The impact of primary-care led, faecal immunochemical test-based, triage of new-onset colorectal symptoms on time to diagnosis of colorectal cancer-An observational study.

AIM: Since December 2015, a faecal immunochemical test (FIT) has been provided to primary care in NHS Tayside as an adjunct to clinical acumen in the assessment of new-onset bowel symptoms. The aim of this work was to assess the impact of this approach on time to diagnosis of colorectal cancer (CRC). METHOD: NHS Tayside Cancer audit data from January 2013 to December 2019 were reviewed to identify all CRC patients diagnosed via the primary-care referral pathway for a period before and after the introduction of FIT. Their electronic patient records were accessed and date of referral and any contemporaneous FIT and full blood count (FBC) result were recorded. Time from referral to diagnosis of CRC was calculated for each patient and compared between subgroups. RESULTS: The study cohort consisted of 959 patients: 378 and 581 from the time periods before and after the introduction of FIT, respectively. The median time to diagnosis before FIT was 30 days [interquartile range (IQR) 16-57 days] versus 25 days (IQR 14-47 days) following the introduction of FIT (p = 0.006). Following the introduction of FIT, patients who completed a FIT had a median of time to diagnosis of 23 days (IQR 14-43 days) compared with 30 days (IQR 16-62 days) for patients not completing a FIT (p = 0.019). FBC results were available for 97.5% of FIT patients to aid safety-netting of patients with a low or undetectable faecal haemoglobin concentration. CONCLUSION: The introduction of FIT-based triage of new bowel symptoms in primary care as an adjunct to clinical acumen is associated with a reduced time to CRC diagnosis.

Scoping review of qualitative studies on family planning in Uganda.

Family planning (FP) is an essential component of public health programs and significantly impacts maternal and child health outcomes. In Uganda, there is a need for a comprehensive review of the existing literature on FP to inform future research and programmatic efforts. This scoping review aims to identify factors shaping the use of FP in Uganda. We conducted a systematic search of eight scholarly databases, for qualitative studies on FP in Uganda. We screened the titles and abstracts of identified articles published between 2002-2023 and assessed their eligibility based on predefined criteria. We extracted data from the 71 eligible studies and synthesized the findings using thematic analysis and the Ecological Systems Theory (EST) individual, interpersonal, community, institutional, and policy-level determinants. Findings reveal the interplay of factors at different socio-ecological levels influencing family planning decisions. At the individual level, the most common determinants related to the EST were knowledge and attitudes of FP. Interpersonal dynamics, including partner communication and social support networks, played pivotal roles. Community-level factors, such as cultural norms and accessibility of services, significantly influenced family planning practices. Institutional and policy-level factors, particularly a healthcare system's quality and policies, also shaped use. Other themes included the intersection of HIV/AIDS on FP practice and Ugandan views of comprehensive abortion care. This scoping review underscores the intricate socio-ecological fabric shaping FP in Uganda. The findings highlight the need for targeted interventions to increase knowledge and awareness of FP, improve access to services, and address social and cultural norms that discourage contraceptive use. Policymakers and program implementers should also consider gender dynamics and power imbalances in FP programs to ensure they are equitable and effective.

The impact of libraries and informationists on patient and population care: a mixed-methods study.

Objective: While several studies have examined the effectiveness of librarian interactions with clinicians and impact of librarians on patient care, no studies have explored a library's effects on population care. The goal of this study was to investigate the library's impact on both patient and population care. Methods: Using a sequential exploratory mixed-methods design, we first interviewed a small set of clinicians and researchers active in patient and population care. Based on the themes that we discovered through coding the interviews, we created a survey that was sent to faculty in the health sciences and the health system. Results: We collected data from a representative sample of our population. We discovered that all respondents value the library and informationists, using our services most for teaching, publishing, presenting, and professional development. Conclusion: We now have data to support our value to our population and to show where we can do more work to improve the use of our services. Our study shows the value of doing a mixed-methods sequential exploration in which themes that are important to our user community were identified prior to launching a large-scale survey.

The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

Karyomegalic interstitial nephritis, a fascinating histopathologic entity for pathologists: Be watchful of the FAN1 gene mutations.

ABSTRACT: Karyomegalic interstitial nephritis (KIN) is an uncommon autosomal recessive disease, which is characterized by enlarged and hyperchromatic nuclei of the renal tubular epithelial cells. It is associated with mutations in Fanconi anemia-associated nuclease 1 gene, which is responsible for DNA repair, and these pathogenic mutations are responsible for progressive renal failure in young adults. We present a case of a 29-year-old female with end-stage renal disease who had a family history of early-onset renal failure in two of the siblings. Her elder sister with chronic kidney disease stage III was advised to be biopsied to look for any familial causes. Stained sections of renal biopsy revealed normal glomeruli. Tubular epithelial cells showed nuclear changes focally like hyperchromasia, karyomegaly, and anisonucleosis. On direct immunofluorescence, all glomeruli were negative for deposits with all antisera. Based on these findings, a final opinion of KIN was given.

A Case Series on a Rare Clinical Presentation of Lichen Planopilaris Restricted to the Face.

Lichen planopilaris (LPP) restricted to the face is extremely rare. This case series includes five unique LPP cases that presented with a varied degree of pigmentation and scarring alopecia restricted to the face. We herein describe the clinical characteristics, dermoscopy, and treatment of these histopathologically confirmed facial LPP cases. None of them had lesions anywhere else on the body.

Hippo and PI5P4K signaling intersect to control the transcriptional activation of YAP.

Phosphoinositides are essential signaling molecules. The PI5P4K family of phosphoinositide kinases and their substrates and products, PI5P and PI4,5P2, respectively, are emerging as intracellular metabolic and stress sensors. We performed an unbiased screen to investigate the signals that these kinases relay and the specific upstream regulators controlling this signaling node. We found that the core Hippo pathway kinases MST1/2 phosphorylated PI5P4Ks and inhibited their signaling in vitro and in cells. We further showed that PI5P4K activity regulated several Hippo- and YAP-related phenotypes, specifically decreasing the interaction between the key Hippo proteins MOB1 and LATS and stimulating the YAP-mediated genetic program governing epithelial-to-mesenchymal transition. Mechanistically, we showed that PI5P interacted with MOB1 and enhanced its interaction with LATS, thereby providing a signaling connection between the Hippo pathway and PI5P4Ks. These findings reveal how these two important evolutionarily conserved signaling pathways are integrated to regulate metazoan development and human disease.

Strongyloides stercoralis infection masquerading as malignant ascites in a case of angiosarcoma.

ABSTRACT: Strongyloides stercoralis is a parasitic nematode that infects millions of people worldwide. It primarily infects humans but can also be found in domestic animals and primates. The severity of infection varies from asymptomatic to life-threatening complications. We present a case of a 56-year-old male with a known case of angiosarcoma liver with massive ascites and low-grade fever. He was clinically diagnosed as having malignant ascites and was planned for chemotherapy. During therapeutic cum diagnostic ascitic tap, cell block sections revealed the presence of cross sections of nematode S. stercoralis gravid uterus with eggs. Later, stool for ova and cysts also revealed multiple larval forms of the nematode. S. stercoralis hyperinfection is often accompanied by sepsis or meningitis with enteric organisms. Patient was started on tab. ivermectin 12 mg once a day for two days (in the standard dosage of 200 mcg/kg) was then repeated in the same dosage for another two days after two weeks, and gradually the ascites settled. Post-treatment ascitic tap cell block preparations did not show any parasites. Patient has been on follow-up for 6 months, and he remains asymptomatic.

Impact of chronic obstructive pulmonary disease on right ventricular function and remodeling after aortic valve replacement.

BACKGROUND: Both chronic obstructive pulmonary disease (COPD) and right ventricular (RV) dysfunction are common factors that have been associated with poor prognosis after aortic valve replacement (AVR). Since there is still uncertainty about the impact of COPD on RV function and dilatation in patients undergoing AVR, we sought to explore RV function and remodeling in the presence and absence of COPD as well as their prognostic implications. METHODS: Patients who received surgical or transcatheter AVR due to severe AS were screened for COPD. Demographic and clinical data were collected at baseline while echocardiographic measurements were performed at baseline and 1 year after AVR. The study end-point was all-cause mortality. RESULTS: In total 275 patients were included, with 90 (33%) patients having COPD. At 1-year follow-up, mild worsening of tricuspid annular planar systolic excursion and RV dilatation were observed in patients without COPD, while there were significant improvements in RV longitudinal strain, RV wall thickness but dilatation of RV outflow tract distal dimension in the COPD group compared to the baseline. On multivariable analysis, the presence of COPD provided significant incremental prognostic value over RV dysfunction and remodeling. CONCLUSIONS: At 1-year after AVR, RV function and dimensions mildly deteriorated in non-COPD group whereas COPD group received significant benefit of AVR in terms of RV function and hypertrophy. COPD was independently associated with >2-fold all-cause mortality and had incremental prognostic value over RV dysfunction and remodeling.

Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis.

The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.

Molecular biomarkers for vascular cognitive impairment and dementia.

As disease-specific interventions for dementia are being developed, the ability to identify the underlying pathology and dementia subtypes is increasingly important. Vascular cognitive impairment and dementia (VCID) is the second most common cause of dementia after Alzheimer disease, but progress in identifying molecular biomarkers for accurate diagnosis of VCID has been relatively limited. In this Review, we examine the roles of large and small vessel disease in VCID, considering the underlying pathophysiological processes that lead to vascular brain injury, including atherosclerosis, arteriolosclerosis, ischaemic injury, haemorrhage, hypoperfusion, endothelial dysfunction, blood-brain barrier breakdown, inflammation, oxidative stress, hypoxia, and neuronal and glial degeneration. We consider the key molecules in these processes, including proteins and peptides, metabolites, lipids and circulating RNA, and consider their potential as molecular biomarkers alone and in combination. We also discuss the challenges in translating the promise of these biomarkers into clinical application.

Airway Epithelial-Derived Immune Mediators in COVID-19.

The airway epithelium, which lines the conducting airways, is central to the defense of the lungs against inhaled particulate matter and pathogens such as SARS-CoV-2, the virus that causes COVID-19. Recognition of pathogens results in the activation of an innate and intermediate immune response which involves the release of cytokines and chemokines by the airway epithelium. This response can inhibit further viral invasion and influence adaptive immunity. However, severe COVID-19 is characterized by a hyper-inflammatory response which can give rise to clinical presentations including lung injury and lead to acute respiratory distress syndrome, viral pneumonia, coagulopathy, and multi-system organ failure. In response to SARS-CoV-2 infection, the airway epithelium can mount a maladaptive immune response which can delay viral clearance, perpetuate excessive inflammation, and contribute to the pathogenesis of severe COVID-19. In this article, we will review the barrier and immune functions of the airway epithelium, how SARS-CoV-2 can interact with the epithelium, and epithelial-derived cytokines and chemokines and their roles in COVID-19 and as biomarkers. Finally, we will discuss these immune mediators and their potential as therapeutic targets in COVID-19.

Transforming growth factor-ß1 and SMAD signalling pathway in the small airways of smokers and patients with COPD: potential role in driving fibrotic type-2 epithelial mesenchymal transition.

Background: COPD is a common disease characterized by respiratory airflow obstruction. TGF-ß1 and SMAD pathway is believed to play a role in COPD pathogenesis by driving epithelial mesenchymal transition (EMT). Methods: We investigated TGF-ß1 signalling and pSmad2/3 and Smad7 activity in resected small airway tissue from patients with; normal lung function and a smoking history (NLFS), current smokers and ex-smokers with COPD GOLD stage 1 and 2 (COPD-CS and COPD-ES) and compared these with normal non-smoking controls (NC). Using immunohistochemistry, we measured activity for these markers in the epithelium, basal epithelium, and reticular basement membrane (RBM). Tissue was also stained for EMT markers E-cadherin, S100A4 and vimentin. Results: The Staining of pSMAD2/3 was significantly increased in the epithelium, and RBM of all COPD groups compared to NC (p <0.0005). There was a less significant increase in COPD-ES basal cell numbers compared to NC (p= 0.02). SMAD7 staining showed a similar pattern (p <0.0001). All COPD group levels of TGF-ß1 in the epithelium, basal cells, and RBM cells were significantly lower than NC (p <0.0001). Ratio analysis showed a disproportionate increase in SMAD7 levels compared to pSMAD2/3 in NLFS, COPD-CS and COPD-ES. pSMAD negatively correlated with small airway calibre (FEF25-75%; p= 0.03 r= -0.36). EMT markers were active in the small airway epithelium of all the pathological groups compared to patients with COPD. Conclusion: Activation of the SMAD pathway via pSMAD2/3 is triggered by smoking and active in patients with mild to moderate COPD. These changes correlated to decline in lung function. Activation of the SMADs in the small airways is independent of TGF-ß1, suggesting factors other than TGF-ß1 are driving these pathways. These factors may have implications for small airway pathology in smokers and COPD through the process of EMT, however more mechanistic work is needed to prove these correlations.

Rationalizing the Use of COVID-19 Questionable Efficacy Drugs in a Low Middle-income Country: A Hospital Tocilizumab Committee Experience.

BACKGROUND: Only corticosteroids have confirmed mortality benefits in coronavirus disease of 2019 (COVID-19). Rational use of costlier drugs with questionable benefits poses a great concern to hospital pharmacies in low middle-income countriesAim: The present study aimed to assess the rational utilization of hospital supply tocilizumab and understand its clinical benefits in hospitalized COVID-19 pneumonia patientsMethods: The Hospital Tocilizumab Committee (HTC) decision support system framework was developed to make patients eligible or ineligible for tocilizumab procurement from the hospital pharmacy. A total of 33 consecutive patients receiving tocilizumab were analyzed retrospectively in the 3-month study period. The records of the inpatient stay of the patients were observed for pulse, blood pressure, respiratory rate (RR), oxygen saturation (SpO2), fraction of inspired oxygen (FiO2) laboratory work-up, hospital stay duration, and mortality benefit, if any. Patients were analyzed as "died," "survived," and "composite" subgroupsResults: The study observed death as a final outcome in 48% of patients. The study observed a significant effect of tocilizumab on C-reactive protein (CRP) (p = 0.02) and ferritin (p = 0.018) levels on a 10-day follow-up when all patients were analyzed together. Rising and declining trends of RR and FiO2 were observed among the "died" (RR, p = 0.02; FiO2, p = 0.03) and survived (RR, p = 0.03; FiO2, p = 0.05) subgroups. The second dose of tocilizumab was received by 88% of survivors as against 50% of patients who died (p = 0.04)Conclusion: Hospital Tocilizumab Committee (HTC) was successfully established to continue the assessment of the costlier drug with uncertain treatment benefits. A repeat dose of tocilizumab may provide a mortality benefit in Asian Indians.

Changes in Computed-Tomography-Derived Segmental Left Ventricular Longitudinal Strain After Transcatheter Aortic Valve Implantation.

Patients with severe aortic stenosis (AS) may show left ventricular (LV) apical longitudinal strain sparing. Transcatheter aortic valve implantation (TAVI) improves LV systolic function in patients with severe AS. However, the changes in regional longitudinal strain after TAVI have not been extensively evaluated. This study aimed to characterize the effect of the pressure overload relief after TAVI on LV apical longitudinal strain sparing. A total of 156 patients (mean age 80 ± 7 years, 53% men) with severe AS who underwent computed tomography before and within 1 year after TAVI (mean time to follow-up 50 ± 30 days) were included. LV global and segmental longitudinal strain were assessed using feature tracking computed tomography. LV apical longitudinal strain sparing was evaluated as the ratio between the apical and midbasal longitudinal strain and was defined as an LV apical to midbasal longitudinal strain ratio >1. LV apical longitudinal strain remained stable after TAVI (from 19.5 ± 7.2% to 18.7 ± 7.7%, p = 0.20), whereas LV midbasal longitudinal strain showed a significant increase (from 12.9 ± 4.2% to 14.2 ± 4.0%, p ≤0.001). Before TAVI, 88% of the patients presented with LV apical strain ratio >1% and 19% presented with an LV apical strain ratio >2. After TAVI, these percentages significantly decreased to 77% and 5% (p = 0.009, p ≤0.001), respectively. In conclusion, LV apical sparing of strain is a relatively common finding in patients with severe AS who underwent TAVI and its prevalence decreases after the afterload relief after TAVI.

Contact time and disinfectant formulation significantly impact the efficacies of disinfectant towelettes against Candida auris on hard, non-porous surfaces.

There has been an increase in Candida auris healthcare-associated infections, which result from cross-contamination from surfaces and equipment. In this study, we tested the efficacies of EPA-registered disinfectant towelettes products that are increasingly used for infection control against C. auris at a range of contact times following modifications to standard EPA protocol MB-33-00. Hydrogen peroxide (HP)-based disinfectant towelettes were more efficacious against C. auris than the quaternary ammonium chloride (QAC)-alcohol-based disinfectant towelettes irrespective of tested contact times. Thirty s contact time was significantly less effective in reducing C. auris compared to 1-, 2-, 3-, and 10-min contact times. However, there were no statistically significant differences in the level of disinfection among 1-min and longer contact times regardless of product chemistry. None of the products achieved a standard six-log10 reduction at any tested contact times. Overall, the HP-based disinfectant towelette was significantly more fungicidal than the QAC-alcohol-based disinfectant towelette. For all product types, 30 s contact time did not achieve the same level of disinfection as 1-min or longer contact times. Overall, disinfectant towelette efficacy is dependent upon product formulation and contact time.

Scoping review of qualitative studies investigating reproductive health knowledge, attitudes, and practices among men and women across Rwanda.

BACKGROUND: Research efforts in Rwanda to improve sexual and reproductive health and rights (SRHR) are increasing; however, comprehensive literature reviews on SRHR are limited. This scoping review examines individual and contextual factors shaping knowledge, attitudes, and practices in the domains of: 1) family planning, 2) abortion care, and 3) other SRHR in Rwanda. Recognizing that individual, community, and societal factors influence RH, this review is guided by Bronfenbrenner's Ecological Systems Theory. METHODS: Eligible studies were conducted in Rwanda, included males and/or females of any age, and were published within the past 20 years. Studies reporting views of only healthcare or other professionals were excluded. RESULTS: Thirty-six studies were included. The majority addressed individual and contextual considerations. At the individual level, studies explored knowledge about SRHR problems while at the interpersonal level, the support and attitudes of men and community members for adolescent SRHR were investigated. In terms of healthcare organization, maternal health practices, increased access to family planning programs, and the need for sexually transmitted infection programs was explored. At the social and cultural level, researchers investigated beliefs and traditional gender roles. Regarding public health policy, studies mentioned promoting and increasing funding for SRHR and reducing gender inequities. CONCLUSION: Our findings can inform SRHR research programs, public health campaigns, and policy advances in Rwanda.

PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition.

Phosphatidylinositol (PI)regulating enzymes are frequently altered in cancer and have become a focus for drug development. Here, we explore the phosphatidylinositol-5-phosphate 4-kinases (PI5P4K), a family of lipid kinases that regulate pools of intracellular PI, and demonstrate that the PI5P4Kα isoform influences androgen receptor (AR) signaling, which supports prostate cancer (PCa) cell survival. The regulation of PI becomes increasingly important in the setting of metabolic stress adaptation of PCa during androgen deprivation (AD), as we show that AD influences PI abundance and enhances intracellular pools of PI-4,5-P2. We suggest that this PI5P4Kα-AR relationship is mitigated through mTORC1 dysregulation and show that PI5P4Kα colocalizes to the lysosome, the intracellular site of mTORC1 complex activation. Notably, this relationship becomes prominent in mouse prostate tissue following surgical castration. Finally, multiple PCa cell models demonstrate marked survival vulnerability following stable PI5P4Kα inhibition. These results nominate PI5P4Kα as a target to disrupt PCa metabolic adaptation to castrate resistance.