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The etiology of Insulin Dependent Diabetes Mellitus (IDDM) is reviewed and discussed using Rothman's deterministic model for causal inference. Intercontinental comparisons, familial aggregation, seasonal variation, maternal age, breast-feeding and infectious agents are reviewed within the context of IDDM causation. Genetic, viral and other environmental factors play a major role in this etiologic model.
BACKGROUND: The ability of hostility and type-A personality to predict cardiovascular outcomes makes understanding antecedents of these personality traits an important public health objective. OBJECTIVES: This study aimed to examine whether blood-measured fatty acids (the exposure) are associated with hostility and type-A personality (the outcome), while accounting for lifestyle, sociodemographic factors, and polygenic background. METHODS: Personality traits, sociodemographic, and lifestyle data were obtained in 1992-1993 from 452 family members living in kibbutz settlements in Israel (visit 1) and remeasured 8 to 10 y later in 379 individuals (visit 2). Red blood cell (RBC) fatty acid concentrations were determined in visit 1 by gas chromatography. Longitudinal associations of visit 1 fatty acids with visit 2 personality traits were examined using linear models, before and after controlling for baseline personality scores. The contribution of environmental factors to personality scores beyond heritability was estimated by variance decomposition. RESULTS: In longitudinal analysis, 1% increase in visit 1 total n-6 (ω-6) fatty acid was associated with a 0.328-unit decrease in visit 2 type-A score [95% confidence interval (CI): -0.571, -0.085]. After adjustment for baseline personality levels, the association was slightly attenuated (β= -0.204; CI: -0.399, -0.009). One percent higher total n-6 was also associated with 1.119 units lower visit 2 hostility score (CI: -2.777, 0.038; P = 0.055). Finally, independent of the genetic contribution (32%-38% of adjusted variability in hostility and type-A personality), 1% increase in total n-3 and total n-6 was associated with 2.539 (CI: -3.907, -1.171) and 0.201 (CI: -0.365, -0.037) units lower hostility and type-A scores, respectively. CONCLUSIONS: Higher RBC total n-6 fatty acid concentrations are associated with lower type-A personality scores. After adjustment for baseline personality levels, the associations between total n-6 and hostility and between total n-3 and hostility are attenuated. These findings support further investigation of the relationship between fatty acid biology and personality traits using study designs better suited to causal inference.
The objective of this study was to assess the effect of insurance status and demographic characteristics on ED disposition among patients with traumatic brain injury (TBI). Statewide hospital discharge and ED datasets in South Carolina, 1996-2001, were analyzed by primary or secondary diagnosis of TBI in a multivariable logistic regression model. Of 70,671 unduplicated patients with TBI evaluated in the ED, 76% were treated and released; 26% had no insurance. The strongest predictors of hospital admission were TBI severity and preexisting health conditions. However, the uninsured and black females were less likely to be hospitalized after adjusting for demographic, clinical, and hospital characteristics (odds ratio [OR], 0.52; 95% confidence interval [CI], 0.48-0.55 and OR, 0.79; CI, 0.72-0.87, respectively). Although this study does not infer causality, insurance status, race, and gender were significant predictors of hospital admission. These results suggest that inpatient resources are not equitably used.
PURPOSE: To correlate pulmonary artery catheterization (PAC) use and 30-day outcomes and to characterize the use of pulmonary artery catheters among patients with acute coronary syndromes (ACS). SUBJECTS AND METHODS: We retrospectively studied 26437 ACS patients from two large multicenter, international randomized clinical trials. Multivariable and causal inference analyses were applied to adjust for differences in baseline risk. RESULTS: PAC was performed in 735 patients (2.8%), with a median time to insertion of 24 hours. Patients undergoing PAC were older (median, 67 vs. 64 years), more often diabetic (25.7% vs.16.2%), and more likely to present with ST-segment elevation (81.6% vs. 70.2%) or Killip class III or IV (7.9% vs. 1.4%). US patients were 3.8 times more likely than non-US patients to undergo PAC. Patients managed with PAC also underwent more procedures, including percutaneous intervention (40.7% vs. 18.1%), coronary artery bypass grafting (12.5% vs. 7.7%), and endotracheal intubation (29.3% vs. 2.2%). Mortality at 30 days was substantially higher among patients with PAC for both unadjusted (odds ratio [OR] 8.7; 95% confidence interval [CI] 7.3-10.2) and adjusted analyses (OR 6.4; 95% CI 5.4-7.6) in all groups except in patients with cardiogenic shock (OR 0.99; 95% CI 0.80-1.23). CONCLUSIONS: PAC was associated with increased mortality, both before and after adjustment for baseline patient differences and subsequent events that may have led to PAC use, except in patients with cardiogenic shock. The definitive role of PAC in managing patients with ACS is still to be determined.
BACKGROUND: Peer recovery support services (PRS) delivered by individuals with lived experience of substance use, are increasingly incorporated into substance use disorder (SUD) care systems to improve care engagement, reduce acute care use, and support recovery. However, existing systematic reviews have focused on substance use outcomes, with limited attention to healthcare utilization, psychosocial functioning, and outcomes across settings, and populations. METHODS: This systematic review, registered in PROSPERO (CRD42023469279), synthesized peer-reviewed studies from 2003 to 2026 evaluating PRS for individuals with alcohol or drug-related SUD. Using MEDLINE, Embase, PsycINFO, and CINAHL, the review included 53 studies primarily conducted in high-income countries that reported quantitative outcomes across substance use, healthcare utilization, behavioral health, and treatment engagement. Risk of bias was assessed using Cochrane RoB 2, ROBINS-I, and ROBINS-E tools. RESULTS: Overall, evidence was most favorable for selected treatment-linkage and engagement outcomes, whereas findings for substance use, emergency department use, hospitalization, overdose, and mortality were inconsistent. Uncontrolled longitudinal studies frequently reported improvements in depression and anxiety, but no randomized trials evaluated these outcomes, limiting causal inference. Exploratory cross-study patterns suggested that sustained navigation, practical assistance, and repeated peer contact were more often present in programs reporting favorable outcomes; however, these components were not independently evaluated. Substantial heterogeneity, frequent multicomponent interventions, high risk of bias in many nonrandomized studies, and limited long-term and economic data constrain conclusions. CONCLUSIONS: Findings support the promise of PRS while underscoring the need for more rigorous comparative studies, cost-effectiveness data, and further research in low- and middle-income countries.
Bayesian Networks have been advocated as useful tools to describe the relations of dependence/independence among random variables and relevant hypotheses in a crime case. Moreover, they have been applied to help the investigator structure the problem and evaluate the impact of the observed evidence, typically with respect to the hypothesis of guilt of a suspect. In this paper we describe a model to handle the possibility that one or more pieces of evidence have been manipulated in order to mislead the investigations. This method is based on causal inference models, although it is developed in a different, specific framework.
BACKGROUND: Concerns have been raised about the potential of deliberate self-harm and suicide among patients with dermatologic conditions. OBJECTIVE: We sought to estimate the prevalence of suicidal ideation among patients with dermatologic conditions, and to identify demographic, clinical, and psychosocial correlates. METHODS: Two samples of outpatients with dermatologic conditions (N = 294) and inpatients (N = 172) completed the 12-item General Health Questionnaire, the Skindex-29, and the Patient Health Questionnaire. RESULTS: Forty patients (8.6%) reported suicidal ideation during the previous 2 weeks. In univariate analysis, the presence of suicidal ideation was associated with female sex, inpatient status, presence of a depressive or anxiety disorder, and higher 12-item General Health Questionnaire and Skindex-29 scores. The size of the diagnostic groups allowed reasonable prevalence estimates only for psoriasis (10%) and acne (7.1%). In multivariate analysis, only emotional distress (12-item General Health Questionnaire) and impaired social functioning (Skindex-29) were independently associated with suicidal ideation. LIMITATIONS: We lacked an observer-rated evaluation of skin condition and could rely only on the Skindex-29 symptoms subscale as a measure of disease severity. In addition, the measurement of suicidal ideation was limited as a result of the use of only one question to assess it. Furthermore, the cross-sectional design prevented causal inferences. CONCLUSION: Suicidal ideation is not rare among patients with dermatologic conditions. Assessing suicidality would be warranted in dermatologic practice among patients at particular risk such as women with high psychologic distress and impaired social functioning. The development of psychiatric consultation-liaison services is mandatory to provide effective treatment and careful follow-up of patients who are suicidal.
BACKGROUND: This study sought to extend findings from a preliminary clinical investigation [J. Affect. Disord. 57 (2000) 223] by examining relations between the personality dimension of self-criticism and diagnostic prevalence of social phobia in a large nationally representative sample. METHODS: Participants were from the national comorbidity survey Part II [n=5877; Arch. Gen. Psychiatry 51 (1994) 8]. Psychiatric diagnoses were made using a modified version of the composite international psychiatric interview. Personality dimensions and distress were assessed using brief self-report measures with strong psychometric properties. RESULTS: Self-criticism was elevated in NCS respondents with a diagnosis of social phobia, even in cases of only past history of social phobia (i.e. >1 year ago), compared to individuals with no psychiatric disorder. The highest levels of self-criticism were reported by people with the complex subtype of social phobia, both with and without comorbid major depression. These levels were significantly greater compared to those observed in another anxiety disorder (panic disorder), the pure speaking subtype of social phobia, and cases of major depression alone. In a regression analysis that controlled for current emotional distress, the broad personality trait of neuroticism, and lifetime histories of mood, anxiety, and substance use disorders, self-criticism remained significantly associated with lifetime prevalence of social phobia. LIMITATIONS: The cross-sectional design of the study does not permit causal inferences. CONCLUSIONS: Findings from this general population mental health survey demonstrated that self-criticism is robustly associated with social phobia. It may represent an important core psychological process in the complex subtype of this anxiety disorder.
BACKGROUND: Suicide is a major public health problem and depression is among the most important risk factors for suicide. Treatment of depression might prevent suicide. To study this hypothesis further we conducted an ecological study. METHODS: An ecological study using sales data for antidepressants and numbers of suicides in Norway and Norwegian counties 1980-2004 was performed. Data on alcohol consumption and unemployment rates were registered and taken into account. Data were analyzed using Cochrane-Orcutt time series for the country as a whole. The county specific data were analyzed with a random coefficient model with county as subject and intercept and time (slope) as random variables using an unstructured covariance matrix. RESULTS: Sales of non-tricyclic antidepressants (non-TCAs) and suicide were clearly negatively related, even when controlling for alcohol and unemployment (adjusted r(2): 0.57). There was an effect modification between time and level of sales of non-TCAs. Studying the relationship between the sales of non-TCAs and the suicide rate, we found that it was significant and stronger for the low sales figures, but non-existent for the high sales figures. LIMITATIONS: Ecological studies cannot infer causality. CONCLUSIONS: The fall in suicide rates in Norway and its counties was related to the increased sales of non-TCAs. The effect was mostly a result of a sales increase in the lower sales segment, indicating that a change from the more toxic TCAs, or heightened awareness of depression and its treatment, could explain the relationship found between sales of newer antidepressants and a decrease in suicide rate.
BACKGROUND: With the increasing prevalence of depression, there is an urgent clinical need for early screening in depression. The retina offers a promising window for early screening in depression due to its rapid, non-invasive, objective, eye-brain correlated characteristics, but previous research has yielded conflicting alterations in retinal microstructure in depression. METHODS: We screened retinal optical coherence tomography and brain magnetic resonance imaging data in the UK Biobank to enroll 23,225 participants for retinal study of depression occurrence, and 1475 participants for the eye-brain association study. We also used genetic data (ID: ebi-a-GCST90014267 and ukb-d-20,448) from the Integrative Epidemiology Unit Open Genome-Wide Association Study for Mendelian randomization analysis. We used Cox regression to assess the association between retinal microstructure and depression risk, Mendelian randomization to infer causality, and mediation analysis to explore retina-brain pathway association. RESULTS: The Cox regression analysis showed that retinal ganglion cell-inner plexiform layer (GCIPL) thickness remained a significant predictor of depression. The Mendelian randomization analysis indicated a positive statistical association between GCIPL thickness and depression. Moreover, there was a significant positive correlation (all p < 0.001) between the volume of specific depression-related brain regions and the GCIPL thickness. Adjusting for age, sex, and head size, the mediation analysis provided preliminary evidence for a potential anatomical pathway linking retinal GCIPL thickness to depression-related brain regions through primary visual cortex and secondary visual cortex volumes. CONCLUSION: Thickened retinal GCIPL is a potential early phenotype of depression and has a potential association pathway with depression-related brain regions using a radiogenomics approach.
BACKGROUND/PURPOSE: Pleomorphic adenoma (PA) is the most common salivary gland benign tumor, with its molecular drivers elusive due to a lack of experimental models. This study aimed to decipher novel targets in PA by systematically integrating plasma protein quantitative trait loci (pQTL)-based Mendelian randomization (MR) with multi-omics profiling of parotid gland tissues. MATERIALS AND METHODS: We performed two-sample MR using 5450 plasma pQTLs and genome-wide association study summary for benign or broader salivary gland diseases from FinnGen consortium. Bulk RNA-sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) comparing PA to normal tissue were used for transcriptomic validation. Immunohistochemistry (IHC) was applied for protein-level validation in human PA, adenoid cystic carcinoma (ACC), and murine inflammatory lesions. RESULTS: MR identified 12 plasma proteins associated with benign salivary gland tumor risk. Transmembrane serine protease 6 (TMPRSS6) was the only protein significantly risk-increasing for both benign and broader salivary gland diseases. Strikingly, mitogen-activated protein kinase kinase 4 (MAP2K4) showed opposite MR effects between benign and all-lesion outcomes. Bulk RNA-seq showed limited concordance with MR findings, while scRNA-seq revealed a unique plastic epithelium and partially validated candidates at cellular resolution. Critically, IHC confirmed MAP2K4 protein overexpression specifically in human PA, but not in ACC or inflammatory lesions, while TMPRSS6 was downregulated in established pathologies despite its genetic risk association. CONCLUSION: By integrating plasma proteome-based causal inference with parotid tissue multi-omics, this study unveils MAP2K4 as a potential PA-specific driver. This integrative framework provides novel, context-specific targets for further functional investigation in salivary gland tumorigenesis.
Large-scale randomised trials influence the clinical management of millions of patients throughout the world and are believed to be the most reliable source of evidence on which to base therapeutic decisions. But do they really deserve the accolades bestowed upon them? The decision to perform these studies implies that the treatment difference is expected to be small and, thus, that large numbers of patients are required to achieve statistical significance. This small treatment difference is a direct consequence of limited knowledge of the subject matter which precludes the formation of homogeneous classes of patients with respect to the outcome. In fact, the majority of patients recruited are redundant in the sense that they would not develop the outcome regardless of treatment and, hence, could not participate in testing the efficacy of the drug in question. The conventional view is that randomisation satisfactorily addresses the issues resulting from heterogeneous study populations. However, the statistical approach to causation--which ignores the fundamental features of causal inference characteristic of both everyday discourse and the scientific method--that is used in large-scale randomised trials fails to deliver reliable generalisations even if the many potential obstacles to internal validity are set aside. Moreover, the results of large-scale randomised trials are not open to independent verification. Given the enormous profits to be made from the long-term treatment of common chronic diseases, the absence of any satisfactory method to detect research fraud is of some concern. Fewer than 5% of patients given treatment on the basis of large-scale randomised trials derive any benefit whatsoever. Arguments based on the benefits of such treatment to the wider community of patients are weakened by the dubious external validity of these studies but, in any case, cannot be used to promote the treatment of individual patients. Interestingly, when patients are provided with detailed information about the size of the benefits, most decline treatment. This is hardly surprising as it is debatable whether or not such meagre treatment effects could have any meaning to an individual patient. Large-scale randomised trials continue to be regarded as the gold standard of clinical research. This, of course, merely reflects the ability of powerful vested interests--in particular the pharmaceutical industry--to defy the sound arguments which demonstrate that the methodology of these studies is deeply flawed. Sooner or later, though, common sense must prevail.
Research is beginning to outline a role for the endocannabinoid system in cocaine addiction. Human and animal studies indicate that exogenous cannabinoids modulate the acute rewarding effects of cocaine. These studies, however, cannot directly investigate the necessity of endocannabinoid transmission in cocaine addiction. Studies that do offer a direct assessment show that neither pharmacological antagonism nor deletion of the CB1 receptor alters the acute rewarding effects of cocaine. In contrast, CB1 receptors appear to be involved in the association of cocaine reward with environmental cues and reinstatement of cocaine self-administration. Together, these results point to CB1 receptor antagonists as potential anti-craving compounds in the treatment of cocaine addiction. Given the limitations of human population studies, animal research may be useful in discerning causal inferences between cannabis and cocaine use. While animal research suggests cannabis use may precipitate cocaine relapse, cross-sensitization between cannabinoids and cocaine has not been demonstrated and CB1 receptors do not mediate behavioral sensitization to cocaine. The effect of acute or chronic cocaine on endocannabinoid transmission in reward-related areas of the brain is relatively under-researched. Acute cocaine administration increases anandamide levels in the striatum, an effect that is mediated by dopamine D2-like receptors. Conversely, chronic cocaine exposure has no effect on anandamide, but decreases 2-arachidonylglycerol levels in the limbic forebrain. This review highlights research indicating that the endocannabinoid system may subserve certain aspects of cocaine addiction and suggests avenues for future investigation.
The Chicken Genotype-Tissue Expression (ChickenGTEx) project was established to systematically characterize the regulatory landscape of the chicken genome and to accelerate the translation of functional genomics into precision breeding. By integrating whole-genome sequencing with multi-tissue transcriptomic profiling, ChickenGTEx provides a comprehensive atlas of gene expression regulation across diverse tissues and physiological systems. Current findings demonstrate that complex production traits are governed by coordinated regulatory networks rather than isolated loci, with substantial contributions from tissue-specific gene expression, structural variation, and genotype-by-sex interactions. Sex-dependent regulatory effects further refine the genetic architecture of metabolic, immune, and reproductive traits, highlighting the importance of incorporating sex as a biological variable in genomic analyses. Application of integrative omics frameworks within elite layer populations has revealed multilayer regulatory mechanisms underlying extended laying performance, feed efficiency, metabolic health, and eggshell quality. By partitioning phenotypic variance into genetic, regulatory, and host-microbiome components, these approaches move beyond association-based mapping toward causal inference and biological interpretation. Importantly, validated regulatory loci identified through ChickenGTEx and related analyses provide actionable markers for genomic selection and rational targets for precision genome modification. Looking forward, continued expansion of regulatory atlases, incorporation of single-cell and longitudinal data in diverse environmental conditions, and integration of functional annotation into breeding pipelines will further enhance prediction accuracy and sustainable genetic improvement. The ChickenGTEx project thus represents a foundational platform bridging functional genomics and practical poultry breeding.
The aim of this study is to examine the association of smoking status with income inequality, relative deprivation, perception of relative material well-being and community-level social capital, controlling for individual-level indicators of social capital, and common socio-economic variables. Data were from telephone interviews of approximately 126 residents selected at random (using the Electronic White Pages) from each of 22 local government areas (LGAs) in the Melbourne metropolitan region, Victoria, Australia (total n = 2762). We used logistic regression to assess the association of covariates with smoking status. Being a smoker was associated with a higher level of perceived income inequality, lower perception of relative material well-being and living in a community with a lower degree of trust and safety. While the cross-sectional design of the study does not allow causal inferences, the results imply that smoking is less prevalent in communities that are more egalitarian and have a higher stock of social capital.
Two of every three American homicide victims are killed with firearms, yet little is known about the role played by household firearms in homicide victimization. The present study is the first to examine the cross sectional association between household firearm ownership and homicide victimization across the 50 US states, by age and gender, using nationally representative state-level survey-based estimates of household firearm ownership. Household firearm prevalence for each of the 50 states was obtained from the 2001 Behavioral Risk Factor Surveillance System. Homicide mortality data for each state were aggregated over the three-year study period, 2001-2003. Analyses controlled for state-level rates of aggravated assault, robbery, unemployment, urbanization, per capita alcohol consumption, and a resource deprivation index (a construct that includes median family income, the percentage of families living beneath the poverty line, the Gini index of family income inequality, the percentage of the population that is black and the percentage of families headed by a single female parent). Multivariate analyses found that states with higher rates of household firearm ownership had significantly higher homicide victimization rates of men, women and children. The association between firearm prevalence and homicide victimization in our study was driven by gun-related homicide victimization rates; non-gun-related victimization rates were not significantly associated with rates of firearm ownership. Although causal inference is not warranted on the basis of the present study alone, our findings suggest that the household may be an important source of firearms used to kill men, women and children in the United States.
Mechanisms of selective attention are vital for coherent perception and action. Recent advances in cognitive neuroscience have yielded key insights into the relationship between neural mechanisms of attention and eye movements, and the role of frontal and parietal brain regions as sources of attentional control. Here we explore the growing contribution of reversible neurodisruption techniques, including transcranial magnetic stimulation and microelectrode stimulation, to the cognitive neuroscience of spatial attention. These approaches permit unique causal inferences concerning the relationship between neural processes and behaviour, and have revealed fundamental mechanisms of attention in the human and animal brain. We conclude by suggesting that further advances in the neuroscience of attention will be facilitated by the combination of neurodisruption techniques with established neuroimaging methods.
OBJECTIVES: To describe the prevalence and correlates of self-reported history of prostatitis in terms of lower urinary tract symptoms and associated dissatisfaction in community-dwelling older men. METHODS: We performed a cross-sectional analysis from a prospective cohort study of 5821 men aged 65 years and older recruited from six clinical centers. RESULTS: Overall, 1439 men (25%) self-reported a history of prostatitis. Men with a history of prostatitis were more likely to self-report a history of prostate cancer (26% versus 7%; P < 0.0001) and a history of benign prostatic hyperplasia (83% versus 38%; P < 0.0001) within a lifetime compared with men without a history of prostatitis. Men with a history of prostatitis also had a greater mean American Urological Association symptom score (mean +/- SD, 10.1 +/- 7.1 versus 7.7 +/- 5.9; P < 0.0001) than men without a history of prostatitis. Also, a greater percentage of men with a history of prostatitis reported being dissatisfied with their present urinary condition than did men without a history of prostatitis (21% versus 11%; P < 0.0001). We found positive associations for a history of prostatitis with a history of benign prostatic hyperplasia (odds ratio 8.0, 95% confidence interval 6.8 to 9.5), a history of prostate cancer (odds ratio 5.4, 95% confidence interval 4.4 to 6.6), and dissatisfaction with current urinary condition (odds ratio 1.2, 95% confidence interval 1.01 to 1.5). CONCLUSIONS: A self-reported history of prostatitis is common in older men and was associated with self-reported prostate cancer and benign prostatic hyperplasia and increased severity of lower urinary tract symptoms and associated dissatisfaction. Because of the potential detection bias, recall bias, and the cross-sectional nature of the study, limiting causal inference, the associations among these urologic conditions require additional study.