Advancing Prostate Cancer Staging: A Single-Step Approach With Bi-parametric and Whole-Body Diffusion MRI in an African Cohort.

OBJECTIVES:  To document our initial experience using whole-body diffusion-weighted magnetic resonance imaging (WB-DWI/MRI) and bi-parametric magnetic resonance imaging (bpMRI) as a single exam in the staging of biopsy-proven prostate cancers. METHODS: This retrospective study involved 120 African men with biopsy-confirmed prostate cancer (PCa). All the participants had a single exam that included both a bpMRI and a WB-DWI/MRI. The results were analyzed based on the American Urological Association's risk stratification system and evaluated using descriptive statistics. RESULTS: The combined imaging approach confirmed PCa in all cases, identifying pelvic lymph node metastases in 21 (17.5%) patients. Among 72 high-risk patients, bpMRI+WB-DWI/MRI detected pelvic lymph node metastases in 18 (25.0%), bone metastases in 15 (20.8%), retroperitoneal lymph node metastases in six (8.3%), and extraprostatic extension in 18 (25%), with no solid organ metastases observed. CONCLUSION: The combination of WB-DWI/MRI and bpMRI in a single-step approach demonstrates diagnostic potential in primary prostate cancer staging for high-risk groups, with the added advantage of shorter examination times, lower patients' costs, and elimination of the risks of adverse events associated with the use of contrast agents and exposure to radiation.

FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms.

AIMS: Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD). Distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. Phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development. METHODS AND RESULTS: Here, we show that FLT4 variants identified in TOF patients, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wildtype FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of wildtype human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants. CONCLUSIONS: Taken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms. TRANSLATIONAL PERSPECTIVE: Proteostatic dysfunction, if confirmed as a mechanism of CHD pathogenesis for other predisposing genes, may identify pathways to therapeutic interventions. Distinguishing mechanistically how variants in FLT4 give rise to CHD may have potential to individualise genetic counselling in affected families.

The response of the Irish pharmaceutical manufacturing sector to the COVID-19 pandemic with a focus on Lean and JIT.

Background: Just in Time (JIT) and Lean manufacturing are concepts that originated in the automotive industry and were then adopted by pharmaceutical and biopharmaceutical companies during the 1990s. However, the Covid-19 pandemic and the urgent demand for pharmaceutical treatment challenged JIT and Lean manufacturing processes. Production of Covid-19-related medicines increased, putting pressure on global supply chains and operations. This also hindered the production of medicines using the same or similar materials. Thus, questions are raised concerning JIT and Lean supply chains in the pharmaceutical industry. Objectives: The present study aimed to explore (1) if material and supply constraints occurred due to the Covid-19 pandemic, (2) how companies were impacted and managed and (3) if changes are required to future proof the JIT supply chain approach for future global events. Design: A mixed-method cross-sectional survey design was used and focused on material supply, qualification and validation in Irish pharmaceutical manufacturing sites. Methods: Employees working in the Irish pharmaceutical manufacturing industry were recruited using convenience sampling through online advertisement using the social media platform 'LinkedIn'. Quantitative data was analysed using percentages and qualitative data from free-text responses were used to add context to the quantitative survey questions. Results: A total of 41 participants were recruited. The results suggested that the pandemic had a negative effect on material availability according to 81% of participants. This translated to delays or stoppage of production activity and was mainly handled by sourcing new materials (70%). To cope with future global crises, 60% of participants recommended more flexibility in future validation processes while 78% of participants acknowledged the importance of validating additional suppliers. A hybrid model of manufacturing and supply chain management was also a preferred approach to exclusive Lean and JIT (42%). Conclusions: The production of non-Covid-19 medicines was adversely affected by the Covid-19 pandemic, but the pharmaceutical industry in Ireland demonstrated resilience and collaboration in response to these challenges. This study suggests that the JIT and Lean manufacturing model should be adjusted to ensure medicine supply chains are not disrupted during future global events.

Testing for t(3;8) in MYC/BCL6-rearranged large B-cell lymphoma identifies a high-risk subgroup with inferior survival.

ABSTRACT: A reciprocal t(3;8) BCL6::MYC fusion is common in large B-cell lymphoma (LBCL) with MYC and BCL6 disruption. These pseudo-double-hit cases are not adverse, whereas t(3;8)-MYC/BCL6 lymphoma has an inferior prognosis relative to other MYC-rearranged LBCL.

Science on the mind: Examining question ordering effects when asking about science on large-scale surveys.

Previous research has examined people's attitudes toward science and scientists, highlighting how religious identities, beliefs, or behavior shapes these attitudes. However, survey design choices have been previously shown to influence individuals' attitudes toward religion and science. We investigated the extent to which question ordering (i.e. presenting questions about science before questions about religion or the paranormal) in a large-scale survey would influence respondents' attitudes toward science and religion. Utilizing an experimental design, we found that responding to science questions first led to (1) more interest in science, (2) more confidence in the scientific community, (3) increased agreement that science is a way of knowing truth, (4) more confidence in responding to science knowledge items, (5) more agreement to scientific statements, and (6) more trust in scientists. We discuss the implications of question ordering when analyzing attitudes toward science and religion within the same surveys and future directions for research.

The Impact of Climate Change on Health Services in Low- and Middle-Income Countries: A Systematised Review and Thematic Analysis.

Aim: The aim of this study was to assess the impact of climate change on health services as categorized by the WHO's Building Blocks for creating Climate-Resilient Health Systems. Objective: The objective was to conduct a systematized review of the published literature concerning the impact of climate change, using a thematic analysis approach to address our aim and identify areas for further research. Design: A search was conducted on 8 February 2022 using the Embase and PubMed research databases. Peer-reviewed scientific studies that were published in English from 2012 to 2022, which described at least one report concerning the impact of climate change on health services in LMICs, were included. Studies were organized based on their key characteristics, which included the date of publication, objective, method, limitations, participants, and geographical focus. The Mixed-Methods Appraisal Tool (MMAT) was used to assess the risk of bias in the included studies. Results: Twenty-three studies were included in this review. Five areas of health services which align with the WHO building blocks framework were impacted by climate change. These health service areas included: (1) Service Delivery, (2) Human Resources, (3) Health Finance, (4) Healthcare Products and Technology, and (5) Leadership and Governance. However, research concerning the impact of climate change on health information systems, which is part of the WHO building blocks framework, did not feature in our study. The climatic effects were divided into three themes: meteorological effects, extreme weather events, and general. The research in this study found that climate change had a detrimental impact on a variety of health services, with service delivery being the most frequently reported. The risk of bias varied greatly between studies. Conclusions: Climate change has negatively impacted health services in a variety of different ways, and without further actions, this problem is likely to worsen. The WHO building blocks have provided a useful lens through which to review health services. We built an aligned framework to describe our findings and to support future climate change impact assessments in this area. We propose that further research concerning the impact of climate change on health information systems would be valuable, as well as further education and responsible policy changes to help build resilience in health services affected by climate change.

Early sevoflurane sedation in severe COVID-19-related lung injury patients. A pilot randomized controlled trial.

BACKGROUND: This study aimed to assess a potential organ protective effect of volatile sedation in a scenario of severe inflammation with an early cytokine storm (in particular IL-6 elevation) in patients suffering from COVID-19-related lung injury with invasive mechanical ventilation and sedation. METHODS: This is a small-scale pilot multicenter randomized controlled trial from four tertiary hospitals in Switzerland, conducted between April 2020 and May 2021. 60 patients requiring mechanical ventilation due to severe COVID-19-related lung injury were included and randomized to 48-hour sedation with sevoflurane vs. continuous intravenous sedation (= control) within 24 h after intubation. The primary composite outcome was determined as mortality or persistent organ dysfunction (POD), defined as the need for mechanical ventilation, vasopressors, or renal replacement therapy at day 28. Secondary outcomes were the length of ICU and hospital stay, adverse events, routine laboratory parameters (creatinine, urea), and plasma inflammatory mediators. RESULTS: 28 patients were randomized to sevoflurane, 32 to the control arm. The intention-to-treat analysis revealed no difference in the primary endpoint with 11 (39%) sevoflurane and 13 (41%) control patients (p = 0.916) reaching the primary outcome. Five patients died within 28 days in each group (16% vs. 18%, p = 0.817). Of the 28-day survivors, 6 (26%) and 8 (30%) presented with POD (p = 0.781). There was a significant difference regarding the need for vasopressors (1 (4%) patient in the sevoflurane arm, 7 (26%) in the control one (p = 0.028)). Length of ICU stay, hospital stay, and registered adverse events within 28 days were comparable, except for acute kidney injury (AKI), with 11 (39%) sevoflurane vs. 2 (6%) control patients (p = 0.001). The blood levels of IL-6 in the first few days after the onset of the lung injury were less distinctly elevated than expected. CONCLUSIONS: No evident benefits were observed with short sevoflurane sedation on mortality and POD. Unexpectedly low blood levels of IL-6 might indicate a moderate injury with therefore limited improvement options of sevoflurane. Acute renal issues suggest caution in using sevoflurane for sedation in COVID-19. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov (NCT04355962) on 2020/04/21.

What is the impact of antidepressant side effects on medication adherence among adult patients diagnosed with depressive disorder: A systematic review.

BACKGROUND: Medication adherence is a prerequisite to achieving beneficial treatment outcomes. In major depressive disorder, many patients fail to complete medication regimens, raising concern for poor treatment outcomes. It is usual to experience adverse drug reactions (ADRs) while taking antidepressants, and relative discomfort is reported by patients. AIMS: The present review focuses on the presence of antidepressant-related side effects and the subsequent relationship with medication non-adherence. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Following the preliminary research, the research question and eligibility criteria were created based on the PICO framework. All articles retrieved from the selected databases were exported to Covidence, a Systematic Review managing software tool. Two reviewers assessed the papers to identify the risk of bias using the Joanna Briggs Institute critical appraisal tool for cross-sectional studies. Seven studies with a low-moderate risk of bias fulfilled the eligibility criteria and were conducted from 2013 to 2020 in Europe, Africa and Asia. RESULTS: The results demonstrated high levels of suboptimal adherence ranging from 46% to 83% amongst the studied population. A variety of side effects were reported by a significant number of participants predominantly with moderate severity. A correlation between the presence of ADRs and suboptimal rates of adherence to antidepressants was found. Somnolence and headaches among other unspecified ADRs were found to increase the dropout rates for selective serotonin reuptake inhibitors. CONCLUSIONS: The present study elucidates the need for effective interventions to facilitate antidepressant adherence and enhance doctor-patient communication, benefiting both the individuals and the healthcare system and leading to better clinical outcomes and reduction of relapse-related costs.

Impact of the COVID-19 Pandemic on Global TAVR Activity: The COVID-TAVI Study.

BACKGROUND: The COVID-19 pandemic adversely affected health care systems. Patients in need of transcatheter aortic valve replacement (TAVR) are especially susceptible to treatment delays. OBJECTIVES: This study sought to evaluate the impact of the COVID-19 pandemic on global TAVR activity. METHODS: This international registry reported monthly TAVR case volume in participating institutions prior to and during the COVID-19 pandemic (January 2018 to December 2021). Hospital-level information on public vs private, urban vs rural, and TAVR volume was collected, as was country-level information on socioeconomic status, COVID-19 incidence, and governmental public health responses. RESULTS: We included 130 centers from 61 countries, including 65,980 TAVR procedures. The first and second pandemic waves were associated with a significant reduction of 15% (P < 0.001) and 7% (P < 0.001) in monthly TAVR case volume, respectively, compared with the prepandemic period. The third pandemic wave was not associated with reduced TAVR activity. A greater reduction in TAVR activity was observed in Africa (-52%; P = 0.001), Central-South America (-33%; P < 0.001), and Asia (-29%; P < 0.001). Private hospitals (P = 0.005), urban areas (P = 0.011), low-volume centers (P = 0.002), countries with lower development (P < 0.001) and economic status (P < 0.001), higher COVID-19 incidence (P < 0.001), and more stringent public health restrictions (P < 0.001) experienced a greater reduction in TAVR activity. CONCLUSIONS: TAVR procedural volume declined substantially during the first and second waves of the COVID-19 pandemic, especially in Africa, Central-South America, and Asia. National socioeconomic status, COVID-19 incidence, and public health responses were associated with treatment delays. This information should inform public health policy in case of future global health crises.

Lipid-rich particles of processed food waste for microalgae harvest through lipid-enriched floating biomat formation.

Food waste was collected from the campus canteen and lipid-rich particles (LRP) phase was evaluated to harvest Tetradesmus obliquus. Box-Behnken design showed the highest harvest efficiency (HE) of 84.69 % in run#1 (LRP = 30 %; initial OD680 = 1.75; and harvest time = 6 h). Numerical optimization ramps suggested 24.15 % (v/v) LRP ratio, initial OD680 3.00, and harvest time 3.82 h for maximum HE. Two flocs were observed, a precipitate at the bottom (B-Floc) and a floating biomat (F-Floc). Experimental results showed HE of 88.3 %, with 67 % and 33 % of the harvested biomass forming F-Floc and B-Floc, respectively. Pre-heating of LRP in a boiling water bath for 10 min (HFB-T10) promoted F-Floc proportion up to 91.6 %. In addition, HFB-T10 showed the highest FAMEs yield of 11.17 g/L of the total used volume, which was significantly higher than that of the centrifuged cells and heat-untreated biomat. Moreover, HFB-T10 showed better iodine value and cetane number of the produced biodiesel.

Search for Evidence of Baryogenesis and Dark Matter in B

A new dark sector antibaryon, denoted ψ_{D}, could be produced in decays of B mesons. This Letter presents a search for B^{+}→ψ_{D}+p (and the charge conjugate) decays in e^{+}e^{-} annihilations at 10.58 GeV, using data collected in the BABAR experiment. Data corresponding to an integrated luminosity of 398 fb^{-1} are analyzed. No evidence for a signal is observed. Branching fraction upper limits in the range from 10^{-7}-10^{-5} are obtained at 90% confidence level for masses of 1.0

Clinical risk associated with COVID-19 among 86000 patients with congenital heart disease.

OBJECTIVE: To determine the magnitude of any excess risk of mortality and hospitalisation due to COVID-19 infection in patients with congenital heart disease (CHD) in the UK healthcare system. METHODS: Matched case-control study within the Clinical Practice Research Datalink study of anonymised general practice records in the National Health Service in England. Patients with CHD were stratified for disease severity according to the European Society of Cardiology guidelines. Presence of a positive COVID-19 test, hospitalisation with a diagnosis of COVID-19 and COVID-19-related mortality were compared in case and control groups. RESULTS: 86 441 patients with CHD and 335 839 controls were studied. Of patients with a positive COVID-19 test, patients with CHD were more likely than controls to be hospitalised (22.4% vs 14.5%; OR=1.77 (95% CI 1.60 to 1.96); p=2.11e-28) and suffer COVID-19-related death (6.1% vs 3.8%; OR=1.60 (95% CI 1.35 to 1.89); p=7.00e-08). The excess risk of COVID-19 hospitalisation and death rose with increasing physiological severity of CHD (presence of pulmonary vascular disease and/or cyanosis), rather than anatomical complexity. CONCLUSIONS: In this study of the COVID-19 pandemic experience, using population health records in over 86000 patients with CHD in England, patients with CHD with COVID-19 were at around 50-75% higher risk of hospitalisation and mortality compared with matched controls with COVID-19. We provide the first primary care-derived estimates for COVID-19 hospitalisation and case-fatality rates in patients with CHD. Some factors predictive of worse COVID-19 outcome in general populations (such as non-white ethnic group), and other CHD-specific comorbidities (such as pulmonary hypertension), influenced outcomes among patients with CHD.

Access and use of immunoglobulins in secondary supportive cancer care: A systematic literature review.

Background: Immunoglobulin replacement therapy (IgRT) benefits patients with primary immuno deficiency (PID) originating from the innate or polygenic defects in the immune system. However, evidence supporting their therapeutic role is not as explicit in secondary immuno deficiency (SID) resulting from the treatment of haematological malignancies. Objectives: This study aimed to (1) create a dataset of relevant research papers, which explore the use of IgRT in SID for analysis, (2) assess the risk of bias within this dataset and (3) study the characteristics of these papers. Design: This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. In addition to the risk of bias, the study characteristics explored in this article included study design, study geographical location and year of publication. Data Sources and Methods: To identify studies relevant to the research question, EMBASE and PubMed databases were searched. The Population, Intervention, Comparison and Outcome (PICO) framework was used to assess study quality. Risk of bias and quality of studies were assessed in accordance with the study design. As one model was not appropriate to assess bias in all articles, several tools were used. Results: A total of 43 studies were identified from the literature search as relevant to the research objective. The most common study design was a retrospective case-control cohort study (n = 16/43), and randomised trials were among the least commonly used approaches (n = 1). Research in this area is occurring around the globe including the United States (n = 7), Italy (n = 7), China, India, Japan and throughout Europe. The annual number of papers in this area has varied from 2012 (n = 1) to 2021 (n = 7). The studies in this article demonstrated a varied risk of bias, with 9 of the 20 cohort studies scoring less than 5 out of 9 stars. Conclusions: Randomised controlled trials are less frequently used to assess access and use of immunoglobulins. More commonly, a retrospective case-control cohort study was used which correlates with the higher risk of bias seen in the studies in this article. Most of the research concerning immunoglobulin use and access occurs in higher-income countries.

Coding Sequence Insertions in Fungal Genomes are Intrinsically Disordered and can Impart Functionally-Important Properties on the Host Protein.

Insertion and deletion mutations (indels) are important mechanisms of generating protein diversity. Indels in coding sequences are under considerable selective pressure to maintain reading frames and to preserve protein function, but once generated, indels provide raw material for the acquisition of new protein properties and functions. We reported recently that coding sequence insertions in the Candida albicans NDU1 protein, a mitochondrial protein involved in the assembly of the NADH:ubiquinone oxidoreductase are imperative for respiration, biofilm formation and pathogenesis. NDU1 inserts are specific to CTG-clade fungi, absent in human ortholog and successfully harnessed as drug targets. Here, we present the first comprehensive report investigating indels and clade-defining insertions (CDIs) in fungal proteomes. We investigated 80 ascomycete proteomes encompassing CTG clade species, the Saccharomycetaceae family, the Aspergillaceae family and the Herpotrichiellaceae (black yeasts) family. We identified over 30,000 insertions, 4,000 CDIs and 2,500 clade-defining deletions (CDDs). Insert sizes range from 1 to over 1,000 residues in length, while maximum deletion length is 19 residues. Inserts are strikingly over-represented in protein kinases, and excluded from structural domains and transmembrane segments. Inserts are predicted to be highly disordered. The amino acid compositions of the inserts are highly depleted in hydrophobic residues and enriched in polar residues. An indel in the Saccharomyces cerevisiae Sth1 protein, the catalytic subunit of the RSC (Remodel the Structure of Chromatin) complex is predicted to be disordered until it forms a ß-strand upon interaction. This interaction performs a vital role in RSC-mediated transcriptional regulation, thereby expanding protein function.

Endocarditis, invasive dental procedures, and antibiotic prophylaxis efficacy in US Medicaid patients.

OBJECTIVE: Antibiotic prophylaxis is recommended before invasive dental procedures to prevent endocarditis in those at high risk, but supporting data are sparse. We therefore investigated any association between invasive dental procedures and endocarditis, and any antibiotic prophylaxis effect on endocarditis incidence. SUBJECTS AND METHODS: Cohort and case-crossover studies were performed on 1,678,190 Medicaid patients with linked medical, dental, and prescription data. RESULTS: The cohort study identified increased endocarditis incidence within 30 days of invasive dental procedures in those at high risk, particularly after extractions (OR 14.17, 95% CI 5.40-52.11, p < 0.0001) or oral surgery (OR 29.98, 95% CI 9.62-119.34, p < 0.0001). Furthermore, antibiotic prophylaxis significantly reduced endocarditis incidence following invasive dental procedures (OR 0.20, 95% CI 0.06-0.53, p < 0.0001). Case-crossover analysis confirmed the association between invasive dental procedures and endocarditis in those at high risk, particularly following extractions (OR 3.74, 95% CI 2.65-5.27, p < 0.005) and oral surgery (OR 10.66, 95% CI 5.18-21.92, p < 0.0001). The number of invasive procedures, extractions, or surgical procedures needing antibiotic prophylaxis to prevent one endocarditis case was 244, 143 and 71, respectively. CONCLUSIONS: Invasive dental procedures (particularly extractions and oral surgery) were significantly associated with endocarditis in high-risk individuals, but AP significantly reduced endocarditis incidence following these procedures, thereby supporting current guideline recommendations.

Expert consensus recommendations for the provision of infective endocarditis services: updated guidance from the Joint British Societies.

Infective endocarditis (IE) remains a difficult condition to diagnose and treat and is an infection of high consequence for patients, causing long hospital stays, life-changing complications and high mortality. A new multidisciplinary, multiprofessional, British Society for Antimicrobial Chemotherapy (BSAC)-ledWorking Party was convened to undertake a focused systematical review of the literature and to update the previous BSAC guidelines relating delivery of services for patients with IE. A scoping exercise identified new questions concerning optimal delivery of care, and the systematic review identified 16 231 papers of which 20 met the inclusion criteria. Recommendations relating to endocarditis teams, infrastructure and support, endocarditis referral processes, patient follow-up and patient information, and governance are made as well as research recommendations. This is a report of a joint Working Party of the BSAC, British Cardiovascular Society, British Heart Valve Society, British Society of Echocardiography, Society of Cardiothoracic Surgeons of Great Britain and Ireland, British Congenital Cardiac Association and British Infection Association.