Role of the HLA-G regulatory region polymorphisms in idiopathic recurrent spontaneous abortions (RSA).

PROBLEM: HLA-G polymorphisms have a functional impact on its expression and may cause a breakdown of maternal tolerance towards the semi-allogenic fetus, resulting in recurrent spontaneous abortions (RSA). This study reports on the association of HLA-G regulatory region polymorphisms with idiopathic RSA. METHODS: Seventy-five couples with ≥2 spontaneous abortions were recruited in comparison to 75 healthy couples who had normal pregnancies. About 5 mL of blood samples were collected from all the participants, and DNA was extracted. Screening of HLA-G 5'-upstream regulatory region (5'-URR) was done by direct sequencing in 50 each of RSA and healthy couples, respectively. The 14 bp deletion/insertion polymorphism in the 3'-untranslated region (3'-UTR) was genotyped in 75 each of RSA and healthy couples, respectively, by PCR amplification of HLA-G exon 8. MedCalc, GraphPad Prism, Haploview, PLINK, and multifactor dimensionality reduction were used to analyze the data. RESULTS: HLA-G screening revealed the presence of -762C/T, -725C/G, -716T/G, -689A/G, -486C/A, and -477C/G single nucleotide polymorphisms (SNPs) in the 5'-URR. At positions -762 and -477, the frequency of CC homozygotes was significantly higher in controls compared to the patients. The 14 bp deletion/insertion polymorphism in the 3'-UTR showed an association with RSA with the heterozygous genotype being significantly higher in RSA compared to controls. CONCLUSIONS: The study indicates a protective role of the CC genotypes of the two HLA-G 5'-URR polymorphisms, -762C/T and -477C/G, against RSA. It also suggests that women with the 14 bp deletion/insertion genotype have a significantly higher risk of RSA.

A Qualitative Assessment among Personnel Working in Community-Led Development Program Settings Regarding Sexualized Substance Use.

Sexualized substance use (SSU) is the practice of psychotropic substance use before or during sex to increase sexual pleasure. The growing use of SSU has a strong association with sexually transmitted infections (STIs). Community health mobilizers (CHMs) are agents who assist in decreasing the global burden of disease in the communities they serve. They work as unit managers, counselors, or field workers. The managers and counselors have a minimum of a bachelor's degree, and field workers have a minimum of a higher secondary education. This study aimed to qualitatively assess the knowledge gaps regarding SSU among CHMs. In-depth interviews (IDIs) were conducted in New Delhi, India with nineteen CHMs. Majority of the CHMs were men (n = 9, 47%) followed by transgender (TG) persons (TG females n = 5, 26.3%; TG males n = 1, 5.2%), and women (n = 4, 21.1%). Knowledge gaps were identified among the CHMs regarding different types of sexualized substances, drug procurement, human immunodeficiency virus (HIV) infection prevention, and complex health issues associated with SSU. It suggested the need for periodic workshops and training for upgradation of existing knowledge and practices among the CHMs. This formative research may help social scientists to develop protocols for conducting multi-centric, community-based studies across the country for further validation and exploration.

Genetic and clinical profile of patients with hypophosphatemic rickets.

Nutritional vitamin D deficiency is the most frequent cause of rickets followed by genetic causes, that include entities like classic hypophosphatemic rickets (FGF23 related), Dent disease, Fanconi syndrome, renal tubular acidosis, and vitamin D dependent rickets. Hypophosphatemia is a feature in all these forms. The diagnosis relies on a combination of clinical, biochemical and radiological features, but genetic testing is required to confirm the diagnosis. We screened 66 patients with hypophosphatemic rickets referred to this center between May 2015 and July 2019 using whole exome sequencing (WES) in addition to the measurement of their intact serum fibroblast growth factor 23 (FGF23) levels. WES revealed 36 pathogenic and 28 likely pathogenic variants in 16 different genes (PHEX, FGF23, DMP1, ENPP1, CLCN5, CTNS, SLC2A2, GATM, SLC34A1, EHHADH, SLC4A1, ATP6V1B1, ATP6V0A4, CYP27B1, VDR and FGFR1) in 63 patients which helped differentiate between the various forms of hypophosphatemic rickets. Intact serum FGF23 levels were significantly higher in patients with variations in PHEX, FGF23, DMP1 or ENPP1 genes. The major genetic causes of rickets were classic hypophosphatemic rickets with elevated FGF23 levels, distal renal tubular acidosis, and vitamin D dependent rickets. Based on the present results, we propose a customized gene panel for targeted exome sequencing, which will be useful for confirming the diagnosis in most patients with hypophosphatemic rickets.

Anti-factor H antibody associated hemolytic uremic syndrome following SARS-CoV-2 infection.

BACKGROUND: The pathogenesis of autoantibody generation in anti-factor H (FH) antibody associated atypical hemolytic uremic syndrome (aHUS) is unknown and is perhaps triggered by an infectious or environmental agent. We observed an unusual increase of patients with anti-FH antibody associated aHUS coinciding with the second pandemic wave in New Delhi and suspected that SARS-CoV-2 infection might be a potential trigger. METHODS: We screened for SARS-CoV-2 infection using reverse transcriptase polymerase chain reaction (RT-PCR) and serology in 13 consecutive patients with anti-FH antibody associated aHUS during the past year in New Delhi. RESULTS: We report 5 patients, 4-13 years old, who presented with a febrile illness without respiratory symptoms during the second pandemic wave. Of these, 3 patients presented with a relapse 25-85 months following the initial episode of aHUS. SARS-CoV-2 was detected by RT-PCR in 1 patient and by serology in 4 patients (median titer 47.1 cut-off index). Patients had high titers of anti-FH antibodies (median 2,300 AU/ml). Genetic studies, done in 3 of the 5 patients, showed homozygous CFHR1 deletion without other significant genetic abnormalities. Specific management comprised plasma exchanges and oral prednisolone, combined with either cyclophosphamide or mycophenolate mofetil. At median follow-up of 3.3 months, the estimated glomerular filtration rate in 4 patients ranged from 62 to 110 ml/min/1.73 m2; one patient was dialysis-dependent. CONCLUSION: Increased vigilance is required during the pandemic, especially in patients with anti-FH associated aHUS, who might relapse despite quiescent disease for a prolonged period. A higher resolution version of the Graphical abstract is available as Supplementary information.

Genetics of Refractory Rickets: Identification of Novel PHEX Mutations in Indian Patients and a Literature Update.

Refractory rickets is a genetic disorder that cannot be treated by vitamin D supplementation and adequate dietary calcium and phosphorus. Hereditary hypophosphatemic rickets is one of the major forms of refractory rickets in Indian children and caused due to mutations in the PHEX , FGF23 , DMP1 , ENPP1 , and SLC34A3 genes. This is the first study in India on a large number of patients reporting on mutational screening of the PHEX gene. Direct sequencing in 37 patients with refractory rickets revealed eight mutations in 13 patients of which 1 was nonsense, 2 were deletions, 1 was a deletion-insertion, and 4 were missense mutations. Of these mutations, four (c.566_567 delAG, c.651_654delACAT, c.1337delinsAATAA, and c.2048T > A) were novel mutations. This article discusses the mutations in Indian patients, collates information on the genetic causes of refractory rickets, and emphasizes the significance of genetic testing for precise diagnosis, timely treatment, and management of the condition, especially in developing countries.