Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation

Potential drug-drug interactions of frequently prescribed medications in long COVID detected by two electronic databases.

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to a wide range of acute and chronic complications including long COVID, a well-known chronic sequela. Long COVID often necessitates long-term treatment, which may lead to an increased potential for drug-drug interactions (DDIs). The objective of this study was to assess potential DDIs among frequently prescribed medications in long COVID by using two electronic databases. Sixty frequently prescribed agents were selected from Thailand's National List of Essential Medicine 2022 for potential DDI analysis by Micromedex and Drugs.com. From these databases, 488 potential DDIs were identified. There were 271 and 434 DDI pairs based on Micromedex and Drugs.com, respectively. Among these DDIs, 77 pairs were labeled as contraindicated or major by both databases. The most common mechanisms for these serious interactions are cytochrome P450 (CYP) inhibition (45%), CYP induction (19%), and QT interval prolongation (7.8%). Based on Fleiss' kappa (0.073), there was only slight agreement of the DDI severity classifications between these two databases. In conclusion, a large number of potential DDIs were detected among frequently prescribed medications for long COVID. Health care providers should be aware of these DDIs, particularly those that are deemed as contraindicated or major. These DDIs are most likely to cause significant adverse events in patients with long COVID because polypharmacy is common

The association between body mass index and severity of Coronavirus Disease 2019 (COVID-19): A cohort study.

ObjectivesThe coronavirus disease 2019 (COVID-19) has become a worst pandemic. The clinical characteristics vary from asymptomatic to fatal. This study aims to examine the association between body mass index (BMI) levels and the severity of COVID-19.Methods and study designA cohort study included 147 adult patients with confirmed COVID-19 were categorized into 4 groups by BMI levels on admission: ResultsOf the totals, patients having a BMI ConclusionsObesity in patients with COVID-19 was associated with severe pneumonia and adverse outcomes such as AKI, transaminitis and ICU stay. Underweight patients should be closely monitored for AKI. Further studies in body composition are warranted to explore the links between adiposity and COVID-19 pathogenesis

Increased platelet activation and lower platelet-monocyte aggregates in COVID-19 patients with severe pneumonia.

BackgroundThe increased procoagulant platelets and platelet activation are associated with thrombosis in COVID-19. In this study, we investigated platelet activation in COVID-19 patients and their association with other disease markers.MethodsCOVID-19 patients were classified into three severity groups: no pneumonia, mild-to-moderate pneumonia, and severe pneumonia. The expression of P-selectin and activated glycoprotein (aGP) IIb/IIIa on the platelet surface and platelet-leukocyte aggregates were measured prospectively on admission days 1, 7, and 10 by flow cytometry.ResultsP-selectin expression, platelet-neutrophil, platelet-lymphocyte, and platelet-monocyte aggregates were higher in COVID-19 patients than in uninfected control individuals. In contrast, aGPIIb/IIIa expression was not different between patients and controls. Severe pneumonia patients had lower platelet-monocyte aggregates than patients without pneumonia and patients with mild-to-moderate pneumonia. Platelet-neutrophil and platelet-lymphocyte aggregates were not different among groups. There was no change in platelet-leukocyte aggregates and P-selectin expression on days 1, 7, and 10. aGPIIb/IIIa expression was not different among patient groups. Still, adenosine diphosphate (ADP)-induced aGPIIb/IIIa expression was lower in severe pneumonia than in patients without and with mild-to-moderate pneumonia. Platelet-monocyte aggregates exhibited a weak positive correlation with lymphocyte count and weak negative correlations with interleukin-6, D-dimer, lactate dehydrogenase, and nitrite.ConclusionCOVID-19 patients have higher platelet-leukocyte aggregates and P-selectin expression than controls, indicating increased platelet activation. Compared within patient groups, platelet-monocyte aggregates were lower in severe pneumonia patients

Immunogenicity of a fractional or full third dose of AZD1222 vaccine or BNT162b2 messenger RNA vaccine after two doses of CoronaVac vaccines against the Delta and Omicron variants

Objectives: The study aimed to compare the immunogenicity and safety of fractional (half) third doses of heterologous COVID-19 vaccines (AZD1222 or BNT162b2) to full doses after the two-dose CoronaVac and when boosting after three different extended intervals. Methods: At 60-<90, 90-<120, or 120-180 days intervals after the two-dose CoronaVac, participants were randomized to full-dose or half-dose AZD1222 or BNT162b2, followed up at day 28, 60, and 90. Vaccination-induced immune responses to Ancestral, Delta, and Omicron BA.1 strains were evaluated by antispike, pseudovirus, and microneutralization and T cell assays. Descriptive statistics and noninferiority cut-offs were reported as geometric mean concentration or titer and concentration or titer ratios comparing baseline to day 28 and day 90 and different intervals. Results: No safety concerns were detected. All assays and intervals showed noninferior immunogenicity between full doses and half doses. However, full-dose vaccines and/or longer 120-180-day intervals substantially improved the immunogenicity (measured by antispike or measured by pseudotyped virus neutralizing titers 50; P <0.001). Seroconversion rates were over 90% against the SARS-CoV-2 strains by all assays. Immunogenicity waned more quickly with half doses than full doses but remained high against the Ancestral or Delta strains. Against Omicron, the day 28 immunogenicity increased with longer intervals than shorter intervals for full-dose vaccines. Conclusion: Immune responses after day 28 when boosting at longer intervals after the two-dose CoronaVac was optimal. Half doses met the noninferiority criteria compared with the full dose by all the immune assays assessed

Mice Immunized with the Vaccine Candidate HexaPro Spike Produce Neutralizing Antibodies against SARS-CoV-2

Updated and revised versions of COVID-19 vaccines are vital due to genetic variations of the SARS-CoV-2 spike antigen. Furthermore, vaccines that are safe, cost-effective, and logistic-friendly are critically needed for global equity, especially for middle- to low-income countries. Recombinant protein-based subunit vaccines against SARS-CoV-2 have been reported using the receptor-binding domain (RBD) and the prefusion spike trimers (S-2P). Recently, a new version of prefusion spike trimers, named HexaPro, has been shown to possess two RBD in the “up” conformation, due to its physical property, as opposed to just one exposed RBD found in S-2P. Importantly, this HexaPro spike antigen is more stable than S-2P, raising its feasibility for global logistics and supply chain. Here, we report that the spike protein HexaPro offers a promising candidate for the SARS-CoV-2 vaccine. Mice immunized by the recombinant HexaPro adjuvanted with aluminum hydroxide using a prime-boost regimen produced high-titer neutralizing antibodies for up to 56 days after initial immunization against live SARS-CoV-2 infection. Also, the level of neutralization activity is comparable to that of convalescence sera. Our results indicate that the HexaPro subunit vaccine confers neutralization activity in sera collected from mice receiving the prime-boost regimen

Mutations in XPR1 Cause Primary Familial Brain Calcification Associated With Altered Phosphate Export

Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC

Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41 % of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation

Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export

Primary familial brain calcification (PFBC) is a neurological disease characterized by calcium phosphate deposits in the basal ganglia and other brain regions and has thus far been associated with SLC20A2, PDGFB or PDGFRB mutations. We identified in multiple families with PFBC mutations in XPR1, a gene encoding a retroviral receptor with phosphate export function. These mutations alter phosphate export, implicating XPR1 and phosphate homeostasis in PFBC