BACKGROUND: The last COVID-19 vaccine offered to all adults in England became available from November 2021. The most recent booster programme commenced in September 2023. Bivalent BA.4-5 or monovalent XBB.1.5 boosters were given. During the study period, the JN.1 variant became dominant in England.
METHODS: Vaccine effectiveness against hospitalisation was estimated throughout using the test-negative case-control study design where positive PCR tests from hospitalised individuals are cases and comparable negative PCR tests are controls. Multivariable logistic regression was used to assess vaccine effectiveness against hospitalisation with the test result as the outcome, vaccination status as the primary exposure variable of interest and confounder adjustment.
RESULTS: There was no evidence of residual protection for boosters given as part of previous campaigns. There were 28,916 eligible tests included to estimate the effectiveness of the autumn 2023 boosters in those aged 65 years and older. VE peaked at 50.6% (95% CI: 44.2-56.3%) after 2-4 weeks, followed by waning to 13.6% (95% CI: -11.7 to 33.2%). Estimates were generally higher for the XBB.1.5 booster than the BA.4-5 booster, but this difference was not statistically significant. Point estimates were highest against XBB sub-lineages. Effectiveness was lower against both JN.1 and EG.5.1 variants with confidence intervals non-overlapping with the effectiveness of the XBB sub-lineages at 2-4 weeks for EG.5.1 where VE was 44.5% (95% CI: 20.2-61.4%) and at 5-9 weeks for JN.1 where VE was 26.4% (95%CI: -3.4 to 47.6%).
CONCLUSIONS: The recent monovalent XBB.1.5 and bivalent BA.4-5 boosters provided comparable and good protection against hospitalisation, however there was evidence of lower VE against hospitalisation of these boosters against JN.1.

As in any observational study, in a case-control study a primary concern is potential unmeasured confounders. Bias, due to unmeasured confounders, can result in a false discovery of an apparent treatment effect when there is none. Replication of an observational study, which tries to provide multiple analyses of the data where the biases affecting each analysis are thought to be different, is one way to strengthen the evidence from an observational study. Evidence factors allow for internal replication by testing a hypothesis using multiple comparisons in a way that the comparisons yield independent evidence and differ in the sources of potential bias. We construct evidence factors in a case-control study in which there are two types of cases, \"narrow\" cases which are thought to be potentially more affected by the exposure and \"marginal\" cases which are thought to have more heterogeneous causes. We develop and study an inference procedure for using such evidence factors and apply it to a study of the effect of sigmoidoscopy screening on colorectal cancer.

BACKGROUND: Surgical skill, a summation of acquired wisdom, deliberate practice and experience, has been linked to improved patient outcomes. Graded mentored exposure to pathologies and operative techniques is a cornerstone of surgical training. Appendectomy is one of the first procedures surgical trainees perform independently. We hypothesize that, given the embedded training ethos in surgery, coupled with the steep learning curve required to achieve trainer-recognition of independent competency, \'real-world\' clinical outcomes following appendectomy for the treatment of acute appendicitis are operator agnostic. The principle of graded autonomy matches trainees with clinical conditions that they can manage independently, and increased complexity drives attending input or assumption of the technical aspects of care, and therefore, one cannot detect an impact of operator experience on outcomes.
METHODS: This study is a subgroup analysis of the SnapAppy international time-bound prospective observational cohort study (ClinicalTrials.gov Trial #NCT04365491), including all consecutive patients aged ≥ 15 who underwent appendectomy for appendicitis during a three-month period in 2020-2021. Patient- and surgeon-specific variables, as well as 90-day postoperative outcomes, were collected. Patients were grouped based on operating surgeon experience (trainee only, trainee with direct attending supervision, attending only). Poisson and quantile regression models were used to (adjusted for patient-associated confounders) assess the relationship between surgical experience and postoperative complications or hospital length of stay (hLOS), respectively, adjusted for patient-associated confounders. The primary outcome of interest was any complications within 90 days.
RESULTS: A total of 4,347 patients from 71 centers in 14 countries were included. Patients operated on by trainees were younger (Median (IQR) 33 [24-46] vs 38 [26-55] years, p < 0.001), had lower ASA classifications (ASA ≥ 3: 6.6% vs 11.6%, p < 0.001) and fewer comorbidities compared to those operated on by attendings. Additionally, trainees operated alone on fewer patients with appendiceal perforation (AAST severity grade ≥ 3: 8.7% vs 15.6%, p < 0.001). Regression analyses revealed no association between operator experience and complications (IRR 1.03 95%CI 0.83-1.28 for trainee vs attending; IRR 1.13 95%CI 0.89-1.42 for supervised trainee vs attending) or hLOS.
CONCLUSIONS: The linkage of case complexity with operator experience within the context of graduated autonomy is a central tenet of surgical training. Either subconsciously, or by design, patients operated on by trainees were younger, fitter and with earlier stage disease. At least in part, these explain why clinical outcomes following appendectomy do not differ depending on the experience of the operating surgeon.

Propensity score matching (PSM) is an increasingly applied method of ensuring comparability between groups of interest. However, PSM is often applied unconditionally, without precise considerations. The purpose of this study is to provide a nonmathematical guide for clinicians at the stage of designing a PSM-based study. We provide a seed of thought for considering whether applying PSM would be appropriate and, if so, the scope of the list of variables. Although PSM may be simple, its results could vary substantially according to how the propensity score is constructed. Misleading results can be avoided through a critical review of the process of PSM.

Anticoagulants are a potential treatment for the thrombotic complications resulting from COVID-19. We aimed to determine the association between anticoagulant use and adverse outcomes among hospitalized patients with COVID-19. We used data from the COVID-19 International Collaborative Research Project in South Korea from January to June 2020. We defined exposure using an intention-to-treat approach, with person-time classified as use or non-use of anticoagulants at cohort entry, and a time-varying approach. The primary outcome was all-cause, in-hospital mortality; the secondary outcome was a composite including respiratory outcomes, cardiovascular outcomes, venous thromboembolism, major bleeding, and intensive care unit admission. Cox proportional hazards models estimated adjusted hazard ratios (HRs) of the outcomes comparing use versus non-use of anticoagulants. Our cohort included 2,677 hospitalized COVID-19 patients, of whom 24 received anticoagulants at cohort entry. Users were older and had more comorbidities. The crude incidence rate (per 1,000 person-days) of mortality was 5.83 (95% CI: 2.80, 10.72) among anticoagulant users and 1.36 (95% CI: 1.14, 1.59) for non-users. Crude rates of the composite outcome were 3.20 (95% CI: 1.04, 7.47) and 1.80 (95% CI: 1.54, 2.08), respectively. Adjusted HRs for mortality (HR: 1.12, 95% CI: 0.48, 2.64) and the composite outcome (HR: 0.79, 95% CI: 0.28, 2.18) were inconclusive. Although our study was not able to draw conclusions on anticoagulant effectiveness for COVID-19 outcomes, these results can contribute to future knowledge syntheses of this important question. Our study demonstrated that the dynamic pandemic environment may have important implications for observational studies of COVID-19 treatment effectiveness.

BACKGROUND: Story recall is a simple and sensitive cognitive test that is commonly used to measure changes in episodic memory function in early Alzheimer disease (AD). Recent advances in digital technology and natural language processing methods make this test a candidate for automated administration and scoring. Multiple parallel test stimuli are required for higher-frequency disease monitoring.
OBJECTIVE: This study aims to develop and validate a remote and fully automated story recall task, suitable for longitudinal assessment, in a population of older adults with and without mild cognitive impairment (MCI) or mild AD.
METHODS: The \"Amyloid Prediction in Early Stage Alzheimer\'s disease\" (AMYPRED) studies recruited participants in the United Kingdom (AMYPRED-UK: NCT04828122) and the United States (AMYPRED-US: NCT04928976). Participants were asked to complete optional daily self-administered assessments remotely on their smart devices over 7 to 8 days. Assessments included immediate and delayed recall of 3 stories from the Automatic Story Recall Task (ASRT), a test with multiple parallel stimuli (18 short stories and 18 long stories) balanced for key linguistic and discourse metrics. Verbal responses were recorded and securely transferred from participants\' personal devices and automatically transcribed and scored using text similarity metrics between the source text and retelling to derive a generalized match score. Group differences in adherence and task performance were examined using logistic and linear mixed models, respectively. Correlational analysis examined parallel-forms reliability of ASRTs and convergent validity with cognitive tests (Logical Memory Test and Preclinical Alzheimer\'s Cognitive Composite with semantic processing). Acceptability and usability data were obtained using a remotely administered questionnaire.
RESULTS: Of the 200 participants recruited in the AMYPRED studies, 151 (75.5%)-78 cognitively unimpaired (CU) and 73 MCI or mild AD-engaged in optional remote assessments. Adherence to daily assessment was moderate and did not decline over time but was higher in CU participants (ASRTs were completed each day by 73/106, 68.9% participants with MCI or mild AD and 78/94, 83% CU participants). Participants reported favorable task usability: infrequent technical problems, easy use of the app, and a broad interest in the tasks. Task performance improved modestly across the week and was better for immediate recall. The generalized match scores were lower in participants with MCI or mild AD (Cohen d=1.54). Parallel-forms reliability of ASRT stories was moderate to strong for immediate recall (mean rho 0.73, range 0.56-0.88) and delayed recall (mean rho=0.73, range=0.54-0.86). The ASRTs showed moderate convergent validity with established cognitive tests.
CONCLUSIONS: The unsupervised, self-administered ASRT task is sensitive to cognitive impairments in MCI and mild AD. The task showed good usability, high parallel-forms reliability, and high convergent validity with established cognitive tests. Remote, low-cost, low-burden, and automatically scored speech assessments could support diagnostic screening, health care, and treatment monitoring.

Collecting new data from cross-sectional/survey and cohort observational study designs can be expensive and time-consuming. Nested (hierarchically cocooned within an existing parent study) and/or Multipart (≥ 2 integrally interlinked projects) study designs can expand the scope of a prospective observational research program beyond what might otherwise be possible with available funding and personnel. The Brain, Bone, Heart (BBH) study provides an exemplary case to describe the real-world advantages, challenges, considerations, and insights from these complex designs. MAIN: BBH is a Nested, Multipart study conducted by the Specialized Center for Research Excellence (SCORE) on Sex Differences at Emory University. BBH is designed to examine whether estrogen insufficiency-induced inflammation compounds HIV-induced inflammation, leading to end-organ damage and aging-related co-morbidities affecting the neuro-hypothalamic-pituitary-adrenal axis (brain), musculoskeletal (bone), and cardiovascular (heart) organ systems. Using BBH as a real-world case study, we describe the advantages and challenges of Nested and Multipart prospective cohort study design in practice. While excessive dependence on its parent study can pose challenges in a Nested study, there are significant advantages to the study design as well. These include the ability to leverage a parent study\'s resources and personnel; more comprehensive data collection and data sharing options; a broadened community of researchers for collaboration; dedicated longitudinal research participants; and, access to historical data. Multipart, interlinked studies that share a common cohort of participants and pool of resources have the advantage of dedicated key personnel and the challenge of increased organizational complexity. Important considerations for each study design include the stability and administration of the parent study (Nested) and the cohesiveness of linkage elements and staff organizational capacity (Multipart).
Using the experience of BBH as an example, Nested and/or Multipart study designs have both distinct advantages and potential vulnerabilities that warrant consideration and require strong biostatistics and data management leadership to optimize programmatic success and impact.

When drawing causal inference from observed data, failure time outcomes present additional challenges of censoring often combined with other missing data patterns. In this article, we follow incident cases of end-stage renal disease to examine the effect on all-cause mortality of starting treatment with transplant, so-called pre-emptive kidney transplantation, vs starting with dialysis possibly followed by delayed transplantation. The question is relatively simple: which start-off treatment is expected to bring the best survival for a target population? To address it, we emulate a target trial drawing on the long term Swedish Renal Registry, where a growing common set of baseline covariates was measured nationwide. Several lessons are learned which pertain to long term disease registers more generally. With characteristics of cases and versions of treatment evolving over time, informative censoring is already introduced in unadjusted Kaplan-Meier curves. This leads to misrepresented survival chances in observed treatment groups. The resulting biased treatment association may be aggravated upon implementing IPW for treatment. Aware of additional challenges, we further recall how similar studies to date have selected patients into treatment groups based on events occurring post treatment initiation. Our study reveals the dramatic impact of resulting immortal time bias combined with other typical features of long-term incident disease registers, including missing covariates during the early phases of the register. We discuss feasible ways of accommodating these features when targeting relevant estimands, and demonstrate how more than one causal question can be answered relying on the no unmeasured baseline confounders assumption.

BACKGROUND: Efmoroctocog alfa, the first recombinant factor VIII fusion protein with extended half-life (rFVIII-Fc), has been hypothesized to lower FVIII consumption in patients with severe Haemophilia A (pwSHA), without reducing clinical efficacy. What about real life?
METHODS: MOTHIF-II was a noninterventional, multicentre, before/after study, via the collection of retrospective data from July 2015 to June 2016 (called T1), and from July 2017 to June 2018 (called T2), in 7 French haemophilia treatment centres. We examined the prescriptions and dispensations of factor VIII and the Annual Bleeding Rate (ABR), in pwSHA without current inhibitors on prophylaxis, before and after the introduction of rFVIII-Fc. The data gathered from the BERHLINGO research database and from the French Healthcare claims database with a determinist pairing process based on the national unique identification number.
RESULTS: A total of 156 pwSHA were included in the prescription cohort and 83 in the ABR cohort. For switched patients, the mean amounts of prescribed FVIII were significantly higher during T1 compared to T2 (4333 (2052) vs. 3921 (2029) IU/kg/year/patient, p: 0.028); a significant decrease in their ABR was also observed between T1 and T2 (6.3 (6.0) vs. 4.4 (5.4), p: 0.047). These patients had a more severe bleeding profile centred on haemarthrosis.
CONCLUSIONS: The results are related to those of the pivotal clinical trials for the reduction in FVIII consumption following the switch to rFVIII-Fc, with a significant improvement in the haemorrhagic phenotype for pwSHA.

OBJECTIVE: To determine whether obesity-associated metabolites are associated with type 2 diabetes (T2DM) risk among South Asians.
METHODS: Serum-based nuclear magnetic resonance imaging metabolomics data were generated from two South Asian population-based prospective cohorts from Karachi, Pakistan: CARRS1 (N = 4017) and CARRS2 (N = 4802). Participants in both cohorts were followed up for 5 years and incident T2DM was ascertained. A nested case-control study approach was developed to select participants from CARRS1 (Ncases  = 197 and Ncontrols  = 195) and CARRS2 (Ncases  = 194 and Ncontrols  = 200), respectively. First, we investigated the association of 224 metabolites with general obesity based on body mass index and with central obesity based on waist-hip ratio, and then the top obesity-associated metabolites were studied in relation to incident T2DM.
RESULTS: In a combined sample of the CARRS1 and CARRS2 cohorts, out of 224 metabolites, 12 were associated with general obesity and, of these, one was associated with incident T2DM. Fifteen out of 224 metabolites were associated with central obesity and, of these, 10 were associated with incident T2DM. The higher level of total cholesterol in high-density lipoprotein (HDL) was associated with reduced T2DM risk (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.53, 0.86; P = 1.2 × 10-3 ), while higher cholesterol esters in large very-low-density lipoprotein (VLDL) particles were associated with increased T2DM risk (OR 1.90, 95% CI 1.40, 2.58; P = 3.5 × 10-5 ).
CONCLUSIONS: Total cholesterol in HDL and cholesterol esters in large VLDL particles may be an important biomarker in the identification of early development of obesity-associated T2DM risk among South Asian adults.