Landslide hazard cascades can trigger earthquakes.

While earthquakes are well-known to trigger surface hazards and initiate hazard cascades, whether surface hazards can instead trigger earthquakes remains underexplored. In 2018, two landslides on the Tibetan plateau created landslide-dammed lakes which subsequently breached and caused catastrophic outburst floods. Here we build an earthquake catalog using machine-learning and cross-correlation-based methods which shows there was a statistically significant increase in earthquake activity (local magnitude ≤ 2.6) as the landslide-dammed lake approached peak water level which returned to the background level after dam breach. We further find that ~90% of the seismicity occurred where Coulomb stress increased due to the combined effect of direct loading and pore pressure diffusion. The close spatial and temporal correlation between the calculated Coulomb stress increase and earthquake activity suggests that the earthquakes were triggered by these landslide hazard cascades. Finally, our Coulomb stress modeling considering the properties of landslide-dammed lakes and reservoir-induced earthquakes globally suggests that earthquake triggering by landslide-dammed lakes and similar structures may be a ubiquitous phenomenon. Therefore, we propose that earthquake-surface hazard interaction can include bidirectional triggering which should be properly accounted for during geological hazard assessment and management in mountainous regions.

Diet, lifestyle and gut microbiota composition among Malaysian women with gestational diabetes mellitus: a prospective cohort study.

The study addressed a significant gap in the profiling and understanding of the gut microbiota's influence on Malaysian Malay women with gestational diabetes mellitus (GDM). This prospective cohort study aimed to explore the intricate relationship between gut microbiota, dietary choices, and lifestyle factors among Malay women, both with and without GDM. The research specifically focused on participants during the second (T0) and third (T1) trimesters of pregnancy in Johor Bahru, Malaysia. In Part 1 of the study, a diverse pool of pregnant women at T0 was categorized into two groups: those diagnosed with GDM and those without GDM, with a total sample size of 105 individuals. The assessments encompassed demographic, clinical, lifestyle, and dietary factors at the T0 and T1 trimesters. Part 2 of the study delved into microbiome analysis, targeting a better understanding of the gut microbiota among the participants. Stool samples were randomly collected from 50% of the individuals in each group (GDM and non-GDM) at T0 and T1. The collected samples underwent processing, and 16s rRNA metagenomic analysis was employed to study the microbial composition. The results suggested an association between elevated body weight and glucose levels, poor sleep quality, lack of physical activity, greater intake of iron and meat, and reduced fruit consumption among women with GDM compared to non-GDM groups. The microbiome analysis revealed changes in microbial composition over time, with reduced diversity observed in the GDM group during the third trimester. The genera Lactiplantibacillus, Parvibacter, Prevotellaceae UCG001, and Vagococcus positively correlated with physical activity levels in GDM women in the second trimester. Similarly, the genus Victivallis exhibited a strong positive correlation with gravida and parity. On the contrary, the genus Bacteroides and Roseburia showed a negative correlation with omega-3 polyunsaturated fatty acids (PUFAs) in women without GDM in the third trimester. The study highlighted the multifaceted nature of GDM, involving a combination of lifestyle factors, dietary choices, and changes in gut microbiota composition. The findings emphasized the importance of considering these interconnected elements in understanding and managing gestational diabetes among Malaysian Malay women. Further exploration is essential to comprehend the mechanisms underlying this relationship and develop targeted interventions for effective GDM management.

A de Novo BRCA1 Pathogenic Variant in a 29-Year-Old Woman with Triple-Negative Breast Cancer.

Introduction: Germline pathogenic variants in the BRCA1 and BRCA2 genes lead to a highly increased lifetime risk for breast and ovarian cancer. These variants are usually inherited and reports of de novo occurrences are a very rare phenomenon. Case Presentation: We report on a breast cancer patient with a de novo BRCA1 variant c.121C>T (p.His41Tyr). The pathogenic variant was detected in leukocyte DNA of a patient with negative family history who had developed early onset, triple-negative breast cancer. The variant was not found in any of the maternal and paternal tissues tested, but it was detected in multiple samples representing all three germ layers of the affected carrier, which renders somatic mosaicism unlikely. Conclusion: This case highlights the importance of including early onset of disease and triple negativity of the tumor as criteria for genetic testing, even in patients without family history. Considering the availability of effective breast cancer treatments in patients with pathogenic variants in the BRCA genes, this finding underscores the importance of genetic testing in breast cancer patients.

Before and after COVID-19 pandemic: impact on hepatobiliary and pancreatic surgical services in a Singapore Tertiary Hospital.

BACKGROUND: Reallocation of healthcare resources to prioritize the COVID-19 pandemic-related incremental healthcare needs resulted in longer waiting times for routine elective clinical services. AIMS: We aimed to analyze the effects of the pandemic on the hepatopancreatobiliary (HPB) unit's surgical workload. METHODS: The HPB unit's surgical workload for the months of January-June from 2019 to 2022 was extracted, retrospectively compared, and analyzed. This study was registered in ClinicalTrials.gov (NCT05572866) and complies with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. RESULTS: Benign elective surgeries were impacted adversely, with elective gallbladder operations decreasing by 45.2% (146 in 2019 vs 80 in 2020, p = 0.89) before slowly increasing to 120 cases in 2021 and rebounding to 179 cases in 2022 (p = 0.001). Elective oncology operations paradoxically increased, with liver resections rising by 12.9% (31 in 2019 vs 35 in 2020, p = 0.002) and maintaining 37 cases in 2021 (p = 0.0337) and 34 cases in 2022 (p = 0.69). Elective pancreatic resections increased by 171.4% (7 in 2019 vs 19 in 2020, p < 0.0001) and were maintained at 15 cases in 2021 (p = 0.013) and 18 cases in 2022 (p = 0.022). The overall emergency workload decreased from 2019 (n = 198) to 2020 (n = 129) to 2021 (n = 122) before recovering to baseline in 2022 (n = 184). The month-on-month volume generally showed similar trends compared to the other years except for February 2022 and May 2021. CONCLUSION: This audit shows that despite large-scale disruption of the local healthcare system, essential surgeries can still proceed with careful resource planning by steadfast and vigilant clinical teams.

Association between IL-10 gene polymorphisms (- 1082 A/G, -819 T/C, -592 A/C) and hepatocellular carcinoma: a meta-analysis and trial sequential analysis.

BACKGROUND: The carcinogenesis of hepatocellular carcinoma is complicated, and genetic factor may have the role in the malignant transformation of liver cells. IL-10 gene polymorphisms have been investigated for their potential roles in hepatocellular carcinoma This study aimed to investigate the relationship between polymorphisms of IL-10 (-1082 A/G, -819 T/C, -592 A/C), and hepatocellular carcinoma by performing a meta-analysis with eligible individual studies. METHODS: This study followed the PRISMA 2020 Checklist. Relevant studies were searched in health-related databases. The Newcastle-Ottawa Scale criteria were used to evaluate the studies quality. Pooled odds ratio (OR) and its 95% confidence interval (CI) were used to determine the strength of association between each polymorphism and hepatocellular carcinoma using five genetic models. Stratification was done by ethnic groups. Trial sequential analysis (TSA) was performed to determine the required information size. RESULTS: Fifteen case-control studies (n = 8182) were identified. Overall, the heterozygous model showed a marginal significant association only between IL-10 (-1082 A/G) and hepatocellular carcinoma risk (OR: 0.82, 95% CI: 0.67-1.00, 9 studies). On stratification, IL-10 (-1082 A/G) was significantly associated with hepatocellular carcinoma risk in the non-Asian population under dominant (OR: 0.62, 95% CI: 0.45-0.86, 4 studies), heterozygous (OR: 0.60, 95% CI: 0.43-0.85) and allelic models (OR: 0.79, 95% CI: 0.64-0.99). IL-10 (-819 T/C) was significantly associated with hepatocellular carcinoma risk only among non-Asians under the dominant (OR: 1.47, 95% CI: 1.02-2.13, 8 studies), recessive (OR: 1.99, 95% CI: 1.03-3.86, and homozygous models (OR: 2.18, 95% CI: 1.13-4.23). For IL-10 (-592 A/C) with 11 studies, there was no significant association with hepatocellular carcinoma in all five genetic models (P values > 0.5). TSA plots indicated that the information size for firm evidence of effect was sufficient only for the analysis of IL-10 (-592 A/C), but not for the - 1082 A/G or -819 T/C. CONCLUSIONS: Findings suggest that IL-10 (-1082 A/G and - 819 T/C) polymorphisms are associated with hepatocellular carcinoma in ethnic-specific manner. However, this evidence is not conclusive because the sample size was insufficient. IL-10 (-592 A/C) polymorphism was not associated with hepatocellular carcinoma albeit with sufficient information size. Future well-designed large case-control studies on IL-10 (-1082 A/G and - 819 T/C) with different ethnicities are recommended.

Differential innate immune responses of human macrophages and bronchial epithelial cells against Talaromyces marneffei.

Talaromyces marneffei is a thermally dimorphic fungal pathogen endemic in Southeast Asia. As inhalation of airborne conidia is believed as the major infection route, airway epithelial cells followed by pulmonary macrophages are the first cell types which the fungus encounters inside the host. In this study, we established an in vitro infection model based on human peripheral blood-derived macrophages (hPBDMs) cultured with the supplementation of autologous plasma. Using this model, we determined the transcriptomic changes of hPBDMs in response to T. marneffei infection by quantitative real-time reverse-transcription polymerase chain reaction as well as high-throughput RNA sequencing. Results showed that T. marneffei infection could activate hPBDMs to the M1-like phenotype and trigger a potent induction of chemokine and pro-inflammatory cytokine production as well as the expression of other immunoregulatory genes. In contrast to hPBDMs, there was no detectable innate cytokine response against T. marneffei in human bronchial epithelial cells (hBECs). Using a green fluorescent protein-tagged T. marneffei strain and confocal microscopy, internalization of the fungus by hBECs was confirmed. Live cell imaging further demonstrated that the infected cells exhibited normal cellular physiology, especially that the process of cell division could be observed. Moreover, T. marneffei also survived better inside hBECs than hPBDMs. Our results illustrated a potential role of hBECs to serve as reservoir cells for T. marneffei to evade immunosurveillance by phagocytes, from which the fungus reactivates when the host immunity is weakened and causes infection. Such immunoevasion and reactivation may also help explain the long incubation period observed for talaromycosis, in particular the travel-related cases. IMPORTANCE Talaromyces marneffei is an important fungal pathogen especially in Southeast Asia. To understand the innate immune response to talaromycosis, a suitable infection model is needed. Here, we established an in vitro T. marneffei infection model using human peripheral blood-derived macrophages (hPBDMs). We then examined the transcriptomic changes of hPBDMs in response to T. marneffei infection with this model. We found that contact with T. marneffei could activate hPBDMs to the M1-like phenotype and induced mRNA expressions of five cytokines and eight immunoregulatory genes. Contrary to hPBDMs, such immunoresponse was not elicited in human bronchial epithelial cells (hBECs), despite normal physiology observed in infected cells. We also found that infected hBECs did not eliminate T. marneffei as efficiently as hPBDMs. Our observation suggested that hBECs may potentially serve as reservoir cells for T. marneffei to evade immunosurveillance. When the host immunity deteriorates later, then the fungus reactivates and causes infection.

Performance of clinical risk scores and prediction models to identify pathogenic germline variants in patients with advanced prostate cancer.

PURPOSE: Determining the frequency and distribution of pathogenic germline variants (PGVs) in Austrian prostate cancer (PCa) patients and to assess the accuracy of different clinical risk scores to correctly predict PGVs. METHODS: This cross-sectional study included 313 men with advanced PCa. A comprehensive personal and family history was obtained based on predefined questionnaires. Germline DNA sequencing was performed between 2019 and 2021 irrespective of family history, metastatic or castration status or age at diagnosis. Clinical risk scores for hereditary cancer syndromes were evaluated and a PCa-specific score was developed to assess the presence of PGVs. RESULTS: PGV presence was associated with metastasis (p = 0.047) and castration resistance (p = 0.011), but not with personal cancer history or with relatives with any type of cancer. Clinical risk scores (Manchester score, PREMM5 score, Amsterdam II criteria or Johns Hopkins criteria) showed low sensitivities (3.3-20%) for assessing the probability of PGV presence. A score specifically designed for PCa patients stratifying patients into low- or high-risk regarding PGV probability, correctly classified all PGV carriers as high-risk, whereas a third of PCa patients without PGVs was classified as low risk of the presence of PGVs. CONCLUSION: Application of common clinical risk scores based on family history are not suitable to identify PCa patients with high PGV probabilities. A PCa-specific score stratified PCa patients into low- or high-risk of PGV presence with sufficient accuracy, and germline DNA sequencing may be omitted in patients with a low score. Further studies are needed to evaluate the score.

Associations of height, body mass index, and weight gain with breast cancer risk in carriers of a pathogenic variant in BRCA1 or BRCA2: the BRCA1 and BRCA2 Cohort Consortium.

INTRODUCTION: Height, body mass index (BMI), and weight gain are associated with breast cancer risk in the general population. It is unclear whether these associations also exist for carriers of pathogenic variants in the BRCA1 or BRCA2 genes. PATIENTS AND METHODS: An international pooled cohort of 8091 BRCA1/2 variant carriers was used for retrospective and prospective analyses separately for premenopausal and postmenopausal women. Cox regression was used to estimate breast cancer risk associations with height, BMI, and weight change. RESULTS: In the retrospective analysis, taller height was associated with risk of premenopausal breast cancer for BRCA2 variant carriers (HR 1.20 per 10 cm increase, 95% CI 1.04-1.38). Higher young-adult BMI was associated with lower premenopausal breast cancer risk for both BRCA1 (HR 0.75 per 5 kg/m2, 95% CI 0.66-0.84) and BRCA2 (HR 0.76, 95% CI 0.65-0.89) variant carriers in the retrospective analysis, with consistent, though not statistically significant, findings from the prospective analysis. In the prospective analysis, higher BMI and adult weight gain were associated with higher postmenopausal breast cancer risk for BRCA1 carriers (HR 1.20 per 5 kg/m2, 95% CI 1.02-1.42; and HR 1.10 per 5 kg weight gain, 95% CI 1.01-1.19, respectively). CONCLUSION: Anthropometric measures are associated with breast cancer risk for BRCA1 and BRCA2 variant carriers, with relative risk estimates that are generally consistent with those for women from the general population.

Using a whole genome co-expression network to inform the functional characterisation of predicted genomic elements from Mycobacterium tuberculosis transcriptomic data.

A whole genome co-expression network was created using Mycobacterium tuberculosis transcriptomic data from publicly available RNA-sequencing experiments covering a wide variety of experimental conditions. The network includes expressed regions with no formal annotation, including putative short RNAs and untranslated regions of expressed transcripts, along with the protein-coding genes. These unannotated expressed transcripts were among the best-connected members of the module sub-networks, making up more than half of the 'hub' elements in modules that include protein-coding genes known to be part of regulatory systems involved in stress response and host adaptation. This data set provides a valuable resource for investigating the role of non-coding RNA, and conserved hypothetical proteins, in transcriptomic remodelling. Based on their connections to genes with known functional groupings and correlations with replicated host conditions, predicted expressed transcripts can be screened as suitable candidates for further experimental validation.

Proton-pump inhibitor use amongst patients with severe hypomagnesemia.

Introduction: Long-term proton pump inhibitor (PPI) use has been associated with hypomagnesemia. It is unknown how frequently PPI use is implicated in patients with severe hypomagnesemia, and its clinical course or risk factors. Methods: All patients with severe hypomagnesemia from 2013 to 2016 in a tertiary center were assessed for likelihood of PPI-related hypomagnesemia using Naranjo algorithm, and we described the clinical course. The clinical characteristics of each case of PPI-related severe hypomagnesemia was compared with three controls on long-term PPI without hypomagnesemia, to assess for risk factors of developing severe hypomagnesemia. Results: Amongst 53,149 patients with serum magnesium measurements, 360 patients had severe hypomagnesemia (<0.4 mmol/L). 189 of 360 (52.5%) patients had at least possible PPI-related hypomagnesemia (128 possible, 59 probable, two definite). 49 of 189 (24.7%) patients had no other etiology for hypomagnesemia. PPI was stopped in 43 (22.8%) patients. Seventy (37.0%) patients had no indication for long-term PPI use. Hypomagnesemia resolved in most patients after supplementation, but recurrence was higher in patients who continued PPI, 69.7% versus 35.7%, p = 0.009. On multivariate analysis, risk factors for hypomagnesemia were female gender (OR 1.73; 95% CI: 1.17-2.57), diabetes mellitus (OR, 4.62; 95% CI: 3.05-7.00), low BMI (OR, 0.90; 95% CI: 0.86-0.94), high-dose PPI (OR, 1.96; 95% CI: 1.29-2.98), renal impairment (OR, 3.85; 95% CI: 2.58-5.75), and diuretic use (OR, 1.68; 95% CI: 1.09-2.61). Conclusion: In patients with severe hypomagnesemia, clinicians should consider the possibility of PPI-related hypomagnesemia and re-examine the indication for continued PPI use, or consider a lower dose.

Gold nanostar and graphitic carbon nitride nanocomposite for serotonin detection in biological fluids and human embryonic kidney cell microenvironment.

A nanosensor comprising of gold nanostars (Au-Nstars)-graphitic carbon nitride (g-C3N4) nanocomposite layered on a glassy carbon electrode (GCE) to detect serotonin (ST) in various body fluids has been fabricated. The nanocomposite and the sensing platform have been thoroughly characterized with UV-visible spectroscopy (UV-vis), transmission electron microscopy (TEM), selected area electron diffraction (SAED), energy dispersive X-ray photoelectron spectroscopy (EDX), and electrochemical techniques such as cyclic voltammetry (CV), linear sweep voltammetry (LSV), and electrochemical impedance spectroscopy (EIS). The designed ST detection probe has achieved a linear dynamic range (LDR) in the range 5 × 10-7 and 1 × 10-3 M with a limit of detection (LOD) of 15.1 nM (RSD < 3.3%). The ST detection capability of the fabricated sensor ranges between the normal and several abnormal pathophysiological situations. The sensor effectively detects ST in real matrices such as urine and blood serum, thus, showing its direct diagnostic applicability. Additionally, the sensor has been tested in the microenvironment of human embryonic kidney (HEK) cells to assess the possibility of ST secretion in cell lines. Interferences because of co-existing molecules have been evaluated, and the shelf-life of the fabricated sensor has been obtained as 8 weeks.

A comprehensive suite of earthquake catalogues for the 2016-2017 Central Italy seismic sequence.

The protracted nature of the 2016-2017 central Italy seismic sequence, with multiple damaging earthquakes spaced over months, presented serious challenges for the duty seismologists and emergency managers as they assimilated the growing sequence to advise the local population. Uncertainty concerning where and when it was safe to occupy vulnerable structures highlighted the need for timely delivery of scientifically based understanding of the evolving hazard and risk. Seismic hazard assessment during complex sequences depends critically on up-to-date earthquake catalogues-i.e., data on locations, magnitudes, and activity of earthquakes-to characterize the ongoing seismicity and fuel earthquake forecasting models. Here we document six earthquake catalogues of this sequence that were developed using a variety of methods. The catalogues possess different levels of resolution and completeness resulting from progressive enhancements in the data availability, detection sensitivity, and hypocentral location accuracy. The catalogues range from real-time to advanced machine-learning procedures and highlight both the promises as well as the challenges of implementing advanced workflows in an operational environment.

Outcomes of an outpatient home-based prehabilitation program before pancreaticoduodenectomy: A retrospective cohort study.

Backgrounds/Aims: Prehabilitation aims for preoperative optimisation to reduce postoperative complications. However, there is a paucity of data on its use in patients undergoing pancreaticoduodenectomy (PD). Thus, this study aims to evaluate the outcomes of a home-based outpatient prehabilitation program (PP) versus no-PP in patients undergoing PD. Methods: This retrospective cohort study compared patients who underwent PP versus no-PP before elective PD from January 2016 to December 2020. Inclusion criteria for PP were < 65 years or 65-74 years with FRAIL score < 3. No-PP included dietician, case manager and anesthesia review. PP included additional physiotherapy sessions, caregiver training and interim phone consultation. Univariate and multivariate analysis were used to evaluate length of stay (LOS), morbidity, 30-day readmission, and 90-day mortality. Results: Seventy-one patients (PP: n = 50 [70.4%]; no-PP: n = 21 [29.6%]) were included in this study. Median age was 65 years (interquartile range [IQR]: 58-72 years). Majority (n = 58 [81.7%]) of patients underwent open surgery. Ductal adenocarcinoma was the most common histology (49.3%). Patient demographics were comparable between both groups. Overall median LOS was 11.0 days (IQR: 8.0-17.0 days). Compared to no-PP, PP was not independently associated with reduced intra-abdominal collections (odds ratio [OR]: 0.43; 95% confidence interval [CI]: 0.03-6.11, p = 0.532), major morbidity (OR: 1.31; 95% CI: 0.09-19.47; p = 0.845) or 30-day readmission (OR: 3.16; 95% CI: 0.26-38.27; p = 0.365). There was one (1.4%) 30-day mortality. Conclusions: Our outpatient PP with unsupervised exercise regimes did not improve postoperative outcomes following elective PD.

pH-Responsive PEGylated Niosomal Nanoparticles as an Active-Targeting Cyclophosphamide Delivery System for Gastric Cancer Therapy.

A PEGylated niosomal formulation of cyclophosphamide (Nio-Cyclo-PEG) was prepared using a central composite design and characterized in terms of drug loading, size distribution, and average size. The stability of formulations was also studied at different conditions. In vitro cytotoxicity of drug delivery formulations was assessed on gastric cancer cells using MTT assay. The mechanism of cytotoxicity was studied at the transcriptional level by real-time PCR on Caspase3, Caspase9, CyclinD, CyclinE, MMP-2, and MMP-9 genes, while apoptosis was investigated with flow cytometry. The anti-metastatic property was evaluated using the scratch method. Propidium iodide staining was used to study the cell cycle. The results indicated that the as-designed nanocarrier exhibited a controlled drug release pattern with improved nanoparticle stability. It was found that the living cancer cells treated with Nio-Cyclo-PEG showed a significant decrease in number when compared with the niosomal carrier without PEG (Nio-Cyclo) and free drug (Cyclo). Moreover, the drug-loaded nanocarrier induced planned death (apoptosis) in the cancer cells through the regulation of Caspase3, Caspase9, CyclinD, CyclinE, MMP-9, and MMP-2 gene expression, indicating that the Nio-Cyclo-PEG formulation could significantly inhibit the cell cycle at the sub G1 phase as well as prevent the migration of cancer cells. In conclusion, Nio-Cyclo-PEG as developed in this study could serve as an active-targeting drug delivery nanocarriers for gastric cancer therapy with high efficacy and minimal side effects on healthy tissues/cells.

Comparing clinical trial population representativeness to real-world populations: an external validity analysis encompassing 43 895 trials and 5 685 738 individuals across 989 unique drugs and 286 conditions in England.

BACKGROUND: Randomised controlled trials (RCTs) inform prescription guidelines, but stringent eligibility criteria exclude individuals with vulnerable characteristics, which we define as comorbidities, concomitant medication use, and vulnerabilities due to age. Poor external validity can result in inadequate treatment decision information. Our first aim was to quantify the extent of exclusion of individuals with vulnerable characteristics from RCTs for all prescription drugs. Our second aim was to quantify the prevalence of individuals with vulnerable characteristics from population electronic health records who are actively prescribed such drugs. In tandem, these two aims will allow us to assess the representativeness between RCT and real-world populations and identify vulnerable populations potentially at risk of inadequate treatment decision information. When a vulnerable population is highly excluded from RCTs but has a high prevalence of individuals actively being prescribed the same medication, there is likely to be a gap in treatment decision information. Our third aim was to investigate the use of real-world evidence in contributing towards quantifying missing treatment risk or benefit through an observational study. METHODS: We extracted RCTs from ClinicalTrials.gov from its inception to April 28, 2021, and primary care records from the Clinical Practice Research Datalink Gold database from Jan 1, 1998, to Dec 31, 2020. We referred to the British National Formulary to classify prescription drugs into drug categories. We conducted descriptive analyses and quantified RCT exclusion and prevalence of individuals with vulnerable characteristics for comparison to identify populations without treatment decision information. Exclusion and prevalence were assessed separately for different age groups, individual clinical specialities, and for quantities of concomitant conditions by clinical specialities, where multimorbidity was defined as having two or more clinical specialties, and medications prescribed, where polypharmacy was defined as having five or more medications prescribed. Population trends of individuals with multimorbidity or polypharmacy were assessed separately by age group. We conducted an observational cohort study to validate the use of real-world evidence in contributing towards quantifying treatment risk or benefit for patients with dementia on anti-dementia drugs with and without a contraindicated clinical speciality. To do so, we identified the clinical specialities that anti-dementia drug RCTs highly excluded yet had corresponding high prevalence in the real-world population, forming the groups with highest risk of having scarce treatment decision information. Cox regression was used to assess if the risk of mortality outcomes differs between both groups. FINDINGS: 43 895 RCTs from ClinicalTrials.gov and 5 685 738 million individuals from primary care records were used. We considered 989 unique drugs and 286 conditions across 13 drug-category cohorts. For the descriptive analyses, the median RCT exclusion proportion across 13 drug categories was 81·5% (IQR 76·7-85·5) for adolescents (aged <18 years), 26·3% (IQR 21·0-29·5) for individuals older than 60 years, 40·5% (IQR 33·7-43·0) for individuals older than 70 years, and 52·9% (IQR 47·1-56·0) for individuals older than 80 years. Multimorbidity had a median exclusion proportion of 91·1% (IQR 88·9-91·8) and median prevalence of 41·0% (IQR 34·9-46·0). Concomitant medication use had a median exclusion proportion of 52·5% (IQR 50·0-53·7) and a median prevalence of 94·3% (IQR 84·3-97·2), and polypharmacy had a median prevalence of 47·7% (IQR 38·0-56·1). Population trends show increasing multimorbidity with age and consistently high polypharmacy across age groups. Populations with cardiovascular or otorhinolaryngological comorbidities had the highest risk of having scarce treatment decision information. For the observational study, populations with cardiovascular or psychiatric comorbidities had highest risk of having scarce treatment decision information. Patients with dementia with an anti-dementia prescription and contraindicated cardiovascular condition had a higher risk of mortality (hazard ratio [HR] 1·20 [95% CI 1·13-1·28 ; p<0·0001]) compared with patients with dementia without a contraindicated cardiovascular condition. Patients with dementia with comorbid delirium (HR 1·25 [95% CI 1·06-1·48]; p<0·0088), intellectual disability (HR 2·72 [95% CI 1·53-4·81]; p=0·0006), and schizophrenia and schizotypal delusional disorders (HR 1·36 [95% CI 1·02-1·82]; p=0·036) had a higher risk of mortality compared with patients with dementia without these conditions. INTERPRETATION: Overly stringent RCT exclusion criteria do not appropriately account for the heterogeneity of vulnerable characteristics observed in real-world populations. Treatment decision information is scarce for such individuals, which might affect health outcomes. We discuss the challenges facing the inclusivity of such individuals and highlight the strength of real-world evidence as an integrative solution in complementing RCTs and increasing the completeness of evidence-based medicine assessments in evaluating the effectiveness of treatment decisions. FUNDING: Wellcome Trust, National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre, Academy of Medical Sciences, and the University College London Overseas Research Scholarship.

Clonal serotype 1c multidrug-resistant Shigella flexneri detected in multiple institutions by sentinel-site sequencing.

Shigella flexneri is a major diarrhoeal pathogen, and the emergence of multidrug-resistant S. flexneri is of public health concern. We report the detection of a clonal cluster of multidrug-resistant serotype 1c (7a) S. flexneri in Singapore in April 2022. Long-read whole-genome sequence analysis found five S. flexneri isolates to be clonal and harboring the extended-spectrum ß-lactamases bla CTX-M-15 and bla TEM-1. The isolates were phenotypically resistant to ceftriaxone and had intermediate susceptibility to ciprofloxacin. The S. flexneri clonal cluster was first detected in a tertiary hospital diagnostic laboratory (sentinel-site), to which the S. flexneri isolates were sent from other hospitals for routine serogrouping. Long-read whole-genome sequence analysis was performed in the sentinel-site near real-time in view of the unusually high number of S. flexneri isolates received within a short time frame. This study demonstrates that near real-time sentinel-site sequence-based surveillance of convenience samples can detect possible clonal outbreak clusters and may provide alerts useful for public health mitigations at the earliest possible opportunity.

Outcomes of surgical resection of super-giant (≥15 cm) hepatocellular carcinoma: Volume does matter, if not the size.

Background and Aim: Resection for giant hepatocellular carcinoma (HCC) (≥10 cm) is deemed safe and feasible. However, a super-giant HCC (≥15 cm) poses unique technical complexity for hepatectomy with limited data suggesting feasibility and oncologic efficiency. This study aims to evaluate the short-term and long-term outcomes of hepatectomy in patients with super-giant HCC. Methods: A retrospective review was conducted on patients with super-giant HCC who underwent hepatectomy from 2011 to 2021. We report perioperative and oncologic outcomes such as length of stay (LOS), 30-day readmission, 90-day mortality, and cumulative survival rate. Results: Of the 18 patients, the median tumor diameter was 172.5 mm (range 150-250). The most common risk factor was chronic hepatitis B virus (HBV) infection (n=7, 38.9%). Most of the patients were Barcelona Clinic Liver Cancer (BCLC) Stage B (n=14, 77.8%) and Hong Kong Liver Cancer (HKLC) Stage IIb (n=15, 83.3%). Extended right hepatectomy was the most common procedure. The median LOS was 11 days (range 3-90). The most common post-operative complication was pneumonia (n=4, 22.2%). Fourteen patients were discharged well without any need for invasive therapy (n=7, 38.9% no complications, n=1, 5.6% Clavien Grade I, n=6, 33.3% Clavien Grade II). Thirty-day readmission rate was 5.6% (n=1) and 90-day mortality rate was 5.6% (n=1). There were 12 patients (66.7%) with microvascular invasion and three patients (16.7%) with macrovascular invasion. Most patients had Grade III (poorly differentiated) HCC (n=9, 50%). At a median follow-up of 11 months (range 2-95), 12 (66.7%) patients had local recurrence, and 9 (50%) developed distant metastasis. The 1-, 2-, and 3-year cumulative disease-free survival (DFS) was 36%, 18%, and 18%, respectively. The 1-, 2-, and 3-year cumulative overall survival was 49% and 39%, and 29%, respectively. Conclusion: Primary hepatic resection is safe in patients with super-giant HCC. However, long-term outcomes are poor, and high tumor volume may be associated with inferior oncological outcomes in HCC. Relevance for Patients: The presentation of super-giant HCCs may be asymptomatic and some patients are diagnosed late with limited treatment options. In some centers, this group of patients are denied surgical resection and recommended for only locoregional therapies like TACE. This paper demonstrates that hepatic resection is safe and may be an option in patients who present at an advanced stage with a high tumor burden.

Treatment of Primary Aldosteronism and Reversal of Renin Suppression Improves Left Ventricular Systolic Function.

Introduction: Primary aldosteronism (PA) is associated with increased risk of cardiovascular events. However, treatment of PA has not been shown to improve left ventricular (LV) systolic function using the conventional assessment with LV ejection fraction (LVEF). We aim to use speckle-tracking echocardiography to assess for improvement in subclinical systolic function after treatment of PA. Methods: We prospectively recruited 57 patients with PA, who underwent 24-h ambulatory blood pressure (BP) measurements and echocardiography, including global longitudinal strain (GLS) assessment of left ventricle, at baseline and 12 months post-treatment. Results: At baseline, GLS was low in 14 of 50 (28.0%) patients. On multivariable analysis, GLS was associated with diastolic BP (P = 0.038) and glomerular filtration rate (P = 0.026). GLS improved post-surgery by -2.3, 95% CI: -3.9 to -0.6, P = 0.010, and post-medications by -1.3, 95% CI: -2.6 to 0.03, P = 0.089, whereas there were no changes in LVEF in either group. Improvement in GLS was independently correlated with baseline GLS (P < 0.001) and increase in plasma renin activity (P = 0.007). Patients with post-treatment plasma renin activity ≥1 ng/ml/h had improvements in GLS (P = 0.0019), whereas patients with persistently suppressed renin had no improvement. Post-adrenalectomy, there were also improvements in LV mass index (P = 0.012), left atrial volume index (P = 0.002), and mitral E/e' (P = 0.006), whereas it was not statistically significant in patients treated with medications. Conclusion: Treatment of hyperaldosteronism is effective in improving subclinical LV systolic dysfunction. Elevation of renin levels after treatment, which reflects adequate reversal of sodium overload state, is associated with better systolic function after treatment. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03174847.