Does randomization assert the balance across trial arms? Revisiting Worrall's criticism.

We revisit John Worrall's old but still prominent argument against the view that randomization balances the impact of both known and unknown confounders across the treatment and control arms. We argue that his argument involving indefinitely many possible confounders is at odds with statistical theory as it (1) presumes that the purpose of randomized studies is obtaining perfect point estimates for which perfect balance is needed; (2) mistakes equalizing each confounder with the overall (average) impact of all confounders, and (3) assumes that the joint effect of an infinite series of confounders cannot be bounded. We defend the role of randomization in balancing the impact of confounders across the treatment and control arms by putting forward the statistical sense of the balance claim.

Blood-based epigenetic biomarkers associated with incident chronic kidney disease in individuals with type 2 diabetes.

There is an increasing need for new biomarkers improving prediction of chronic kidney disease (CKD) in individuals with type 2 diabetes (T2D). We aimed to identify blood-based epigenetic biomarkers associated with incident CKD and develop a methylation risk score (MRS) predicting CKD in newlydiagnosed individuals with T2D. DNA methylation was analysed epigenome-wide in blood from 487 newly-diagnosed individuals with T2D, of whom 88 developed CKD during 11.

DNA methylation in cord blood partially mediates the effects of prepregnancy BMI on early childhood offspring BMI.

Objective: We investigated whether prepregnancy BMI (prePregBMI) in women with obesity was associated with differential DNA methylation (DNAm) in cord blood (CB) and whether DNAm may mediate the association of prePregBMI and early childhood BMI z score (BMIz).

Methods: From the Treatment of Obese Pregnant Women (TOP) study, 232 mother-child pairs were included. We conducted an epigenome-wide association study on prePregBMI and CB DNAm (450k array), followed by causal mediation analyses to test whether DNAm may mediate effects of prePregBMI on  BMIz at age 36 months (BMIz36).

Causal Pluralism in Medicine and its Implications for Clinical Practice.

The existing philosophical views on what is the meaning of causality adequate to medicine are vastly divided. We approach this question and offer two arguments in favor of pluralism regarding concepts of causality. First, we analyze the three main types of research designs (randomized-controlled trials, observational epidemiology and laboratory research).

The Relationship between miR-5682 and Nutritional Status of Radiotherapy-Treated Male Laryngeal Cancer Patients.

Background: Nutritional deficiencies are frequently observed in patients with head and neck cancer (HNC) undergoing radiation therapy. microRNAs (miRNAs) were found to play an important role in the development of metabolic disorders throughout regulation of genes involved in inflammatory responses. This study aimed to explore the correlation between pre-treatment miR-5682 expression and parameters reflecting nutritional deficits in laryngeal cancer (LC) patients subjected to radiotherapy (RT).

Direct interrogation of context-dependent GPCR activity with a universal biosensor platform.

G protein-coupled receptors (GPCRs) are the largest family of druggable proteins encoded in the human genome, but progress in understanding and targeting them is hindered by the lack of tools to reliably measure their nuanced behavior in physiologically relevant contexts. Here, we developed a collection of compact ONE vector G-protein Optical (ONE-GO) biosensor constructs as a scalable platform that can be conveniently deployed to measure G-protein activation by virtually any GPCR with high fidelity even when expressed endogenously in primary cells. By characterizing dozens of GPCRs across many cell types like primary cardiovascular cells or neurons, we revealed insights into the molecular basis for G-protein coupling selectivity of GPCRs, pharmacogenomic profiles of anti-psychotics on naturally occurring GPCR variants, and G-protein subtype signaling bias by endogenous GPCRs depending on cell type or upon inducing disease-like states.

Direct interrogation of context-dependent GPCR activity with a universal biosensor platform.

G protein-coupled receptors (GPCRs) are the largest family of druggable proteins in the human genome, but progress in understanding and targeting them is hindered by the lack of tools to reliably measure their nuanced behavior in physiologically-relevant contexts. Here, we developed a collection of compact ONE vector G-protein Optical (ONE-GO) biosensor constructs as a scalable platform that can be conveniently deployed to measure G-protein activation by virtually any GPCR with high fidelity even when expressed endogenously in primary cells. By characterizing dozens of GPCRs across many cell types like primary cardiovascular cells or neurons, we revealed new insights into the molecular basis for G-protein coupling selectivity of GPCRs, pharmacogenomic profiles of anti-psychotics on naturally-occurring GPCR variants, and G-protein subtype signaling bias by endogenous GPCRs depending on cell type or upon inducing disease-like states.

Wood warbler population dynamics in response to mast seeding regimes in Europe.

Mast seeding is the episodic, massive production of plant seeds synchronized over large areas. The resulting superabundance of seeds represents a resource pulse that can profoundly affect animal populations across trophic levels. Following years of high seed production, the abundance of both seed consumers and their predators increase.

Temporal avoidance as a means of reducing competition between sympatric species.

Human activity has modified the availability of natural resources and the abundance of species that rely on them, potentially changing interspecific competition dynamics. Here, we use large-scale automated data collection to quantify spatio-temporal competition among species with contrasting population trends. We focus on the spatial and temporal foraging behaviour of subordinate marsh tits among groups of socially and numerically dominant blue tits and great tits .

Slow development of woodland vegetation and bird communities during 33 years of passive rewilding in open farmland.

Passive rewilding is a potential tool for expanding woodland cover and restoring biodiversity by abandoning land management and allowing natural vegetation succession to occur. Land can be abandoned to passive rewilding deliberately or due to socio-economic change. Despite abandonment being a major driver of land use change, few have studied the long-term outcomes for vegetation and biodiversity in Western Europe.

Weather impacts on interactions between nesting birds, nest-dwelling ectoparasites and ants.

Weather has a dominant impact on organisms, including their life histories and interspecific interactions. Yet, for nesting birds, and the arthropods inhabiting bird nests, the direct and cascading effects of weather are poorly known. We explored the influence of ambient temperatures and rainfall on the cohabitation of dome-shaped bird nests by Wood Warblers Phylloscopus sibilatrix, their blowfly Protocalliphora azurea ectoparasites, and predatory Myrmica and Lasius ants that may provide nest sanitation.

The failure of drug repurposing for COVID-19 as an effect of excessive hypothesis testing and weak mechanistic evidence.

The current strategy of searching for an effective treatment for COVID-19 relies mainly on repurposing existing therapies developed to target other diseases. Conflicting results have emerged in regard to the efficacy of several tested compounds but later results were negative. The number of conducted and ongoing trials and the urgent need for a treatment pose the risk that false-positive results will be incorrectly interpreted as evidence for treatments' efficacy and a ground for drug approval.

Quantifying the utility of islet autoantibody levels in the prediction of type 1 diabetes in children.

Aims/hypothesis: The aim of this study was to explore the utility of islet autoantibody (IAb) levels for the prediction of type 1 diabetes in autoantibody-positive children.

Methods: Prospective cohort studies in Finland, Germany, Sweden and the USA followed 24,662 children at increased genetic or familial risk of developing islet autoimmunity and diabetes. For the 1403 who developed IAbs (523 of whom developed diabetes), levels of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonised for analysis.

Possible Relationship between the HLA-DRA1 Intron Haplotype of Three Single-Nucleotide Polymorphisms in Intron 1 of the HLA-DRA1 Gene and Autoantibodies in Children at Increased Genetic Risk for Autoimmune Type 1 Diabetes.

Recently, a haplotype of three single-nucleotide polymorphisms (tri-SNP) in intron 1 of the HLA-DRA1 gene was found to be strongly associated with type 1 diabetes risk in HLA-DR3/3 individuals. The tri-SNP reportedly function as "expression quantitative trait loci," modulating HLA-DR and -DQ expression. The aim was to investigate HLA-DRA1 tri-SNPs in relation to extended HLA class II haplotypes and human peripheral blood cell HLA-DQ cell-surface median fluorescence intensity (MFI), the first-appearing islet autoantibody, and autoimmunity burden.

Long-Term GAD-alum Treatment Effect on Different T-Cell Subpopulations in Healthy Children Positive for Multiple Beta Cell Autoantibodies.

Objective: The objective of this study was to explore whether recombinant GAD65 conjugated hydroxide (GAD-alum) treatment affected peripheral blood T-cell subpopulations in healthy children with multiple beta cell autoantibodies.

Method: The Diabetes Prevention-Immune Tolerance 2 (DiAPREV-IT 2) clinical trial enrolled 26 children between 4 and 13 years of age, positive for glutamic acid decarboxylase autoantibody (GADA) and at least one other autoantibody (insulin, insulinoma antigen-2, or zinc transporter 8 autoantibody (IAA, IA-2A, or ZnT8A)) at baseline. The children were randomized to two doses of subcutaneously administered GAD-alum treatment or placebo, 30 days apart.

App-based COVID-19 syndromic surveillance and prediction of hospital admissions in COVID Symptom Study Sweden.

The app-based COVID Symptom Study was launched in Sweden in April 2020 to contribute to real-time COVID-19 surveillance. We enrolled 143,531 study participants (≥18 years) who contributed 10.6 million daily symptom reports between April 29, 2020 and February 10, 2021.

Multiplex agglutination-PCR (ADAP) autoantibody assays compared to radiobinding autoantibodies in type 1 diabetes and celiac disease.

Multiplex Antibody-Detection by Agglutination-PCR (ADAP) assay was compared to singleplex standard radiobinding assays (RBA) to detect autoantibodies against insulin (IAA), GAD65 (GADA), islet antigen-2 (IA-2A), ZnT8 (ZnT8A) and tissue transglutaminase (TGA). Serum samples from 273 (114F/158M), 15-73 years of age healthy controls and 227 (109F/118M) newly diagnosed type 1 diabetes children, 1-11 years of age, were analyzed in both assay systems.The original WHO standard 97/550 and in-house reference standards for RBA were compared to ADAP.

Childhood Height Growth Rate Association With the Risk of Islet Autoimmunity and Development of Type 1 Diabetes.

Context: Rapid growth has been suggested to promote islet autoimmunity and progression to type 1 diabetes (T1D). Childhood growth has not been analyzed separately from the infant growth period in most previous studies, but it may have distinct features due to differences between the stages of development.

Objective: We aimed to analyze the association of childhood growth with development of islet autoimmunity and progression to T1D diagnosis in children 1 to 8 years of age.

Heterogeneity of beta-cell function in subjects with multiple islet autoantibodies in the TEDDY family prevention study - TEFA.

Background: Individuals with multiple islet autoantibodies are at increased risk for clinical type 1 diabetes and may proceed gradually from stage to stage complicating the recruitment to secondary prevention studies. We evaluated multiple islet autoantibody positive subjects before randomisation for a clinical trial 1 month apart for beta-cell function, glucose metabolism and continuous glucose monitoring (CGM). We hypothesized that the number and type of islet autoantibodies in combination with different measures of glucose metabolism including fasting glucose, HbA1c, oral glucose tolerance test (OGTT), intra venous glucose tolerance test (IvGTT) and CGM allows for more precise staging of autoimmune type 1 diabetes than the number of islet autoantibodies alone.

Is meta-analysis of RCTs assessing the efficacy of interventions a reliable source of evidence for therapeutic decisions?

Literature-based meta-analysis is a standard technique applied to pool results of individual studies used in medicine and social sciences. It has been criticized for being too malleable to constrain results, averaging incomparable values, lacking a measure of evidence's strength, and problems with a systematic bias of individual studies. We argue against using literature-based meta-analysis of RCTs to assess treatment efficacy and show that therapeutic decisions based on meta-analytic average are not optimal given the full scope of existing evidence.