reactivity of the drug methimazole and its iodine adduct with elemental zinc

The reactivity of zinc complexes with N,S-donor molecules may be of relevance to the study of Zn-metalloproteins and -metalloenzymes. In this context, the zinc complex [Zn(MeImSH)2I2] was synthesised by the reaction of zinc powder with the 1:1 iodine adduct of the drug methimazole [(MeImSH)·I2]. The molecular structure of the complex, elucidated by X-ray diffraction analysis, showed a tetrahedral zinc(II) centre coordinated by two neutral methimazole units (through the sulfur atoms) and two iodides. From the reaction of MeImSH and Zn powder, the complex [Zn(MeImSH)(MeImS)2] (MeImS = deprotonated form of methimazole) was separated and characterised. An analysis of the crystal packing of the neutral complexes [Zn(MeImSH)2X2] (X = I, Br and Cl) and the ionic complex [Zn(MeImSH)3I]I showed that in all of the complexes the sulfur atom, in addition to binding to the metal centre, contributes to the formation of 1-D chains built via C(4)–H⋯S and N–H⋯X interactions in the neutral complexes, and via C(4)–H⋯S and N–CH3⋯S interactions in the ionic complex [Zn(MeImSH)3I]I. The deprotonation/protonation of the coordinated methimazole units can modulate the coordination environment at the Zn core. From the reaction of complex [Zn(MeImSH)3I]I with a strong non-coordinating organic base, we have shown that, as a consequence of the NH deprotonation of methimazole S-coordinated to zinc(II), the ligand coordination mode changes from S-monodentate to N,S-bridging. Correspondingly, in the complex [Zn(MeImSH)(MeImS)2], the MeImS that displays the N,S-bridging mode at zinc can be N-protonated and thereby changes to the S-monodentate coordination

The potential shared role of inflammation in insulin resistance and schizophrenia:a bidirectional two-sample mendelian randomization study

BACKGROUND: Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia. METHODS AND FINDINGS: We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38–6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36–0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37–2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85–1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant. CONCLUSIONS: Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance

Evidence for Shared Genetic Aetiology Between Schizophrenia, Cardiometabolic, and Inflammation-Related Traits: Genetic Correlation and Colocalization Analyses.

Funder: MQ: Transforming Mental Health; Grant(s): MQDS17/40BACKGROUND: Schizophrenia commonly co-occurs with cardiometabolic and inflammation-related traits. It is unclear to what extent the comorbidity could be explained by shared genetic aetiology. METHODS: We used GWAS data to estimate shared genetic aetiology between schizophrenia, cardiometabolic, and inflammation-related traits: fasting insulin (FI), fasting glucose, glycated haemoglobin, glucose tolerance, type 2 diabetes (T2D), lipids, body mass index (BMI), coronary artery disease (CAD), and C-reactive protein (CRP). We examined genome-wide correlation using linkage disequilibrium score regression (LDSC); stratified by minor-allele frequency using genetic covariance analyzer (GNOVA); then refined to locus-level using heritability estimation from summary statistics (ρ-HESS). Regions with local correlation were used in hypothesis prioritization multi-trait colocalization to examine for colocalisation, implying common genetic aetiology. RESULTS: We found evidence for weak genome-wide negative correlation of schizophrenia with T2D (rg = -0.07; 95% C.I., -0.03,0.12; P = .002) and BMI (rg = -0.09; 95% C.I., -0.06, -0.12; P = 1.83 × 10-5). We found a trend of evidence for positive genetic correlation between schizophrenia and cardiometabolic traits confined to lower-frequency variants. This was underpinned by 85 regions of locus-level correlation with evidence of opposing mechanisms. Ten loci showed strong evidence of colocalization. Four of those (rs6265 (BDNF); rs8192675 (SLC2A2); rs3800229 (FOXO3); rs17514846 (FURIN)) are implicated in brain-derived neurotrophic factor (BDNF)-related pathways. CONCLUSIONS: LDSC may lead to downwardly-biased genetic correlation estimates between schizophrenia, cardiometabolic, and inflammation-related traits. Common genetic aetiology for these traits could be confined to lower-frequency common variants and involve opposing mechanisms. Genes related to BDNF and glucose transport amongst others may partly explain the comorbidity between schizophrenia and cardiometabolic disorders

Type Ia Supernova Nucleosynthesis: Metallicity-dependent Yields

Type Ia supernova explosions (SN Ia) are fundamental sources of elements for the chemical evolution of galaxies. They efficiently produce intermediate-mass (with Z between 11 and 20) and iron group elements - for example, about 70% of the solar iron is expected to be made by SN Ia. In this work, we calculate complete abundance yields for 39 models of SN Ia explosions, based on three progenitors - a 1.4 M ⊙ deflagration detonation model, a 1.0 M ⊙ double detonation model, and a 0.8 M ⊙ double detonation model - and 13 metallicities, with 22Ne mass fractions of 0, 1 × 10-7, 1 × 10-6, 1 × 10-5, 1 × 10-4, 1 × 10-3, 2 × 10-3, 5 × 10-3, 1 × 10-2, 1.4 × 10-2, 5 × 10-2, and 0.1, respectively. Nucleosynthesis calculations are done using the NuGrid suite of codes, using a consistent nuclear reaction network between the models. Complete tables with yields and production factors are provided online at Zenodo:Yields (https://doi.org/10.5281/zenodo.8060323). We discuss the main properties of our yields in light of the present understanding of SN Ia nucleosynthesis, depending on different progenitor mass and composition. Finally, we compare our results with a number of relevant models from the literature

Type Ia Supernova Nucleosynthesis: Metallicity-Dependent Yields

Type Ia supernova explosions (SNIa) are fundamental sources of elements for the chemical evolution of galaxies. They efficiently produce intermediate-mass (with Z between 11 and 20) and iron group elements - for example, about 70% of the solar iron is expected to be made by SNIa. In this work, we calculate complete abundance yields for 39 models of SNIa explosions, based on three progenitors - a 1.4M deflagration detonation model, a 1.0 double detonation model and a 0.8 M double detonation model - and 13 metallicities, with 22Ne mass fractions of 0, 1x10-7, 1x10-6, 1x10-5, 1x10-4, 1x10-3, 2x10-3, 5x10-3, 1x10-2, 1.4x10-2, 5x10-2, and 0.1 respectively. Nucleosynthesis calculations are done using the NuGrid suite of codes, using a consistent nuclear reaction network between the models. Complete tables with yields and production factors are provided online at Zenodo: Yields. We discuss the main properties of our yields in the light of the present understanding of SNIa nucleosynthesis, depending on different progenitor mass and composition. Finally, we compare our results with a number of relevant models from the literature.Comment: 42 pages, 21 figures. Accepted for publication in ApJS 21-06-2

Long-term surveillance study of rituximab originator treated patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)

Lay Summary: What does this mean for patients? Rituximab is used to treat active disease and to prevent relapses in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Serious complications, including infections, low natural antibody levels, cancers, low white blood cell levels, heart disease and blood clots are common in AAV patients in general. Whether these complications are more or less common with rituximab is unclear. This study assessed the frequency of serious complications and compared time to first serious complications between patients, either treated with or without rituximab. Over 40% of the patients in this study experienced at least one serious complication. Overall, first serious complication occurred earlier and higher risk of serious infection was seen in rituximab patients. However, these findings should be interpreted with caution as the rituximab patients had been diagnosed with vasculitis for longer and had received a greater amount of immunosuppression in the past, compared with the patients who had not been treated with rituximab

The effectiveness and cost-effectiveness of treatments for idiopathic pulmonary fibrosis: systematic review, network meta-analysis and health economic evaluation

Background: Idiopathic pulmonary fibrosis (IPF) is a life-limiting lung disease with considerable impact on patients and carers as the disease progresses. Currently few treatments are available. We aimed to evaluate the clinical and cost-effectiveness of available treatments for IPF. Methods: Systematic reviews of clinical effectiveness, quality of life and cost effectiveness were undertaken. Eleven bibliographic databases were searched from inception to July 2013 and studies were assessed for eligibility against a set of pre-defined criteria. Two reviewers screened references, extracted data from included studies and appraised their quality. An advisory group was consulted about the choice of interventions. A narrative review was undertaken and where feasible fixed effect and random effects meta-analysis were undertaken including a network meta-analysis (NMA). A decision-analytic Markov model was developed to estimate cost-effectiveness of pharmacological treatments for IPF. Following best practice recommendations, the model perspective was of the national health service and personal social services, a discount rate of 3.5% for costs and health benefits was applied and outcomes were expressed as cost per quality adjusted life-year gained. Parameter values were obtained from the NMA and systematic reviews. Sensitivity analyses were undertaken. Results: Fourteen studies were included in the review of clinical effectiveness, of which one evaluated azathioprine, three N-acetylcysteine [NAC] (alone or in combination), four pirfenidone, one nintedanib, one sildenafil, one thalidomide, two pulmonary rehabilitation, and one a disease management programme. Study quality was generally good. Evidence suggests that some effective treatments are available. In NMA only nintedanib and pirfenidone show statistically significant improvements. The model results show increased survival for five pharmacological treatments (NAC triple therapy, inhaled NAC, nintedanib, pirfenidone, and sildenafil) compared with best supportive care, at increased cost. Only inhaled NAC was cost-effective at current willingness to pay thresholds but it may not be clinically effective. Conclusions: Few interventions have any statistically significant effect and the cost-effectiveness of treatments is uncertain. A lack of studies on palliative care approaches was identified and there is a need for further research into pulmonary rehabilitation and thalidomide in particular. A well conducted RCT on inhaled NAC therapy should also be considered

Patient-Clinician Decision Making for Stable Angina: The Role of Health Literacy

Background: Stable angina patients have difficulty understanding the tradeoffs between treatment alternatives. In this analysis, we assessed treatment planning conversations for stable angina to determine whether inadequate health literacy acts as a barrier to communication that may partially explain this difficulty. Methods: We conducted a descriptive analysis of patient questionnaire data from the PCI Choice Trial. The main outcomes were the responses to the Decisional Conflict Scale and the proportion of correct responses to knowledge questions about stable angina. We also conducted a qualitative analysis on recordings of patient-clinician discussions about treatment planning. The recordings were coded with the OPTION12 instrument for shared decision-making. Two analysts independently assessed the number and types of patient questions and expressions of preferences. Results: Patient engagement did not differ by health literacy level and was generally low for all patients with respect to OPTION12 scores and the number of questions related to clinical aspects of treatment. Patients with inadequate health literacy had significantly higher decisional conflict. However, the proportion of knowledge questions answered correctly did not differ significantly by health literacy level. Conclusions: Patients with inadequate health literacy had greater decisional conflict but no difference in knowledge compared to patients with adequate health literacy. Inadequate health literacy may act as a barrier to communication, but gaps were found in patient engagement and knowledge for patients of all health literacy levels. The recorded patient-clinician encounters and the health literacy measure were valuable resources for conducting research on care delivery

Anterior nasal versus nasal mid-turbinate sampling for a SARS-CoV-2 antigen-detecting rapid test: does localisation or professional collection matter?

INTRODUCTION: Most SARS-CoV-2 antigen-detecting rapid diagnostic tests require nasopharyngeal sampling, which is frequently perceived as uncomfortable and requires healthcare professionals, thus limiting scale-up. Nasal sampling could enable self-sampling and increase acceptability. The term nasal sampling is often not used uniformly and sampling protocols differ. METHODS: This manufacturer-independent, prospective diagnostic accuracy study, compared professional anterior nasal and nasal mid-turbinate sampling for a WHO-listed SARS-CoV-2 antigen-detecting rapid diagnostic test. The second group of participants collected a nasal mid-turbinate sample themselves and underwent a professional nasopharyngeal swab for comparison. The reference standard was real-time polymerase chain reaction (RT-PCR) using combined oro-/nasopharyngeal sampling. Individuals with high suspicion of SARS-CoV-2 infection were tested. Sensitivity, specificity, and percent agreement were calculated. Self-sampling was observed without intervention. Feasibility was evaluated by observer and participant questionnaires. RESULTS: Among 132 symptomatic adults, both professional anterior nasal and nasal mid-turbinate sampling yielded a sensitivity of 86.1% (31/36 RT-PCR positives detected; 95%CI: 71.3-93.9) and a specificity of 100.0% (95%CI: 95.7-100). The positive percent agreement was 100% (95%CI: 89.0-100). Among 96 additional adults, self nasal mid-turbinate and professional nasopharyngeal sampling yielded an identical sensitivity of 91.2% (31/34; 95%CI 77.0-97.0). Specificity was 98.4% (95%CI: 91.4-99.9) with nasal mid-turbinate and 100.0% (95%CI: 94.2-100) with nasopharyngeal sampling. The positive percent agreement was 96.8% (95%CI: 83.8-99.8). Most participants (85.3%) considered self-sampling as easy to perform. CONCLUSION: Professional anterior nasal and nasal mid-turbinate sampling are of equivalent accuracy for an antigen-detecting rapid diagnostic test in ambulatory symptomatic adults. Participants were able to reliably perform nasal mid-turbinate sampling themselves, following written and illustrated instructions. Nasal self-sampling will facilitate scaling of SARS-CoV-2 antigen testing