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INTRODUCTION Biomarkers identify Alzheimer's disease pathology in cognitively unimpaired adults, but the timing and rate of cognitive decline vary widely. This study aimed to identify subgroups of cognitive decline and baseline predictors of heterogeneity in preclinical progression. METHODS Data were drawn from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer's Disease Study, which enrolled amyloid beta‐positive (Aβ+) participants, and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) Study, which enrolled amyloid beta‐negative (Aβ−) individuals. Latent class mixed‐effects models identified cognitive trajectory classes. Associations between class membership and demographic, clinical, and biomarker variables were evaluated. The primary outcome was change in the Preclinical Alzheimer Cognitive Composite. RESULTS Three trajectory classes were identified: stable, slow decliners, and fast decliners. Higher phosphorylated tau at 217 (p‐tau217), smaller hippocampal volume, and elevated tau positron emission tomography were associated with declining classes. About 70% of Aβ+ individuals were stable. DISCUSSION Latent class modeling reveals substantial heterogeneity in preclinical trajectories with important implications for prevention trial design. Highlights Latent class analysis of A4 and LEARN data identified distinct patterns of preclinical cognitive trajectories among biomarker‐positive individuals. Recently developed biomarkers, including plasma p‐tau217 and tau PET, improved prediction of latent class membership. Most Aβ+ individuals showed cognitive stability, which reduces statistical power for traditional cognitive endpoints. Declining individuals contributed disproportionately to statistical power despite representing a minority of the Aβ+ population. Findings highlight the need for power analyses and/or trial simulations that account for heterogeneity in preclinical cognitive decline

Hospitalization for major diabetes complications, including myocardial infarction, stroke, lower-extremity amputation, and end-stage kidney disease, is on the rise and represents a great health burden for patients with type 2 diabetes (T2D), in particular for older people. Newer glucose-lowering medications have generated some optimism on the possibility to influence the natural history of cardiorenal complications of T2D. This review summarizes work in the area of sodium–glucose cotransporter 2 inhibitors (SGLT-2i) treatment and prevention of cardiorenal complications in patients with T2D (major adverse cardiovascular events, hospitalization for heart failure, kidney outcomes), with a particular emphasis on the effect of age, the role of primary versus secondary prevention and the possible extension of their cardiorenal benefits to the entire class of SGLT-2i.

The definition of class effect for SGLT-2 inhibitors may be based on three concepts: a similar chemical structure, a similar mechanism of action and similar pharmacological effects. We have also assumed that a class effect does exist when an effect on a particular outcome is present and is significant for each drug within the class of SGLT-2 inhibitors. For major cardiovascular events (MACE), there is no class effect for SGLT-2 inhibitors, as the 7% reduction of MACE risk observed with dapagliflozin in the DECLARE trial was not significant; on the other hand, a class effect is evident for both heart failure and diabetic kidney disease, as in all four trials so far completed (EMPAREG-OUTCOME, CANVAS, DECLARE, CREDENCE) the risk of hospitalization for heart failure and progression of diabetic kidney disease was significantly reduced by all SGLT-2 inhibitors.

Programmed-death-1/ligand-1 inhibitors (PD-1/L1is) have emerged as pivotal treatments for many cancers. A notable feature of this class of medicines is the dichotomous response pattern: A small (but clinically relevant) percentage of patients (5%–20%) benefit from deep and durable responses resembling functional cures (durable responders), while most patients experience only a modest or negligible response. Accurately predicting durable responders remains elusive due to the lack of a reliable biomarker. Another notable feature of these medicines is that different PD-1/L1 is have obtained statistically significant results, leading to marketing approval for some cancer indications but not for others, with no discernible pattern. These puzzling inconsistencies have generated extensive discussions among oncologists. Proposed (but not entirely convincing) explanations include true underlying differences in efficacy for some types of cancer but not others; or subtle differences in trial design. To investigate a less-explored hypothesis—the durable-responder effect: An initially unidentified group of durable responders generates more statistical noise than anticipated, leading to low-powered randomized controlled trials (RCTs) that report randomly variable results. Employing simulation, this investigation divides participants in PD-(L)1i RCTs into two groups: durable responders and patients with a more modest response. Drawing on published data for melanoma, lung and urothelial cancers, multiple prespecified scenarios are replicated 50,000 times, systematically varying the durable-responder percentage from 5% to 20% and the modest-response hazard ratio for overall survival [HR(OS)] from 0.8 to 1.0. This allowed evaluation of the effect of durable responders on power, point estimates of the treatment effect for OS, and the probability of a misleading signal for harm. When the treatment effect for the modest responders is similar to the comparator arm, statistical power remains below 80%, limiting the ability to reliably detect durable responders. Conversely, there is a material probability of obtaining a statistically significant result that exaggerates the treatment effect by chance. For instance, with an average HR(OS) of 0.93 (corresponding to 5% durable responders), statistically significant trials (7.2%) show an average HR(OS) of 0.77. Additionally, when 5% are durable responders, there is a 20% probability that the HR(OS) will exceed 1.0—suggesting potential harm when none exists. This article adds to the possible explanations for the puzzlingly inconsistent results from PD-(L)1i RCTs. Initially, unidentified durable responders introduce features typical of imprecise, low-powered studies: a propensity for false-negative results; estimates of benefit that might not replicate; and misleading signals for harm. Programmed-death-1/ligand-1 (PD-1(L)1) inhibitors are crucial cancer treatments, with global spending expected to surpass $75 billion by 2026. Multiple versions of these medicines are available, all designed to boost the immune system to fight cancer. We would expect them all to work similarly, but clinical trials show mixed results—some seem effective for certain cancers but not others, without a clear pattern. This article uses simulations (virtual trials) to suggest that these inconsistent results may be due to chance, caused by a small group of patients who respond very well to the treatment. Larger trials or specific analysis methods could help reduce the chance effects and provide more robust data for clinician and patient decision-making. •PD-(L)1 inhibitor trials report inconsistent results more often than expected.•Durable responses to PD-(L)1 inhibitors occur in approximately 5% to 20% of patients.•Via simulation we show that durable responders introduce excess statistical noise.•PD-(L)1i trials are prone to randomly variable results that might not replicate.•We should be careful not to overinterpret different results for same-class PD-(L)1 inhibitors.

This study explores the connections between aspects of the school environment and emotional problems among boys and girls. The sample comprised 2,120 adolescents aged 17 and 18 years, in 129 school classes from 13 upper secondary schools in Trøndelag county, Norway. The response rate was 79%. The girls reported more emotional problems than the boys. Variations in perceptions of emotional problems between schools and classes is an under-researched topic. Multilevel models revealed a substantial class-level effect regarding emotional problems and a smaller school-level effect. Emotional problems varied between classes because of the class composition (share of boys and girls) and the class context. Contextual factors relevant to emotional problems were peer support, teacher support, and that emotional problems could 'spread' in a class. Relations between emotional problems and peer support, teacher support, and parental support were stronger for girls than boys. The study emphasizes the importance of the classroom environment, and it suggests that fostering strong relationships between adolescents and teachers, as well as addressing emotional issues among adolescents, can have a positive impact on emotional well-being. An important topic for future studies is whether the inclusion of the health and life skills theme improves mental health support in schools.

Peptides derived from exogenous proteins are presented by both MHC class I and II. Despite extensive study, the features of the endocytic pathway that mediate cross-presentation of exogenous antigens on MHC class I are not entirely understood and difficult to generalize to all proteins. Here, we used dendritic cells and macrophages to examine MHC class I and II presentation of hen egg-white lysozyme (HEL) in different forms, soluble and liposome encapsulated. Soluble HEL or HEL targeted to a late endosomal compartment only allowed for MHC class II presentation, in a process that was blocked by chloroquine and a cathepsin S (CatS) inhibitor; brefeldin A (BFA) also blocked presentation, indicating a requirement for nascent MHC class II. In contrast, liposome-encapsulated HEL targeted to early endosomes entered the MHC class I and II presentation pathways. Cross-presentation of HEL in early endosomal liposomes had several unique features: it was markedly increased by BFA and by blockade of the proteasome or Cats activity, it occurred independently of the transporter associated with antigen processing but required an MHC class I surface stabilizing peptide, and it was inhibited by chloroquine. Remarkably, chloroquine facilitated MHC class I cross-presentation of soluble HEL and HEL in late endosomal liposomes. Altogether, MHC class I and II presentation of HEL occurred through pathways having distinct molecular and proteolytic requirements. Moreover, MHC class I sampled antigenic peptides from various points along the endocytic route.

PI3Kδ controls the expression of the recombinogenic enzyme AID; excessive AID activity caused by PI3Kδ inhibition can induce genomic instability in leukaemia and lymphoma cells, as well as in patients with chronic lymphocytic leukaemia treated with PI3Kδ inhibitors. Unwanted DNA effects of cancer drugs The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway is highly active in many types of cancer. Several PI3Kδ inhibitors have been approved for the treatment of B-cell cancers such as leukaemias and lymphomas. Besides its cancer-promoting effects, PI3Kδ also controls the activity of the activation-induced cytidine deaminase (AID) enzyme, which promotes DNA recombination. Excessive AID activity due to PI3Kδ inhibition induced genomic instability in leukaemia and lymphoma cell lines in culture, as well as in patients with chronic lymphocytic leukaemia treated with PI3Kδ inhibitors. The authors recommend that these adverse genomic effects are taken into account in patients receiving long-term therapy with this class of drugs. Activation-induced cytidine deaminase (AID) is a B-cell-specific enzyme that targets immunoglobulin genes to initiate class switch recombination and somatic hypermutation 1 . In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma 2 . AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation 3 . The phosphatidylinositol 3-kinase δ (PI3Kδ) pathway regulates AID by suppressing its expression in B cells 4 . Drugs for leukaemia or lymphoma therapy such as idelalisib, duvelisib and ibrutinib block PI3Kδ activity directly or indirectly 5 , 6 , 7 , 8 , potentially affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. Both of these effects were completely abrogated in AID-deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumours in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IGH and AID off-target sites in human chronic lymphocytic leukaemia and mantle cell lymphoma cell lines, and patients treated with idelalisib, but not ibrutinib, showed increased somatic hypermutation in AID off-targets. In summary, we show that PI3Kδ or Bruton’s tyrosine kinase inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. This effect should be carefully considered, as such inhibitors can be administered to patients for years.

Climatic change is expected to affect individual life histories and population dynamics, potentially increasing vulnerability to extinction. The importance of genetic diversity has been highlighted for adaptation and population persistence. However, whether responses of life-history traits to a given environmental condition depend on the genetic characteristics of a population remains elusive. Here we tested this hypothesis in the lizard Zootoca vivipara by simultaneously manipulating habitat humidity, a major climatic predictor of Zootoca’s distribution, and adult male color morph frequency, a trait with genome-wide linkage. Interactive effects of humidity and morph frequency had immediate effects on growth and body condition of juveniles and yearlings, as well as on adult survival, and delayed effects on offspring size. In yearlings, higher humidity led to larger female body size and lower humidity led to higher male compared to female survival. In juveniles and yearlings, some treatment effects were compensated over time. The results show that individual responses to environmental conditions depend on the population’s color morph frequency, age class, and sex and that these affect intra– and inter–age class competition. Moreover, humidity affected the competitive environment rather than imposing trait-based selection on specific color morphs. This indicates that species’ responses to changing environments (e.g., to climate change) are highly complex and difficult to accurately reconstruct and predict without information on the genetic characteristics and demographic structure of populations.

We study the treatment effect of grade retention using a panel of French junior high-school students, taking unobserved heterogeneity and the endogeneity of grade repetitions into account. We specify a multistage model of human-capital accumulation with a finite number of types representing unobserved individual characteristics. Class-size and latent student-performance indices are assumed to follow finite mixtures of normal distributions. Grade retention may increase or decrease the student's knowledge capital in a type-dependent way. Our estimation results show that the average treatment effect on the treated (ATT) of grade reten- tion on test scores is positive but small at the end of grade 9. Treatment effects are heterogeneous: we find that the ATT of grade retention is higher for the weak- est students. We also show that class size is endogenous and tends to increase with unobserved student ability. The average treatment effect of grade retention is neg- ative, again with the exception of the weakest group of students. Grade repetitions reduce the probability of access to grade 9 of all student types.