Ultra-processed food consumption has increased worldwide, but associations with cancer risk remain unclear and potential underlying mechanisms are speculative. A robust, multidisciplinary, research agenda is needed to address current research limitations and gaps.
Background: The International Society of Nephrology proposes an acute kidney disease (AKD) management strategy that includes a risk score to aid AKD identification in low- and low-middle-income countries (LLMICs). We investigated the performance of the risk score and determined kidney and patient outcomes from AKD at multiple LLMIC sites.
Methods and findings: Adult patients presenting to healthcare facilities in Bolivia, Brazil, South Africa, and Nepal were screened using a symptom-based risk score and clinical judgment. Those at AKD risk underwent serum creatinine testing, predominantly with a point-of-care (POC) device. Clinical data were collected prospectively between September 2018 and November 2020. We analyzed risk score performance and determined AKD outcomes at discharge and over follow-up of 90 days. A total of 4,311 patients were at increased risk of AKD, and 2,922 (67.8%) had AKD confirmed. AKD prevalence was 80.2% in patients enrolled based on the risk score and 32.5% when enrolled on clinical judgment alone (p < 0.0001). The area under the receiver operating characteristic curve was 0.73 for the risk score to detect AKD. Death during admission occurred in 84 (2.9%) patients with AKD and 3 (0.2%) patients without kidney disease (p < 0.0001). Death after discharge occurred in 206 (9.7%) AKD patients, and 1865 AKD patients underwent reassessment of kidney function after discharge; 902 (48.4%) patients had persistent kidney disease including 740 (39.7%) patients reclassified with de novo or previously undiagnosed chronic kidney disease (CKD). The study was pragmatically designed to assess outcomes as part of routine healthcare, and there was heterogeneity in clinical practice and outcomes between sites, in addition to selection bias during cohort identification.
Conclusions: The use of a risk score can aid AKD identification in LLMICs. High rates of persistent kidney disease and mortality after discharge highlight the importance of AKD follow-up in low-resource settings.
Background: The risk of re-operation, otherwise known as revision, following primary hip replacement depends in part on the prosthesis implant materials used. Current performance evidences are based on a broad categorisation grouping together different materials with potentially varying revision risks. We investigated the revision rate of primary total hip replacement (THR) reported in the National Joint Registry by specific types of bearing surfaces used.
Methods and findings: We analysed THR procedures across all orthopaedic units in England and Wales. All patients who received a primary THR between 2003 and 2019 in the public and private sectors were included. We investigated the all-cause and indication-specific risks of revision using flexible parametric survival analyses to estimate adjusted hazard ratios (HRs). We identified primary THRs with heads and monobloc cups or modular acetabular component THRs with head and shell/liner combinations. A total of 1,026,481 primary THRs were analysed (Monobloc: n = 378,979 and Modular: n = 647,502) with 20,869 (2%) of these primary THRs subsequently undergoing a revision episode (Monobloc: n = 7,381 and Modular: n = 13,488). For monobloc implants, compared to implants with a cobalt chrome head and highly crosslinked polyethylene (HCLPE) cup, the all-cause risk of revision for monobloc acetabular implant was higher for patients with cobalt chrome (hazard rate at 10 years after surgery: 1.28 95% confidence intervals [1.10, 1.48]) or stainless steel head (1.18 [1.02, 1.36]) and non-HCLPE cup. The risk of revision was lower for patients with a delta ceramic head and HCLPE cup implant, at any postoperative period (1.18 [1.02, 1.36]). For modular implants, compared to patients with a cobalt chrome head and HCLPE liner primary THR, the all-cause risk of revision for modular acetabular implant varied non-constantly. THRs with a delta ceramic (0.79 [0.73, 0.85]) or oxidised zirconium (0.65 [0.55, 0.77]) head and HCLPE liner had a lower risk of revision throughout the entire postoperative period. Similar results were found when investigating the indication-specific risks of revision for both the monobloc and modular acetabular implants. While this large, nonselective analysis is the first to adjust for numerous characteristics collected in the registry, residual confounding cannot be rule out.
Conclusions: Prosthesis revision is influenced by the prosthesis materials used in the primary procedure with the lowest risk for implants with delta ceramic or oxidised zirconium head and an HCLPE liner/cup. Further work is required to determine the association of implant bearing materials with the risk of rehospitalisation, re-operation other than revision, mortality, and the cost-effectiveness of these materials.
Background: Community active case finding (ACF) for tuberculosis was widely implemented in Europe and North America between 1940 and 1970, when incidence was comparable to many present-day high-burden countries. Using an interrupted time series analysis, we analysed the effect of the 1957 Glasgow mass chest X-ray campaign to inform contemporary approaches to screening.
Methods and findings: Case notifications for 1950 to 1963 were extracted from public health records and linked to demographic data. We fitted Bayesian multilevel regression models to estimate annual relative case notification rates (CNRs) during and after a mass screening intervention implemented over 5 weeks in 1957 compared to the counterfactual scenario where the intervention had not occurred. We additionally estimated case detection ratios and incidence. From 11 March 1957 to 12 April 1957, 714,915 people (622,349 of 819,301 [76.0%] resident adults ≥15 years) were screened with miniature chest X-ray; 2,369 (0.4%) were diagnosed with tuberculosis. Pre-intervention (1950 to 1956), pulmonary CNRs were declining at 2.3% per year from a CNR of 222/100,000 in 1950. With the intervention in 1957, there was a doubling in the pulmonary CNR (RR: 1.95, 95% uncertainty interval [UI] [1.81, 2.11]) and 35% decline in the year after (RR: 0.65, 95% UI [0.59, 0.71]). Post-intervention (1958 to 1963) annual rates of decline (5.4% per year) were greater (RR: 0.77, 95% UI [0.69, 0.85]), and there were an estimated 4,599 (95% UI [3,641, 5,683]) pulmonary case notifications averted due to the intervention. Effects were consistent across all city wards and notifications declined in young children (0 to 5 years) with the intervention. Limitations include the lack of data in historical reports on microbiological testing for tuberculosis, and uncertainty in contributory effects of other contemporaneous interventions including slum clearances, introduction of BCG vaccination programmes, and the ending of postwar food rationing.
Conclusions: A single, rapid round of mass screening with chest X-ray (probably the largest ever conducted) likely resulted in a major and sustained reduction in tuberculosis case notifications. Synthesis of evidence from other historical tuberculosis screening programmes is needed to confirm findings from Glasgow and to provide insights into ongoing efforts to successfully implement ACF interventions in today's high tuberculosis burden countries and with new screening tools and technologies.
Background: The interaction of CD40L and its receptor CD40 on activated T cells and B cells respectively control pro-inflammatory activation in the pathophysiology of autoimmunity and transplant rejection. Previous studies have implicated signaling pathways involving CD40L (interchangeably referred to as CD154), as well as adaptive and innate immune cell activation, in the induction of neuroinflammation in neurodegenerative diseases. This study aimed to assess the safety, tolerability, and impact on pro-inflammatory biomarker profiles of an anti CD40L antibody, tegoprubart, in individuals with amyotrophic lateral sclerosis (ALS).
Methods and findings: In this multicenter dose-escalating open-label Phase 2A study, 54 participants with a diagnosis of ALS received 6 infusions of tegoprubart administered intravenously every 2 weeks. The study was comprised of 4 dose cohorts: 1 mg/kg, 2 mg/kg, 4 mg/kg, and 8 mg/kg. The primary endpoint of the study was safety and tolerability. Exploratory endpoints assessed the pharmacokinetics of tegoprubart as well as anti-drug antibody (ADA) responses, changes in disease progression utilizing the Revised ALS Functional Rating Scale (ALSFRS-R), CD154 target engagement, changes in pro-inflammatory biomarkers, and neurofilament light chain (NFL). Seventy subjects were screened, and 54 subjects were enrolled in the study. Forty-nine of 54 subjects completed the study (90.7%) receiving all 6 infusions of tegoprubart and completing their final follow-up visit. The most common treatment emergent adverse events (TEAEs) overall (>10%) were fatigue (25.9%), falls (22.2%), headaches (20.4%), and muscle spasms (11.1%). Mean tegoprubart plasma concentrations increased proportionally with increasing dose with a half-life of approximately 24 days. ADA titers were low and circulating levels of tegoprubart were as predicted for all cohorts. Tegoprubart demonstrated dose dependent target engagement associated and a reduction in 18 pro-inflammatory biomarkers in circulation.
Conclusions: Tegoprubart appeared to be safe and well tolerated in adults with ALS demonstrating dose-dependent reduction in pro-inflammatory chemokines and cytokines associated with ALS. These results warrant further clinical studies with sufficient power and duration to assess clinical outcomes as a potential treatment for adults with ALS.
Trial registration: Clintrials.gov ID:NCT04322149.
Background: Detailed subgroup incidence rates for steatotic liver disease (SLD)-related hepatocellular carcinoma (HCC) are critical to inform practice and public health interventions but remain sparse. We aimed to fill in this gap.
Methods and findings: In a retrospective cohort study of adults with SLD from the United States (US) Merative Marketscan Research Databases (1/2007 to 12/2021), we estimated HCC incidence stratified by sex, age, cirrhosis, diabetes mellitus (DM), and a combination of all these 4 factors. We excluded patients with significant alcohol use and chronic viral hepatitis. We analyzed data from 741,816 patients with SLD (mean age 51.5 ± 12.8 years, 46% male, 14.7% cirrhosis). During a 2,410,166 person-years (PY) follow-up, 1,740 patients developed HCC. The overall HCC incidence yielded 0.72 per 1,000 PY (95% confidence interval [CI, 0.68, 0.75]). The incidence was higher in males (0.95, 95% CI [0.89, 1.01]) compared to females (0.52, 95% CI [0.48, 0.56]) (p < 0.001). For those with cirrhosis, the incidence was significantly higher at 4.29 (95% CI [4.06, 4.51]) compared to those without cirrhosis (0.14, 95% CI [0.13, 0.16]) (p < 0.001). Additionally, the incidence was higher in patients with DM (1.19, 95% CI [1.12, 1.26]) compared to those without DM (0.41, 95% CI [0.38, 0.44]) (p < 0.001). Chronic kidney disease (CKD) was also associated with a higher HCC incidence of 2.20 (95% CI [2.00, 2.41]) compared to those without CKD (0.58, 95% CI [0.55, 0.62]) (p < 0.001). Similarly, individuals with cardiovascular disease (CVD) had a higher HCC incidence of 1.89 (95% CI [1.75, 2.03]) compared to those without CVD (0.51, 95% CI [0.48, 0.54]) (p < 0.001). Finally, the incidence of HCC was significantly higher in patients with non-liver cancer (3.90, 95% CI [3.67, 4.12]) compared to those without other cancers (0.29, 95% CI [0.26, 0.31]) (p < 0.001). On further stratification, HCC incidence incrementally rose by 10-year age intervals, male sex, cirrhosis, and DM, reaching 19.06 (95% CI [16.10, 22.01]) and 8.44 (95% CI [6.78, 10.10]) in males and females, respectively, but only 0.04 for non-diabetic, noncirrhotic aged <40 years patients in both sexes. The main limitation of this methodology is the potential misclassification of the International Classification of Diseases (ICD) codes inherent in claims database studies.
Conclusions: This nationwide study provided robust granular estimates for SLD-related HCC incidence stratified by several key risk factors. In addition to cirrhosis, future surveillance strategies, prevention, public health initiatives, and future research models should also take into account the impact of sex, age, and DM.
Adolescent girls and young women (AGYW) in southern Africa face triple the HIV incidence of their male peers due to multiple factors, including economic deprivation and age-disparate relationships. A new study by Aurélia Lépine and colleagues has demonstrated that addressing healthcare costs among AGYW has the potential to reduce HIV incidence.
Background: Parental drinking can cause harm to the offspring. A parent's diagnosis of alcohol-related liver disease (ALD) might be an opportunity to reach offspring with preventive interventions. We investigated offspring risk of adverse health outcomes throughout life, their association with their parent's educational level and diagnosis of ALD.
Methods and findings: We used nationwide health registries to identify offspring of parents diagnosed with ALD in Denmark 1996 to 2018 and age- and sex-matched comparators (20:1). We estimated the incidence rate ratios (IRRs) of hospital contacts with adverse health outcomes, overall and in socioeconomic strata. We used a self-controlled design to examine whether health outcomes were more likely to occur during the first year after the parent's ALD diagnosis. The 60,804 offspring of parents with ALD had a higher incidence rate of hospital contacts from age 15 to 60 years for psychiatric disease, poisoning, fracture or injury, alcohol-specific diagnoses, other substance abuse, and of death than comparators. Associations were stronger for offspring with low compared to high socioeconomic position: The IRR for admission due to poisoning was 2.2 versus 1.0 for offspring of an ALD parent with a primary level versus a highly educated ALD parent. Offspring had an increased risk for admission with psychiatric disease and poisoning in the year after their parent's ALD diagnosis. For example, among offspring whose first hospital contact with psychiatric disease was at age 13 to 25 years, the IRR in the first year after their parent's ALD diagnosis versus at another time was 1.29 (95% CI 1.13, 1.47). Main limitation was inability to include adverse health outcomes not involving hospital contact.
Conclusions: Offspring of parents with ALD had a long-lasting higher rate of health outcomes associated with poor mental health and self-harm that increased shortly after their parent's diagnosis of ALD. Offspring of parents of low educational level were particularly vulnerable. This study highlights an opportunity to reach out to offspring in connection with their parent's hospitalization with ALD.
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