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Entrepreneurial orientation is found to influence Project success along with the moderation of adaptive organizational culture and people centered management in most of the cases. This study, by addressing the moderation brings clarity to the assessment of the relation of entrepreneurial orientation dimensions on project success and is a contribution to the advancement of knowledge enhancement and improvement in Pakistan. A predominantly quantitative research strategy supported by qualitative inputs employed to obtain empirical data from 256 corporate firms in Punjab Pakistan. The gathered data examined by the structural equation modeling through Partial least square method. The results indicate that innovativeness, risk taking and proactiveness reflect the entrepreneurial orientation components. The findings of this study conclude that three dimensions of entrepreneurial orientation Innovation, Risk-taking and Proactiveness have significant and positive influence on project success. When these three dimensions of entrepreneurial orientation are moderated with adaptive organizational culture and People-Centered Management shows moderate to strong relations between different variables with a few insignificant results.

BackgroundThe recent proliferation of digital health technology in low- and middle-income countries has made it possible for community health workers (CHWs) to use mobile health (mHealth) to perform tasks such as data collection and training. Although most studies focus on the prospect of digital apps to motivate and connect CHW, only a few have captured end-user experiences with mobile-based apps. We examined the experience of frontline health workers with a move towards digitalized real-time data to record maternal and childcare services in remote areas of Afghanistan and Pakistan. ObjectiveOur study aimed to explore CHW perceptions on the operability of the mHealth app in a community setting, usefulness of the app in the delivery of assigned maternal and childcare functions, and the task-technology fit with monitoring information systems. MethodsThe Hayat app, designed to digitalize and facilitate electronic record keeping, was evaluated to be embedded into mainstream health systems. The app had 2 components: smartphone app for data entry and web dashboard for visualization of the maternal, newborn, and child health reports. Using a qualitative exploratory study design, we conducted a total of 8 focus group discussions with purposively selected lady health workers (LHWs) and CHWs in 3 districts of Pakistan and 3 hamlets of Afghanistan, respectively. Focus group discussions were conducted in the local language, audio recorded, and converted into expanded notes for thematic analysis. ResultsAlthough a majority of LHWs used the app with ease, some initially faced difficulties in operating it and requested a longer duration of training. Contrary to LHWs, the CHWs were able to use the app without difficulty, as they were using it only to register clients. Overall, use of the mHealth app in both countries resulted in a positive impact on health education sessions, easier communication with parents or clients, tracking of routine immunization defaulters and follow-ups, improved data validity, easily accessible vaccination schedules, and faster registration. In addition to building up their image in the community and personal development, the improved reporting and monitoring mechanisms also set the stage for the LHWs to get recognized for their hard work. CHWs in Afghanistan also reported the app provided immediate access to information when requested by their supervisor. Although the Hayat app eliminates the need to carry multiple registers and helps in recalling client information at the touch of a button, technical issues around connectivity and data inputting tabs were highlighted by the participants. ConclusionsThe digitization of records not only provided CHWs support in their daily routine but also strengthened monitoring mechanisms and improved motivation. We recommend conducting end user experience studies before embedding apps into mainstream health systems as high acceptability does not always result in high uptake of digital technology.

BackgroundThere has been a recent spate of mobile health (mHealth) app use for immunizations and other public health concerns in low- and middle-income countries. However, recent evidence has largely focused on app development or before-and-after effects on awareness or service coverage. There is little evidence on the factors that facilitate adoption of mHealth programs, which is critical to effectively embed digital technology into mainstream health systems. ObjectiveThis study aimed to provide the qualitative experiences of frontline health staff and district managers while engaging with real-time digital technology to improve the coverage of routine childhood immunization in an underserved rural district in Pakistan. MethodsAn Android-based app was iteratively developed and used for a 2-year period in 11 union councils of the Tando Muhammad Khan district, an underserved rural district with poor immunization coverage in Pakistan. We used iterative methods to examine the (1) acceptability and operability of the app, (2) validity of the collected data, and (3) use of the collected data. In addition, we collected the barriers and enablers for uptake of the mHealth app. Each of these topics was further explored related to changes in work as well as the enabling factors for and barriers to app use. In-depth interviews were conducted with the 26 vaccinators posted in the 11 union councils and 7 purposively selected key informants (government district managers) involved with the Expanded Program for Immunization. Findings were triangulated in line with the three broad research areas. ResultsDigital immunization tracking was considered acceptable by vaccinators and district managers. Real-time immunization data were used to monitor vaccination volume, track children with incomplete vaccinations, develop outreach visit plans, correct existing microplans, and disburse a fuel allowance for outreach sessions. The validity of the app data was perceived to be superior to that of data from manual records. Ease of operability, satisfaction with data, personal recognition, links to field support, and a sense of empowerment served as powerful enablers. Taking twice the time to complete both manual and digital entries and outdated phones over time were considered constraints. An unintended knock-on effect was improved coordination and strengthening of Expanded Program for Immunization review platforms across district stakeholders through digitalized data. ConclusionsEmbedding digital technology into mainstream health systems relies on use by both end users and district stakeholders. Ease of operability, satisfaction with data reliability, personal recognition, links to field support, and empowerment are powerful enablers, whereas improved coordination as a result of easy, transparent data access can be an important by-product of digitalization. Findings are relevant not only for wide-scale implementation of immunization tracking apps in Pakistan but also for informing the use of digital technology for results-based delivery by frontline health workers.

Background: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer., Objective: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing., Design: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors., Results: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways., Conclusions: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Shared decision-making (SDM) is an essential component of patient-centered healthcare and disease management. However, the association of SDM with healthcare resource utilization and patient-reported outcomes among multimorbid individuals is not well understood. This study sought to evaluate the association of SDM with healthcare resource utilization and patient-reported outcomes among United States (US) adults with multimorbidity. Data were collected from the 2020 Medical Expenditure Panel Survey (MEPS) for this cross-sectional study. Eligible participants were US adults with two or more comorbidities. The predictor variable was SDM (optimal versus not optimal). The outcome variables were healthcare resource utilization and patient-reported outcomes. Logistic regression models, adjusted for demographic characteristics, assessed associations with SDM for each healthcare resource utilization and patient-reported outcome variable. The analysis maintained the complex survey data and was weighted to produce nationally representative estimates. Individuals who reported optimal SDM in adjusted analyses utilized more healthcare resources compared to those who reported not optimal SDM. Individuals with optimal SDM had more than one outpatient visit (odds ratio OR = 1.23, 95% CI = 1.03-1.47), emergency room visit (OR = 1.55, 95% CI = 1.17-2.06), and inpatient discharge (OR = 1.44, 95% CI = 1.05-1.96). Additionally, these individuals had higher odds of reporting limitations in their ability to work or engage in other activities due to their physical health in the past four weeks (OR = 1.27, 95% CI = 1.01-1.60). This study indicated evidence of increased healthcare resource utilization among patients who participate in SDM with their providers, which should be explored in future studies.

Urinary tract infections are widely recognized as prevalent bacterial infections frequently encountered in both hospital and community settings. The most common gram-negative bacterial pathogen in humans, extra-intestinal pathogenic Escherichia coli, causes these diseases. A retrospective cross-sectional study in Karachi, Pakistan examined Escherichia coli's susceptibility to doxycycline, nalidixic acid and meropenem. One hundred isolates of Escherichia coli from urine samples of patients were collected. The Kirby Bauer disc diffusion testing method was used following CLSI guidelines. The results showed variability because of differences in patient's gender and age. 84 out of 100 samples were of females and 16 samples were of males. Infection prevalence by age showed that 15% of isolates were from children (0-12 years), 2% from adolescents (13-18 years), 52% from adults (19-59 years) and 31% from seniors. This study concluded that females and adults (aged 19-59 years) are at highest risk of prevalence. Meropenem is a potential antibiotic choice for urinary tract infections due to its demonstrated 100% susceptibility. However, in light of increasing resistance trends, the administration of doxycycline and nalidixic acid should be reserved until antimicrobial susceptibility testing has been conducted. The study ensures that antibiotics are used judiciously and effectively in combating urinary tract infections while minimizing the risk of further antimicrobial resistance development.

This work presents an innovative and environmentally friendly biological synthesis approach for producing α-Fe 2 O 3 nanoparticles (NPs) and the successful synthesis of α-Fe 2 O 3 /reduced graphene oxide (rGO) nanocomposites (NCs). This novel synthesis route utilizes freshly extracted albumin, serving as both a reducing agent and a stabilizing agent, rendering it eco-friendly, cost-effective, and sustainable. A combination of characterization techniques including X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), Raman spectroscopy, and field emission scanning electron microscopy (FE-SEM) was employed to predict and confirm the formation of the as-synthesized α-Fe 2 O 3 NPs and α-Fe 2 O 3 /rGO NCs. Transmission electron microscopy (TEM) verified the anisotropic nature of the synthesized nanoparticles. To gain insight into the enhanced capacitance of the α-Fe 2 O 3 /rGO NCs, a series of electrochemical tests, namely cyclic voltammetry (CV), galvanostatic charge-discharge (GCD), electrochemical impedance spectroscopy (EIS), and stability assessments, were conducted in a conventional three-electrode configuration. Furthermore, a two-electrode asymmetric supercapacitor (ASC) device was fabricated to assess the practical viability of this material. The α-Fe 2 O 3 /rGO NCs exhibited a remarkable potential window of 2 V in an aqueous electrolyte, coupled with exceptional cycling stability. Even after undergoing 10 000 cycles, the capacitive retention exceeded 100%, underlining the promising potential of this material for advanced energy storage applications.

Background: The genotoxin colibactin causes a tumor single-base substitution (SBS) mutational signature, SBS88. It is unknown whether epidemiologic factors' association with colorectal cancer risk and survival differs by SBS88., Methods: Within the Genetic Epidemiology of Colorectal Cancer Consortium and Colon Cancer Family Registry, we measured SBS88 in 4,308 microsatellite stable/microsatellite instability low tumors. Associations of epidemiologic factors with colorectal cancer risk by SBS88 were assessed using multinomial regression (N = 4,308 cases, 14,192 controls; cohort-only cases N = 1,911), and with colorectal cancer-specific survival using Cox proportional hazards regression (N = 3,465 cases)., Results: 392 (9%) tumors were SBS88 positive. Among all cases, the highest quartile of fruit intake was associated with lower risk of SBS88-positive colorectal cancer than SBS88-negative colorectal cancer [odds ratio (OR) = 0.53, 95% confidence interval (CI) 0.37-0.76; OR = 0.75, 95% CI 0.66-0.85, respectively, Pheterogeneity = 0.047]. Among cohort studies, associations of body mass index (BMI), alcohol, and fruit intake with colorectal cancer risk differed by SBS88. BMI ≥30 kg/m2 was associated with worse colorectal cancer-specific survival among those SBS88-positive [hazard ratio (HR) = 3.40, 95% CI 1.47-7.84], but not among those SBS88-negative (HR = 0.97, 95% CI 0.78-1.21, Pheterogeneity = 0.066)., Conclusions: Most epidemiologic factors did not differ by SBS88 for colorectal cancer risk or survival. Higher BMI may be associated with worse colorectal cancer-specific survival among those SBS88-positive; however, validation is needed in samples with whole-genome or whole-exome sequencing available., Impact: This study highlights the importance of identification of tumor phenotypes related to colorectal cancer and understanding potential heterogeneity for risk and survival., (©2024 American Association for Cancer Research.)

Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including EWS:FLI1 and EWS:ERG fusions in Ewing sarcoma (EwS) and TMPRSS2:ERG in prostate cancer (PCa), drive oncogenic programs via binding to GGAA repeats. We report here that both EWS:FLI1 and ERG bind and transcriptionally activate GGAA-rich pericentromeric heterochromatin. The respective pathogen-like HSAT2 and HSAT3 RNAs, together with LINE, SINE, ERV, and other repeat transcripts, are expressed in EwS and PCa tumors, secreted in extracellular vesicles (EVs), and are highly elevated in plasma of patients with EwS with metastatic disease. High human satellite 2 and 3 (HSAT2,3) levels in EWS:FLI1- or ERG-expressing cells and tumors were associated with induction of G2/M checkpoint, mitotic spindle, and DNA damage programs. These programs were also activated in EwS EV-treated fibroblasts, coincident with accumulation of HSAT2,3 RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically, HSAT2,3-enriched cancer EVs induced cGAS-TBK1 innate immune signaling and formation of cytosolic granules positive for double-strand RNAs, RNA-DNA, and cGAS. Hence, aberrantly expressed ETS proteins derepress pericentromeric heterochromatin, yielding pathogenic RNAs that transmit genotoxic stress and inflammation to local and distant sites. Monitoring HSAT2,3 plasma levels and preventing their dissemination may thus improve therapeutic strategies and blood-based diagnostics.

Background: Obesity has been positively associated with most molecular subtypes of colorectal cancer (CRC); however, the magnitude and the causality of these associations is uncertain., Methods: We used Mendelian randomization (MR) to examine potential causal relationships between body size traits (body mass index [BMI], waist circumference, and body fat percentage) with risks of Jass classification types and individual subtypes of CRC (microsatellite instability [MSI] status, CpG island methylator phenotype [CIMP] status, BRAF and KRAS mutations). Summary data on tumour markers were obtained from two genetic consortia (CCFR, GECCO)., Findings: A 1-standard deviation (SD:5.1 kg/m 2 ) increment in BMI levels was found to increase risks of Jass type 1 MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype (odds ratio [OR]: 2.14, 95% confidence interval [CI]: 1.46, 3.13; p-value = 9 × 10 -5 ) and Jass type 2 non-MSI-high,CIMP-high,BRAF-mutated,KRAS-wildtype CRC (OR: 2.20, 95% CI: 1.26, 3.86; p-value = 0.005). The magnitude of these associations was stronger compared with Jass type 4 non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-wildtype CRC (p-differences: 0.03 and 0.04, respectively). A 1-SD (SD:13.4 cm) increment in waist circumference increased risk of Jass type 3 non-MSI-high,CIMP-low/negative,BRAF-wildtype,KRAS-mutated (OR 1.73, 95% CI: 1.34, 2.25; p-value = 9 × 10 -5 ) that was stronger compared with Jass type 4 CRC (p-difference: 0.03). A higher body fat percentage (SD:8.5%) increased risk of Jass type 1 CRC (OR: 2.59, 95% CI: 1.49, 4.48; p-value = 0.001), which was greater than Jass type 4 CRC (p-difference: 0.03)., Interpretation: Body size was more strongly linked to the serrated (Jass types 1 and 2) and alternate (Jass type 3) pathways of colorectal carcinogenesis in comparison to the traditional pathway (Jass type 4)., Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council, National Institutes of Health, National Cancer Institute, American Institute for Cancer Research, Brigham and Women's Hospital, Prevent Cancer Foundation, Victorian Cancer Agency, Swedish Research Council, Swedish Cancer Society, Region Västerbotten, Knut and Alice Wallenberg Foundation, Lion's Cancer Research Foundation, Insamlingsstiftelsen, Umeå University. Full funding details are provided in acknowledgements., Competing Interests: Declaration of interests AB has received a Scholar-in-Training Award from AACR for 2023. VM has received grants from Instituto de Salud Carlos III and FC AECC. BML has received support from Uppsala University as a part of a presentation in the Svedberg Seminar Series, and she was the president of the Australasian Epidemiological Association (2020–2023). BVG has received support grant from World Cancer Research Fund for a separate project within the same research field. AET has received an editorial board fee from NIH PDQ Cancer Genetics. MG has received research funding from Janssen and Servier, consulting fees from Nerviano Medical Sciences, Chromacode, and AstraZeneca and support to attend a meeting from Dava Oncology. JN has received research funding from Natera Inc and consulting fees from Leica Biosciences. MAJ has received an NIH funding. The remaining authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Background: With the advancement in device technology, the use of durable left ventricular assist devices (LVADs) has increased significantly in recent years. However, there is a dearth of evidence to conclude whether patients who undergo LVAD implantation at high-volume centers have better clinical outcomes than those receiving care at low- or medium-volume centers., Methods: We analyzed the hospitalizations using the Nationwide Readmission Database for the year 2019 for new LVAD implantation. Baseline comorbidities and hospital characteristics were compared among low- (1-5 procedures/year), medium- (6-16 procedures/year) and high-volume (17-72 procedures/year) hospitals. The volume/outcome relationship was analyzed using the annualized hospital volume as a categorical variable (tertiles) as well as a continuous variable. Multilevel mixed-effect logistic regression and negative binomial regression models were used to determine the association of hospital volume and outcomes, with tertile 1 (low-volume hospitals) as the reference category., Results: A total of 1533 new LVAD procedures were included in the analysis. The inpatient mortality rate was lower in the high-volume centers compared with the low-volume centers (9.04% vs 18.49%, aOR 0.41, CI0.21-0.80; P = 0.009). There was a trend toward lower mortality rates in medium-volume centers compared with low-volume centers; however, it did not reach statistical significance (13.27% vs 18.49%, aOR 0.57, CI0.27-1.23; P = 0.153). Similar results were seen for major adverse events (composite of stroke/transient ischemic attack and in-hospital mortality). There was no significant difference in bleeding/transfusion, acute kidney injury, vascular complications, pericardial effusion/hemopericardium/tamponade, length of stay, cost, or 30-day readmission rates between medium- and high-volume centers compared to low-volume centers., Conclusion: Our findings indicate lower inpatient mortality rates in high-volume LVAD implantation centers and a trend toward lower mortality rates in medium-volume LVAD implantation centers compared to lower-volume centers., (Copyright © 2023. Published by Elsevier Inc.)

Background: The coronavirus disease 2019 (COVID-19) pandemic has transformed the global view of education, including graduate and postgraduate education making the development of an alternative approach in times of social isolation an academic imperative. The present review aims to investigate the challenges experienced among undergraduate and postgraduate education and the strategies adopted to address these challenges during the pandemic., Method: The preferred reporting items for the systematic review and meta-analyses extension for Scoping Reviews (PRISMA-ScR) were followed. The aim was to include journal articles published in the English language that discussed the influence of the pandemic on educational processes and applied innovative approaches as a solution to educational challenges. From January to August 2020, PubMed, EMBASE, and Google Scholar were searched for articles, yielding 10,019 articles. Two groups of authors examined the retrieved articles separately to avoid any risk of bias. The title and abstract of the articles were used for scrutiny, followed by full-text screening based on the established inclusion and exclusion criteria. The facts and findings of the studies were also discussed based on per capita income, literacy rate, and Internet accessibility., Results: Thirty of the obtained articles were included in the study. The selected articles were from North and South/Latin America, Asia & Pacific, South Africa, and Europe regions. Nineteen of the selected articles dealt with undergraduate education, ten with postgraduate, and one with both groups. The affordability of digital devices and the availability of Internet services were the major challenges for low- and middle-income economies. The ZOOM platform has been adopted by more than 90% of the education systems., Conclusion: Means of communication, including visual media, digitized content, and other web-based platforms, have been recognized as efficient learning and training tools, but have not been fully accessible for mass application and use due to the lack of availability of resources, their cost, and insufficient training among the users. In light of this review, it is suggested that harmonized and collaborative efforts should be made to develop cost-effective and user-friendly tools to overcome the current challenges and prevent future educational crises., Systemic Review Registration: The review was not registered., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Acute pancreatitis (AP) and acute coronary syndrome (ACS) are common conditions, occasionally sharing overlapping symptoms, posing various clinical challenges. This study aims to investigate the demographics, outcomes, and risk factors of patients admitted with AP and ACS using the National Inpatient Sample database. The database from 2016 to 2019 was analyzed, identifying patients with a primary diagnosis of AP and dividing them into 2 groups: those with ACS and those without (non-ACS). Of the 112,874 patients with AP, 5,210 (0.46%) had ACS. The patients with AP with concomitant ACS were older, predominantly male, and had a higher prevalence of co-morbidities. Inpatient mortality was significantly higher in the AP with concomitant ACS cohort compared with the AP without ACS cohort (8.4% vs 0.5%, adjusted odds ratio 9.94, 95% confidence interval 7.79 to 12.67, p <0.05). In conclusion, patients with AP and ACS experienced worse clinical outcomes., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Heart failure (HF) is a leading cause of morbidity and mortality worldwide, with projections showing a further rise in incidence, impacting a decline in quality of life and the costs incurred in its diagnosis and treatment. The authors aim to establish the correlation between the prediction of left ventricular diastolic dysfunction based on a change in QT wave intervals., Methods: A cross-sectional at Holy-family Hospital, Rawalpindi Medical University, Pakistan. One thousand five hundred patients were referred for electrocardiography (ECG) for clinical suspicion of HF between May and July 2022. Ejection fraction (EF), lateral mitral annulus velocity (e'), mitral inflow early (E) and late (A) velocities, left ventricular filling pressure (E/e' ratio), and QT interval (QTc) was calculated. Odds ratios with a 95% CI (odds) were obtained by comparing QTc with all variables., Results: The patients were mostly middle-aged adults with a mean age of 30.27 (±7.64). Male to female ratio was nearly balanced, with 771 (51.4%) males included in the clinical survey. The ECG parameters were; QT interval-494.07 (±63.61), EF-57.11 (±11.96), early to atrial filling velocity ratio-0.71 (±0.20), and lateral mitral annulus velocity-8.29 (±1.64)., Conclusion: The promising results for correlation between QT interval and ECG parameters, particularly EF and lateral mitral annulus velocity, should not be considered as the alternative in diagnosing left ventricular diastolic dysfunction thus far. Prolonged electrocardiographic QTc interval in patients with HF is useful in predicting diastolic dysfunction., Competing Interests: No conflict of interests declared by the authors., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Early-onset colorectal cancer diagnosed before the age of 50 years has been increasing. Likely reflecting the pathogenic role of the intestinal microbiome, which gradually changes across the entire colorectal length, the prevalence of certain tumor molecular characteristics gradually changes along colorectal subsites. Understanding how colorectal tumor molecular features differ by age and tumor location is important in personalized patient management., Methods: Using 14,004 cases with colorectal cancer including 3,089 early-onset cases, we examined microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF mutations in carcinomas of the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum and compared early-onset cases with later-onset cases., Results: The proportions of MSI-high, CIMP-high, and BRAF -mutated early-onset tumors were lowest in the rectum (8.8%, 3.4%, and 3.5%, respectively) and highest in the ascending colon (46% MSI-high; 15% CIMP-high) or transverse colon (8.6% BRAF -mutated) (all Ptrend <0.001 across the rectum to ascending colon). Compared with later-onset tumors, early-onset tumors showed a higher prevalence of MSI-high status and a lower prevalence of CIMP-high status and BRAF mutations in most subsites. KRAS mutation prevalence was higher in the cecum compared with that in the other subsites in both early-onset and later-onset tumors ( P < 0.001). Notably, later-onset MSI-high tumors showed a continuous decrease in KRAS mutation prevalence from the rectum (36%) to ascending colon (9%; Ptrend <0.001), followed by an increase in the cecum (14%), while early-onset MSI-high cancers showed no such trend., Discussion: Our findings support biogeographical and pathogenic heterogeneity of colorectal carcinomas in different colorectal subsites and age groups., (Copyright © 2023 by The American College of Gastroenterology.)

Background: The pathogenic effect of colorectal tumor molecular features may be influenced by several factors, including those related to microbiota, inflammation, metabolism, and epigenetics, which may change along colorectal segments. We hypothesized that the prognostic association of colon cancer location might differ by tumor molecular characteristics., Methods: Utilizing a consortium dataset of 13,101 colorectal cancer cases, including 2994 early-onset cases, we conducted survival analyses of detailed tumor location stratified by statuses of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and KRAS and BRAF oncogenic mutation., Results: There was a statistically significant trend for better colon cancer-specific survival in relation to tumor location from the cecum to sigmoid colon (P trend  = 0.002), excluding the rectum. The prognostic association of colon location differed by MSI status (P interaction  = 0.001). Non-MSI-high tumors exhibited the cecum-to-sigmoid trend for better colon cancer-specific survival [P trend  < 0.001; multivariable hazard ratio (HR) for the sigmoid colon (vs. cecum), 0.80; 95% confidence interval (CI) 0.70-0.92], whereas MSI-high tumors demonstrated a suggestive cecum-to-sigmoid trend for worse survival (P trend  = 0.020; the corresponding HR, 2.13; 95% CI 1.15-3.92). The prognostic association of colon tumor location also differed by CIMP status (P interaction  = 0.003) but not significantly by age, stage, or other features. Furthermore, MSI-high status was a favorable prognostic indicator in all stages., Conclusions: Both detailed colonic location and tumor molecular features need to be accounted for colon cancer prognostication to advance precision medicine. Our study indicates the important role of large-scale studies to robustly examine detailed colonic subsites in molecular oncology research., (© 2023. Japanese Society of Gastroenterology.)

According to an estimate, 20% of patients with heart valve disease have multivalve involvement necessitating combined valve surgery. There is a dearth of data about the clinical outcomes of patients with combined mitral and tricuspid valve disease who go through tricuspid valve surgery with concomitant mitral valve replacement or repair. We utilized National Inpatient Sample (NIS) between January 1, 2004, and December 31, 2014, to analyze the outcomes of patients who underwent tricuspid valve surgery with either mitral valve replacement or repair. We identified 21,141 weighted hospitalizations for combined TVS with MVr (TVS/MVr) or TVS with MVR (TVS/MVR). The overall inpatient mortality in the TVS/MVR cohort was higher than in the TVS/MVr cohort (7.36% vs 5.33%, P < 0.01). There was a trend toward decreased mortality over the years in the TVS/MVr cohort (P = 0.04) while mortality remained unchanged in the TVS/MVR cohort (P = 0.88). Overall, the TVS/MVr cohort had better clinical outcomes profile compared with TVS/MVR cohort., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Despite increased female representation in medical training, women physicians continue to be under-represented in academic cardiology, particularly in senior roles of authorship and leadership. We analyzed the top 20 most-cited cardiology journals (31,540 total articles) between January 1, 2018 and October 31, 2021 for gender distribution of editorial staff and authorship. Our data demonstrated that only 27% of articles had women as first authors and 20% as senior authors. Women constituted 23% of editorial staff. There is a statistically significant negative correlation (R = 0.67, P = 0.0011) between the percentage of women as first authors and the percentage of men on editorial boards. Overall, female authorship increased from 26% first and 19% senior authors in 2018, to 29% first and 22% senior authors in 2021. Women authors are significantly under-represented in academic cardiology publications, and additional work is needed to identify and address barriers to publishing and academic advancement for women in cardiology., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Obesity is an established risk factor for colorectal cancer (CRC), but the evidence for the association is inconsistent across molecular subtypes of the disease., Methods: We pooled data on body mass index (BMI), tumor microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, and Jass classification types for 11 872 CRC cases and 11 013 controls from 11 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusted for covariables., Results: Higher BMI was associated with increased CRC risk (OR per 5 kg/m2 = 1.18, 95% CI = 1.15 to 1.22). The positive association was stronger for men than women but similar across tumor subtypes defined by individual molecular markers. In analyses by Jass type, higher BMI was associated with elevated CRC risk for types 1-4 cases but not for type 5 CRC cases (considered familial-like/Lynch syndrome microsatellite instability-H, CpG island methylator phenotype-low or negative, BRAF-wild type, KRAS-wild type, OR = 1.04, 95% CI = 0.90 to 1.20). This pattern of associations for BMI and Jass types was consistent by sex and design of contributing studies (cohort or case-control)., Conclusions: In contrast to previous reports with fewer study participants, we found limited evidence of heterogeneity for the association between BMI and CRC risk according to molecular subtype, suggesting that obesity influences nearly all major pathways involved in colorectal carcinogenesis. The null association observed for the Jass type 5 suggests that BMI is not a risk factor for the development of CRC for individuals with Lynch syndrome., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Acute pancreatitis can rarely present with electrocardiographic changes that imitate myocardial ischemia. Even rarer is for acute pancreatitis to present with ST segment elevation in contiguous leads, suggestive of an acute coronary syndrome. In this comprehensive review article, we highlight diagnostic challenges and examine possible pathophysiological causes as seen through 34 total cases in which acute pancreatitis has been found to mimic an acute myocardial infarction., Summary: It has been shown that regardless of the severity of acute pancreatitis, it can be associated with myocardial injury of varying presentation. Thus far, there have been 34 total cases where acute pancreatitis presented with electrocardiographic changes consistent with acute myocardial infarction without true coronary artery thrombosis. An inferior wall ST-elevation myocardial infarction pattern was the most frequently demonstrated. Many hypotheses have been proposed as to the mechanism of injury including decreased coronary perfusion, direct myocyte damage by pancreatic proteolytic enzymes, indirect parasympathetic injury, electrolyte derangements, and coronary vasospasms. Given the complexity of the clinical presentation, thorough subjective and objective evaluation can be vital in guiding to diagnosis and possibly more invasive testing., Key Messages: It is imperative that clinicians are aware that acute pancreatitis can mimic an acute myocardial infarction. Although we have started to better understand the pathological mechanisms for this phenomenon, further research focused on specific molecular target areas is needed., (© 2023 S. Karger AG, Basel.)

University of Karbala College of Medicine (UKCM), Iraq, conducted a three days' workshop on Medical Education and medical writing. The UKCM is now transforming to conform with the latest trends of modern education. This will help to re-shape the future of medical education and produce capable doctors. This requires a strong faculty, which is sound in teaching, training, learning improvement, research capacity building, and leadership development. The capacity building of faculty at UKCM has been initiated in collaboration with Medics International at a local and government level and includes a series of workshops and online symposia. This educational activity was conducted after a delay of three years due to COVID-19. A three -day refresher course was conducted in the first week of August, 2022. Medical writing is another important feature which has been continuously covered by UKMM since many years with the collaboration of Al-Sadiq International Virtual University (SIVU) and Imamia Medics International (IM).

Approximately 25% of patients with staphylococcus aureus bacteremia (SAB) develop infective endocarditis (IE), which has a consequent mortality of 25-46%. Current guidelines recommend routine transthoracic echocardiography (TTE) for patients with SAB; transesophageal echocardiogram (TEE) is reserved for those in whom initial TTE is negative and clinical suspicion for IE remains high. We sought to elucidate high risk features of SAB associated with the development of IE that warrant a TEE after a negative TTE. This retrospective study included 213 patients who were diagnosed with SAB at the University of New Mexico Hospital between 2010-2020. A pre-determined list of clinical risk factors along with TTE and TEE status was extracted from the electronic medical record. The primary outcome was development of IE in patients with SAB. Multivariate logistic regression analysis was used to identify clinical risk factors for IE. Moreover, sensitivity and specificity of TTE and TEE was calculated. Out of 213 patients with SAB, 68 patients met diagnostic criteria for IE. Most patients (n = 209) underwent TTE and 171 patients underwent subsequent TEE. The overall sensitivity of TTE was 63% and overall sensitivity of TEE was 88%. Multivariate analysis showed significantly increased risk of IE in patients who had implanted permanent pacemaker (aOR 32.3, CI 5.23 - 281, p < 0.001) and persistent fever (aOR 6.97, CI 2.42 - 21.0 P < 0.001). Based on our analysis, we recommend that TEE should be strongly considered after negative TTE in SAB patients with intracardiac prosthetics or persistent fever despite appropriate antibiotic therapy., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Hospital readmissions post-acute myocardial infarctions (AMIs) are associated with adverse cardiovascular outcomes and also incur huge healthcare costs. Patients with systemic lupus erythematosus (SLE) are at an increased risk of AMI likely due to multifactorial mechanisms including higher levels of inflammation and accelerated atherosclerosis. We investigated if patients with SLE are at higher risk of hospital readmissions post-AMI compared to the patients without SLE. Furthermore, we sought to assess if inpatient outcomes of AMI in SLE patients are different than AMI without SLE. We conducted a retrospective analysis of adult hospital discharges with the principal diagnosis of AMI using the Nationwide Readmissions Database in 2018. We used the International Classification of Diseases, Tenth Revision, Clinical Modification/Procedure Coding System (ICD-10-CM/PCS) to identify comorbid conditions. The primary outcome was all-cause 30-day readmission. Secondary outcomes were cardiac procedures at index hospitalization (percutaneous coronary intervention [PCI] and coronary artery bypass grafting [CABG]), and adverse events at index hospitalization, including inpatient mortality, cardiac arrest, cardiogenic shock, cardiac assist device, coronary artery dissection, acute kidney injury, gastrointestinal bleeding, stroke, post-procedural hemorrhage, sepsis, and hospital costs. Complex samples multivariable logistic regression models were used to determine the association of SLE with outcomes. The patients with AMI and SLE had a higher 30-day readmission rate (15.5% vs 12.5%, aOR = 1.33, CI 1.12-1.57, P = 0.001), and inpatient mortality (aOR = 1.40 CI 1.1-1.79, P = 0.006) compared to the AMI without SLE cohort. The rates of acute kidney injury (aOR = 1.41 CI 1.21-1.64, P < 0.0001) and sepsis (aOR = 1.61 CI 1.16-2.23, P = 0.004) were higher among AMI with SLE group as compared to AMI without SLE group. Within the AMI with SLE cohort, the independent predictors of readmission were diabetes mellitus (aOR = 1.38 CI 0.99-1.91, P = 0.054), peripheral vascular disease (aOR = 2.10 CI 1.22-3.62, P = 0.007), anemia (aOR = 1.50 CI 1.07-2.11, P = 0.019), end-stage renal disease (aOR = 1.91 CI 1.10-3.31, P = 0.021), and congestive heart failure (aOR = 1.55 CI 1.12-2.16, P = 0.009). The length of stay in days during index hospitalization (5.10 vs 4.67) was similar in both cohorts. In the multivariable-adjusted regression model, no statistically significant differences were noted between the AMI with SLE and AMI without SLE cohorts for most inpatient adverse events during the index hospitalization. Patients with AMI and SLE had higher inpatient mortality during the index hospitalization and higher 30-day hospital readmissions compared to AMI patients without SLE. There were no significant differences in most of the other major inpatient outcomes between the 2 cohorts., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Patients with left ventricular assist device (LVAD) often develop aortic insufficiency requiring an intervention on the aortic valve. We sought to analyze the outcomes of patients with a history of LVAD who underwent either transcatheter aortic valve replacement or surgical aortic valve replacement. The Nationwide Readmission Database was used to extract relevant patient information from January 1, 2016, to December 31, 2018. The Nationwide Readmission Database is a nationally representative sample of all-payer discharges from United States nonfederal hospitals. The primary outcome of interest was in-hospital mortality. Secondary outcomes included length of stay, clinical outcomes, costs, and 30-day all-cause readmissions. Complex samples multivariable logistic and linear regression models were used to determine the association of procedure type with outcomes. Among 148 hospitalizations with a history of LVAD, 87 underwent transcatheter aortic valve replacement (TAVR), and 61 underwent surgical aortic valve replacement (SAVR). The inpatient mortality in SAVR group was numerically higher compared to the TAVR cohort, however, it did not reach statistical significance. The use of invasive mechanical ventilation, and rates of cardiogenic shock, bleeding, and vascular complications were higher in the SAVR cohort compared to the TAVR cohort. The mean length of stay and costs were higher in the SAVR cohort compared to the TAVR cohort. The 30-day all-cause readmission rate was numerically higher in the SAVR group but not statistically significant. TAVR in patients with LVAD may be a viable treatment option for patients with AI with potential for better inpatient mortality and inpatient outcomes compared to patients who undergo SAVR in appropriately selected patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Size-based assessments are inaccurate indicators of tumor response in soft-tissue sarcoma (STS), motivating the requirement for new response imaging biomarkers for this rare and heterogeneous disease. In this study, we assess the test-retest repeatability of radiomic features from MR diffusion-weighted imaging (DWI) and derived maps of apparent diffusion coefficient (ADC) in retroperitoneal STS and compare baseline repeatability with changes in radiomic features following radiotherapy (RT)., Materials and Methods: Thirty patients with retroperitoneal STS received an MR examination prior to treatment, of whom 23/30 were investigated in our repeatability analysis having received repeat baseline examinations and 14/30 patients were investigated in our post-treatment analysis having received an MR examination after completing pre-operative RT. One hundred and seven radiomic features were extracted from the full manually delineated tumor region using PyRadiomics. Test-retest repeatability was assessed using an intraclass correlation coefficient (baseline ICC), and post-radiotherapy variance analysis (post-RT-IMS) was used to compare the change in radiomic feature value to baseline repeatability., Results: For the ADC maps and DWI images, 101 and 102 features demonstrated good baseline repeatability (baseline ICC > 0.85), respectively. Forty-three and 2 features demonstrated both good baseline repeatability and a high post-RT-IMS (>0.85), respectively. Pearson correlation between the baseline ICC and post-RT-IMS was weak (0.432 and 0.133, respectively)., Conclusions: The ADC-based radiomic analysis shows better test-retest repeatability compared with features derived from DWI images in STS, and some of these features are sensitive to post-treatment change. However, good repeatability at baseline does not imply sensitivity to post-treatment change., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Thrussell, Winfield, Orton, Miah, Zaidi, Arthur, Thway, Strauss, Collins, Koh, Oelfke, Huang, O’Connor, Messiou and Blackledge.)

Colorectal cancer (CRC) is a heterogeneous disease with evidence of distinct tumor types that develop through different somatically altered pathways. To better understand the impact of the host genome on somatically mutated genes and pathways, we assessed associations of germline variations with somatic events via two complementary approaches. We first analyzed the association between individual germline genetic variants and the presence of non-silent somatic mutations in genes in 1375 CRC cases with genome-wide SNPs data and a tumor sequencing panel targeting 205 genes. In the second analysis, we tested if germline variants located within previously identified regions of somatic allelic imbalance were associated with overall CRC risk using summary statistics from a recent large scale GWAS (n≃125 k CRC cases and controls). The first analysis revealed that a variant (rs78963230) located within a CNA region associated with TLR3 was also associated with a non-silent mutation within gene FBXW7. In the secondary analysis, the variant rs2302274 located in CDX1/PDGFRB frequently gained/lost in colorectal tumors was associated with overall CRC risk (OR = 0.96, p = 7.50e-7). In summary, we demonstrate that an integrative analysis of somatic and germline variation can lead to new insights about CRC., (© 2022. The Author(s).)

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 × 10 -23 and p = 6 × 10 -11 , respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers., (© 2022. The Author(s).)

Objective: Genome sequencing (GS >30x) is beginning to be adopted as a comprehensive genome-wide test for the diagnosis of rare disease in the post-natal setting. Recent studies demonstrated the utility of exome sequencing (ES) in prenatal diagnosis, we investigate the potential benefits for GS to act as a comprehensive prenatal test for diagnosis of fetal abnormalities., Methods: We performed GS on a prospective cohort of 37 singleton fetuses with ultrasound-identified structural abnormalities undergoing invasive prenatal testing. GS was performed in parallel with standard diagnostic testing, and the prioritized variants were classified according to ACMG guidelines and reviewed by a panel of board-certified laboratory and clinical geneticists., Results: Diagnostic sequence variants were identified in 5 fetuses (14%), with pathogenic variants found in NIPBL, FOXF1, RERE, AMMECR1, and FLT4. A further 7 fetuses (19%) had variants of uncertain significance (VUS) that may explain the phenotypes. Importantly, GS also identified all pathogenic variants reported by clinical microarray (2 CNVs, 5%)., Conclusion: Prenatal GS offered diagnoses (sequence variants and CNVs) in 19% of fetuses with structural anomalies. GS has the potential of replacing multiple consecutive tests, including microarray, gene panels, and WES, to provide the most comprehensive analysis in a timely manner necessary for prenatal diagnosis., (© 2022 John Wiley & Sons Ltd.)

Background: Colorectal cancer has a strong epigenetic component that is accompanied by frequent DNA methylation (DNAm) alterations in addition to heritable genetic risk. It is of interest to understand the interrelationship of germline genetics, DNAm, and colorectal cancer risk., Methods: We performed a genome-wide methylation quantitative trait locus (meQTL) analysis in 1,355 people, assessing the pairwise associations between genetic variants and lymphocytes methylation data. In addition, we used penalized regression with cis-genetic variants ± 1 Mb of methylation to identify genome-wide heritable DNAm. We evaluated the association of genetically predicted methylation with colorectal cancer risk based on genome-wide association studies (GWAS) of over 125,000 cases and controls using the multivariate sMiST as well as univariately via examination of marginal association with colorectal cancer risk., Results: Of the 142 known colorectal cancer GWAS loci, 47 were identified as meQTLs. We identified four novel colorectal cancer-associated loci (NID2, ATXN10, KLHDC10, and CEP41) that reside over 1 Mb outside of known colorectal cancer loci and 10 secondary signals within 1 Mb of known loci., Conclusions: Leveraging information of DNAm regulation into genetic association of colorectal cancer risk reveals novel pathways in colorectal cancer tumorigenesis. Our summary statistics-based framework sMiST provides a powerful approach by combining information from the effect through methylation and residual direct effects of the meQTLs on disease risk. Further validation and functional follow-up of these novel pathways are needed., Impact: Using genotype, DNAm, and GWAS, we identified four new colorectal cancer risk loci. We studied the landscape of genetic regulation of DNAm via single-SNP and multi-SNP meQTL analyses., (©2022 American Association for Cancer Research.)