Potential Causal Role Research Articles

Inherited Thrombophilia and the Risk of Arterial Ischemic Stroke: A Systematic Review and Meta-Analysis

Introduction:The inherited thrombophilias Factor V Leiden (FVL), the Prothrombin G20210A mutation (PTM), Protein C deficiency (PCD), Protein S deficiency (PSD), and Antithrombin deficiency (ATD) are well-established predisposing factors for venous thromboembolism, but their role in arterial thrombosis such as arterial ischemic stroke remains uncertain. The 2018 American Heart Association/American Stroke Association clinical practice guideline recommends against thrombophilia testing in patients with ischemic stroke, though such testing remains common in clinical practice. We conducted a systematic review and meta-analysis to evaluate the association of inherited thrombophilias and risk of arterial ischemic stroke in adults.Methods:A systematic literature search was performed using MEDLINE, EMBASE, and Cochrane Library Databases from inception to December 31, 2017 without language restrictions. Manual reviews of conference abstracts and bibliographies of included studies were performed to identify additional eligible studies. We included case-control studies of adults age ≥15 years that reported the prevalence of at least one of the inherited thrombophilias of interest (FVL, PTM, PCD, PSD, ATD) in both subjects with a history of arterial ischemic stroke (cases) and subjects without arterial ischemic stroke (controls). Studies were required to have ≥10 subjects in each group. Studies that enrolled patients with transient ischemic attack, hemorrhagic stroke, cerebral venous sinus thrombosis, and other arterial thromboses were excluded. Two reviewers (T.C. and E.D.) independently searched the literature and extracted data from eligible studies. Disagreements were resolved by consensus or a third reviewer (A.C.) when necessary. Methodological quality of included studies was appraised using the NIH Quality Assessment of Case-Control Studies assessment tool. Data analysis was performed using R version 3.4.4. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Inter-study heterogeneity was evaluated using Cochran's Q test and I2statistics. Prespecified subgroup analyses were performed in young patients (<65 years), patients with a patent foramen ovale (PFO), and patients with cryptogenic stroke. Funnel plots and Egger's test were used to assess for the presence of publication bias. The study protocol is available on PROSPERO (CRD42018090020).Results:A total of 1,730 records were retrieved from the literature search. After screening by title and abstract, 1527 records were excluded. The remaining 203 references underwent full text review, 71 of which met eligibility criteria and were included in the analysis. These 71 studies collectively enrolled 13,347 stroke patients and 31,676 controls. The number of studies that reported on FVL, PTM, PCD, PSD, and ATD were 59, 47, 14, 15, and 11, respectively. Heterogeneity among studies was low. Compared with controls, inherited thrombophilia was significantly more common in patients with arterial ischemic stroke for the following defects: homozygous FVL (OR 2.24; 95%CI, 1.24-4.07; I2=0%), heterozygous FVL (OR 1.32; 95%CI, 1.11-1.57; I2=33%), homozygous PTM (OR 7.19; 95%CI 2.47-20.95; I2=0%), heterozygous PTM (OR 1.53; 95%CI, 1.27-1.84; I2=2%), PCD (OR 2.70; 95%CI, 1.44-5.04; I2=0%), and PSD (OR 2.75; 95%CI, 1.56-4.85; I2=34%) (Figure 1). Statistical significance was not reached for ATD (OR 1.84; 95%CI, 0.92-3.71; I2=11%). Subgroup analyses showed a higher magnitude of stroke risk in young patients across all thrombophilias. The associations were non-significant for patients with PFO and cryptogenic stroke (Table 1). Funnel plots were symmetrical and Egger's test was non-significant (p>0.05), suggesting absence of publication bias, for all thrombophilias except heterozygous FVL (p=0.003).Conclusions: Our results suggest that inherited thrombophilias including FVL, PTM, PCD, and PSD are associated with an increased risk of arterial ischemic stroke, particularly in young patients. The association with FVL and PTM is stronger in the homozygous than in the heterozygous state, suggesting a potential dose-response relationship and causal role for inherited thrombophilias. The implications of these findings with respect to the evaluation and management of patients with ischemic stroke require further investigation. [Display omitted] DisclosuresCrowther:Alnylam: Equity Ownership; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Shinogi: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Leo Pharma: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Speakers Bureau. Garcia:Bristol Meyers Squibb: Consultancy; Daiichi Sankyo: Research Funding; Janssen: Consultancy, Research Funding; Pfizer: Consultancy; Portola: Research Funding; Incyte: Research Funding; Retham Technologies LLC: Consultancy; Shingoi: Consultancy; Boehringer Ingelheim: Consultancy. Cuker:Kedrion: Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Research Funding; Synergy: Consultancy; Genzyme: Consultancy.

The combined influence of cognitions in adolescent depression: Biases of interpretation, self-evaluation, and memory.

ObjectivesDepression is characterized by a range of systematic negative biases in thinking and information processing. These biases are believed to play a causal role in the aetiology and maintenance of depression, and it has been proposed that the combined effect of cognitive biases may have greater impact on depression than individual biases alone. Yet little is known about how these biases interact during adolescence when onset is most common.MethodsIn this study, adolescents were recruited from the community (n = 212) and from a Child And Adolescent Mental Health Service (n = 84). Participants completed measures of depressive symptoms, interpretation bias, self‐evaluation, and recall memory. These included the Mood and Feelings Questionnaire, Ambiguous Scenarios Test for Depression in Adolescents, Self‐Description Questionnaire, and an immediate recall task. The clinically referred sample also took part in a formal diagnostic interview.ResultsIndividual cognitive biases were significantly intercorrelated and associated with depression severity. The combination of cognitive biases was a stronger predictor of depression severity than individual biases alone, predicting 60% of the variance in depression severity across all participants. There were two significant predictors, interpretation bias and negative self‐evaluation; however, almost all of the variance was explained by negative self‐evaluation.ConclusionsThe findings support the interrelationship and additive effect of biases in explaining depression and suggest that understanding the way in which cognitive biases interact could be important in advancing methods of identification, early intervention, and treatment.Practitioner points A combination of biases was a better predictor of depression symptom severity than individual biases.Interpretation and self‐evaluation were better predictors of depression symptom severity than recall.Negative self‐evaluation was the strongest individual predictor of depression symptom severity.Negative self‐evaluation was able to classify depressed from non‐depressed adolescents.The cross‐sectional design of the study precludes any conclusions about the potential causal role of these variables.Different tasks were used to assess different types of cognitive bias meaning that the possible linear operation along an information processing ‘pathway’ could not be examined.

S32. ANXIETY IN THE DEVELOPMENT OF PSYCHOTIC EXPERIENCES IN CHILDREN AND ADOLESCENTS: A SYSTEMATIC REVIEW

BackgroundAlthough traditionally separated in psychiatry, the overlap between psychosis and neurosis is becoming clear. It has been argued that emotional processes are not only a core component of psychotic experiences (PEs), but also have a causal role in symptom development. In particular, increasing evidence has highlighted anxiety may be especially important in the emergence of psychotic experiences. As the time when psychotic symptoms first emerge, understanding how anxiety influences their development in childhood and adolescence will inform early intervention. In this systematic review, we investigate the role of anxiety across the spectra of psychotic experiences in children and young people. We examine the available evidence whilst aiming to answer the questions of whether anxiety and psychotic experiences co-occur in young people and if anxiety plays a contributory causal role.MethodsA systematic literature search was conducted on PsychINFO, Medline, EMBASE, and Scopus (updated October 2017). Papers published in peer-reviewed journals were identified that investigated the relationship between anxiety and PEs in children and adolescents within both non-clinical and clinical populations. Twenty-three papers met inclusion criteria. The RTI item bank assessment framework for observational studies was used to evaluate the precision and risk of bias of each individual study.ResultsThe findings of this review demonstrated clear evidence for a consistent relationship between anxiety and psychotic experiences in non-clinical populations of young people, which generally displayed the highest quality of evidence. Although of overall lower quality, this relationship was also evident in clinical populations of young people with mental health problems other than psychosis. Evidence for the role of anxiety in those at clinical risk high for psychosis or diagnosed with psychosis was less conclusive, with very few studies, of variable quality, identified. These studies provided mixed findings, with some evidence for a co-occurrence between anxiety and psychosis risk/disorder, but no clear evidence of a causal role for anxiety in the transition to psychotic disorder. The size of the associations with anxiety appeared to vary by psychotic experience, with moderate evidence for hallucinations and little evidence grandiosity or anhedonia. Paranoia has the strongest evidence for a relationship with anxiety. Most studies were cross-sectional with few longitudinal studies preventing clear conclusions on a causal role of anxiety.DiscussionEvidence suggests that anxiety and psychotic experiences may co-occur in young people. This relationship appears to be transdiagnostic and potentially specific to individual psychotic experiences. As a result, more studies focusing on specific psychotic symptoms and psychological mechanisms are needed. However, research must move beyond cross-sectional associations and test the potential contributory causal role of anxiety using prospective, experimental, and interventionist designs. Despite the unknown direction of causality, the notable associations of psychotic experiences and anxiety in child mental health services indicate that this relationship may be of clinical importance. Establishing higher quality research in clinical settings is essential. Testing the effect of treating anxiety on the severity of psychotic symptoms will inform early intervention.

S67. INTEGRATION OF SENSORY AND SOCIAL INFORMATION DURING DECISION MAKING IN SCHIZOPHRENIA

BackgroundPrevious findings suggest that schizophrenia is associated with abnormalities in information integration. The recent Bayesian model of circular inference attempts to characterize the information integration style in schizophrenia (Jardri et al. (2017). Nat Commun, 8:14218). The model suggests that during information integration of prior beliefs and sensory evidence, patients tend to put too much weight on the sensory evidence and to take it into account multiple times (over-count) compared to healthy individuals. An imbalance in excitatory/inhibitory regulation of hierarchical neural processing has been suggested to cause of this phenomenon (Jardri et al., 2017). Here, we investigated whether circular inference could be extended to describe the integration of sensory information and socially acquired information and whether the specific information integration style could contribute to the characteristic symptomatology and the social impairments seen in the disorder.MethodsThirty-five patients with schizophrenia or schizo-affective disorder and 40 matched healthy controls performed the task. Participants had to guess the color (red or green) of the next marble to be drawn from a hidden urn based on information from their own sample (eight marbles) and the choices and confidence (high or low) of four other people. We fitted and comparatively assessed four multilevel Bayesian models (generalized linear model, simple Bayes, weighted Bayes, circular inference) describing how patients and controls integrated information. Positive and negative symptom severity and social functioning were also assessed.ResultsThe circular inference model best described the information integration in both patients and controls (WAIC weight = 1). Patients tended to over-weigh (β = 0.48, 95% CI: 0.30; 0.62) and over-count (β = 0.30, 95% CI: 0.12; 0.47) sensory information and under-weigh (β = -0.29, 95% CI: -0.42; -0.13) and under-count (β = -0.23, 95% CI: -0.35; -0.06) social information compared to controls. Crucially, this varied with symptomatology: the higher the symptom severity, the more over-counting and the higher the weight on sensory information and the more under-counting and the less weight on social information. More weight on social information was associated with higher level of functioning in the patients (β = 0.88, 95% CI: 0.01; 3.73).DiscussionAll participants integrated social and sensory information in a non-linear fashion. Patients displayed a distinctive tendency to rely more and less discriminatively on sensory than on social information. This information integration style may contribute to the characteristic symptoms and the social impairments in schizophrenia. Further exploration of this potential causal role is warranted.

Do local employment centers modify the association between neighborhood urban form and individual obesity?

Extensive literature examines the relation between land use patterns and obesity, but less work explores whether local employment centers may reduce obesity. Local employment centers may affect obesity via providing agglomeration benefits such as increased job/transportation opportunities and closer proximity to local facilities/destinations. We utilized a large serial cross-sectional health survey from Los Angeles, California, conducted over three periods, to examine whether the presence of local employment centers modifies the association between land use patterns and individual body mass index. We retrieved individual health and sociodemographic data from the Los Angeles County Health Survey (2002, 2005, and 2007). To this Health Survey, we linked land use attributes at the census tract level collected from the Southern California Association of Governments. Our log-transformed regression models present interactions between local employment centers, neighborhood urban form features, and body mass index. Although most findings are consistent with previous studies, some of land use factors hypothesized to reduce the risk of obesity could have counterintuitive associations unless local employment centers were controlled. The unexpected results of our land use coefficients indicate that the tenet of New Urbanism may not necessarily promote health benefits. Our findings suggest that modifying the built environment may be effective in reducing obesity only in areas with high degree of local employment centers. Future studies would benefit from longitudinal and experimental, rather than cross-sectional, study designs that rigorously test the potential causal role of New Urbanism on obesity.

Genetic markers for urine haptoglobin is associated with decline in renal function in type 2 diabetes in East Asians

Urine haptoglobin (uHP) level prospectively predicts diabetic kidney disease (DKD) progression. Here, we aim to identify genetic determinants of uHP level and evaluate association with renal function in East Asians (EA) with type 2 diabetes (T2D). Genome-wide association study (GWAS) among 805 [236 Chinese (discovery) and 569 (57 Malay and 512 Chinese) (validation)] found that rs75444904/kgp16506790 variant was robustly associated with uHP level (MetaP = 1.21 × 10−60). rs75444904 correlates well with plasma HP protein levels and multimerization in EA but was not in perfect LD (r2 = 0.911 in Chinese, r2 = 0.536 in Malay) and is monomorphic in Europeans (1000 G data). Conditional probability analysis indicated weakening of effects but residual significant associations between rs75444904 and uHP when adjusted on HP structural variant (MetaP = 8.22 × 10−7). The rs75444904 variant was associated with DKD progression (OR = 1.77, P = 0.014) independent of traditional risk factors. In an additional validation-cohort of EA (410 end-stage renal disease (ESRD) cases and 1308 controls), rs75444904 was associated with ESRD (OR = 1.22, P = 0.036). Furthermore, increased risk of DKD progression (OR = 2.09, P = 0.007) with elevated uHP level through Mendelian randomisation analysis provide support for potential causal role of uHP in DKD progression in EA. However, further replication of our findings in larger study populations is warranted.

A thought in the park: The influence of naturalness and low-level visual features on expressed thoughts

Prior research has shown that the physical characteristics of one’s environment have wide ranging effects on affect and cognition. Other research has demonstrated that one’s thoughts have impacts on mood and behavior, and in this three-part research program we investigated how physical features of the environment can alter thought content. In one study, we analyzed thousands of journal entries written by park visitors to examine how low-level and semantic visual features of the parks correlate with different thought topics. In a second study, we validated our ecological results by conducting an online study where participants were asked to write journal entries while imagining they were visiting a park, to ensure that results from Study 1 were not due to selection bias of park visitors. In the third study, we experimentally manipulated exposure to specific visual features to determine if they induced thinking about the same thought topics under more generalized conditions. Results from Study 3 demonstrated a potential causal role for perceived naturalness and high non-straight edges on thinking about “Nature”, with a significant positive interaction. Results also showed a potential causal effect of naturalness and non-straight edges on thinking about topics related to “Spiritual & Life Journey”, with perceived naturalness having a negative relationship and non-straight edges having a positive relationship. We also observed a significant positive interaction between non-straight edge density and naturalness in relation to “Spiritual & Life Journey”. These results have implications for the design of the built environment to influence human reflection and well-being.

The Pros and Cons of Mendelian Randomization Studies to Evaluate Emerging Cardiovascular Risk Factors

Mendelian randomization (MR) is a technique that uses natural genetic variation to assess the potential causal role of a modifiable risk factor on cardiovascular disease. Advances have led to the identification of single nucleotide polymorphisms linked with risk factors that act as naturally randomized instruments to investigate the risk factor-disease relationship. There are several pros and cons when using MR. It can address many limitations of observational study design including confounding, reverse causation, and demonstration of causality when a randomized controlled trial is not practical or feasible. However, several limitations do exist and include pleiotropy (multiple downstream effects of a single genetic variant), linkage disequilibrium (non-random association of genetic variation), and imprecise estimates of causal effects. MR is an important tool in cardiovascular research and has been applied to assess cardiovascular risk factors including obesity and atrial fibrillation. While these studies provide insight into disease causation, understanding the strengths and limitations of the technique is important for appropriate interpretation of results.

Computing sleep deficiency.

Sleep deficiency is a major public health concern. Since epidemiological studies play an important role in public health evaluations, this theoretical paper pursues answers to the question: 'How can we compute sleep deficiency as informative measures of exposures or doses in observational research?' Starting from the social jetlag concept and based on the chronodisruption rationale, we illustrate and discuss five approaches (one established and four untested, each with unique strengths and limitations) to quantify sleep deficiency by focusing on the timing and duration of sleep. Hitherto, social jetlag and chronodisruption rationale were neither explicitly proposed nor developed as assessments of sleep deficiency but, as we suggest, could potentially be utilized to this end. This first foray into computing sleep deficiency in epidemiological studies makes clear that laboratory, field and epidemiological collaboration is pre-requisite to elucidating potential (co-)causal roles of sleep deficiency in disease endpoints.

Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that can be caused by inherited mutations in the gene encoding copper-zinc superoxide dismutase 1 (SOD1). The structural instability of SOD1 and the detection of SOD1-positive inclusions in familial-ALS patients supports a potential causal role for misfolded and/or aggregated SOD1 in ALS pathology. In this study, we describe the development of a cell-based assay designed to quantify the dynamics of SOD1 aggregation in living cells by high content screening approaches. Using lentiviral vectors, we generated stable cell lines expressing wild-type and mutant A4V SOD1 tagged with yellow fluorescent protein and found that both proteins were expressed in the cytosol without any sign of aggregation. Interestingly, only SOD1 A4V stably expressed in HEK-293, but not in U2OS or SH-SY5Y cell lines, formed aggregates upon proteasome inhibitor treatment. We show that it is possible to quantify aggregation based on dose-response analysis of various proteasome inhibitors, and to track aggregate-formation kinetics by time-lapse microscopy. Our approach introduces the possibility of quantifying the effect of ALS mutations on the role of SOD1 in aggregate formation as well as screening for small molecules that prevent SOD1 A4V aggregation.

Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that can be caused by inherited mutations in the gene encoding copper-zinc superoxide dismutase 1 (SOD1). The structural instability of SOD1 and the detection of SOD1-positive inclusions in familial-ALS patients supports a potential causal role for misfolded and/or aggregated SOD1 in ALS pathology. In this study, we describe the development of a cell-based assay designed to quantify the dynamics of SOD1 aggregation in living cells by high content screening approaches. Using lentiviral vectors, we generated stable cell lines expressing wild-type and mutant A4V SOD1 tagged with yellow fluorescent protein and found that both proteins were expressed in the cytosol without any sign of aggregation. Interestingly, only SOD1 A4V stably expressed in HEK-293, but not in U2OS or SH-SY5Y cell lines, formed aggregates upon proteasome inhibitor treatment. We show that it is possible to quantify aggregation based on dose-response analysis of various proteasome inhibitors, and to track aggregate-formation kinetics by time-lapse microscopy. Our approach introduces the possibility of quantifying the effect of ALS mutations on the role of SOD1 in aggregate formation as well as screening for small molecules that prevent SOD1 A4V aggregation.

Effect of Coronary Artery Disease risk SNPs on serum cytokine levels and cytokine imbalance in Premature Coronary Artery Disease

BackgroundPremature Coronary Artery Disease (PCAD) occurs almost a decade earlier in the South Asian population as compared to the West. Inclusion of genetic information can prove to be a robust measure to improve early risk prediction of PCAD. Aim was to estimate the genotypic distribution and risk allele frequencies of 13 Coronary Artery Disease (CAD) risk Single Nucleotide Polymorphisms in loci identified by the CARDIoGRAMplusC4D consortium namely MIA3 rs17465637; 9p21 rs10757274; CXCL12 rs1746048; APOA5 rs662799; APOB rs1042031; LPA rs3798220; LPA 10455872; MRAS rs9818870; LPL rs328; SORT1 rs646776; PCSK9 rs11591147; APOE rs429358; APOE rs7412 in Pakistani PCAD patients and controls. Moreover, the differential serum cytokine levels (IL-18, IL-10, IL-6, TNF-alpha, IL-18:IL-10 & TNF-alpha:IL-10 ratios) with respect to the genotypic distribution of these selected SNPs were determined. Material and methodsThe case-control study was carried out in National University of Sciences and Technology, Islamabad in collaboration with the Cardiovascular Genetics Institute, University College London, UK. Subjects (n=340) with >70% stenosis in at least a single major coronary artery on angiography were taken as PCAD cases along with 310 angiographically verified controls. ELISA was performed for measuring the concentrations of serum IL18, TNFA, IL6 and IL10. Genotyping was done using TAQMAN and KASPar assays. ResultsThe risk allele frequencies (RAF) of APOE rs7412, CXCL12 rs1746048, 9p21 rs10757274, MIA3 rs17465637 and SORT1 rs646776 were significantly higher in the PCAD cases as compared to the controls. APOE rs429358 had the greatest influence among the selected GWAS/CARDIoGRAMplusC4D consortium CAD risk SNPs by significantly altering the serum levels of TNF-alpha, IL-10 and TNF-alpha:IL-10 ratio. It was followed by APOE rs7412 and CXCL12 rs1746048 which significantly altered the serum levels of IL-18; TNF-alpha and IL-18; IL-18:IL-10 ratio respectively. The cytokine imbalance denoted by IL-18:IL-10 was significantly higher in the risk allele carriers MIA3 rs17465637 and CXCL12 rs1746048 while TNF-alpha:IL-10 ratio was significantly raised in the risk allele carriers of APOE rs429358; MRAS rs9818870 and LPL rs328. ConclusionThe association of the selected SNPs with differential serum cytokine levels especially the cytokine imbalance points towards their potential causal role in the immune inflammatory pathogenic pathway of PCAD.

CRISPR/Cas9 editing of Nf1 gene identifies CRMP2 as a therapeutic target in neurofibromatosis type 1-related pain that is reversed by (S)-Lacosamide.

Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disease linked to mutations of the Nf1 gene. Patients with NF1 commonly experience severe pain. Studies on mice with Nf1 haploinsufficiency have been instructive in identifying sensitization of ion channels as a possible cause underlying the heightened pain suffered by patients with NF1. However, behavioral assessments of Nf1 mice have led to uncertain conclusions about the potential causal role of Nf1 in pain. We used the clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) genome editing system to create and mechanistically characterize a novel rat model of NF1-related pain. Targeted intrathecal delivery of guide RNA/Cas9 nuclease plasmid in combination with a cationic polymer was used to generate allele-specific C-terminal truncation of neurofibromin, the protein encoded by the Nf1 gene. Rats with truncation of neurofibromin, showed increases in voltage-gated calcium (specifically N-type or CaV2.2) and voltage-gated sodium (particularly tetrodotoxin-sensitive) currents in dorsal root ganglion neurons. These gains-of-function resulted in increased nociceptor excitability and behavioral hyperalgesia. The cytosolic regulatory protein collapsin response mediator protein 2 (CRMP2) regulates activity of these channels, and also binds to the targeted C-terminus of neurofibromin in a tripartite complex, suggesting a possible mechanism underlying NF1 pain. Prevention of CRMP2 phosphorylation with (S)-lacosamide resulted in normalization of channel current densities, excitability, as well as of hyperalgesia following CRISPR/Cas9 truncation of neurofibromin. These studies reveal the protein partners that drive NF1 pain and suggest that CRMP2 is a key target for therapeutic intervention.

Mendelian randomization to establish the causality of uric acid with diabetic nephropathy in type 1 diabetics

Previous studies have demonstrated an association of serum uric acid with kidney disease. However, it is unknown whether this relationship is causal. Mendelian randomization takes advantage of allele randomization at birth to assess causation. Using this technique Ahola etal. found strong evidence against causation in Finnish Caucasians with type 1 diabetes mellitus. However, replication in other populations is needed to further assess a potential causal role for hyperuricemia in kidney disease.

Neighborhood Socioeconomic Status and Health: A Longitudinal Analysis.

Higher income neighborhoods are associated with better health, a relation observed in many cross-sectional studies. However, prior research focused on the prevalence of health conditions, and examining the incidence of new health conditions may provide stronger support for a potential causal role of neighborhoods on health. We used the 2004 and 2014 waves of the Midlife in the United States Study (n = 1726; ages 34-83) to examine health condition incidence as a function of neighborhood income. Among participants who had lived in the same neighborhood across the time period, we hypothesized that higher neighborhood income would be associated with a lower incidence of health conditions ten years later. Health included 18 chronic conditions related to mental (anxiety, depression) and physical (cardiovascular, immune) health. Multinomial logistic regression analyses adjusting for individual income and sociodemographics indicated that the odds of developing two or more new health conditions (no new health conditions as referent), was significantly lower (OR = 0.92, CI: 0.86, 0.99) for every $10,000 increment in neighborhood income. Associations did not vary by age or neighborhood tenure. Results add to a literature documenting that higher neighborhood income is associated with better health.

Cefixime-Induced Oromandibular Dystonia in an Adult: A Case Report.

Cefixime, a third-generation cephalosporin, is commonly used in different infections. Tolerance is pretty good even if some side effects can be frequent like digestive disorders. Other effects, not mentioned in the Summary of Product Characteristics, can occur. We report a case of recurrent, acute oromandibular dystonia in a cefixime-treated adult. After the third dose of cefixime, prescribed for a bronchial infection, a patient experienced a first episode of oromandibular dystonia. Then, after each ingestion, the same effects appeared. After the discontinuation of cefixime, there was no recurrence. The diagnosis of acute oromandibular dystonia has been confirmed by a neurologist. Some cases of dystonia have been published with other β-lactams antibiotics and with cefixime but they concerned children. Different mechanisms are proposed to explain the occurrence of dystonia during a treatment with cefixime. They involved certain neurotransmitters like dopamine, acetylcholine or GABA. Even if dystonia is not a side effect mentioned in the SPC, the drug's potential causal role must always be considered in case of involuntary contraction of muscles in a patient treated with cefixime or any other β-lactam antibiotics.

Serum magnesium and the risk of prediabetes: a population-based cohort study

Aims/hypothesisPrevious studies have found an association between serum magnesium and incident diabetes; however, this association may be due to reverse causation, whereby diabetes may induce urinary magnesium loss. In contrast, in prediabetes (defined as impaired fasting glucose), serum glucose levels are below the threshold for urinary magnesium wasting and, hence, unlikely to influence serum magnesium levels. Thus, to study the directionality of the association between serum magnesium levels and diabetes, we investigated its association with prediabetes. We also investigated whether magnesium-regulating genes influence diabetes risk through serum magnesium levels. Additionally, we quantified the effect of insulin resistance in the association between serum magnesium levels and diabetes risk.MethodsWithin the population-based Rotterdam Study, we used Cox models, adjusted for age, sex, lifestyle factors, comorbidities, kidney function, serum levels of electrolytes and diuretic use, to study the association between serum magnesium and prediabetes/diabetes. In addition, we performed two mediation analyses: (1) to study if common genetic variation in eight magnesium-regulating genes influence diabetes risk through serum magnesium levels; and (2) to quantify the proportion of the effect of serum magnesium levels on diabetes that is mediated through insulin resistance (quantified by HOMA-IR).ResultsA total of 8555 participants (mean age, 64.7 years; median follow-up, 5.7 years) with normal glucose levels (mean ± SD: 5.46 ± 0.58 mmol/l) at baseline were included. A 0.1 mmol/l decrease in serum magnesium level was associated with an increase in diabetes risk (HR 1.18 [95% CI 1.04, 1.33]), confirming findings from previous studies. Of interest, a similar association was found between serum magnesium levels and prediabetes risk (HR 1.12 [95% CI 1.01, 1.25]). Genetic variation in CLDN19, CNNM2, FXYD2, SLC41A2, and TRPM6 significantly influenced diabetes risk (p < 0.05), and for CNNM2, FXYD2, SLC41A2 and TRPM6 this risk was completely mediated by serum magnesium levels. We found that 29.1% of the effect of serum magnesium levels on diabetes was mediated through insulin resistance, whereas for prediabetes 13.4% was mediated through insulin resistance.Conclusions/interpretationLow serum magnesium levels are associated with an increased risk of prediabetes and this increased risk is similar to that of diabetes. Furthermore, common variants in magnesium-regulating genes modify diabetes risk through serum magnesium levels. Both findings support a potential causal role of magnesium in the development of diabetes, where the hypothesised pathway is partly mediated through insulin resistance.

Effects of Cognitive Load on Driving Performance: The Cognitive Control Hypothesis.

The objective of this paper was to outline an explanatory framework for understanding effects of cognitive load on driving performance and to review the existing experimental literature in the light of this framework. Although there is general consensus that taking the eyes off the forward roadway significantly impairs most aspects of driving, the effects of primarily cognitively loading tasks on driving performance are not well understood. Based on existing models of driver attention, an explanatory framework was outlined. This framework can be summarized in terms of the cognitive control hypothesis: Cognitive load selectively impairs driving subtasks that rely on cognitive control but leaves automatic performance unaffected. An extensive literature review was conducted wherein existing results were reinterpreted based on the proposed framework. It was demonstrated that the general pattern of experimental results reported in the literature aligns well with the cognitive control hypothesis and that several apparent discrepancies between studies can be reconciled based on the proposed framework. More specifically, performance on nonpracticed or inherently variable tasks, relying on cognitive control, is consistently impaired by cognitive load, whereas the performance on automatized (well-practiced and consistently mapped) tasks is unaffected and sometimes even improved. Effects of cognitive load on driving are strongly selective and task dependent. The present results have important implications for the generalization of results obtained from experimental studies to real-world driving. The proposed framework can also serve to guide future research on the potential causal role of cognitive load in real-world crashes.

Low distress tolerance predicts heightened drug seeking and taking after extended abstinence from cocaine self-administration.

Distress tolerance (DT), defined as the ability to persist in goal-directed behavior while experiencing psychological distress, is associated with greater frequency of substance use and poor treatment outcomes. To examine a potential causal role substance use may play in DT, we developed a rodent model of DT in which rats had to press a lever within a continuously decreasing time window for reward while receiving negative feedback on failure trials. DT was defined as the time rats continued to seek reward before quitting the task. We assessed the relationship of DT with cocaine seeking/taking by measuring DT before cocaine self-administration (SA), and after 1week and 1month of drug abstinence. We found that DT prior to cocaine SA did not predict cocaine seeking/taking, yet DT measured after 1month abstinence significantly predicted subsequent high levels of early session cocaine taking. Additionally, high DT measured after abstinence protected against high cocaine seeking, but this protective effect was blocked in rats with high impulsivity. Finally, while a decrease in 1month-abstinent DT was observed following SA across treatment conditions, among cocaine-exposed rats, greater cocaine SA correlated with a steeper decrease in DT. These results show that low DT after drug abstinence is associated with heightened levels of cocaine seeking and taking behavior and that impulsivity influences this effect. Collectively, these results support the validity of our rodent DT model while extending the human literature and set the foundation for future animal studies designed to determine neural mechanisms underlying DT.

Inverse reasoning processes in obsessive-compulsive disorder

The inference-based approach (IBA) is one cognitive model that aims to explain the aetiology and maintenance of obsessive-compulsive disorder (OCD). The model proposes that certain reasoning processes lead an individual with OCD to confuse an imagined possibility with an actual probability, a state termed inferential confusion. One such reasoning process is inverse reasoning, in which hypothetical causes form the basis of conclusions about reality. Although previous research has found associations between a self-report measure of inferential confusion and OCD symptoms, evidence of a specific association between inverse reasoning and OCD symptoms is lacking. In the present study, we developed a task-based measure of inverse reasoning in order to investigate whether performance on this task is associated with OCD symptoms in an online sample. The results provide some evidence for the IBA assertion: greater endorsement of inverse reasoning was significantly associated with OCD symptoms, even when controlling for general distress and OCD-related beliefs. Future research is needed to replicate this result in a clinical sample and to investigate a potential causal role for inverse reasoning in OCD.