Intestinal cell diversity and treatment responses in a parasitic nematode at single cell resolution.

BACKGROUND: Parasitic nematodes, significant pathogens for humans, animals, and plants, depend on diverse organ systems for intra-host survival. Understanding the cellular diversity and molecular variations underlying these functions holds promise for developing novel therapeutics, with specific emphasis on the neuromuscular system's functional diversity. The nematode intestine, crucial for anthelmintic therapies, exhibits diverse cellular phenotypes, and unraveling this diversity at the single-cell level is essential for advancing knowledge in anthelmintic research across various organ systems. RESULTS: Here, using novel single-cell transcriptomics datasets, we delineate cellular diversity within the intestine of adult female Ascaris suum, a parasitic nematode species that infects animals and people. Gene transcripts expressed in individual nuclei of untreated intestinal cells resolved three phenotypic clusters, while lower stringency resolved additional subclusters and more potential diversity. Clusters 1 and 3 phenotypes displayed variable congruence with scRNA phenotypes of C. elegans intestinal cells, whereas the A. suum cluster 2 phenotype was markedly unique. Distinct functional pathway enrichment characterized each A. suum intestinal cell cluster. Cluster 2 was distinctly enriched for Clade III-associated genes, suggesting it evolved within clade III nematodes. Clusters also demonstrated differential transcriptional responsiveness to nematode intestinal toxic treatments, with Cluster 2 displaying the least responses to short-term intra-pseudocoelomic nematode intestinal toxin treatments. CONCLUSIONS: This investigation presents advances in knowledge related to biological differences among major cell populations of adult A. suum intestinal cells. For the first time, diverse nematode intestinal cell populations were characterized, and associated biological markers of these cells were identified to support tracking of constituent cells under experimental conditions. These advances will promote better understanding of this and other parasitic nematodes of global importance, and will help to guide future anthelmintic treatments.

Transmission patterns of C1-INH deficiency hereditary angioedema favors a wild-type male offspring: Our experience at Chandigarh, India.

BACKGROUND: Deficiency of C1-inhibitor (C1-INH) protein, caused by pathogenic variants in the Serpin family G member 1 (SERPING1) gene, is the commonest pathophysiological abnormality (in ∼95 % cases) in patients with hereditary angioedema (HAE). C1-INH protein provides negative control over kallikrein-kinin system (KKS). Although the inheritance of the HAE-C1-INH is autosomal dominant, female predominance has often been observed in patients with HAE. OBJECTIVE: To analyze the risk of transmission of SERPING1 gene variant from father or mother to their offspring. METHODS: Pedigree charts of 42 families with a confirmed diagnosis of HAE-C1-INH and a pathogenic variant in the SERPING1 gene were analysed. Patients with HAE who had had at least one child were included for analyses to assess the risk of transmission from the father or mother to their offspring. RESULTS: Overall, 49 % (189/385) of all offspring inherited the genetic defect. In the subgroup analyses, 54.8 % (90/164) female offspring and 44.8 % (99/221; p < 0.02) male offspring inherited the genetic defect. Inheritance of the genetic defect was significantly lower in male offspring. Fathers with SERPING1 gene variant had a statistically significant skewed transmission of the wild type to the male offspring as compared to the variant (57.8 % wild type vs. 42.1 % variant; p < 0.02), whereas no statistically significant difference was found when a father transmitted the variant to a female offspring. Mothers with SERPING1 gene variant had no statistically significant difference in variant transmission to male or female offsprings. CONCLUSION: Results of the study suggest that the transmission pattern of SERPING1 gene variant favours the transmission of wild-type alleles in males, especially when the father is the carrier; hence, overall, fewer males and more female offspring inherited the variant. This could be because of a selection of wild-type male sperms during spermatogenesis, as the KLK system has been reported to play a crucial role in the regulation of spermatogenesis. Although, a similar pattern was observed in the maternal transmission of the SERPING1 gene variant; the difference was not statistically significant, likely because of a small sample size.

Managing Binge Eating Disorder in a Young Adolescent Female: Barriers to Treatment and Recommendations.

Binge eating disorder (BED) is a behavioral disorder characterized by chronic and compulsive overeating. It is the most prevalent eating disorder in the USA, affecting almost 3% of the US population. In this study, we describe a case of BED in an adolescent Caucasian female who could not obtain specialized treatment because of financial constraints and saw a child and adolescent psychiatrist for medication management. Her treatment plan combined bupropion with family therapy and resulted in successful alleviation of her symptoms, allowing her to achieve a better quality of life. This case shows how pragmatism by PCPs can help manage patients who cannot obtain specialized care for their BED.

X-Linked Lymphoproliferative Syndrome: A Spectrum of Clinical and Immunological Profile and Novel Pathogenic Variants from Chandigarh, India.

INTRODUCTION: X-linked lymphoproliferative syndrome (XLP) is a rare primary immune deficiency. Two types of XLP have been described: XLP-1 and XLP-2. METHODS: We found 7 patients with XLP (3 had XLP-1 and 4 had XLP-2) after reviewing the data from Pediatric Immunodeficiency Clinic from 1997 to 2021. RESULTS: Mean age at diagnosis was 3.8 years, and mean delay in diagnosis was 2.6 years. Five patients had recurrent episodes of infections. Four patients developed at least one episode of hemophagocytic lymphohistiocytosis (HLH) (2 with XLP-1 and 2 with XLP-2). Of these, 2 had recurrent HLH (both with XLP-2). Epstein-Barr virus (EBV) infection was detected in 2 (1 with XLP-1 and 1 with XLP-2). Both these patients had HLH. One child with XLP-2 had inflammatory bowel disease. Hypogammaglobulinemia was seen in 3 (2 with XLP-1 and 1 with XLP-2). Genetic analysis showed previously reported variants in 5, while 2 had novel variants (one in exon 7 of XIAP gene [c.1370dup p.Asn457Lysfs Ter16] and other had splice site variant in intron 1 of SH2D1A gene [c.138-2_138-1insG]). Episodes of HLH were managed with intravenous immunoglobulin (IVIg), methylprednisolone, oral prednisolone, cyclosporine, and rituximab. Inflammatory bowel disease was managed using oral prednisolone and azathioprine. One patient underwent haploidentical hematopoietic stem cell transplantation. One child with XLP-2 and WAS died because of fulminant pneumonia. DISCUSSION/CONCLUSIONS: XLP should be considered as a strong possibility in any patient with features of HLH, repeated infections with hypogammaglobulinemia, persistent EBV infection, and early-onset IBD.

Clinical, immunological and molecular profiles of DOCK8 deficiency in six patients from a tertiary care centre in North India.

BACKGROUND: Dedicator of cytokinesis protein 8 (DOCK8) deficiency is an autosomal recessive form of combined immunodeficiency. This rare disorder is characterized by an increased predisposition to allergy, autoimmunity and malignancies. OBJECTIVES: To analyse clinical, immunological and molecular profiles of patients with DOCK8 deficiency. METHODS: Clinic records of all patients attending the primary immunodeficiency clinic from 2018 to 2021 were reviewed. Six patients from five families were found to have DOCK8 deficiency. RESULTS: Median age at diagnosis was 7.5 years (range 2-13), with a male/female ratio of 5 : 1. Among the six patients, recurrent eczematous skin lesions were the predominant cutaneous manifestation, present in five patients (83%). Warts and molluscum contagiosum were evident in two patients (33%) and one patient (16%), respectively. Two patients had recalcitrant prurigo nodularis lesions and two had epidermodysplasia verruciformis-like lesions. Food allergies and asthma were reported by one patient each. Of the six patients, recurrent sinopulmonary infections were detected in five (83%). Epstein-Barr virus-driven non-Hodgkin lymphoma with liver metastases was the only case of malignancy, in a 4-year-old boy. IgE was elevated in all patients. Lymphopenia and eosinophilia were observed in three patients (50%) and five patients (83.3%), respectively. Genetic analysis showed DOCK8 pathogenic variants in all patients: homozygous deletion mutations in two patients, compound heterozygous deletion mutations in one, and homozygous nonsense mutations in two. A novel pathogenic homozygous missense variant in the DOCK8 gene was identified in one patient. CONCLUSIONS: DOCK8 deficiency should be considered as a possibility in any patient with early onset eczema, cutaneous viral infections and increased predisposition to allergy, autoimmunity and malignancy.

Delays in diagnosis is the commonest proximate reason for mortality in hereditary angioedema: our experience at Chandigarh, India.

BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized clinically by recurrent episodes of non-pruritic subcutaneous and/or submucosal edema. Laryngeal edema is the commonest cause of mortality in patients with HAE. Prior to the availability of first-line treatment options for management of HAE, the mortality used to be as high as 30%. The mortality has significantly reduced in countries where first-line treatment options are available and patients can access these therapies. There is paucity of literature on the outcomes of patients with HAE in developing countries where availability and access to first-line treatment options is still a challenge. OBJECTIVE: To report our experience with mortality in patients with HAE and to report factors associated with death of these patients. METHODS: We carried out a record review of all patients diagnosed to have HAE between January 1996 and August 2022. Families with HAE who had reported death of at least one family member/relative because of laryngeal edema were studied in detail. RESULTS: Of the sixty-five families (one hundred and seventy patients) registered in the clinic, sixteen families reported death of at least one family member/relative because of laryngeal edema (total thirty-six deaths). Of these sixteen families, fourteen families reported that one or more family members had experienced at least one attack of laryngeal edema. One patient died during follow-up when she was taking long-term prophylaxis with stanozolol and tranexamic acid while remaining thirty-five patients were not diagnosed to have HAE at the time of their death. At the time of death of all thirty-six patients, at least one other family member had symptoms suggestive of HAE but the diagnosis was not established for the family. CONCLUSIONS: This is the largest single centre cohort of patients with HAE in India reporting mortality data and factors associated with death in these families. Delay in diagnosis is the commonest reason for mortality.

Gender Disparity of First Authors in Review Article Publications Related to Schizophrenia.

Schizophrenia is a severe psychotic condition that can be diagnosed when certain symptoms, such as disorganized speech, disorganized thoughts, or negative feelings, are present for at least six months in a person's life. Gender equity and representation in academic writing are significant issues that have received more attention recently. Understanding the gender discrepancies in authorship can help researchers studying schizophrenia overcome obstacles and potential biases. The purpose of this study was to determine the degree of gender discrepancy among initial authors of articles that focused on schizophrenia and to identify potential causes of such inequalities. A bibliometric analysis of articles related to schizophrenia published from 2019 to 2022 was conducted. The authors' genders were determined through available public records and professional affiliations. The analysis included assessing the proportion of male and female first authors and examining trends over time. A total of 982 articles were included in the analysis. The results revealed a significant gender disparity in first authorship, with a higher representation of male first authors (546, 55.6%) compared to female first authors (436, 44.4%). There is a significant increase in the percentage of female authors from 2019 to 2022 (i.e., from 25% to 48.5%). The number of female and male authors is predicted to remain at a constant from 2023 to 2027, with male authors at 175 and female authors at slightly above 150. The findings of this study underscore the need for continued efforts to address gender imbalances in academic publishing and promote gender equity in the field of schizophrenia research. Recognizing and rectifying these disparities can contribute to a more inclusive and diverse scientific community.

A cross sectional observational study on uncontrolled bronchial asthma and inhaler technique among out patients in a tertiary care centre in Western Maharashtra.

Background: The 2014 Asia Pacific - Asthma Insight and Management (AP-AIM) study showed that none of the Indian asthmatics had controlled asthma when evaluated objectively. Our study aims to detect through objective measurements, uncontrolled asthma in OPD patients, the adequacy of their inhaler technique, and their awareness regarding the importance of inhaler technique. Method: The asthma Control Test (ACT) score was used to screen for uncontrolled asthma. A validated objective questionnaire and scoring were used to objectively assess the correctness and awareness of the inhalation technique. Result: The study was carried out over 2 month period and 80 patients meeting the inclusion criteria were enrolled. Out of 80 patients; 47 (58.75%) had well-controlled asthma and 33 (41.25%) had uncontrolled asthma. 64 (80%) patients had good, and 16 (20%) had poor inhalation techniques. Among the 64 patients with good inhalation technique 43 (67.18%) had well-controlled asthma and 21 (32.82%) had uncontrolled asthma. Among the 16 patients with poor inhalation technique 4 (25%) had well-controlled asthma and 12 (75%) had uncontrolled asthma. There was a statistically significant association between asthma control and inhaler technique (P value 0.002). In the study population 56 (70%) patients were aware of the inhalation technique and 24 (30%) were unaware of the inhalation technique. Out of the 56 patients who were aware of the inhalation technique 53 (94.64%) had good inhaler technique and 3 (5.36%) had poor inhalation technique. Among the 24 patients who were unaware of the inhaler technique 11 (45.83%) had good inhaler technique and 13 (54.17%) had poor inhaler technique. There was a statistically significant association between awareness of inhaler technique and good inhaler technique (P value 0.001). Conclusion: There is a statistically significant association between asthma control and inhaler technique and between inhaler technique and inhaler awareness. Improving the awareness regarding inhaler technique among bronchial asthma patients is the way forward to improve asthma control in our country.

A young boy with rash, arthritis, and developmental delay: Monogenic lupus due to DNASE2 gene defect.

Monogenic causes are increasingly being recognized in patients with lupus, especially in early-onset disease. We herein report a boy with a novel mutation in the DNase 2 (DNASE2) gene presenting with monogenic lupus. A 6-year-old boy with a global developmental delay with microcephaly presented with chronic febrile illness with anemia, rash, polyarthritis, renal involvement, and hepatosplenomegaly. Laboratory investigations revealed positive antinuclear antibody, high anti-dsDNA antibody titers, hypocomplementemia, hypergammaglobulinemia, nephrotic range proteinuria, and diffuse proliferative glomerulonephritis. Magnetic resonance imaging of brain showed altered signal intensity in subcortical white matter in bilateral fronto-parieto-temporal lobes. Targeted next-generation sequencing revealed a novel pathogenic variant in DNASE2. He was treated with oral prednisolone, mycophenolate mofetil, cyclosporine, and hydroxychloroquine and is doing well on follow up. DNASE2 deficiency has been reported as a rare genetic cause of monogenic lupus. DNASE2 deficiency should be suspected in patients with early-onset lupus with polyarthritis, erythematous rash, and neurological involvement.

Association of air pollution and coronavirus disease 2019 (COVID-19) in India.

The COVID-19 pandemic has affected the world, leading to significant morbidity and mortality. Various meteorological parameters are considered essential for the viability and transmission of the virus. Multiple reports from various parts of the world suggest a correlation between the disease spread and air pollution severity. This study was carried out to identify the relationship between meteorological parameters, air pollution, and COVID-19 in New Delhi, one of the worst-affected states in India. We studied air pollution and meteorological parameters in New Delhi, India. We obtained data about COVID-19 occurrence, meteorological parameters, and air pollution indicators from various sources from Apr 1, 2020, till Nov 12, 2020. We performed correlational analysis and employed autoregressive distributed lag models (ARDLM) for identifying the relationship between COVID-19 cases with air pollution and meteorological parameters. We found a significant impact of PM 2.5, PM 10, and meteorological parameters on COVID-19. There was a significant positive correlation between daily COVID-19 cases and COVID-19-related deaths with PM2.5 and PM10 levels. Increasing temperature and windspeed were associated with a reduction in the number of cases while increasing humidity was associated with increased cases. This study demonstrated a significant association of PM2.5 and PM10 with daily COVID-19 cases and COVID-19-related mortality. This knowledge will likely help us prepare well for the future and implement air pollution control measures for other airborne disease epidemics.

Microbiome and Its Dysbiosis in Inborn Errors of Immunity.

Inborn errors of immunity (IEI) can present with infections, autoimmunity, lymphoproliferation, granulomas, and malignancy. IEIs are due to genetic abnormalities that disrupt normal host-immune response or immune regulation. The microbiome appears essential for maintaining host immunity, especially in patients with a defective immune system. Altered gut microbiota in patients with IEI can lead to clinical symptoms. Microbial dysbiosis is the consequence of an increase in pro-inflammatory bacteria or a reduction in anti-inflammatory bacteria. However, functional and compositional differences in microbiota are also involved. Dysbiosis and a reduced alpha-diversity are well documented, particularly in conditions like common variable immunodeficiency. Deranged microbiota is also seen in Wiskott-Aldrich syndrome, severe combined immunodeficiency, chronic granulomatous disease, selective immunoglobulin-A deficiency, Hyper IgE syndrome (HIGES), X-linked lymphoproliferative disease-2, immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome, and defects of IL10 signalling. Distinct gastrointestinal, respiratory, and cutaneous symptoms linked to dysbiosis are seen in several IEIs, emphasizing the importance of microbiome identification. In this study, we discuss the processes that maintain immunological homeostasis between commensals and the host and the disruptions thereof in patients with IEIs. As the connection between microbiota, host immunity, and infectious illnesses is better understood, microbiota manipulation as a treatment strategy or infection prevention method would be more readily employed. Therefore, optimal prebiotics, probiotics, postbiotics, and fecal microbial transplantation can be promising strategies to restore the microbiota and decrease disease pathology in patients with IEIs.

T Cell Abnormalities in X-Linked Agammaglobulinaemia: an Updated Review.

X-linked agammaglobulinaemia (XLA) is a primary immunodeficiency (PID) resulting from a defect in the B cell development. It has conventionally been thought that T cells play a major role in the development and function of the B cell compartment. However, it has also been shown that B cells and T cells undergo bidirectional interactions and B cells also influence the structure and function of the T cell compartment. Patients with XLA offer a unique opportunity to understand the effect of absent B cells on the T cell compartment. In this review, we provide an update on abnormalities in the T cell compartment in patients with XLA. Studies have shown impaired memory T cells, follicular helper T cells, T regulatory cells and T helper 17 in patients with XLA. In addition, these patients have also been reported to have abnormal delayed cell-mediated immune responses and vaccine-specific T cell-mediated immune responses; defective T helper cell polarization and impaired T cell receptor diversity. At present, the clinical significance of these T cell abnormalities has not been studied in detail. However, these abnormalities may result in an increased risk of viral infections, autoimmunity, autoinflammation and possibly chronic lung disease. Abnormal response to SARS-Cov2 vaccine in patients with XLA and prolonged persistence of SARS-Cov2 virus in the respiratory tract of these patients may be related to abnormalities in the T cell compartment.

Anorexia Nervosa: Evaluating Disparities in Places of Death in the United States Over 22 Years Using the CDC WONDER Database.

INTRODUCTION: Anorexia nervosa is a severe and occasionally fatal eating disorder characterized by extreme weight loss and a distorted body image in which the affected individuals typically exhibit a strong fear of gaining weight, leading to rigid dietary restrictions and excessive activity. This condition can cause severe health problems, such as hunger, cardiovascular issues, and organ destruction. Anorexia nervosa is a key subject for research in the context of end-of-life care disparities due to its psychological and physical challenges.  Aims: This study examines differences in the places of death for people with anorexia nervosa during a 22-year period in the USA, taking into account four important factors: age group, gender, race, and U.S. census region. METHODOLOGY: Data were collected from the CDC WONDER website on August 31, 2023, and spans years 1999 to 2020, using the particular ICD-11 code F50.0 for anorexia nervosa. The study aims to uncover the important determinants impacting the location of death within this specific population using sophisticated statistical methods, including univariate logistic regression. RESULTS: The analysis of aggregate data yielded notable findings. The patient's principal site of death was at home or in hospice care. Other sites were less prevalent, with medical facilities or nursing homes ranking second. The place of death was highly influenced by age groups with diverse patterns. Gender had no significant impact; however, geographical inequalities were noticeable. Individuals in the Northeast, Midwest, and South were less likely than those in the West to die at home or in hospice care. The location of death was unaffected by race. CONCLUSIONS: In conclusion, this study found that death in home and hospice was more common than in medical or hospital nursing facilities in all four analyzed groups. These findings highlight the critical need for significant advancements in end-of-life care, particularly in home and hospice settings.

Swimming-induced pulmonary edema with review of literature.

Swimming-induced pulmonary edema (SIPE) is a rare form of non-cardiogenic pulmonary edema occurring in swimmers. It is important to consider the diagnosis of SIPE and differentiate it from aspiration pneumonitis in patients presenting with respiratory distress after swimming. We report a case of military recruit who developed SIPE. This is the first reported case of SIPE from India. Owing to the paucity of reported cases, the treatment of this entity in the literature is anecdotal, and we present successful management of SIPE with non-invasive ventilation and diuretics. A review of literature is made to understand the diagnosis, pathophysiology, and management of SIPE.

Bilateral congenital pulmonary airway malformation presenting in adulthood with a review of the literature.

We report a rare case of congenital pulmonary airway malformation (CPAM) in a middle-aged female patient with bilateral involvement. In view of its presentation in adulthood, it presents a rare picture of a disease often diagnosed in early childhood. Until now, 65 cases of this disease have been reported in adults, including 3 cases with bilateral involvement. A classical radiological picture of CPAM can often be confused with bronchiectasis or pulmonary sequestration. A definite treatment with surgical resection poses a challenge in bilateral involvement. We highlight a rare case with its challenges in diagnosis and management. A review of literature of cases of CPAM with bilateral involvement is conducted in an effort to better understand this entity in adulthood.

A Mediastinal Mass in a Middle-Aged Woman From a Rare Cause.

CASE PRESENTATION: A 50-year-old woman who was a nonsmoker presented to the out-patient-department with history of dry cough and breathlessness on exertion for the past 4 months along with onset of dull aching chest pain for the last 2 weeks. Her breathlessness had gradually deteriorated to the point that she experienced dyspnea even on walking a few steps on level ground. Loss of appetite and significant weight loss during the same period also formed part of her clinical semiology. There was no history of fever, night sweats, orthopnea, paroxysmal nocturnal dyspnea, hemoptysis, dysphagia, hoarseness of voice, edema, headache, visual disturbance, weakness of any extremity, or drooping of eyelids. Her medical history revealed that she had undergone hysterectomy 8 years earlier for removal of a probable uterine mass, for which no documentation was available.

Meningoencephalitis in primary antibody deficiency: Our experience from northwest India.

BACKGROUND/OBJECTIVES: Patients with primary antibody deficiency (PAD) are predisposed to develop meningoencephalitis, often considered to be enteroviral. However, there is a paucity of literature on this subject, and there are no studies from developing countries. METHODS: We analyzed our cohort of children with PAD who developed meningoencephalitis. RESULTS: This complication was observed in 13/135 (10.4%) patients with PAD - 5 patients had X-linked agammaglobulinemia (XLA), 7 had common variable immunodeficiency (CVID) and 1 had suspected nuclear factor kappa B essential modulator (NEMO) defect. Mean age at onset of neurological illness was 9.3 years. Presenting features included seizures (n=8), neurodevelopmental delay (n=2), regression of milestones (n=2), and acute flaccid paralysis (n=1). Trough IgG levels were found to be low in 12/13 patients at the time of development of neurological symptoms. Herpes simplex virus (HSV), cytomegalovirus (CMV), and Streptococcus pneumoniae were isolated in 1 each. Eight (72.7%) patients had altered signal hyperintensities in gray matter and deep white matter on magnetic resonance imaging (MRI), while 4 patients showed global cerebral atrophy. All patients were treated with high-dose intravenous immunoglobulin (IVIg). Fluoxetine was given to 3 patients. Eight patients in the present series have died, 3 have recovered with varying degrees of neurological sequelae and 2 patients are showing gradual recovery. CONCLUSIONS: To conclude, meningoencephalitis is an uncommon complication in patients with PAD and is associated with high morbidity and mortality. Early diagnosis of immune deficiency and initiation of replacement immunoglobulin therapy may prevent the development of neurological complications.