anti-diabetes medications. The hazard ratios (HRs) and 95% confidence intervals (CIs) of incident and recurrent suicidal ideation were calculated for the 6-month follow-up by comparing propensity score-matched patient groups. The study population included 240,618 patients with overweight or obesity who were prescribed semaglutide or non-GLP1R agonist anti-obesity medications, with the findings replicated in 1,589,855 patients with T2DM. In patients with overweight or obesity (mean age 50.1 years, 72.6% female), semaglutide compared with non-GLP1R agonist anti-obesity medications was associated with lower risk for incident (HR = 0.27, 95% CI = 0.200.32-0.600.36) and recurrent (HR = 0.44, 95% CI = 0.32-0.60) suicidal ideation, consistent across sex, age and ethnicity stratification. Similar findings were replicated in patients with T2DM (mean age 57.5 years, 49.2% female). Our findings do not support higher risks of suicidal ideation with semaglutide compared with non-GLP1R agonist anti-obesity or anti-diabetes medications.

Comprehensive Factors for Predicting the Complications of Diabetes Mellitus: A Systematic Review.

BACKGROUND: This article focuses on extracting a standard feature set for predicting the complications of diabetes mellitus by systematically reviewing the literature. It is conducted and reported by following the guidelines of PRISMA, a well-known systematic review and meta-analysis method. The research articles included in this study are extracted using the search engine "Web of Science" over eight years. The most common complications of diabetes, diabetic neuropathy, retinopathy, nephropathy, and cardiovascular diseases are considered in the study. METHOD: The features used to predict the complications are identified and categorised by scrutinising the standards of electronic health records. RESULT: Overall, 102 research articles have been reviewed, resulting in 59 frequent features being identified. Nineteen attributes are recognised as a standard in all four considered complications, which are age, gender, ethnicity, weight, height, BMI, smoking history, HbA1c, SBP, eGFR, DBP, HDL, LDL, total cholesterol, triglyceride, use of insulin, duration of diabetes, family history of CVD, and diabetes. The existence of a well-accepted and updated feature set for health analytics models to predict the complications of diabetes mellitus is a vital and contemporary requirement. A widely accepted feature set is beneficial for benchmarking the risk factors of complications of diabetes. CONCLUSION: This study is a thorough literature review to provide a clear state of the art for academicians, clinicians, and other stakeholders regarding the risk factors and their importance.

Metacarpal Shortening with Intramedullary Screw Fixation: A Cadaveric Study.

Background Intramedullary screw fixation is a commonly used technique for the management of metacarpal fractures. However, compression across the fracture site can lead to unintentional shortening of the metacarpal. Questions/Purposes Our aim was to evaluate the risk of overshortening with differing intramedullary device designs for fixation of metacarpals. Methods The small finger metacarpal of nine fresh-frozen cadavers were included. A metacarpal neck fracture was simulated with a 5-mm osteotomy. Three different intramedullary screw designs were compared. Each screw was placed in a retrograde fashion into the intramedullary canal and the amount of shortening measured. Screws were reversed and the number of reverse turns with the screwdriver needed to release overshortening were measured. Results The average shortening at the osteotomy site was 2.5 mm. The mean shortening was 80%, 58%, and 12% for the partially threaded screw, fully threaded screw, and threaded nail, respectively. The mean differences of the distance shortened were statistically significant for the threaded nail compared with the partially and fully threaded screws. The partially threaded screw had the most shortening, while the threaded nail provided the least amount of shortening. When the screws were reversed, the screws did not disengage until the screw was fully removed from the osteotomy site. Conclusion The fully threaded nail demonstrates less shortening and possibly minimizes overshortening of fractures compared with partially threaded and fully threaded screw designs. Overshortening cannot be corrected by unscrewing the screw unless completely removed from the distal fragment. Clinical Relevance Orthopaedic surgeons may select intermedullary screws based on the design that is suited for the particular metacarpal fracture pattern.

Safety signal detection with control of latent factors.

Postmarket drug safety database like vaccine adverse event reporting system (VAERS) collect thousands of spontaneous reports annually, with each report recording occurrences of any adverse events (AEs) and use of vaccines. We hope to identify signal vaccine-AE pairs, for which certain vaccines are statistically associated with certain adverse events (AE), using such data. Thus, the outcomes of interest are multiple AEs, which are binary outcomes and could be correlated because they might share certain latent factors; and the primary covariates are vaccines. Appropriately accounting for the complex correlation among AEs could improve the sensitivity and specificity of identifying signal vaccine-AE pairs. We propose a two-step approach in which we first estimate the shared latent factors among AEs using a working multivariate logistic regression model, and then use univariate logistic regression model to examine the vaccine-AE associations after controlling for the latent factors. Our simulation studies show that this approach outperforms current approaches in terms of sensitivity and specificity. We apply our approach in analyzing VAERS data and report our findings.

Emergent human-like covert attention in feedforward convolutional neural networks.

Covert attention allows the selection of locations or features of the visual scene without moving the eyes. Cues and contexts predictive of a target's location orient covert attention and improve perceptual performance. The performance benefits are widely attributed to theories of covert attention as a limited resource, zoom, spotlight, or weighting of visual information. However, such concepts are difficult to map to neuronal populations. We show that a feedforward convolutional neural network (CNN) trained on images to optimize target detection accuracy and with no explicit incorporation of an attention mechanism, a limited resource, or feedback connections learns to utilize cues and contexts in the three most prominent covert attention tasks (Posner cueing, set size effects in search, and contextual cueing) and predicts the cue/context influences on human accuracy. The CNN's cueing/context effects generalize across network training schemes, to peripheral and central pre-cues, discrimination tasks, and reaction time measures, and critically do not vary with reductions in network resources (size). The CNN shows comparable cueing/context effects to a model that optimally uses image information to make decisions (Bayesian ideal observer) but generalizes these effects to cue instances unseen during training. Together, the findings suggest that human-like behavioral signatures of covert attention in the three landmark paradigms might be an emergent property of task accuracy optimization in neuronal populations without positing limited attentional resources. The findings might explain recent behavioral results showing cueing and context effects across a variety of simple organisms with no neocortex, from archerfish to fruit flies.

GLP-1 Receptor Agonists and Colorectal Cancer Risk in Drug-Naive Patients With Type 2 Diabetes, With and Without Overweight/Obesity.

This cohort study compares glucagon-like peptide 1 receptor agonists (GLP-1RAs) with 7 non­GLP-1RA antidiabetics among drug-naive patients with type 2 diabetes.

Gastric Alimetry Expands Patient Phenotyping in Gastroduodenal Disorders Compared with Gastric Emptying Scintigraphy.

INTRODUCTION: Gastric emptying testing (GET) assesses gastric motility, however, is nonspecific and insensitive for neuromuscular disorders. Gastric Alimetry (GA) is a new medical device combining noninvasive gastric electrophysiological mapping and validated symptom profiling. This study assessed patient-specific phenotyping using GA compared with GET. METHODS: Patients with chronic gastroduodenal symptoms underwent simultaneous GET and GA, comprising a 30-minute baseline, 99m TC-labelled egg meal, and 4-hour postprandial recording. Results were referenced to normative ranges. Symptoms were profiled in the validated GA App and phenotyped using rule-based criteria based on their relationships to the meal and gastric activity: (i) sensorimotor, (ii) continuous, and (iii) other. RESULTS: Seventy-five patients were assessed, 77% female. Motility abnormality detection rates were as follows: GET 22.7% (14 delayed, 3 rapid), GA spectral analysis 33.3% (14 low rhythm stability/low amplitude, 5 high amplitude, and 6 abnormal frequency), and combined yield 42.7%. In patients with normal spectral analysis, GA symptom phenotypes included sensorimotor 17% (where symptoms strongly paired with gastric amplitude, median r = 0.61), continuous 30%, and other 53%. GA phenotypes showed superior correlations with Gastroparesis Cardinal Symptom Index, Patient Assessment of Upper Gastrointestinal Symptom Severity Index, and anxiety scales, whereas Rome IV Criteria did not correlate with psychometric scores ( P > 0.05). Delayed emptying was not predictive of specific GA phenotypes. DISCUSSION: GA improves patient phenotyping in chronic gastroduodenal disorders in the presence and absence of motility abnormalities with increased correlation with symptoms and psychometrics compared with gastric emptying status and Rome IV criteria. These findings have implications for the diagnostic profiling and personalized management of gastroduodenal disorders.

Gender differences in cardiovascular disease risk: Adolescence to young adulthood.

BACKGROUND AND AIMS: Gender differences in cardiovascular disease (CVD) have been well documented but rarely for young adults and the extent to which gender related lifestyle differences may contribute to gender differences in CVD risk experienced by young adults have not been reported. METHODS AND RESULTS: Data are from a long-running cohort study, the Mater-University of Queensland Study of Pregnancy (MUSP). We track gender differences in CVD related behaviours at 21 and 30 years (consumption of a Western Diet/Health-Oriented Diet, cigarette smoking, vigorous physical exercise, heavy alcohol consumption). At 30 years we compare males and females for CVD risk, and the extent to which lifestyle behaviours at 21 and 30 years contribute to CVD risk. At both 21 and 30 years of age, males more frequently consume a Western Diet and less often a Health Oriented Diet. By contrast, males are also much more likely to report engaging in vigorous physical activity. On most CVD markers, males exhibit much higher levels of risk than do females at both 21 and 30 years. At 30 years of age males have about five times the odds of being at high risk of CVD. Some lifestyle behaviours contribute to this additional risk. CONCLUSION: Young adult males much more frequently engage in most CVD related risk behaviours and males have a higher level of CVD risk. Gender differences in CVD risk remain high even after adjustment for CVD lifestyles, though dietary factors independently contribute to CVD risk at 30 years.

Mechanical Intercellular Communication via Matrix-Borne Cell Force Transmission During Vascular Network Formation.

Intercellular communication is critical to the formation and homeostatic function of all tissues. Previous work has shown that cells can communicate mechanically via the transmission of cell-generated forces through their surrounding extracellular matrix, but this process is not well understood. Here, mechanically defined, synthetic electrospun fibrous matrices are utilized in conjunction with a microfabrication-based cell patterning approach to examine mechanical intercellular communication (MIC) between endothelial cells (ECs) during their assembly into interconnected multicellular networks. It is found that cell force-mediated matrix displacements in deformable fibrous matrices underly directional extension and migration of neighboring ECs toward each other prior to the formation of stable cell-cell connections enriched with vascular endothelial cadherin (VE-cadherin). A critical role is also identified for calcium signaling mediated by focal adhesion kinase and mechanosensitive ion channels in MIC that extends to multicellular assembly of 3D vessel-like networks when ECs are embedded within fibrin hydrogels. These results illustrate a role for cell-generated forces and ECM mechanical properties in multicellular assembly of capillary-like EC networks and motivates the design of biomaterials that promote MIC for vascular tissue engineering.