Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities.

BACKGROUND: Immune mechanisms are indicated in schizophrenia (SCZ). Recent genome-wide association studies (GWAS) have identified genetic variants associated with SCZ and immune-related phenotypes. Here, we use cutting edge statistical tools to identify shared genetic variants between SCZ and white blood cell (WBC) counts and further understand the role of the immune system in SCZ. STUDY DESIGN: GWAS results from SCZ (patients, n = 53 386; controls, n = 77 258) and WBC counts (n = 56 3085) were analyzed. We applied linkage disequilibrium score regression, the conditional false discovery rate method and the bivariate causal mixture model for analyses of genetic associations and overlap, and 2 sample Mendelian randomization to estimate causal effects. STUDY RESULTS: The polygenicity for SCZ was 7.5 times higher than for WBC count and constituted 32%-59% of WBC count genetic loci. While there was a significant but weak positive genetic correlation between SCZ and lymphocytes (rg = 0.05), the conditional false discovery rate method identified 383 shared genetic loci (53% concordant effect directions), with shared variants encompassing all investigated WBC subtypes: lymphocytes, n = 215 (56% concordant); neutrophils, n = 158 (49% concordant); monocytes, n = 146 (47% concordant); eosinophils, n = 135 (56% concordant); and basophils, n = 64 (53% concordant). A few causal effects were suggested, but consensus was lacking across different Mendelian randomization methods. Functional analyses indicated cellular functioning and regulation of translation as overlapping mechanisms. CONCLUSIONS: Our results suggest that genetic factors involved in WBC counts are associated with the risk of SCZ, indicating a role of immune mechanisms in subgroups of SCZ with potential for stratification of patients for immune targeted treatment.

Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness.

BACKGROUND AND HYPOTHESIS: Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. STUDY DESIGN: We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. STUDY RESULTS: Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E-11), CCL25 (P = 9.6E-05) and LBP (P = 2.6E-04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E-04) were observed in SCZ and I-FABP (P = 2.5E-10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. CONCLUSIONS: Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.

Systemic Cell Adhesion Molecules in Severe Mental Illness: Potential Role of Intercellular CAM-1 in Linking Peripheral and Neuroinflammation.

BACKGROUND: Cell adhesion molecules (CAMs) orchestrate leukocyte trafficking and could link peripheral and neuroinflammation in patients with severe mental illness (SMI), by promoting inflammatory and immune-mediated responses and mediating signals across blood-brain barrier. We hypothesized that CAMs would be dysregulated in SMI and evaluated plasma levels of different vascular and neural CAMs. Dysregulated CAMs in plasma were further evaluated in vivo in leukocytes and brain tissue and in vitro in induced pluripotent stem cells. METHODS: We compared plasma soluble levels of different vascular (VCAM-1, ICAM-1, P-SEL) and neural (JAM-A, NCAD) CAMs in circulating leukocytes in a large SMI sample of schizophrenia (SCZ) spectrum disorder (n = 895) and affective disorder (n = 737) and healthy control participants (n = 1070) controlling for age, sex, body mass index, C-reactive protein, and freezer storage time. We also evaluated messenger RNA expression of ICAM1 and related genes encoding ICAM-1 receptors in leukocytes using microarray (n = 842) and in available RNA sequencing data from the CommonMind Consortium (CMC) in postmortem samples from the dorsolateral prefrontal cortex (n = 474). The regulation of soluble ICAM-1 in induced pluripotent stem cell-derived neurons and astrocytes was assessed in patients with SCZ and healthy control participants (n = 8 of each). RESULTS: Our major findings were 1) increased soluble ICAM-1 in patients with SMI compared with healthy control participants; 2) increased ITGB2 messenger RNA, encoding the beta chain of the ICAM-1 receptor, in circulating leukocytes from patients with SMI and increased prefrontal cortex messenger RNA expression of ICAM1 in SCZ; and 3) enhanced soluble ICAM-1 release in induced pluripotent stem cell-derived neurons from patients with SCZ. CONCLUSIONS: Our results support a systemic and cerebral dysregulation of soluble ICAM-1 expression in SMI and especially in patients with SCZ.

Progressive loss of corneal nerve fibers is associated with physical inactivity and glucose lowering medication associated with weight gain in type 2 diabetes.

AIMS/INTRODUCTION: Limited studies have identified risk factors linked to the progression of diabetic peripheral neuropathy (DPN) in type 2 diabetes. This study examined the association of risk factors with change in neuropathy measures over 2 years. MATERIALS AND METHODS: Participants with type 2 diabetes (n = 78) and controls (n = 26) underwent assessment of clinical and metabolic parameters and neuropathy using corneal confocal microscopy (CCM), vibration perception threshold (VPT), and the DN4 questionnaire at baseline and 2 year follow-up. RESULTS: Participants with type 2 diabetes had a lower corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P ≤ 0.0001) and a higher VPT (P ≤ 0.01) compared with controls. Over 2 years, despite a modest reduction in HbA1c (P ≤ 0.001), body weight (P ≤ 0.05), and LDL (P ≤ 0.05) the prevalence of DPN (P = 0.28) and painful DPN (P = 0.21) did not change, but there was a significant further reduction in CNBD (P ≤ 0.0001) and CNFL (P ≤ 0.05). CNFD, CNBD, and CNFL decreased significantly in physically inactive subjects (P < 0.05-0.0001), whilst there was no change in CNFD (P = 0.07) or CNFL (P = 0.85) in physically active subjects. Furthermore, there was no change in CNFD (P = 0.82), CNBD (P = 0.08), or CNFL (P = 0.66) in patients treated with glucose lowering medication associated with weight loss, whilst CNBD (P = 0.001) decreased in patients on glucose lowering medication associated with weight gain. CONCLUSIONS: In participants with type 2 diabetes, despite a modest improvement in HbA1c, body weight, and LDL there was a progressive loss of corneal nerve fibers; except in those who were physically active or on glucose lowering medication associated with weight loss.

Prevalence and risk factors for diabetic peripheral neuropathy, neuropathic pain and foot ulceration in the Arabian Gulf region.

AIMS/INTRODUCTION: This study determined the prevalence and risk factors for diabetic peripheral neuropathy (DPN), painful DPN and diabetic foot ulceration (DFU) in patients with type 2 diabetes in secondary healthcare in Qatar, Kuwait and the Kingdom of Saudi Arabia. MATERIALS AND METHODS: Adults aged 18-85 years with type 2 diabetes were randomly enrolled from secondary healthcare, and underwent clinical and metabolic assessment. DPN was evaluated using vibration perception threshold and neuropathic symptoms and painful Diabetic Peripheral Neuropathy was evaluated using the Douleur Neuropathique 4 questionnaire. RESULTS: A total of 3,021 individuals were recruited between June 2017 and May 2019. The prevalence of DPN was 33.3%, of whom 52.2% were at risk of DFU and 53.6% were undiagnosed. The prevalence of painful DPN was 43.3%, of whom 54.3% were undiagnosed. DFU was present in 2.9%. The adjusted odds ratios for DPN and painful DPN were higher with increasing diabetes duration, obesity, poor glycemic control and hyperlipidemia, and lower with greater physical activity. The adjusted odds ratio for DFU was higher with the presence of DPN, severe loss of vibration perception, hypertension and vitamin D deficiency. CONCLUSIONS: This is the largest study to date from the Middle East showing a high prevalence of undiagnosed DPN, painful DPN and those at risk of DFU in patients with type 2 diabetes, and identifies their respective risk factors.

Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. METHODS: We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. RESULTS: We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. CONCLUSIONS: Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.

Prenatal Diagnosis of Third and Fourth Branchial Apparatus Anomalies: Case Series and Comparison with Lymphatic Malformation.

BACKGROUND AND PURPOSE: Third and fourth branchial apparatus anomalies are rare congenital anomalies. The purpose of this study was to investigate imaging features of these lesions on fetal MR imaging in comparison with lymphatic malformations, the major competing differential diagnosis in these cases. MATERIALS AND METHODS: A retrospective review of our institutional fetal MR imaging database between 1997 and 2019 resulted in 4 patients with confirmed third and fourth branchial apparatus anomalies and 14 patients with confirmed lymphatic malformations. The imaging features were reviewed by consensus, and the Fisher exact test was used to evaluate statistically significant differences between these 2 populations. RESULTS: Four cases of third and fourth branchial apparatus anomalies were imaged at 29 weeks 1 day (range, 23 weeks 1 day to 33 weeks 4 days). All 4 cases demonstrated unilateral, unilocular cysts without reduced diffusion or hemorrhage and a medially directed beaked contour that tapered between the spine and airway at the level of the piriform sinus. Compared with 14 cases of fetal lymphatic malformations imaged at 27 weeks 6 days (range, 21 weeks 3 days to 34 weeks 6 days), third and fourth branchial apparatus cysts were significantly more likely to be unilocular (P < .005) and to have a medially beaked contour (P < .005). The combination of features of unilateral, unilocular, and medially beaked contour was observed only in the fetuses with third and fourth branchial apparatus cysts (P < .001). CONCLUSIONS: The presence of a left-sided unilocular cyst with a medially beaked contour tapering at the level of the piriform sinus suggests the diagnosis of third and fourth branchial apparatus anomaly. Accurate diagnosis in the prenatal period allows proper counseling, genetic work-up, and treatment, potentially sparing patients from recurrent infections and associated morbidity.

Prevalence and risk factors for diabetic neuropathy and painful diabetic neuropathy in primary and secondary healthcare in Qatar.

AIMS/INTRODUCTION: This study determined the prevalence and risk factors for diabetic peripheral neuropathy (DPN) and painful DPN (pDPN) in patients with type 2 diabetes in primary healthcare (PHC) and secondary healthcare (SHC) in Qatar. MATERIALS AND METHODS: This was a cross-sectional multicenter study. Adults with type 2 diabetes were randomly enrolled from four PHC centers and two diabetes centers in SHC in Qatar. Participants underwent assessment of clinical and metabolic parameters, DPN and pDPN. RESULTS: A total of 1,386 individuals with type 2 diabetes (297 from PHC and 1,089 from SHC) were recruited. The prevalence of DPN (14.8% vs 23.9%, P = 0.001) and pDPN (18.1% vs 37.5%, P < 0.0001) was significantly lower in PHC compared with SHC, whereas those with DPN at high risk for diabetic foot ulceration (31.8% vs 40.0%, P = 0.3) was comparable. The prevalence of undiagnosed DPN (79.5% vs 82.3%, P = 0.66) was comparably high, but undiagnosed pDPN (24.1% vs 71.5%, P < 0.0001) was lower in PHC compared with SHC. The odds of DPN and pDPN increased with age and diabetes duration, and DPN increased with poor glycemic control, hyperlipidemia and hypertension, whereas pDPN increased with obesity and reduced physical activity. CONCLUSIONS: The prevalence of DPN and pDPN in type 2 diabetes is lower in PHC compared with SHC, and is attributed to overall better control of risk factors and referral bias due to patients with poorly managed complications being referred to SHC. However, approximately 80% of patients had not been previously diagnosed with DPN in PHC and SHC. Furthermore, we identified a number of modifiable risk factors for PDN and pDPN.

Differential Recall Bias, Intermediate Confounding, and Mediation Analysis in Life Course Epidemiology: An Analytic Framework with Empirical Example.

The mechanisms by which childhood socioeconomic status (CSES) affects adult mental health, general health, and well-being are not clear. Moreover, the analytical assumptions employed when assessing mediation in social and psychiatric epidemiology are rarely explained. The aim of this paper was to explain the intermediate confounding assumption, and to quantify differential recall bias in the association between CSES, childhood abuse, and mental health (SCL-10), general health (EQ-5D), and subjective well-being (SWLS). Furthermore, we assessed the mediating role of psychological and physical abuse in the association between CSES and mental health, general health, and well-being; and the influence of differential recall bias in the estimation of total effects, direct effects, and proportion of mediated effects. The assumptions employed when assessing mediation are explained with reference to a causal diagram. Poisson regression models (relative risk, RR and 99% CIs) were used to assess the association between CSES and psychological and physical abuse in childhood. Mediation analysis (difference method) was used to assess the indirect effect of CSES (through psychological and physical abuse in childhood) on mental health, general health, and well-being. Exposure (CSES) was measured at two time points. Mediation was assessed with both cross-sectional and longitudinal data. Psychological abuse and physical abuse mediated the association between CSES and adult mental health, general health, and well-being (6-16% among men and 7-14% among women, p < 0.001). The results suggest that up to 27% of the association between CSES and childhood abuse, 23% of the association between childhood abuse, and adult mental health, general health, and well-being, and 44% of the association between CSES and adult mental health, general health, and well-being is driven by differential recall bias. Assessing mediation with cross-sectional data (exposure, mediator, and outcome measured at the same time) showed that the total effects and direct effects were vastly overestimated (biased upwards). Consequently, the proportion of mediated effects were underestimated (biased downwards). If there is a true (unobserved) direct or indirect effect, and the direction of the differential recall bias is predictable, then the results of cross-sectional analyses should be discussed in light of that.

Clarifying Associations between Childhood Adversity, Social Support, Behavioral Factors, and Mental Health, Health, and Well-Being in Adulthood: A Population-Based Study.

Previous studies have shown that socio-demographic factors, childhood socioeconomic status (CSES), childhood traumatic experiences (CTEs), social support and behavioral factors are associated with health and well-being in adulthood. However, the relative importance of these factors for mental health, health, and well-being has not been studied. Moreover, the mechanisms by which CTEs affect mental health, health, and well-being in adulthood are not clear. Using data from a representative sample (n = 12,981) of the adult population in Tromsø, Norway, this study examines (i) the relative contribution of structural conditions (gender, age, CSES, psychological abuse, physical abuse, and substance abuse distress) to social support and behavioral factors in adulthood; (ii) the relative contribution of socio-demographic factors, CSES, CTEs, social support, and behavioral factors to three multi-item instruments of mental health (SCL-10), health (EQ-5D), and subjective well-being (SWLS) in adulthood; (iii) the impact of CTEs on mental health, health, and well-being in adulthood, and; (iv) the mediating role of adult social support and behavioral factors in these associations. Instrumental support (24.16%, p < 0.001) explained most of the variation in mental health, while gender (21.32%, p < 0.001) explained most of the variation in health, and emotional support (23.34%, p < 0.001) explained most of the variation in well-being. Psychological abuse was relatively more important for mental health (12.13%), health (7.01%), and well-being (9.09%), as compared to physical abuse, and substance abuse distress. The subjective assessment of childhood financial conditions was relatively more important for mental health (6.02%), health (10.60%), and well-being (20.60%), as compared to mother's and father's education. CTEs were relatively more important for mental health, while, CSES was relatively more important for health and well-being. Respondents exposed to all three types of CTEs had a more than two-fold increased risk of being mentally unhealthy (RR Total Effect = 2.75, 95% CI: 2.19-3.10), an 89% increased risk of being unhealthy (RR Total Effect = 1.89, 95% CI: 1.47-1.99), and a 42% increased risk of having a low level of well-being in adulthood (RR Total Effect = 1.42, 95% CI: 1.29-1.52). Social support and behavioral factors mediate 11-18% (p < 0.01) of these effects. The study advances the theoretical understanding of how CTEs influence adult mental health, health, and well-being.

Epidemiological features of Clostridium difficile infection among inpatients at Hamad General Hospital in the state of Qatar, 2006-2009.

The aim of this retrospective study was to evaluate the epidemiology, clinical course and outcome of Clostridium difficile infection among inpatients at Hamad General Hospital in Qatar, from 2006 to 2009. During this period, 123 patients were diagnosed with C. difficile infection and the overall incidence was 1.6/10,000 patient days. The mean age (±SD) of patients was 50.9 ± 21.2 years. The most frequent underlying disease was hypertension 51/123 (41.5%) and 133 prescriptions of antimicrobials were ordered for 105/123 (86.1%) patients prior to C. difficile infection with piperacillin-tazobactam being the most frequently prescribed antimicrobial 39/131 (29.7%). Nosocomial infection was found in 101/123 (82.0%) of cases, and the most common clinical feature was watery diarrhoea 119/123 (96.7%). Antimicrobials were discontinued in 53/105 (50.5%) cases and 118/123 (95.9%) of them received metronidazole as the initial treatment. The mean treatment duration (±SD) was 9.08 ± 5.6 days. Fifteen (12.7%) patients failed the first course of antimicrobial therapy, of which four were treated with oral vancomycin, and eleven patients received both drugs. Recurrence of infection was observed in 12/118 (10.2%) patients and 30-day mortality was 38/123 (30.9%). Several clinical variables were associated with increased 30-day mortality on univariate analysis. Only occurrence of disease among Qataris, prolonged hospitalisation, positive stool occult blood test, high white blood cells and septic shock were found to be independent predictors of mortality by multivariate logistic regression analysis. In conclusion, C. difficile infection was a recognise cause of morbidity and mortality in our hospital with low and stable incidence. It involved predominantly patients younger than 65 years with underlying illness and metronidazole and vancomycin were effective in resolving symptoms in the majority of our patients.

Anxiety, depression and stress among the husbands of obstetric cases at Karachi.

OBJECTIVE: To determine the level of Anxiety, Depression and Stress among the Husbands of Obstetric Cases. SUBJECTS AND METHODS: This hospital-based prospective study was conducted at Karachi, during the year 1998. A semi-structured proforma along with Hospital Anxiety Depression Scale (HAD) and Life Events Scale were administered to the consenting spouses of obstetric cases. RESULTS: Only 23% of lower socio-economic group husbands accompanied their wives to the hospital compared to 70% of the higher socio-economic group. Out of the 56% of husbands of 82 consecutive obstetric cases interviewed, 13% of those whose wives were NVD showed anxiety and depression as compared to 25% of those with Cesarean Section (C/S). Life Events Scale showed 50% of lower socio-economic group having stress compared to only 10% in higher socio-economic group. CONCLUSION: Contrary to the West, where majority of the Obstetric cases are accompanied by their spouses, in our study only 23% of the cases had their husbands present within the obstetric facility. There is a need of such a study, based on a larger sample in order to address this critical period/issue, considering the concept of 'paternity leaves'. Surprisingly, majority of husbands did not have Anxiety or Depression during the Obstetric period (a critical period needing appropriate attention) of their wives.