Burden of rare genetic disorders in India: twenty-two years' experience of a tertiary centre.

BACKGROUND: Rare disorders comprise of ~ 7500 different conditions affecting multiple systems. Diagnosis of rare diseases is complex due to dearth of specialized medical professionals, testing labs and limited therapeutic options. There is scarcity of data on the prevalence of rare diseases in different populations. India being home to a large population comprising of 4600 population groups, of which several thousand are endogamous, is likely to have a high burden of rare diseases. The present study provides a retrospective overview of a cohort of patients with rare genetic diseases identified at a tertiary genetic test centre in India. RESULTS: Overall, 3294 patients with 305 rare diseases were identified in the present study cohort. These were categorized into 14 disease groups based on the major organ/ organ system affected. Highest number of rare diseases (D = 149/305, 48.9%) were identified in the neuromuscular and neurodevelopmental (NMND) group followed by inborn errors of metabolism (IEM) (D = 47/305; 15.4%). Majority patients in the present cohort (N = 1992, 61%) were diagnosed under IEM group, of which Gaucher disease constituted maximum cases (N = 224, 11.2%). Under the NMND group, Duchenne muscular dystrophy (N = 291/885, 32.9%), trinucleotide repeat expansion disorders (N = 242/885; 27.3%) and spinal muscular atrophy (N = 141/885, 15.9%) were the most common. Majority cases of ß-thalassemia (N = 120/149, 80.5%) and cystic fibrosis (N = 74/75, 98.7%) under the haematological and pulmonary groups were observed, respectively. Founder variants were identified for Tay-Sachs disease and mucopolysaccharidosis IVA diseases. Recurrent variants for Gaucher disease (GBA:c.1448T > C), ß-thalassemia (HBB:c.92.+5G > C), non-syndromic hearing loss (GJB2:c.71G > A), albinism (TYR:c.832 C > T), congenital adrenal hyperplasia (CYP21A2:c.29-13 C > G) and progressive pseudo rheumatoid dysplasia (CCN6:c.298T > A) were observed in the present study. CONCLUSION: The present retrospective study of rare disease patients diagnosed at a tertiary genetic test centre provides first insight into the distribution of rare genetic diseases across the country. This information will likely aid in drafting future health policies, including newborn screening programs, development of target specific panel for affordable diagnosis of rare diseases and eventually build a platform for devising novel treatment strategies for rare diseases.

Treatment with nanosomal paclitaxel lipid suspension versus conventional paclitaxel in metastatic breast cancer patients - a multicenter, randomized, comparative, phase II/III clinical study.

Background: A novel nanosomal paclitaxel lipid suspension (NPLS), free from Cremophor EL (CrEL) and ethanol, was developed to address the solvent-related toxicities associated with conventional paclitaxel formulation. Objective: To evaluate the efficacy and safety of NPLS versus CrEL-based paclitaxel (conventional paclitaxel) in patients with metastatic breast cancer (MBC). Design: A prospective, open-label, randomized, multiple-dose, parallel, phase II/III study. Methods: Adult (18-65 years) female patients with MBC who had previously failed at least one line of chemotherapy were randomized (2:2:1) to NPLS 175 mg/m2 every 3 weeks (Q3W, n = 48, arm A), NPLS 80 mg/m2 every week (QW, n = 45, arm B) without premedication or conventional paclitaxel (Taxol®, manufactured by Bristol-Myers Squibb, Princeton, NJ, USA) 175 mg/m2 Q3W (n = 27, arm C) with premedication. In the extension study, an additional 54 patients were randomized (2:1) to arm A (n = 37) or arm C (n = 17). Results: Pooled data from the primary study and its extension phase included 174 patients. The primary endpoint was the overall response rate (ORR). As per intent-to-treat analysis, ORR was significantly better in the NPLS QW arm as compared to conventional paclitaxel [44.4% (20/45) versus 22.7% (10/44), (p = 0.04)]. An improvement in ORR with NPLS Q3W versus conventional paclitaxel arm [29.4% (25/85) versus 22.7% (10/44)] (p = 0.53) was observed. Disease control rates observed were improved with NPLS Q3W versus conventional paclitaxel Q3W (77.7% versus 72.7%, p = 0.66) and with NPLS QW versus conventional paclitaxel Q3W (84.4% versus 72.7%, p = 0.20), although not significant. A lower incidence of grade III/IV peripheral sensory neuropathy, vomiting, and dyspnea was reported with NPLS Q3W versus conventional paclitaxel Q3W arms. Conclusion: NPLS demonstrated an improved tumor response rate and a favorable safety profile versus conventional paclitaxel. NPLS 80 mg/m2 QW demonstrated a significantly better response versus conventional paclitaxel 175 mg/m2 Q3W. Trial registration: Clinical Trial Registry-India (CTRI), CTRI/2010/091/001344 Registered on: 18 October 2010 (https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MjEzNQ==&Enc=&userName=CTRI/2010/091/001344), CTRI/2015/07/006062 Registered on: 31 July 2015 (https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MTE2Mjc=&Enc=&userName=CTRI/2015/07/006062).

Role of nanosomal paclitaxel lipid suspension (NPLS) in the treatment of patients with metastatic breast cancer (MBC) Why was the study done? Paclitaxel is a commonly used drug for the treatment of breast cancer. Conventional formulation of paclitaxel is known to cause side effects like injection site reactions. A newer formulation named NPLS was developed to overcome the limitations of the conventional paclitaxel. The current study was done to compare the safety and effectiveness of NPLS and conventional paclitaxel in patients with advanced breast cancer. What did the researchers do? The research team conducted a large study in multiple hospitals across India, involving women with advanced breast cancer who had experienced treatment failure with previous chemotherapy. A total of 174 patients were randomly assigned to receive either of the three treatment schedules: (1) NPLS every 3 weeks, (2) NPLS every week, (3) conventional paclitaxel every 3 weeks. What did the researchers find? The results showed that NPLS, in a weekly schedule, led to better tumor response rates compared to conventional paclitaxel given every 3 weeks. Additionally, NPLS demonstrated a favorable safety profile, as compared to conventional paclitaxel. What do the findings mean? These findings suggest that NPLS could be a promising alternative for women with advanced breast cancer. NPLS improved the response to treatment, with a better safety profile compared to conventional paclitaxel.

Integration of pan-omics technologies and three-dimensional in vitro tumor models: an approach toward drug discovery and precision medicine.

Despite advancements in treatment protocols, cancer is one of the leading cause of deaths worldwide. Therefore, there is a need to identify newer and personalized therapeutic targets along with screening technologies to combat cancer. With the advent of pan-omics technologies, such as genomics, transcriptomics, proteomics, metabolomics, and lipidomics, the scientific community has witnessed an improved molecular and metabolomic understanding of various diseases, including cancer. In addition, three-dimensional (3-D) disease models have been efficiently utilized for understanding disease pathophysiology and as screening tools in drug discovery. An integrated approach utilizing pan-omics technologies and 3-D in vitro tumor models has led to improved understanding of the intricate network encompassing various signalling pathways and molecular cross-talk in solid tumors. In the present review, we underscore the current trends in omics technologies and highlight their role in understanding genotypic-phenotypic co-relation in cancer with respect to 3-D in vitro tumor models. We further discuss the challenges associated with omics technologies and provide our outlook on the future applications of these technologies in drug discovery and precision medicine for improved management of cancer.

Solitary Ileal Hemangioma in a 3-year-old Male.

Hemangiomas are rare small bowel tumors requiring a high index of suspicion for diagnosis. We present a case of ileal hemangioma in a 3-year-old male presenting with recurrent anemia. The patient was diagnosed with a contrast-enhanced computed tomography abdomen and managed surgically by resection and anastomosis. Histopathologically, it was a solitary ileal cavernous hemangioma with a submucosal infiltrative pattern with serosa involvement and a normal mucosa.

Diagnosis of tuberculous pleural effusion in a tertiary care hospital of central India: The role of xpert Mycobacterium tuberculosis/rifampicin.

Background: In India, 15%-20% of tuberculosis (TB) cases are categorized as extra-pulmonary TB, and tuberculous pleural effusion (TPE) is the second-most common type after tuberculous lymphadenitis. However, the paucibacillary nature of TPE makes its diagnosis challenging. As a result, relying on empirical anti-TB treatment (ATT) based on clinical diagnosis becomes necessary for achieving the best possible diagnostic outcome. The study aims to determine the diagnostic utility of Xpert Mycobacterium tuberculosis/rifampicin (MTB/RIF) for the detection of TB in TPE in high incidence setting of Central India. Methods: The study enrolled 321 patients who had exudative pleural effusion detected through radiological testing and were suspected of having TB. The medical procedure of thoracentesis was conducted to collect the pleural fluid, which was then subjected to both the Ziehl-Neelsen staining and Xpert MTB/RIF test. The patients who showed improvement after receiving anti-tuberculosis treatment (ATT) were considered the composite reference standard. Results: The sensitivity of smear microscopy was found to be 10.19%, while that of the Xpert MTB/RIF method was 25.93% when compared to the composite reference standard. The accuracy of clinical diagnosis was measured using receiver operating characteristics based on clinical symptoms, and it was found to be 0.858 (area under the curve). Conclusions: The study shows that Xpert MTB/RIF has significant value in diagnosing TPE, despite its low sensitivity of 25.93%. Clinical diagnosis based on symptoms was relatively accurate, but relying on symptoms alone is not enough. Using multiple diagnostic tools, including Xpert MTB/RIF, is crucial for accurate diagnosis. Xpert MTB/RIF has excellent specificity and can detect RIF resistance. Its quick results make it useful in situations where a rapid diagnosis is necessary. While it should not be the only diagnostic tool, it has a valuable role in diagnosing TPE.

Simplified screening and referral protocol for sinonasal mucormycosis in post COVID-19 patients.

Background: To study incidence of sinonasal mucormycosis in active and post COVID-19 patients in a district-level hospital in India and develop a simplified screening and referral protocol for use at peripheral centres to aid rapid diagnosis/treatment. Methods: Study design: A prospective, interventional cohort study conducted from April 2021 to January 2022. Setting: Secondary level hospital in North India. Inclusion criteria: COVID-19 positive patients with diabetes mellitus as co-morbidity and with at least one of the following: received steroid therapy and/or on high flow oxygen therapy and/or had prolonged hospital stay (> 7 days). Exclusion criteria: Patients already immunocompromised/having malignancy/organ transplant recipients. Clinical workup: History, examination, imaging (CECT/MRI nose and paranasal sinuses if indicated), diagnostic nasal endoscopy + Nasal scrapings for KOH mount to detect fungal elements. STROBE guidelines were followed in the study. Results: Fourteen out of 250 patients tested positive for mucormycosis (incidence 5.6%). Thirteen were symptomatic, one patient was asymptomatic and detected on screening. No significant difference was found in mucormycosis versus non-mucormycosis group with respect to HbA1c status, vaccination status or steroid + oxygen treatment (p > 0.05 in all scenarios). Patients were treated with intravenous liposomal amphotericin B and surgical debridement when indicated. Two succumbed to disease (survival 85.7%). A clinical screening protocol was thus developed which can be used as an effective tool even at far-flung and remote healthcare facilities for diagnosis and timely referral of patients. Conclusions: Mucormycosis is a potentially lethal disease which needs rapid diagnosis and timely action to decrease morbidity and mortality.

Structural advances toward understanding the catalytic activity and conformational dynamics of modular nonribosomal peptide synthetases.

Covering: up to fall 2022.Nonribosomal peptide synthetases (NRPSs) are a family of modular, multidomain enzymes that catalyze the biosynthesis of important peptide natural products, including antibiotics, siderophores, and molecules with other biological activity. The NRPS architecture involves an assembly line strategy that tethers amino acid building blocks and the growing peptides to integrated carrier protein domains that migrate between different catalytic domains for peptide bond formation and other chemical modifications. Examination of the structures of individual domains and larger multidomain proteins has identified conserved conformational states within a single module that are adopted by NRPS modules to carry out a coordinated biosynthetic strategy that is shared by diverse systems. In contrast, interactions between modules are much more dynamic and do not yet suggest conserved conformational states between modules. Here we describe the structures of NRPS protein domains and modules and discuss the implications for future natural product discovery.

Adenovirus Meningoencephalitis and Neurocysticercosis Co-infection: First Case from India.

BACKGROUND: Adenovirus generally causes upper and lower respiratory tract infections. It is common in children and occasionally in adults. Neurological involvement is rare, which may be mild aseptic meningitis to potentially fatal acute necrotizing encephalopathy. Recently, viruses have been reported increasingly to cause CNS infections. Viral aetiology typically varies with age. CASE PRESENTATION: Here, we report an unusual adenovirus meningoencephalitis with a co-infection of neurocysticercosis in an immunocompetent adult patient. An 18-year-old healthy female student was admitted with fever and headache for 11 days and progressive altered behaviour for 5 days, followed by altered sensorium for 3 days. This variable and unusual presentation of adenoviral infection involving CNS provoked diagnostic difficulties, but with the help of advanced diagnostics, especially molecular, exact aetiology was detected. Even with the neurocysticercosis infection in this patient, the outcome was not adversely affected. CONCLUSION: This unusual co-infection with a successful outcome is the first case of this type in literature.

2-Aminoethoxydiphenyl borate ameliorates mitochondrial dysfunctions in MPTP/MPP+ model of Parkinson's disease.

Mitochondrial dysfunction is closely linked with the pathophysiology of several neurodegenerative disorders including Parkinson's disease (PD). Despite several therapeutic advancements related to symptomatic modification of PD pathology, strategies targeting mitochondrial dysfunctions remain largely elusive. Recently, transient receptor potential (TRP) channels have been shown to play a pivotal role in the control of mitochondrial and neuronal functioning in PD. In this study, the effect of 2-aminoethoxydiphenyl borate (2-APB), TRP channel blocker was investigated in the context of mitochondrial dysfunctions in 1-methyl-4-phenylpyridinium (MPP+)-treated SH-SY5Y cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-administered Sprague Dawley rats. MPP+-treated SH-SY5Y cells exhibited reductions in cell viability, generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential. Co-treatment with 2-APB led to an increase in cell viability, reduction in intracellular and mitochondrial ROS and improvement in mitochondrial membrane potential compared to MPP+-treated SH-SY5Y cells. In addition, intranigral administration of MPTP led to a significant reduction in motor function in the rats. Fourteen days of 2-APB (3 and 10 mg/kg, i.p.) treatment improved behavioural parameters. MPTP-induced decrease in complex I activity and mitochondrial potential were also blocked by 2-APB in the mitochondria isolated from the brain regions i.e. midbrain and striatum. MPTP-induced decrease in tyrosine hydroxylase levels were also restored by 2-APB. Moreover, MPTP-induced reduction in proteins involved in mitochondrial biogenesis, viz. peroxisome proliferator-activated-receptor-gamma coactivator and mitochondrial transcription factor-A were increased after 2-APB treatment in vivo. In summary, 2-APB has a promising neuroprotective role in the MPP+/MPTP models of PD via targeting mitochondrial dysfunctions and biogenesis.

Public health supply chain for iron and folic acid supplementation in India: Status, bottlenecks and an agenda for corrective action under Anemia Mukt Bharat strategy.

PURPOSE: The IFA supplementation program under the Anemia Mukt Bharat (AMB) program is one of the most ambitious nutrient supplementation programs in India. The delivery of services often suffers due to frequent stock outs and shortages. It is critical to understand the bottleneck in the supply chain adversely affecting the performance and coverage of the program. The paper attempts to identify the bottlenecks of the IFA supply chain in key areas of supply chain i.e., forecasting, procurement, warehousing and inventory management, transportation, distribution, logistic information system and suggests a plan of action aimed at ensuring uninterrupted supplies to the end beneficiaries. DESIGN/METHODOLOGY/APPROACH: The data source for the present paper is the nationwide IFA Supply Chain Assessment (2018-19) conducted across 29 Indian states with a total of 58 districts, 116 blocks, 232 Sub-Centres, 232 Anganwadi centres and 232 schools covered under the assessment as a multi-partner collaborative initiative. Field insights from supply chain strengthening interventions under different public health programs in India and other developing countries were taken to arrive at corrective actions and recommendations. Findings were disseminated to government and an action plan was suggested for connecting service delivery points through an app-based system, developing a micro plan for ensuring fixed distribution schedule, followed by continuous monitoring and review meetings identified for follow up. FINDINGS: The average lead time across states was 35 weeks with top three performing states being Goa, Sikkim, and Telangana. The average per unit cost of procurement was Rs 0.35 for IFA Red, Rs 0.25 for IFA Blue, Rs 0.31 for IFA Pink and Rs 7.30 for IFA syrup. Out of the 704 districts in India, only 213 has IFA Red, only 140 had IFA Blue, 152 had IFA Pink and 163 had IFA Syrup available in four quarters of 2018-19. The key issues identified in the assessment were-a lack of standardized forecasting process, absence of inventory management techniques, no fixed distribution schedule, inadequate availability of transport vehicles and an absence of an integrated MIS. ORIGINALITY/VALUE: The identification of bottlenecks in the IFA supply chain and its impact on the performance of the supply chain would provide policy guidelines for the government as well as development partner agencies to design an effective and efficient supply chain. It would also enable the policy planners to understand the challenges associated with managing different components of a supply chain, their interrelation and impact on the overall performance of the supply chain. The suggested recommendations would equip program managers with the tool to devise and implement field level solutions.

Association of Blood Mercury Level with Liver Enzymes in Korean Adults: An Analysis of 2015-2017 Korean National Environmental Health Survey.

Increased liver enzymes as a result of exposure to mercury and their toxic effects are not well understood in Korea at the population level. The effect of blood mercury concentration on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) was evaluated after adjusting for sex, age, obesity, alcohol consumption habit, smoking, and exercise parameters in 3712 adults. The risk of abnormal liver function was measured using a multiple logistic regression analysis. Blood mercury concentration was divided into quartiles, and liver enzyme levels were compared for each quartile. ALT and AST levels were 10-20% higher in the second, third, and fourth quartiles compared to the first quartile. The risk of liver dysfunction or elevated liver enzymes was significantly higher in the second, third, and fourth quartiles than in the first quartile. As blood mercury levels increased, liver enzymes and mercury-induced hepatotoxicity increased. The increase in liver enzymes caused by mercury was more pronounced in the low-mercury concentration range. To reduce the long-standing problem of abnormal liver enzymes and liver function in Korea and other similar settings, it is important to decrease exposure to mercury through effective implementation of specific health and environmental strategies.

Efficacy of genetically transformed Metarhizium anisopliae against Spodoptera litura and Aphis craccivora.

To increase the insecticidal potency of the entomopathogen, Metarhizium anisopliae (Metsch.) Sorok, the fungus was genetically modified with scorpion neuro ß-toxin LqqIT1a and two different insect specific heterologous toxic proteins viz., Cry1a and GNA. LqqIT1 is an anti-insect neurotoxin derived from yellow scorpion, Leiurus quinquestriatus quinquestriatus (Ehren.). The present study reports the bio-efficacy of genetically modified fungus, M. anisopliae, in which scorpion neurotoxin gene 'LqqIT1' is stacked in its genome, for improved efficacy against the tobacco caterpillar, Spodoptera litura (Fab.) and Aphis craccivora (Koch). All the transformed clones of M. anisopliae were found potent against S. litura and A. craccivora under laboratory conditions. The virulent clones viz., Ma-2(2), Ma-2(7) and MaGKS-14 caused 40 to 90 per cent mortality at fourth day of treatment. Compared to untransformed parent strain, Ma-C, the median lethal time of transformed clones Ma-2(2), Ma-2(7) and MaGKS-14 got reduced by 2, 3 and 3-folds, respectively. No significant differences were noted with respect to percent mortality of transformed clone, MaGKS-13 in comparison to untransformed strain Ma-C. The results indicated that the incorporation of LqqIT1 toxin gene enhanced the potency of strain Ma-C, against immature stages of S. litura and A. craccivora by shortening the median lethal time without affecting conidial development. Therefore, LqqIT1 scorpion toxin gene showed the potential to improve efficacy of M. anisopliae against lepidopteran and hemipteran insects.

COVID-19 Associated Pancytopenia (CAP): A Clinical Impact.

BACKGROUND: SARS-CoV-2 infection has mild and asymptomatic to critical clinical course affecting mainly the lungs. Few case reports of COVID-19-associated pancytopenia are reported, but a series of 18 cases is not described in the literature to date. AIMS AND OBJECTIVES: This study aimed to investigate pancytopenia in COVID-19 and its correlation with severity and to explore the detailed clinical and biochemical information in COVID-19- associated pancytopenia. This study also highlights pancytopenia's rarity and prognostic value among COVID-19 patients. MATERIALS AND METHODS: This was a retrospective observational study conducted in a tertiary care centre at a level 3 COVID care facility that included adults of either sex having positive RT PCR for COVID-19 from October 2020 to May 2021. Data were collected from the online outpatient department and hospitalized patients. RESULTS: A total of 18 cases were included in the study; 13 were males (72.2%). The mean age was calculated as 48.56 years. Cases were categorized as severe 13 (72.2%) and non-severe 5 (27.8%) disease on the first day of pancytopenia. The most common presentations were fever 18 (100%) and cough 18 (100%), followed by generalized weakness 16 (88.9%), breathlessness 15 (83.3%), and diarrhoea 10 (55.6%). One case died in the severe disease group. The mean of haemoglobin, leukocyte count, and platelets in severe vs non-severe disease were calculated as 8.59 vs 8.74, 2339 vs 2578, and 77769 vs 88600, respectively. CONCLUSION: Pancytopenia was more prevalent in severe disease and age group 40-60 years. CAP was most likely due to secondary bone marrow suppression. It has no prognostic value for disease outcomes.

A comparative study between conventional and the Bethesda System for Reporting Thyroid Cytology of 240 cases.

Introduction: Thyroid nodule is a common disorder of thyroid. Despite their benign nature, they can be associated with multiple pathologic conditions including thyroid cancer. Fine-needle aspiration plays an essential role in evaluating thyroid nodules. The Bethesda System for Reporting Thyroid Cytology (TBSRTC) has attempted to standardize reporting and cytological criteria in aspiration smears. Aim: The aim of this study is to compare the conventional and TBSRTC and to compare and correlate the cases with histological findings wherever available. Materials and Methods: The present study was a retrospective study undertaken in the department of pathology from January 2018 to December 2018 to access the validity of TBSRTC considering histopathology as the gold standard. May Grünwald Giemsa and Papanicolaou stained thyroid FNA smears of 240 patients were collected which were reported by the conventional system for reporting thyroid cytology and also categorized as per current Bethesda nomenclature for thyroid cytology. Diagnosis of both the reporting systems was then compared and correlated with the histological diagnosis wherever possible. Results: A total of 240 cases were examined on cytology, out of which histopathological correlation was possible in 110 cases. For benign thyroid lesions, sensitivity and specificity with conventional system were 69.91% and 40.25%, respectively, while with TBSRTC, sensitivity and specificity were 84.04% and 29.94%, respectively. Sensitivity and specificity of conventional system for malignant thyroid lesions were 58.56% and 69.91%, respectively, while with TBSRTC, sensitivity and specificity were 73.69% and 95.12%, respectively. The Bethesda system found to be highly sensitive for benign thyroid lesions and highly specific for malignant thyroid lesions as compared to the conventional method of reporting of thyroid cytology. Conclusion: Bethesda system was found to be superior for reporting thyroid cytology over the conventional system of reporting for thyroid cytology.

Synchrotron radiation based X-ray techniques for analysis of cathodes in Li rechargeable batteries.

Li-ion rechargeable batteries are promising systems for large-scale energy storage solutions. Understanding the electrochemical process in the cathodes of these batteries using suitable techniques is one of the crucial steps for developing them as next-generation energy storage devices. Due to the broad energy range, synchrotron X-ray techniques provide a better option for characterizing the cathodes compared to the conventional laboratory-scale characterization instruments. This work gives an overview of various synchrotron radiation techniques for analyzing cathodes of Li-rechargeable batteries by depicting instrumental details of X-ray diffraction, X-ray absorption spectroscopy, X-ray imaging, and X-ray near-edge fine structure-imaging. Analysis and simulation procedures to get appropriate information of structural order, local electronic/atomic structure, chemical phase mapping and pores in cathodes are discussed by taking examples of various cathode materials. Applications of these synchrotron techniques are also explored to investigate oxidation state, metal-oxygen hybridization, quantitative local atomic structure, Ni oxidation phase and pore distribution in Ni-rich layered oxide cathodes.

Parotid gland swelling as an initial presentation of Multiple Myeloma: a case report.

INTRODUCTION: Parotid swellings are commonly encountered in ENT Clinics, the cause of which could range from neural conditions, endocrine problems, vitamin deficiencies, and sialadenitis, which may even be a manifestation of an underlying systemic disease. Multiple myeloma represents a clonal proliferation of plasma cells and is a condition in which a parotid swelling might be present, although very uncommon. CASE PRESENTATION: We report a case of 60-year-old female presented with unilateral parotid swelling, which led to a diagnosis of multiple myeloma based on the investigations. CONCLUSION: Various imaging modalities are currently available to assess the extent of the swelling and evaluate the soft tissue and osseous involvement. The clinician must have a rigorous insight into the several clinical manifestations and the sites of involvement of the different conditions to make a proper diagnosis.

Uncommon manifestations in tuberculosis: An expanding clinical spectrum from North India.

Background: Despite being given the best by the health department to eradicate the disease, an alarming rise of tuberculosis (TB) remains a significant public health concern in India. Recently, highly variable clinical manifestations of TB have been reported. This study highlights the unusual presentations of TB with a comprehensive overview of epidemiology, demography and risk factors in the expended clinical spectrum of TB patients and their outcomes. Methods: It is a retrospective study using the records of 503 TB patients of all age groups of either sex from July 2017 to January 2021 at two tertiary care hospitals in North India. Results: Out of 503 cases, pulmonary, extrapulmonary, and disseminated TB were 77.7%, 19.5%, and 2.8%, respectively. Among all TB cases, 36 (7.2%) had uncommon manifestations, including the most common was pyrexia of unknown origin in 12 (33.3%) cases and liver abscess in 5 (13.9%) cases, followed by pancytopenia in 4 (11.1%) cases and chyluria in 3 (8.3%) cases. Atypical skin nodules and multiple swellings were also noted in three (8.3%) cases. Male sex (58%) and rural area (66.7%) were dominant in TB with uncommon manifestation (TBU) cases. The mean age in TBU cases was 46.92 years, whereas 34.26 years in all TB cases. It was extremely significant. The statistically significant risk factors in the TBU case were low socioeconomic status (24, 66.7%), inadequate nutrition (11, 30.6%), and smoking (19, 52.8%). Conclusions: Early recognition of uncommon presentations is imperative to respond better.

Profile of Ectopic Pregnancy Cases in a Tertiary Hospital.

BACKGROUND: An ectopic or extra uterine pregnancy is one in which the blastocyst implants anywhere other than the endometrial lining of the uterine cavity. The objective of the study was to find incidence, risk factors, clinical presentation and mode of management of ectopic pregnancy. METHODS: Observational study was conducted at Paropakar Maternity and Women's Hospital, Thapathali, Kathmandu. All the relevant data were recorded in performa. The collected data were entered in MS Excel and exported into SPSS 26 version for statistical analysis. RESULTS: About one third of the patients 10 (33.3%) was of 25-29 age group.The most common risk factor was pelvic infection in 23 (76.6%) cases, abortion in 11 (36.7%), and abdominal surgery in 8 (26.7%) of cases. The of classic triad of amenorrhea (100%), pain abdomen (99.7%) and per vaginal bleeding (66.7%). Ruptured ectopic seen in 26 (86.7%) cases, unruptured status in 1 (3.3%) case, tubal abortion in 1(3.3%) case and organized ectopic in 2(6.7%) cases. The most common site was found to be ampulla in 23 (76.7%) cases, fmbria 3(10%) cases, corneal in 3(10%) cases and ithmus in 1 (3.3%) case. All the cases managed surgically, of them unilateral salphingectomy, unilateral salphingo-opherectomy and wedge resection for corneal pregnancy were done in 25(83.3%), 2(6.7%) and 3(10%) cases respectively. CONCLUSIONS: Ectopic pregnancy mostly present as ruptured form in young females in our context. Pelvic infection is the commonest risk factor with ampulla being the commonest site. All cases required surgical intervention in form of unilateral salphingo-opherectomy and wedge resection.

Ovarian Carcinoma in a Young Pregnant Woman.

Ovarian cancer during pregnancy is a rare event. Little is known about the treatment of this condition due to the lack of randomized trials and cohort studies. A case of 28 years female, from Kathmandu, visited Out-Patients Department with complaint of amenorrhea for 8 weeks associated with nausea and occasional pain abdomen. Dating scan was done which showed a single live intrauterine pregnancy corresponding to 8 weeks 4 days of gestation with incidental finding of adnexal cysts in both adnexa, measuring 3.6 x 3.6 cm on right and on left 3.2 x 3.6 cm. The cysts did not show any septations. At 38 weeks, she underwent caesarean section and delivered a healthy baby girl. Intra-operatively, bilateral ovarian cysts were identified, both 2x2 cm simple-looking cysts. Enucleation of bilateral ovarian cysts was done. The specimen was sent for histopathology which showed serous carcinoma of low grade in bilateral ovaries. Staging surgery was then carried out after 6 weeks. Histopathology report showed serous carcinoma of low grade in both ovaries. We present here the case of ovarian cancer during pregnancy. Keywords: Ovarian cancer; pregnancy.

An integrated approach for modeling uncertainty in human health risk assessment.

A human health risk assessment (HHRA) will not remain simple and straightforward when it involves multiple uncertain input variables. Uncertainties in HHRA result from the unavailability and subjectivity of input variables. Though several studies have performed HHRA, the quantification of uncertainty in HHRA under a situation of data scarcity and the simultaneous application of random and non-random input variables have rarely been reported. The present study proposes an integrated hybrid health risk modeling framework involving the concurrent treatment of random and non-random input variables and estimating the uncertainties linked to the input variables in HHRA. The proposed framework presents the flexibility to classify the input variables into fuzzy and probabilistic categories, based on their data availability and provenience nature. The framework is demonstrated over the Turbhe sanitary landfill in Navi Mumbai, India, where the fate and transport of heavy metals in leachate are investigated through LandSim modeling. The present study considers the LandSim-simulated heavy metal concentration and body weight as a random variable and water intake, exposure duration, frequency, bioavailability, and average time as fuzzy variables. Further, the uncertainties in the non-carcinogenic human health risk have been quantified using Monte Carlo simulations, followed by a comprehensive multivariate sensitivity analysis of the proposed framework. High health risk at Turbhe is estimated for the male and female population. This study presents the first effort to quantify the non-carcinogenic human health risks from leachate-contaminated groundwater considering the health risk input variables as non-deterministic. The proposed framework is generic and applicable to any landfill site and will remain unaltered when integrated health risk assessment and uncertainty assessment are performed for the landfill.