Pre-gestational diabetes mellitus, gestational diabetes mellitus, and its association with the MTHFR C677T polymorphism.

Gestational diabetes mellitus (GDM) is a common condition during pregnancy and is associated with an increased risk of pre-eclampsia. The methylenetetrahydrofolate reductase (MTHFR) gene plays a crucial role in folate metabolism and has been implicated in GDM. To investigate the relationship between the MTHFR C677T gene polymorphism and the conditions of GDM and gestational prediabetes in pregnant women. A case-control study was conducted in 114 pregnant women with GDM and 96 pregnant women without GDM, from the first trimester to the prenatal examination at Can Tho Obstetrics Hospital. The pregnant women underwent a 1-hour (G1) and 2-hour (G2) oral glucose tolerance test (OGTT) and genetic polymorphism analysis based on real-time PCR technique. In pregnant women with GDM, weight, concentrations of G0, G1, G2, and folic acid were higher than those in the non-GDM group, with P < .05. When analyzing the subgroup without gestational diabetes, we found that the rate of prediabetes was 16.6% (16/96 pregnant women). In this group, blood glucose levels at 1 hour and 2 hours during the OGTT were higher compared to the normal glucose group (P < .05). A 2-hour post-OGTT glucose level of 7.78 mmol/L had a sensitivity of 93.8%, a specificity of 100%, and an area under the curve of 0.987 for diagnosing gestational prediabetes (P < .001). However, there were no statistically significant differences in the CC, CT, and TT polymorphisms of the MTHFR C677T gene among pregnant women with or without pre-gestational and GDM. Both fasting blood glucose and 2-hour glucose concentrations during the OGTT, as well as folic acid concentrations, were higher in both the pre-gestational and GDM groups compared to the non-gestational diabetes cohort. However, the analysis of MTHFR C677T polymorphisms revealed no statistically significant differences among the groups, highlighting the necessity for more extensive investigations to gain deeper insights into this relationship.

CLADIN- CLADribine and INnate immune response in multiple sclerosis - A phase IV prospective study.

Cladribine (Mavenclad®) is an oral treatment for relapsing remitting MS (RRMS), but its mechanism of action and its effects on innate immune responses in unknown. This study is a prospective Phase IV study of 41 patients with RRMS, and aims to investigate the mechanism of action of cladribine on peripheral monocytes, and its impact on the P2X7 receptor. There was a significant reduction in monocyte count in vivo at week 1 post cladribine administration, and the subset of cells being most impacted were the CD14lo CD16+ 'non-classical' monocytes. Of the 14 cytokines measured in serum, CCL2 levels increased at week 1. In vitro, cladrabine induced a reduction in P2X7R pore as well as channel activity. This study demonstrates a novel mechanism of action for cladribine. It calls for studying potential benefits of cladribine in progressive forms of MS and other neurodegenerative diseases where innate immune related inflammation is implicated in disease pathogenesis.

Cytometry in the Short-Wave Infrared.

Cytometry plays a crucial role in characterizing cell properties, but its restricted optical window (400-850 nm) limits the number of stained fluorophores that can be detected simultaneously and hampers the study and utilization of short-wave infrared (SWIR; 900-1700 nm) fluorophores in cells. Here we introduce two SWIR-based methods to address these limitations: SWIR flow cytometry and SWIR image cytometry. We develop a quantification protocol for deducing cellular fluorophore mass. Both systems achieve a limit of detection of ∼0.1 fg cell-1 within a 30 min experimental time frame, using individualized, high-purity (6,5) single-wall carbon nanotubes as a model fluorophore and macrophage-like RAW264.7 as a model cell line. This high-sensitivity feature reveals that low-dose (6,5) serves as an antioxidant, and cell morphology and oxidative stress dose-dependently correlate with (6,5) uptake. Our SWIR cytometry holds immediate applicability for existing SWIR fluorophores and offers a solution to the issue of spectral overlapping in conventional cytometry.

Modulation of biophysical properties of nucleocapsid protein in the mutant spectrum of SARS-CoV-2.

Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage of the uniquely large genomic database of SARS-CoV-2, we examine the impact of mutations across the spectrum of viable amino acid sequences on the biophysical phenotypes of the highly expressed and multifunctional nucleocapsid protein. We find variation in the physicochemical parameters of its extended intrinsically disordered regions (IDRs) sufficient to allow local plasticity, but also observe functional constraints that similarly occur in related coronaviruses. In biophysical experiments with several N-protein species carrying mutations associated with major variants, we find that point mutations in the IDRs can have nonlocal impact and modulate thermodynamic stability, secondary structure, protein oligomeric state, particle formation, and liquid-liquid phase separation. In the Omicron variant, distant mutations in different IDRs have compensatory effects in shifting a delicate balance of interactions controlling protein assembly properties, and include the creation of a new protein-protein interaction interface in the N-terminal IDR through the defining P13L mutation. A picture emerges where genetic diversity is accompanied by significant variation in biophysical characteristics of functional N-protein species, in particular in the IDRs.

Like other types of RNA viruses, the genetic material of SARS-CoV-2 (the agent responsible for COVID-19) is formed of an RNA molecule which is prone to accumulating mutations. This gives SARS-CoV-2 the ability to evolve quickly, and often to remain one step ahead of treatments. Understanding how these mutations shape the behavior of RNA viruses is therefore crucial to keep diseases such as COVID-19 under control. The gene that codes for the protein that 'packages' the genetic information inside SARS-CoV-2 is particularly prone to mutations. This nucleocapsid (N) protein participates in many key processes during the life cycle of the virus, including potentially interfering with the immune response. Exactly how the physical properties of the N-Protein are impacted by the mutations in its genetic sequence remains unclear. To investigate this question, Nguyen et al. predicted the various biophysical properties of different regions of the N-protein based on a computer-based analysis of SARS-CoV-2 genetic databases. This allowed them to determine if specific protein regions were positively or negatively charged in different mutants. The analyses showed that some domains exhibited great variability in their charge between protein variants ­ reflecting the fact that the corresponding genetic sequences showed high levels of plasticity. Other regions remained conserved, however, including across related coronaviruses. Nguyen et al. also conducted biochemical experiments on a range of N-proteins obtained from clinically relevant SARS-CoV-2 variants. Their results highlighted the importance of protein segments with no fixed three-dimensional structure. Mutations in the related sequences created high levels of variation in the physical properties of these 'intrinsically disordered' regions, which had wide-ranging consequences. Some of these genetic changes even gave individual N-proteins the ability to interact with each other in a completely new way. These results shed new light on the relationship between genetic mutations and the variable physical properties of RNA virus proteins. Nguyen et al. hope that this knowledge will eventually help to develop more effective treatments for viral infections.

Paediatric non-infectious granulomatous uveitis: a retrospective cohort study.

INTRODUCTION: Paediatric granulomatous uveitis (PGU) is rare. In addition, lack of awareness often leads to delayed diagnosis and poor visual outcome. Identifying the underlying cause and deciding how best to treat each patient is challenging. OBJECTIVES: To evaluate the demographics, aetiologies, complications, treatments, and visual prognosis of paediatric non-infectious granulomatous uveitis. METHODS: Retrospective chart review of non-infectious PGU occurring in children before the age of 16 years recruited from the Paediatric Rheumatology Unit, Bicêtre Hospital, France, from 2001 to 2023. RESULTS: We included 50 patients with 90 affected eyes: 29 with idiopathic uveitis, 15 with sarcoidosis, 5 with juvenile idiopathic arthritis, and one with Vogt-Koyanagi-Harada disease. Median age at diagnosis was 9.8 years (range 7.2-12.5). The sex-ratio M/F was 0.52. The most common features of PGU were: panuveitis (56%), bilateral (84%), and chronic (84%). Sarcoidosis was the most frequent diagnosis after idiopathic disease, particularly in the presence of lymphopenia and hypergammaglobulinemia. Uveomeningitis was present in 12% of cases. Upon diagnosis, ocular complications were present in 68 of 90 eyes (76%) particularly in cases of panuveitis. The most commonly used treatments were systemic corticosteroids (72%) and methotrexate (80%). Twenty-three percent of eyes were in remission at last follow-up, 68% were inactive and 4% remained active. The median duration of follow-up was 5.8 years. CONCLUSION: We report the largest cohort of PGU. PGU were mostly idiopathic and had a high rate of complications. Sarcoid and idiopathic panuveitis are serious illnesses in which disease-modifying therapy should be initiated at diagnosis to improve management.

Safety of Obinutuzumab in Children With Autoimmune Encephalitis and Early B-Cell Repopulation on Rituximab.

BACKGROUND: Rituximab (RTX) resistance or early B-cells repopulation were observed in children but only few publications reported the use of Obinutuzumab and no recommendations were made concerning the dosage for children. METHODS: This study was a single-center retrospective cohort study of all the children followed-up in the Pediatric Neurology Department of Necker-Enfants malades Hospital in Paris, France, and treated with obinutuzumab, between November 1, 2019, and November 1, 2021. RESULTS: A total of eight children (three females, median age 4.5 years) were treated. Seven patients presented with autoimmune encephalitis and one with myeloradiculitis. The median delay of B-cell repopulation after a course of RTX was 87 days (range 41 to 160). A switch to obinutuzumab (anti-CD20) was performed for eight children. The median duration between the first RTX infusion and obinutuzumab administration was 6.6 months. The dosage regimen for obinutuzumab was one infusion of 1000 mg/1.73 m2, that is to say 580 mg/m2 (maximum 1000 mg/infusion), by extrapolation from the adult dosage. The median delay of B-cell repopulation after one course of obinutuzumab was 230 days (range 66 to 303 days) vs 87 days after one course of RTX (P < 0.01). None of the patients presented side effects with obinutuzumab treatment. All patients had a favorable evolution at the last-follow up. Median follow-up was 1.6 years. CONCLUSIONS: This study reports the use of obinutuzumab in neurological inflammatory diseases in a pediatric population. Obinutuzumab seems to have a better biological efficacy than RTX with a longer time of B-cell repopulation.

Assembly of SARS-CoV-2 nucleocapsid protein with nucleic acid.

The viral genome of SARS-CoV-2 is packaged by the nucleocapsid (N-)protein into ribonucleoprotein particles (RNPs), 38 ± 10 of which are contained in each virion. Their architecture has remained unclear due to the pleomorphism of RNPs, the high flexibility of N-protein intrinsically disordered regions, and highly multivalent interactions between viral RNA and N-protein binding sites in both N-terminal (NTD) and C-terminal domain (CTD). Here we explore critical interaction motifs of RNPs by applying a combination of biophysical techniques to ancestral and mutant proteins binding different nucleic acids in an in vitro assay for RNP formation, and by examining nucleocapsid protein variants in a viral assembly assay. We find that nucleic acid-bound N-protein dimers oligomerize via a recently described protein-protein interface presented by a transient helix in its long disordered linker region between NTD and CTD. The resulting hexameric complexes are stabilized by multivalent protein-nucleic acid interactions that establish crosslinks between dimeric subunits. Assemblies are stabilized by the dimeric CTD of N-protein offering more than one binding site for stem-loop RNA. Our study suggests a model for RNP assembly where N-protein scaffolding at high density on viral RNA is followed by cooperative multimerization through protein-protein interactions in the disordered linker.

An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission.

Recombinant adeno-associated viruses (AAVs) allow rapid and efficient gene delivery to the nervous system, are widely used in neuroscience research, and are the basis of FDA-approved neuron-targeting gene therapies. Here we find that an innate immune response to the AAV genome reduces dendritic length and complexity and disrupts synaptic transmission in mouse somatosensory cortex. Dendritic loss is apparent 3 weeks after injection of experimentally relevant viral titers, is not restricted to a particular capsid serotype, transgene, promoter, or production facility, and cannot be explained by responses to surgery or transgene expression. AAV-associated dendritic loss is accompanied by a decrease in the frequency and amplitude of miniature excitatory postsynaptic currents and an increase in the proportion of GluA2-lacking, calcium-permeable AMPA receptors. The AAV genome is rich in unmethylated CpG DNA, which is recognized by the innate immunoreceptor Toll-like receptor 9 (TLR9), and acutely blocking TLR9 preserves dendritic complexity and AMPA receptor subunit composition in AAV-injected mice. These results reveal unexpected impacts of an immune response to the AAV genome on neuronal structure and function and identify approaches to improve the safety and efficacy of AAV-mediated gene delivery in the nervous system.

OFF episode quality of life impact scale (OFFELIA): A new measure of quality of life for off episodes in Parkinson's disease.

INTRODUCTION: OFF Episodes occur in people with Parkinson's disease when their medication wears off, and motor and/or non-motor symptoms emerge. Existing measures used to assess OFF Episodes focus on the time spent in OFF Episodes through diaries or by identifying symptoms, but they are limited in their ability to capture the severity and functional impact of OFF episodes. The aim of this study was to develop and validate a new instrument, called "OFFELIA," that measures the impact of OFF episodes on the quality of life of individuals with Parkinson's disease. METHODS: Participants completed a cross-sectional questionnaire, "Impact and Communication on OFF Periods," while enrolled in the online clinical study Fox Insights. The data collected was used to develop OFFELIA. Psychometric testing was performed on 18 candidate items using classical, exploratory factor analysis, and item response theory methods. RESULTS: 569 individuals with Parkinson's disease completed the questionnaire. All items were retained for the final measure, with 17 items aggregated into two multi-item scales (functioning and psychological well-being) and one item reported separately as it did not function well with the other items (employment). Known group comparisons based on average duration, frequency and unpredictability of OFF episodes indicated that OFFELIA subscales were more sensitive than existing generic and condition-specific measures. CONCLUSION: Initial evidence supports the validity of OFFELIA, a new instrument that assesses the impact of OFF periods on daily life. This instrument can be used in assessing clinical therapeutic strategies targeting OFF episodes in Parkinson's disease.

Risk of Cervical Abnormalities for Women With Multiple Sclerosis Treated With Moderate-Efficacy and High-Efficacy Disease-Modifying Therapies.

BACKGROUND AND OBJECTIVES: The impact of immunomodulatory therapies on the risk of cervical pre-cancer and invasive cancer development is important for the health and safety of women with multiple sclerosis (wwMS). We investigate the risk of cervical abnormalities in wwMS treated with disease-modifying therapies (DMTs). METHODS: This is a multicenter cohort study with data collected from 1998 to 2019 in Victoria, Australia. Data linkage was performed using matching records from the MSBase Registry, the National Human Papillomavirus (HPV) Vaccination Program Register, and the Victorian Cervical Cytology Register. The primary outcome was the detection of any type of cervical abnormality as determined by cytology or histology. Survival methods were used to assess the time to cervical abnormality detection on cervical screening tests (CSTs). Crude and adjusted Cox proportional hazards models were used to determine time to and magnitude of association of DMTs with the risk of cervical abnormality. In a sensitivity analysis, we constructed standardized survival curves averaged over the same set of covariates to determine the commensurate population-average (marginal) causal effects. RESULTS: We included 248 wwMS. The incidence of abnormal CSTs was lower (p < 0.001) for women not exposed to moderate-high-efficacy therapy (10.2 per 1,000 patient-years [95% confidence interval (CI) 5.5-14.9]), compared with those exposed (36.6 per 1,000 patient-years [95% CI 21.7-51.6]). Exposure to higher efficacy treatment was associated with a 3.79-fold increased hazard (95% CI 2.02-7.08, p < 0.001) of developing a cervical abnormality relative to those not exposed. When adjusted for vaccination status, smoking, hormonal contraceptive use, and socioeconomic status, the risk remained elevated at 3.79 (95% CI 1.99-7.21, p < 0.001). Marginal hazard ratios declined over time, ranging from 3.90 (95% CI 2.09-7.27) at 20 years of age to 2.06 (95% CI 1.14-3.73) at 70 years of age. DISCUSSION: A greater than three-and-a-half-fold increased risk of cervical abnormalities was found after exposure to moderate-high-efficacy DMTs. This risk persisted despite adjusting for HPV vaccination status, hormonal contraception use, smoking, and socioeconomic status. If confirmed in future studies, we would advocate for wwMS exposed to moderate-high-efficacy DMTs to be treated in line with immune-deficient paradigm in cervical screening and HPV vaccination programs. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that highly active MS therapy compared with less active therapy increases the risk of developing cervical abnormalities among women with MS.

Psychopathology and psychosocial functioning among young people with first-episode psychosis and/or first-presentation borderline personality disorder.

BACKGROUND: One in five young people with first-episode psychosis (FEP) also presents with borderline personality disorder (BPD) features. Among people diagnosed with BPD, auditory verbal hallucinations occur in 29-50 % and delusions in 10-100 %. Co-occurrence of psychotic symptoms and BPD is associated with greater clinical severity and greater difficulty accessing evidence based FEP care. This study aimed to investigate psychotic symptoms and psychosocial functioning among young people presenting to an early intervention mental health service. METHOD: According to the presence or absence of either FEP or BPD, 141 participants, aged 15-25 years, were assigned to one of four groups: FEP, BPD, combined FEP + BPD, or clinical comparison (CC) participants with neither FEP nor BPD. Participants completed semi-structured diagnostic interviews and interviewer and self-report measures of psychopathology and psychosocial functioning. RESULTS: The FEP + BPD group had significantly more severe psychopathology and poorer psychosocial functioning than the FEP group on every measure, apart from intensity of hallucinations. Comparing the FEP or BPD groups, the BPD group had greater psychopathology, apart from intensity of psychotic symptoms, which was significantly greater in the FEP group. These two groups did not significantly differ in their overall psychosocial functioning. Compared with CC young people, both the FEP + BPD and BPD groups differed significantly on every measure, with medium to large effect sizes. CONCLUSIONS: Young people with co-occurring FEP and BPD experience more severe difficulties than young people with either diagnosis alone. This combination of psychosis and severe personality pathology has been longitudinally associated with poorer outcomes among adults and requires specific clinical attention.

Diagnosis and Management of Non-Infectious Uveitis in Pediatric Patients.

Uveitis in children accounts for 5-10% of all cases. The causes vary considerably. Classically, uveitis is distinguished according to its infectious or inflammatory origin and whether it is part of a systemic disease or represents an isolated ocular disease. It is important to highlight the specificity of certain etiologies among children such as juvenile idiopathic arthritis. The development of visual function can potentially be hindered by amblyopia (children aged < 7 years), in addition to the usual complications (synechiae, macular edema) seen in adult patients. Moreover, the presentation of uveitis in children is often "silent" with few warning signs and few functional complaints from young children, which frequently leads to a substantial diagnostic delay. The diagnostic approach is guided by the presentation of the uveitis, which can be characterized by its location, and corresponds to the initial and main site of intraocular inflammation; its presentation, whether acute or chronic, granulomatous or not; and the response to treatment. Pediatricians have an important role to play and must be aware of the various presentations and etiologies of uveitis in children. Juvenile idiopathic arthritis is the most common etiology of pediatric non-infectious uveitis, but other causes must be recognized. Promptly initiated treatment before complications arise requires early diagnosis, recognition, and treatment. Any dependence on prolonged local corticosteroid therapy justifies discussing the introduction of a corticosteroid-sparing treatment considering the risk to develop corticoid-induced glaucoma and cataracts. Systemic corticosteroid therapy can be required for urgent control of inflammation in the case of severe uveitis. Long-lasting immunosuppressive treatment and biotherapies are most often prescribed at the same time to reinforce treatment efficacy and to prevent relapse and corticosteroid dependency. We review the different causes of uveitis, excluding infection, and the diagnostic and therapeutic management aimed at limiting the risk of irreversible sequelae.

Modulation of Biophysical Properties of Nucleocapsid Protein in the Mutant Spectrum of SARS-CoV-2.

Genetic diversity is a hallmark of RNA viruses and the basis for their evolutionary success. Taking advantage of the uniquely large genomic database of SARS-CoV-2, we examine the impact of mutations across the spectrum of viable amino acid sequences on the biophysical phenotypes of the highly expressed and multifunctional nucleocapsid protein. We find variation in the physicochemical parameters of its extended intrinsically disordered regions (IDRs) sufficient to allow local plasticity, but also exhibiting functional constraints that similarly occur in related coronaviruses. In biophysical experiments with several N-protein species carrying mutations associated with major variants, we find that point mutations in the IDRs can have nonlocal impact and modulate thermodynamic stability, secondary structure, protein oligomeric state, particle formation, and liquid-liquid phase separation. In the Omicron variant, distant mutations in different IDRs have compensatory effects in shifting a delicate balance of interactions controlling protein assembly properties, and include the creation of a new protein-protein interaction interface in the N-terminal IDR through the defining P13L mutation. A picture emerges where genetic diversity is accompanied by significant variation in biophysical characteristics of functional N-protein species, in particular in the IDRs.

Design, synthesis, and biological evaluation of HDAC6 inhibitors targeting L1 loop and serine 531 residue.

Histone deacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones, leading to the silencing of genes. Targeting specific isoforms of HDACs has emerged as a promising approach for cancer therapy, as it can overcome drawbacks associated with pan-HDAC inhibitors. HDAC6 is a unique HDAC isoform that deacetylates non-histone proteins and is primarily located in the cytoplasm. It also has two catalytic domains and a zinc-finger ubiquitin binding domain (Zf-UBD) unlike other HDACs. HDAC6 plays a critical role in various cellular processes, including cell motility, protein degradation, cell proliferation, and transcription. Hence, the deregulation of HDAC6 is associated with various malignancies. In this study, we report the design and synthesis of a series of HDAC6 inhibitors. We evaluated the synthesized compounds by HDAC enzyme assay and identified that compound 8g exhibited an IC50 value of 21 nM and 40-fold selective activity towards HDAC6. We also assessed the effect of compound 8g on various cell lines and determined its ability to increase protein acetylation levels by Western blotting. Furthermore, the increased acetylation of α-tubulin resulted in microtubule polymerization and changes in cell morphology. Our molecular docking study supported these findings by demonstrating that compound 8g binds well to the catalytic pocket via L1 loop of HDAC6 enzyme. Altogether, compound 8g represents a preferential HDAC6 inhibitor that could serve as a lead for the development of more potent and specific inhibitors.

Assembly reactions of SARS-CoV-2 nucleocapsid protein with nucleic acid.

The viral genome of SARS-CoV-2 is packaged by the nucleocapsid (N-) protein into ribonucleoprotein particles (RNPs), 38±10 of which are contained in each virion. Their architecture has remained unclear due to the pleomorphism of RNPs, the high flexibility of N-protein intrinsically disordered regions, and highly multivalent interactions between viral RNA and N-protein binding sites in both N-terminal (NTD) and C-terminal domain (CTD). Here we explore critical interaction motifs of RNPs by applying a combination of biophysical techniques to mutant proteins binding different nucleic acids in an in vitro assay for RNP formation, and by examining mutant proteins in a viral assembly assay. We find that nucleic acid-bound N-protein dimers oligomerize via a recently described protein-protein interface presented by a transient helix in its long disordered linker region between NTD and CTD. The resulting hexameric complexes are stabilized by multi-valent protein-nucleic acid interactions that establish crosslinks between dimeric subunits. Assemblies are stabilized by the dimeric CTD of N-protein offering more than one binding site for stem-loop RNA. Our study suggests a model for RNP assembly where N-protein scaffolding at high density on viral RNA is followed by cooperative multimerization through protein-protein interactions in the disordered linker.

Upper Gastrointestinal Bleeding Caused by Rupture of Pancreatic Pseudoaneurysms.

Pseudoaneurysm rupture in patients with pancreatitis is a rare but fatal etiology of upper gastrointestinal bleeding. We report a rare case of upper gastrointestinal bleeding in a patient who presented simultaneously with two pseudoaneurysms, a potential cause of severe gastrointestinal bleeding. Angiography was successfully performed with coil embolization of the target arteries and both pseudoaneurysmal sacs. The patient was discharged 9 days after admission without further events within a 3-month follow-up period.

The pharmacogenomics of carbamazepine-induced cutaneous adverse drug reaction in the South of Vietnam.

Background: The relationship between HLA-B*15:02 and Severe Cutaneous Adverse Reactions was rigorously examined in Japanese, Han Chinese, Thais, and Caucasians. However, the number of studies about this topic in Vietnamese population is still limited and mostly focuses on the North of Vietnam. Objective: This study aims to clarify the genetic culprit of SCARs in Vietnamese population, particularly in the South of Vietnam, and to validate our result by a meta-analysis about this topic in Vietnamese. Method: A retrospective case-control study with 37 patients treated with carbamazepine monotherapy. Statistical calculation and meta-analysis were performed by R software. Result: HLA-B*15:02 increases the risk of SJS 12.5 times higher in CBZ-treated patients (p-value = 0.017). However, this allele has no impact on MCARs (Mild Cutaneous Adverse Reactions) of CBZ. The number needed to test and the number needed to genotype is two and nine patients respectively. Conclusion: This study recommends more investigations about the cost-effectiveness of this test to accelerate the protection of Southern Vietnamese from SCARs.

Quantification of rare earth elements in Australian and imported rice samples from different origins using ICP-MS.

Rare earth elements (REEs) are also known as lanthanides and are comprised of seventeen elements including lanthanum to lutetium in the periodic table. Despite their increased utilization, little attention is given to them as emerging environmental contaminants and their associated health risks. The concentration of these elements in urban and agronomic soil may trigger bioaccumulation in plants and may enter the food chain. Also, the consumption of fertilizers in agricultural practices on a larger scale is a significant challenge. The REEs enriched fertilizers are a risk factor for contamination in soil and food. However, there is very limited data in the literature regarding the occurrence of these elements in a staple food such as rice. Thus, this study is aimed at quantification of rare earth elements in Australian and imported rice samples from different countries by using Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The developed analytical method was validated by using two certified reference materials (CRMs) for precision and accuracy. The method was applied for analysing rice samples (including polished, brown, and parboiled) imported from different countries and sourced locally and consumed by the Australian population. The average concentration of REEs in Australian, Thailand and Vietnamese rice samples were quantified as 0.013-2.974 µg/kg, 0.012-3.113 µg/kg, 0.009-0.919 µg/kg respectively and were lower than other countries. The highest average concentrations of REEs were found in Pakistan (0.299-128.2 µg/kg), India (0.063-20.574 µg/kg), and Sri Lankan (0.022-11.522 µg/kg) rice samples imported to Australia. Scandium and yttrium were found in the range of 107.463-85.961 µg/kg. The pattern of Light rare earth elements (LREE) was more abundant than heavy rare earth elements (HREE). This study did not include field experiments to find the translocation factors of REEs from soil to different parts of plant bodies, thus cannot establish the correlation between fertilizers and REEs concentration in rice grains. However, this study presented the general interpretation of REEs quantification in rice grains from different Countries. The outcome of this study includes filling the subsequent knowledge gaps in analysing REEs in rice. This study indicated the need to establish a monitoring program for this type of staple cereals, aiming at promoting public health.

Disability accrual in primary and secondary progressive multiple sclerosis.

BACKGROUND: Some studies comparing primary and secondary progressive multiple sclerosis (PPMS, SPMS) report similar ages at onset of the progressive phase and similar rates of subsequent disability accrual. Others report later onset and/or faster accrual in SPMS. Comparisons have been complicated by regional cohort effects, phenotypic differences in sex ratio and management and variable diagnostic criteria for SPMS. METHODS: We compared disability accrual in PPMS and operationally diagnosed SPMS in the international, clinic-based MSBase cohort. Inclusion required PPMS or SPMS with onset at age ≥18 years since 1995. We estimated Andersen-Gill hazard ratios for disability accrual on the Expanded Disability Status Scale (EDSS), adjusted for sex, age, baseline disability, EDSS score frequency and drug therapies, with centre and patient as random effects. We also estimated ages at onset of the progressive phase (Kaplan-Meier) and at EDSS milestones (Turnbull). Analyses were replicated with physician-diagnosed SPMS. RESULTS: Included patients comprised 1872 with PPMS (47% men; 50% with activity) and 2575 with SPMS (32% men; 40% with activity). Relative to PPMS, SPMS had older age at onset of the progressive phase (median 46.7 years (95% CI 46.2-47.3) vs 43.9 (43.3-44.4); p<0.001), greater baseline disability, slower disability accrual (HR 0.86 (0.78-0.94); p<0.001) and similar age at wheelchair dependence. CONCLUSIONS: We demonstrate later onset of the progressive phase and slower disability accrual in SPMS versus PPMS. This may balance greater baseline disability in SPMS, yielding convergent disability trajectories across phenotypes. The different rates of disability accrual should be considered before amalgamating PPMS and SPMS in clinical trials.

A conserved oligomerization domain in the disordered linker of coronavirus nucleocapsid proteins.

The nucleocapsid (N-)protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a key role in viral assembly and scaffolding of the viral RNA. It promotes liquid-liquid phase separation (LLPS), forming dense droplets that support the assembly of ribonucleoprotein particles with as-of-yet unknown macromolecular architecture. Combining biophysical experiments, molecular dynamics simulations, and analysis of the mutational landscape, we describe a heretofore unknown oligomerization site that contributes to LLPS, is required for the assembly of higher-order protein-nucleic acid complexes, and is coupled to large-scale conformational changes of N-protein upon nucleic acid binding. The self-association interface is located in a leucine-rich sequence of the intrinsically disordered linker between N-protein folded domains and formed by transient helices assembling into trimeric coiled-coils. Critical residues stabilizing hydrophobic and electrostatic interactions between adjacent helices are highly protected against mutations in viable SARS-CoV-2 genomes, and the oligomerization motif is conserved across related coronaviruses, thus presenting a target for antiviral therapeutics.