Population Studies Research Articles

Racial Comparison of the Pharmacokinetics and Safety of Fixed-Dose Combination of Dapagliflozin/Sitagliptin in Western and Korean Healthy Adults

PurposeWe evaluated the pharmacokinetics, safety, and tolerability of a fixed-dose combination (FDC) of dapagliflozin/sitagliptin versus individual component (IC) tablets in healthy Western and Korean participants. The combination of these antihyperglycemic drugs provides efficient glucose control, and the use of FDC has generally been shown to improve medication adherence in individuals with type 2 diabetes mellitus (T2DM). MethodsTwo randomized, open-label, two-period, two-treatment, single-dose, single-center, crossover bioequivalence studies conducted on healthy fasted German participants (aged 18–55 years; Western study) and South Korean participants (aged 19–55 years; Korean study) were included. In both studies, pharmacokinetic parameters (maximum [peak] plasma concentration [Cmax], area under the plasma concentration–time curve from zero to the last quantifiable concentration [AUClast], and area under the plasma concentration–time curve from zero to infinity [AUCinf]) were used to assess the bioequivalence of 10 mg dapagliflozin/100 mg sitagliptin FDC (Treatment A) with their ICs (Treatment B) under fasted conditions. Safety and tolerability were assessed throughout the study. FindingsForty-six healthy participants (male, 60.9%; mean age, 39.5 years; mean body mass index [BMI], 23.9 kg/m2) were randomized in the Western study, and 51 healthy participants (male, 100.0%; mean age, 24.6 years; mean BMI, 23.9 kg/m2) were randomized in the Korean study. In both studies, the participants were randomized 1:1 into treatment sequence AB and treatment sequence BA. Dapagliflozin/sitagliptin FDC was bioequivalent to IC tablets in both Western and Korean studies, as the 90% confidence interval of the FDC to IC ratios of the geometric least-squares means of the pharmacokinetic parameters for both dapagliflozin and sitagliptin was within the 0.8000–1.2500 bioequivalence criterion limit. The observed differences in pharmacokinetic parameters, such as Cmax, AUClast, and AUCinf, between the Western and Korean studies were not clinically meaningful. Dapagliflozin/sitagliptin FDC and their ICs were well tolerated, with no serious adverse events reported in any of the study populations. ImplicationsThe 10 mg dapagliflozin/100 mg sitagliptin FDC and IC formulations were bioequivalent in fasted healthy Western and Korean participants, with no new safety concerns identified, thus offering a useful alternative for patients currently receiving individual medications as part of their treatment regimen. Clinical trial registrationWestern study (clinicaltrials.gov: NCT05266404) and Korean study (clinicaltrials.gov: NCT05453786).

Biofluid GPNMB/osteoactivin as a potential biomarker of ageing: A cross-sectional study

BackgroundGlycoprotein non-metastatic melanoma B (GPNMB)/osteoactivin was first identified in the human melanoma cell lines. GPNMB plays a key role in the anti-inflammatory and antioxidative functions as well as osteoblast differentiation, cancer progression, and tissue regeneration. Recently, GPNMB was used as an anti-aging vaccine for mice. The present study aimed to investigate the potential of biofluid GPNMB as an aging biomarker in humans using serum and urine samples from an aging Chinese population. MethodsWe analyzed RNA-sequencing data (GSE132040) from 17 murine organs across different ages to assess the gene expression of potential ageing biomarkers. Spearman's correlation coefficients were used to evaluate the relationship between gene expression and age. Meanwhile, a cross-sectional population study was conducted, which included 473 participants (aged 25–91 years), a representative subset of participants from the Peng Zu Study on Healthy Ageing in China (Peng Zu Cohort). Biofluid GPNMB levels were measured by ELISA. The associations of serum and urine GPNMB levels with various clinical and anthropometrical indices were assessed using ANOVA, Kruskal-Wallis H test, and univariate and multivariate linear regression analyses. ResultsIn mice, the Gpnmb mRNA expression levels showed a significant positive association with age in multiple organs in mice (P < 0.05). In Peng Zu Cohort, biofluid (both serum and urine) GPNMB levels showed a positive correlation with age (P < 0.05). Univariate linear regression analysis revealed that serum GPNMB levels were negatively associated with skeletal muscle mass index (SMI, P < 0.05) and insulin-like growth factor 1 (IGF-1, P < 0.05), and urine GPNMB levels showed a negative association with total bile acids (TBA, P < 0.05). Multivariate linear regression analysis further indicated that serum GPNMB levels negatively correlated with the systemic immune-inflammation index (SII, P < 0.05), and the urine GPNMB levels maintained a negative association with TBA (P < 0.05), additionally, urine GPNMB levels in men were significantly lower than in women (P < 0.05). ConclusionsThe biofluid GPNMB was a strong clinical biomarker candidate for estimating biological aging.

Suicide rates among physicians compared with the general population in studies from 20 countries: gender stratified systematic review and meta-analysis

ObjectivesTo estimate age standardised suicide rate ratios in male and female physicians compared with the general population, and to examine heterogeneity across study results.DesignSystematic review and meta-analysis.Data sourcesStudies published between...

Seorsus aequatorius (Myrtaceae), a Borneon endemic, rediscovered after 129 years: Conservation implications

Seorsus aequatorius (Myrtaceae), endemic to Borneo, was first described from a single herbarium specimen collected by H. Hallier on Mount Kelam in 1893–1894. However, a minor error in the published collection number of the type specimen for S. aequatorius requires correction. In 2019, during an expedition on Mount Kelam, Dr. Muhammad Mansur and his colleagues rediscovered S. aequatorius (locally known as ‘pohon embun’). This research aimed to correct information on the collection number of the type specimen, conduct a conservation assessment, and propose conservation strategies. The study involved examining herbarium specimens. The conservation status of the species was evaluated using IUCN guidelines. We outline the rediscovery of S. aequatorius after 129 years. The correct type specimen identified as “H. Hallier 2308”. Seorsus aequatorius is preliminarily categorized as Endangered on the IUCN Red List of Threatened Species. Short-term conservation strategies include ex-situ conservation of S. aequatorius at the Kuningan Botanical Garden in West Java. This is suitable because the species’ habitat, growing on rocks at around 800 m above sea level, matches the theme and elevation of the botanical garden, dedicated to rocky area plants at 490–870 m above sea level. Meanwhile, in-situ conservation strategies for S. aequatorius include conducting population studies, performing habitat rehabilitation or restoration, protecting both habitats and species through legal regulations, and reintroducing seedlings from ex-situ conservation. Designating S. aequatorius as Mount Kelam’s mascot could also raise public awareness.

Thrombolysis for Ischemic Stroke Despite Recent Ingestion of Direct Oral Anticoagulants - A Growing Dilemma Also in India.

The administration of intravenous thrombolysis (IVT) for patients with acute ischemic stroke who have recently ingested direct oral anticoagulants (DOACs) presents a clinical challenge due to the perceived increased risk of intracranial hemorrhage (ICH). Traditional guidelines from the US and European authorities advise against IVT within 48 h of last DOAC ingestion, unless specific coagulation tests indicate safety. However, emerging observational studies suggest that IVT might be safe in selected patients. A US stroke registry study and a global multicenter cohort study both reported no significant increase in symptomatic ICH among patients on DOACs compared to those not on anticoagulants. A systematic review of all published observational studies further supported these findings, showing comparable bleeding rates and functional outcomes in DOAC-treated patients. Reversal agents like idarucizumab for dabigatran have demonstrated potential in facilitating safer IVT administration, though logistical and cost-related barriers limit their widespread use. The variability in global guidelines reflects differing approaches to risk assessment and resource availability, highlighting the need for individualized treatment decisions. In India, the increasing prevalence of atrial fibrillation and stroke as well as prescription of DOACs necessitate adapted guidelines that consider local health-care infrastructure. Despite the promising observational data, the lack of randomized controlled trials underscores the need for further research to establish robust evidence for IVT use in this context. Collaborative international efforts and inclusion of diverse patient populations in future studies will be crucial to refine treatment protocols and improve outcomes for stroke patients on DOACs.

Acquisition of Data on Kinematic Responses to Unpredictable Gait Perturbations: Collection and Quality Assurance of Data for Use in Machine Learning Algorithms for (Near-)Fall Detection.

Slip, trip, and fall (STF) accidents cause high rates of absence from work in many companies. During the 2022 reporting period, the German Social Accident Insurance recorded 165,420 STF accidents, of which 12 were fatal and 2485 led to disability pensions. Particularly in the traffic, transport and logistics sector, STF accidents are the most frequently reported occupational accidents. Therefore, an accurate detection of near-falls is critical to improve worker safety. Efficient detection algorithms are essential for this, but their performance heavily depends on large, well-curated datasets. However, there are drawbacks to current datasets, including small sample sizes, an emphasis on older demographics, and a reliance on simulated rather than real data. In this paper we report the collection of a standardised kinematic STF dataset from real-world STF events affecting parcel delivery workers and steelworkers. We further discuss the use of the data to evaluate dynamic stability control during locomotion for machine learning and build a standardised database. We present the data collection, discuss the classification of the data, present the totality of the data statistically, and compare it with existing databases. A significant research gap is the limited number of participants and focus on older populations in previous studies, as well as the reliance on simulated rather than real-world data. Our study addresses these gaps by providing a larger dataset of real-world STF events from a working population with physically demanding jobs. The population studied included 110 participants, consisting of 55 parcel delivery drivers and 55 steelworkers, both male and female, aged between 19 and 63 years. This diverse participant base allows for a more comprehensive understanding of STF incidents in different working environments.

Meat consumption and incident type 2 diabetes: an individual-participant federated meta-analysis of 1·97 million adults with 100 000 incident cases from 31 cohorts in 20 countries

Meat consumption could increase the risk of type 2 diabetes. However, evidence is largely based on studies of European and North American populations, with heterogeneous analysis strategies and a greater focus on red meat than on poultry. We aimed to investigate the associations of unprocessed red meat, processed meat, and poultry consumption with type 2 diabetes using data from worldwide cohorts and harmonised analytical approaches. This individual-participant federated meta-analysis involved data from 31 cohorts participating in the InterConnect project. Cohorts were from the region of the Americas (n=12) and the Eastern Mediterranean (n=2), European (n=9), South-East Asia (n=1), and Western Pacific (n=7) regions. Access to individual-participant data was provided by each cohort; participants were eligible for inclusion if they were aged 18 years or older and had available data on dietary consumption and incident type 2 diabetes and were excluded if they had a diagnosis of any type of diabetes at baseline or missing data. Cohort-specific hazard ratios (HRs) and 95% CIs were estimated for each meat type, adjusted for potential confounders (including BMI), and pooled using a random-effects meta-analysis, with meta-regression to investigate potential sources of heterogeneity. Among 1 966 444 adults eligible for participation, 107 271 incident cases of type 2 diabetes were identified during a median follow-up of 10 (IQR 7-15) years. Median meat consumption across cohorts was 0-110 g/day for unprocessed red meat, 0-49 g/day for processed meat, and 0-72 g/day for poultry. Greater consumption of each of the three types of meat was associated with increased incidence of type 2 diabetes, with HRs of 1·10 (95% CI 1·06-1·15) per 100 g/day of unprocessed red meat (I2=61%), 1·15 (1·11-1·20) per 50 g/day of processed meat (I2=59%), and 1·08 (1·02-1·14) per 100 g/day of poultry (I2=68%). Positive associations between meat consumption and type 2 diabetes were observed in North America and in the European and Western Pacific regions; the CIs were wide in other regions. We found no evidence that the heterogeneity was explained by age, sex, or BMI. The findings for poultry consumption were weaker under alternative modelling assumptions. Replacing processed meat with unprocessed red meat or poultry was associated with a lower incidence of type 2 diabetes. The consumption of meat, particularly processed meat and unprocessed red meat, is a risk factor for developing type 2 diabetes across populations. These findings highlight the importance of reducing meat consumption for public health and should inform dietary guidelines. The EU, the Medical Research Council, and the National Institute of Health Research Cambridge Biomedical Research Centre.

Salivary C-reactive protein exhibits a diurnal pattern and relates to biobehavioral health in military men

C-reactive protein is a systemic inflammatory biomarker that is positively associated with the development of disease. Salivary C-reactive protein (sCRP) has previously been reported to have a diurnal rhythm with higher levels upon awakening and lower levels thereafter. The aims of this study were to evaluate the stability of sCRP across two days, characterize the daily sCRP pattern, compute morning sCRP parameters, and evaluate associations with biobehavioral health in US Navy Explosive Ordnance Disposal (EOD) technicians. Seventy male EOD technicians (age = 34.9 ± 6.5 years) participated in this study, which included a tablet-based survey, measures of health and fitness, and saliva collection. In a free-living setting, participants self-collected saliva on 2 consecutive days at WAKE, WAKE+30, WAKE+60, 4p.m., and 9p.m., for a total of 10 samples. Parameters (e.g., area under the curve) were computed to characterize the morning sCRP magnitude and pattern. Pearson product-moment correlation analyses were used to assess the stability of sCRP samples and parameters across the study period and to examine associations with biobehavioral health. Average sCRP concentrations for the 2-day period were evaluated using an analysis of variance with repeated measures. The stabilities between corresponding time points on Days 1 and 2 were very high (rs = 0.87–.94, all ps ≤ 0.001). sCRP concentrations were highest at WAKE, decreased by 73.6 % at WAKE+30, and then plateaued for the rest of the day. Parameters stabilities were good to excellent (rs = 0.77–.98, all ps ≤ 0.001). We also observed associations between sCRP parameters, self-reported health behaviors, and objective measures of health and fitness. In this study of a military population, we characterized sCRP as diurnal with robust stability across 2 consecutive days, which demonstrates the feasibility of sCRP as a biomarker. These results have significant implications for study methodology and for using sCRP as a marker of dysfunction or disease.

A guide to large data sets for population-based cancer research: Strengths, limitations, and pitfalls.

With the proliferation of cancer research based on large databases, misalignment of research questions and data set capabilities is inevitable. Nationally maintained databases are appealing to cancer researchers because of the ease of access to large amounts of patient data available for analysis and risk estimation. Data sets that are commonly used in cancer research include the National Cancer Database, the SEER (Surveillance, Epidemiology, and End Results) program of the National Cancer Institute, the SEER-Medicare database, the American College of Surgeons National Surgical Quality Improvement Program, and the Healthcare Cost and Utilization Project databases, among others. Each data set has pros and cons with respect to variable availability and the ability to analyze cancer-specific outcomes. It is critical for researchers to understand the strengths and limitations of each database. Changing variable definitions, the length of postoperative data collection, and the availability of patient-reported outcomes or social determinants of health data are examples of factors that researchers must consider when selecting a data set for research purposes. For the current review, the authors summarized the advantages and disadvantages of various national data sets for cohort studies in cancer populations.

Associations of multiple blood metals with cardiac structure and function: A cross-sectional study in a CAD population

Coronary artery disease (CAD) is often accompanied by abnormal cardiac structure and function, leading to an increased prognostic risk. However, less is known about the associations of mixed metals with abnormal cardiac structure and function in CAD patients. Here, we aimed to investigate the associations of exposure to metal mixtures with cardiac structure and function and potential interactions in a CAD population. We conducted a cross-sectional study from Southwest China that included 1555 CAD patients. The blood concentrations of 14 metals were measured via inductively coupled plasma spectrometry. CAD was defined as at least one vessel having stenosis ≥50% the vessel diameter. Echocardiography was used for cardiac structural and functional measurements. Bayesian kernel machine regression was applied to explore the overall effect, metal weight, and dose effect. Linear regression analysis was used to analyze the effects of single metals, metal‒metal interactions and metal‒traditional interactions. Finally, we found that the negative associations of mixed metals with cardiac structure was significant when the levels of all metals were below the 60th percentile. For cardiac function, changes in metals from 50th to 75th were associated with 0.954% and 0.683% decrease in left ventricular ejection fraction and left ventricular fractional shortening, respectively. Negative associations of copper and manganese with cardiac structure and function, whereas positive associations of titanium, selenium and molybdenum with several parameters were found. Antagonistic interactions between copper and tin and between selenium and several metals (manganese, copper and aluminum) (all Pinteraction terms < 0.05) were found. In conclusion, mixed metal exposure was negatively associated with cardiac structure and function in CAD patients. The main metals contributing to this negative associations were copper and manganese. Selenium or tin supplementation may reduce the adverse associations of copper and manganese with cardiac structure and function.

Change in physical activity and its association with decline in kidney function: A UK Biobank-based cohort study.

Previous research on the association between physical activity (PA) and kidney function is inconsistent. The association between muscle mass and serum creatinine (SCr) may have implications for interpreting the effect of PA on estimated glomerular filtration rate (eGFR). Few studies have reported changes in physical activity and changes in kidney function. A cohort study was constructed using the UK Biobank. Changes in physical activity were self-reported as metabolic equivalent task (MET) minutes/week. eGFR was calculated using SCr and cystatin C (CysC). Cox and nonlinear regressions with restricted cubic splines were applied to explore the association between changes in physical activity and rapid decline of kidney function (RDKF, eGFR annual decrease ≥3mL/min/1.73m2), and the annual change of eGFR. An exploratory analysis of cardiorespiratory fitness as the exposure was conducted. Among 11757 participants, the median follow-up time was 4.4years. Participants whose PA decreased by 1000 MET minutes/week at the follow-up assessment had a 2% reduction in risk of developing RDKFSCr (HR=0.98, 95% CI: 0.96, 1.00). In contrast, a 1000 MET minutes/week increase in PA was associated with a 4% reduction in risk of developing RDKFCysC (HR=0.96, 95% CI: 0.93, 0.99). A PA increase of 1000 MET minutes/week was associated with eGFRCysC annual increase of 0.04mL/min/1.73m2 (95% CI: 0.03, 0.06) but no significant changes in eGFRSCr. In this general population study, there are differing associations between changes in PA and changes in kidney function depending on the kidney biomarker used. Increasing PA is modestly associated with improving annual eGFRCysC and reduced risk of RDKF.

Ethnic and racial violence and violations in the context of the Brazilian democratic crisis: a study of Black and Quilombola populations

ABSTRACT This article addresses the question of how the recent political context of Brazil shapes violations of various kinds against Quilombola communities in Brazil. Using data from online news sources, we track violations from 2016 to 2020 related to land disputes, physical attacks and threats, and environmental issues. We show that, despite the legal rights accorded to these communities since the 1988 constitutional reform and subsequent processes of democratisation, vested interests in the agricultural lobby and a later authoritarian turn, especially after 2016, led to a dismantling of social and economic policies for Quilombos. The violations suffered by these communities result from the denial of their collective identities as constitutional subjects and the non-recognition of their dignity, which are the product of historical processes of inferiorisation that have treated some people as non-subjects or not eligible to bear rights, based on colonial classifications but still present in the dominant society.

Evaluation of the potential impact and cost-effectiveness of respiratory syncytial virus (RSV) prevention strategies for infants in Argentina

Background. New interventions are available for the prevention of respiratory syncytial virus (RSV) disease in young infants. We aimed to assess the potential impact and cost-effectiveness of using a long-acting monoclonal antibody (RSV mAb) or maternal RSV vaccine in the Argentine context. Methods. We used a static proportionate outcomes model to calculate the costs and consequences of using RSV mAb or maternal RSV vaccine over a ten-year period (2025–2034) in Argentina, assuming both year-round and seasonal administration. We compared each intervention to no pharmaceutical RSV intervention. The primary outcome was the discounted cost per disability-adjusted life year (DALY) averted from a societal perspective. We assumed willingness-to-pay of US$ 12,285 per DALY averted (0.9 times the national gross domestic product per capita). We used population study data on costs and disease burden and the efficacy of clinical trials of both interventions as inputs. We ran deterministic and probabilistic uncertainty analyses. Findings. Either strategy (RSV mAb or maternal RSV vaccine) could prevent >25% of RSV deaths aged <5 years and ∼30% aged <6 months (the age group where most intervention impact occurs). With a dose price of $US 50, both products have a 100% probability of being cost-effective compared to no intervention (US$ 5283 [95%CI $5203–$5363] and US$ 5522 [95%CI $5427 – $5617] per DALY averted for year-round use of RSV mAb and maternal RSV vaccine, respectively). Similar health impact could be achieved by a six-month seasonal strategy, which could improve cost-effectiveness by around 45% (assuming the dose price is unchanged). Interpretation. Either RSV mAb or maternal RSV vaccine are worth consideration in Argentina when priced at ≤US$ 50 per dose. A seasonal strategy could improve cost-effectiveness.

The heart of celiac disease: understanding dilated cardiomyopathy, pathophysiology, and care-a systematic review.

Cardiac manifestations are infrequently reported in association with celiac disease, but clear link has not been established. The aim of this study was to explore the connection of dilated cardiomyopathy in celiac disease. This systematic review also provides a comprehensive overview of the association between celiac disease and various cardiac manifestations with pathophysiology and management. We searched PubMed, Cochrane Library, Google Scholar, Embase, Scopus, and Springer nature databases through June 4th 2023 for preferred studies related to our topic using MeSH and Regular keywords. After comprehensive search analysis, data extraction and quality appraisal 19 studies were included in the study. Although results varied across studies, majority of the studies revealed a positive link. Notably, some studies suggested an association between celiac disease and dilated cardiomyopathy, while others did not. These discrepancies could be attributed to differences in methodologies, study populations, and regional variations. Several studies have shown the association of various cardiac manifestations in celiac disease. Although dilated cardiomyopathy is associated with celiac disease in majority of the studies, there are also studies that conflict with the association. The complex relationship between celiac disease and cardiovascular manifestations potentiates the need for further research with standardized methodologies, larger sample sizes, and consideration of regional variations. Such insights are vital for improving clinical practice by establishing preventive strategies, active screening, early diagnosis, mitigating risks which helps in optimizing cardiovascular health in individuals with celiac disease.

Pharmacogenetics of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in cardiovascular diseases

Cardiovascular diseases (CVDs) have a high mortality rate, and despite the several available therapeutic targets, non-response to antihypertensives remains a common problem. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are important classes of drugs recommended as first-line therapy for several CVDs. However, response to ACEIs and ARBs varies among treated patients. Pharmacogenomics assesses how an individual's genetic characteristics affect their likely response to drug therapy. Currently, numerous studies suggest that genetic polymorphisms may contribute to variability in drug response. Moreover, further studies evaluating gene-gene interactions within signaling pathways in response to antihypertensives might help to unravel potential genetic predictors for antihypertensive response. This review summarizes the pharmacogenetic data for ACEIs and ARBs in patients with CVD, and discusses the potential pharmacogenetics of these classes of antihypertensives in clinical practice. However, replication studies in different populations are needed. In addition, studies that evaluate gene-gene interactions that share signaling pathways in the response to antihypertensive drugs might facilitate the discovery of genetic predictors for antihypertensive response.

A Comprehensive Examination of the Role of Epigenetic Factors in Multiple Sclerosis.

According to various research, the risk of multiple sclerosis (MS) is strongly influenced by genetic variations. Population, familial, and molecular studies provide strong empirical support for a polygenic pattern of inheritance, mainly due to relatively common allelic variants in the general population. The strongest MS susceptibility locus, which was unmistakably identified in tested populations, is the major histocompatibility complex on chromosome 6p21.3. However, the effect of a given predisposing variant remains modest, so there is the possibility that multiple gene-gene and/or gene-environment interactions could significantly increase the contribution of specific variants to the overall genetic risk. Furthermore, as is known, susceptibility genes can be subject to epigenetic modifications, which greatly increase the complexity of MS heritability. Investigating epigenetic and environmental factors can provide new opportunities for the molecular basis of the MS, which shows complicated pathogenesis. Although studies of epigenetic changes in MS only began in the last decade, a growing body of literature suggests that these may be involved in the development of MS. Here, we summarize recent studies regarding epigenetic changes related to MS initiation and progression. Furthermore, we discuss how current studies address important clinical questions and how future studies could be used in clinical practice.

Safety of teplizumab in patients with high-risk for diabetes mellitus type 1: A systematic review

Safety of teplizumab in patients with high-risk for diabetes mellitus type 1: A systematic review

Co-exposure to melamine and phthalates on early kidney injury markers: Findings from the Taiwan Biobank Adult Population Study

Co-exposure to melamine and phthalates on early kidney injury markers: Findings from the Taiwan Biobank Adult Population Study

Psychiatric neuroimaging designs for individualised, cohort, and population studies.

Psychiatric neuroimaging faces challenges to rigour and reproducibility that prompt reconsideration of the relative strengths and limitations of study designs. Owing to high resource demands and varying inferential goals, current designs differentially emphasise sample size, measurement breadth, and longitudinal assessments. In this overview and perspective, we provide a guide to the current landscape of psychiatric neuroimaging study designs with respect to this balance of scientific goals and resource constraints. Through a heuristic data cube contrasting key design features, we discuss a resulting trade-off among small sample, precision longitudinal studies (e.g., individualised studies and cohorts) and large sample, minimally longitudinal, population studies. Precision studies support tests of within-person mechanisms, via intervention and tracking of longitudinal course. Population studies support tests of generalisation across multifaceted individual differences. A proposed reciprocal validation model (RVM) aims to recursively leverage these complementary designs in sequence to accumulate evidence, optimise relative strengths, and build towards improved long-term clinical utility.

Incidence, Nature and Natural History of Additional Histological Findings in Preimplantation and Implantation Kidney Transplant Biopsies.

The quality assurance provided by preimplantation biopsy quantification of chronic damage may allow greater use of kidneys from expanded criteria donors, and thereby expand the deceased donor pool. Preimplantation biopsy may, however, identify additional acute or chronic pathologies not considered in the scoring of chronic damage, and these may influence the decision to implant or discard the kidney. This single-centre retrospective cohort study of a contemporary UK donor population systematically characterised the nature of additional findings in 1,046 preimplantation and implantation biopsies over an eight-year period. A diverse range of findings were identified in 111/1,046 (11%) organs; most frequently diabetic glomerulopathy, focal segmental glomerulosclerosis, (micro)thrombi, neutrophil casts, and immunoglobulin/complement staining. Seventy (63%) of these were transplanted, with subsequent biopsy in 41 (58%) cases confirming that 80% of the initial acute changes had spontaneously resolved, while there was no progression of diabetic glomerulopathy, and the lesions of focal segmental glomerulosclerosis were not identified. Over 75% of assessable grafts with additional histological findings at the time of transplant showed adequate function at one-year following transplant. In conclusion, most histological abnormalities that may be identified in addition to chronic scarring in preimplantation kidney biopsies would not preclude transplantation nor predict poor graft function.