Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

Long term impact on offspring (5-11 years of age) of metformin use in pregnancy in mothers with diabetes: A systematic review and meta-analysis.

BACKGROUND: Data is scant on impact of metformin use in gestational diabetes (GDM)/ diabetes in pregnancy (DIP) on long-term outcomes in children and mothers beyond 5-years of child-birth. This systematic-review and meta-analysis aimed to evaluate the long-term impact of metformin use in pregnancy on children and their mothers. METHODS: Electronic databases were searched for studies evaluating metformin as compared to insulin for managing GDM/DIP. Primary outcome was to evaluate changes in body-mass index (BMI) in children at 5-11 years age. Secondary outcomes were to assess alterations in other anthropometric measures, obesity, changes in lipids and adipo-cytokines in children and mothers. RESULTS: Children at 9-years age, born to mothers who were treated with metformin during pregnancy had similar BMI [MD1.09kg/m2(95%CI:-0.44-2.62);P=0.16;I2=16%], waist-circumference to height-ratio [MD0.13(95%CI:-0.05-0.30);P=0.16;I2=94%], dual-energy X-ray absorptiometry (DXA) total fat-mass [MD0.68kg(95%CI:-2.39-3.79);P=0.66;I2=70%], DXA-total fat-percent [MD 0.04%(95%CI:-3.44-3.51);P=0.98;I2=56%], DXA-total fat-free mass [MD 0.81kg (95%CI:-0.96-2.58);P=0.37;I2=55%], MRI visceral adipose tissue [MD 80.97cm3(95%CI:-136.47-298.41); P=0.47;I2=78%] and magnetic-resonance spectroscopy liver-fat percentage [MD 0.27%(95% CI:-1.26-1.79);P=0.73;I2=0%], compared to those born to mothers who were treated with insulin. Serum adiponectin, leptin, alanine-aminotransferase and ferritin were comparable among groups. In children between 9-11 years age, occurrence of obesity, diabetes or challenges in motor and social development were comparable between the 2 groups. After 9 years of childbirth, BMI and risk of developing diabetes were similar in the two groups of women. CONCLUSION: Metformin use in pregnancy did not show any adverse effects when compared to insulin on long-term outcomes in children and their mothers.

Rapid Decline of SARS-CoV-2 Viral Load in Single vs. Double-Dose (Short-Interval <6 Weeks) ChAdOx nCoV-19 Vaccinated Health-Care Workers.

The present work was carried out during the emergence of Delta Variant of Concern (VoC) and aimed to study the change in SARS CoV-2 viral load in Covishield vaccinated asymptomatic/mildly symptomatic health-care workers (HCWs) to find out the optimum isolation period. The SARS CoV-2 viral load was carried out in sequential samples of 55 eligible HCWs which included unvaccinated (UnV; n = 11), single-dose vaccinated (SDV, n = 20) and double-dose vaccinated [DDV, n = 24; short-interval (<6 weeks)] subjects. The mean load of envelope (E) gene on day 5 in SDV [0.42 × 105 copies/reaction] was significantly lower as compared to DDV [6.3 × 105 copies/reaction, P = 0.005] and UnV [6.6 × 105 copies/reaction, P = 0.001] groups. The rate of decline of SARS CoV-2 viral load in the initial 5 days of PCR positivity was significantly higher in SDV as compared to that in DDV (Mean log decline 0.39 vs. 0.19; P < 0.001). This was possibly due to interference of adenoviral immunity of first dose of adenovirus-vectored vaccine in double-dose vaccinated HCWs who had received vaccines within a shorter interval (<6 weeks).

Cycle threshold values of SARS-CoV-2 RNA in conjunctival swabs and nasopharyngeal secretions: a comparative study from a tertiary care center in India.

PURPOSE: To detect the viral RNA load of SARS-CoV-2 in conjunctival swabs of COVID-19 patients, and compare with nasopharyngeal swabs. METHODS: Conjunctival swabs of COVID-19 patients (with PCR positive nasopharyngeal swabs) were subjected to quantitative reverse transcription-polymerase chain reaction (RT-PCR) for detection of SARS-CoV-2 RNA. The cycle threshold (Ct) values of Open Reading Frame 1 (ORF 1 Ab gene) and nucleoprotein (N gene) PCRs were used to assess the viral RNA load, and compare them with the baseline values of nasopharyngeal swabs. RESULTS: Of 93 patients, 17 (18.27%) demonstrated SARS-CoV-2 RNA in conjunctival swabs. Baseline nasopharyngeal swabs were collected at a median of 2 days; while, the conjunctival swabs were collected at median 7 days, from onset of illness (p < 0.001). Despite a significant delay in conjunctival swab collection than nasopharyngeal swabs, the Ct values (ORF or N gene PCRs) were comparable between nasopharyngeal swab and conjunctival swab samples. Subsequently, during the recovery period, in four of these 17 patients (with conjunctival swab positivity), when the second nasopharyngeal swab was 'negative', the conjunctival swab was 'positive'. CONCLUSION: The conjunctival swabs demonstrated SARS-CoV-2 RNA in 17 (18.27%) of 93 COVID-19 patients. Our results may suggest a delayed or a prolonged shedding of the virus/viral RNA on the ocular surface than in nasopharyngeal mucosa.

Recombinant protein subunit COVID-19 vaccine-induced Guillain-Barré Syndrome in an adolescent: A case report.

Guillain-Barré Syndrome (GBS), an autoimmune neurological disease of peripheral nerves, has been causally associated with COVID-19 vaccination in adults. However, no such report has been published so far in children. We describe a 13-year-old female child who presented to the emergency department with complaints of bilateral upper limb, lower limb and truncal weakness over 3 days following first dose of recombinant protein subunit COVID-19 vaccine (Corbevax). Clinical examination and nerve conduction studies showed pure motor axonal polyneuropathy with absent compound muscle action potential (CMAP) in all sampled nerves of upper and lower limbs which was consistent with the diagnosis of GBS after ruling out possible alternative aetiologies. A temporal association between first dose of protein subunit COVID-19 vaccine administered a day prior and symptom onset was noted. The causality assessment using the World Health Organization (WHO) tool for adverse event following immunization (AEFI) assessment indicated vaccine product-related reaction categorized as A1. The patient's clinical condition improved after seven sessions of plasmapheresis. The purpose of this report is to create awareness among health care professionals about COVID-19 vaccine-induced GBS in children as early diagnosis and management can be critical in avoiding complications and improving patient outcomes.

Frequency, outcomes, and need for intervention in stricturing gastrointestinal tuberculosis: a systematic review and meta-analysis.

BACKGROUND: Gastrointestinal strictures impact clinical presentation in abdominal tuberculosis and are associated with significant morbidity. AIM: To conduct a systematic review of the prevalence of stricturing disease in abdominal and gastrointestinal tuberculosis and response to antitubercular therapy (ATT). METHODS: We searched Pubmed and Embase on 13th January 2022, for papers reporting on the frequency and outcomes of stricturing gastrointestinal tuberculosis. The data were extracted, and pooled prevalence of stricturing disease was estimated in abdominal tuberculosis and gastrointestinal (intestinal) tuberculosis. The pooled clinical response and stricture resolution (endoscopic or radiologic) rates were also estimated. Publication bias was assessed using the Funnel plot and Egger test. The risk of bias assessment was done using a modified Newcastle Ottawa Scale. RESULTS: Thirty-three studies reporting about 1969 patients were included. The pooled prevalence of intestinal strictures in abdominal tuberculosis and gastrointestinal TB was 0.12 (95%CI 0.07-0.20, I2 = 89%) and 0.27 (95% CI 0.21-0.33, I2 = 85%), respectively. The pooled clinical response of stricturing gastrointestinal tuberculosis to antitubercular therapy was 0.77 (95%CI 0.65-0.86, I2 = 74%). The pooled stricture response rate (endoscopic or radiological) was 0.66 (95%CI 0.40-0.85, I2 = 91%). The pooled rate of need for surgical intervention was 0.21 (95%CI 0.13-0.32, I2 = 70%), while endoscopic dilatation was 0.14 (95%CI 0.09-0.21, I2 = 0%). CONCLUSION: Stricturing gastrointestinal tuberculosis occurs in around a quarter of patients with gastrointestinal tuberculosis, and around two-thirds of patients have a clinical response with antitubercular therapy. A subset of patients may need endoscopic or surgical intervention. The estimates for the pooled prevalence of stricturing disease and response to ATT had significant heterogeneity.

The clinical association between Periodontitis and COVID-19.

OBJECTIVES: The study aimed to clinically assess the association between periodontitis and COVID-19-related outcomes. MATERIAL AND METHODS: Data pertaining to patient demographics, medical history, blood parameters, periodontal clinical examination and aMMP-8 point-of-care diagnostics (both site-level and patient-level) was recorded for eighty-two COVID-19-positive patients. COVID-19-related outcomes such as COVID-19 pneumonia, death/survival, types of hospital admission and need of assisted ventilation were also assessed. RESULTS: Males were predominantly afflicted with COVID-19, with advanced age exhibiting a greater association with the presence of periodontitis. Higher severity of periodontitis led to 7.45 odds of requiring assisted ventilation, 36.52 odds of hospital admission, 14.58 odds of being deceased and 4.42 odds of COVID-19-related pneumonia. The aMMP-8 mouthrinse kit was slightly more sensitive but less specific than aMMP-8 site-specific tests. CONCLUSIONS: Based on the findings of the present study, periodontitis seems to be related to poorer COVID-19-related outcomes. However, within the constraints of this work, a direct causality may not be established. Periodontitis, by means of skewing the systemic condition for a number of comorbidities, may eventually influence COVID-19 outcomes in an indirect manner. CLINICAL RELEVANCE: The study is the first to clinically, and by means of a validated point-of-care diagnostic methodology, assess the association between periodontal health and COVID-19-related outcomes. Assessment of the periodontal status of individuals can aid in the identification of risk groups during the pandemic along with reinforcing the need to maintain oral hygiene and seeking periodontal care.

Symptoms and psychosocial effects following hospitalization for Covid-19: A sequential, mixed-methods study from northern India.

Background It is reported that patients who have recovered from Covid-19 continue to experience various symptoms and adverse outcomes. However, this aspect has not been studied well. We aimed to evaluate these variables and the perceived impact of Covid-19 among patients discharged from a Covid hospital in northern India. Methods We conducted this study among patients discharged from a Covid-19 hospital in northern India in June 2020. As per the official policy at that time, patients detected to have Covid-19 (symptomatically or via contact tracing) were mandatorily admitted. A sequential, mixed-methods design was followed. Patients discharged from the hospital were contacted telephonically, and the cross-sectional prevalence of symptoms, the prevalence of depression and anxiety and the social consequences of admission were assessed. A subgroup of patients was interviewed for qualitative assessment of their experience. Results A total of 274 patients provided consent and were assessed, of which 8 patients underwent detailed interviews. The prevalence of somatic symptoms was 3.4%; 36.2% of the patients had depressive and 12% of the patients had anxiety symptoms. A majority of patients experienced adverse social and economic consequences of hospitalization for Covid-19. These themes were reinforced by a qualitative analysis of in-depth interviews. Conclusions Our study population experienced a high prevalence of adverse psychosocial consequences of Covid-19. These included depression and anxiety symptoms, stigma and economic and occupational consequences. These deserve more recognition and study.

Demographic & clinical profile of patients with COVID-19 at a tertiary care hospital in north India.

BACKGROUND & OBJECTIVES: The COVID-19 pandemic emerged as a major public health emergency affecting the healthcare services all over the world. It is essential to analyze the epidemiological and clinical characteristics of patients with COVID-19 in different parts of our country. This study highlights clinical experience in managing patients with COVID-19 at a tertiary care centre in northern India. METHODS: Clinical characteristics and outcomes of consecutive adults patients admitted to a tertiary care hospital at Chandigarh, India, from April 1 to May 25, 2020 were studied. The diagnosis of SARS-CoV-2 infection was confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) on throat and/or nasopharyngeal swabs. All patients were managed according to the institute's consensus protocol and in accordance with Indian Council of Medical Research guidelines. RESULTS: During the study period, 114 patients with SARS-CoV-2 infection were admitted. The history of contact with COVID-19-affected individuals was available in 75 (65.8%) patients. The median age of the patients was 33.5 yr (13-79 yr), and there were 66 (58%) males. Of the total enrolled patients, 48 (42%) were symptomatic. The common presenting complaints were fever (37, 77%), cough (26, 54%) and shortness of breath (10, 20.8%). Nineteen (17%) patients had hypoxia (SpO2<94%) at presentation and 36 (31%) had tachypnoea (RR >24). Thirty four (29.8%) patients had an accompanying comorbid illness. Age more than 60 yr and presence of diabetes and hypertension were significantly associated with severe COVID-19 disease. Admission to the intensive care unit (ICU) was needed in 18 patients (52%), with three (2.6%) patients requiring assisted ventilation. Mortality of 2.6 per cent (3 patients) was observed. INTERPRETATION & CONCLUSIONS: Majority of the patients with COVID-19 infection presenting to our hospital were young and asymptomatic. Fever was noted only in three-fourth of the patients and respiratory symptoms in half of them. Patients with comorbidities were more vulnerable to complications. Triaged classification of patients and protocol-based treatment resulted in good outcomes and low case fatality.

Maternal and fetal outcomes of dengue fever in pregnancy: a large prospective and descriptive observational study.

PURPOSE: The primary objective of the study was to assess maternal and fetal outcomes of pregnancies affected with dengue fever. METHODS: This was a prospective, observational and descriptive study carried out over a period of 1 year. 216 pregnant women with fever were screened. Of these, 44 women tested positive for dengue (non-structural protein antigen 1 or dengue IgM antibodies in the sera). The clinical and laboratory characteristics of women with dengue were recorded. Maternal outcomes, pregnancy outcomes and fetal outcomes were studied. RESULTS: Mean period of gestation was 31.89 ± 7.31 weeks. Thrombocytopenia was seen in 23 (52.3%) women. Of 40 women, 10 (25%) developed post-partum haemorrhage. The incidence of maternal systemic complications was high: eight (18.2%) women developed acute kidney injury and two (4.5%) required haemodialysis support; eight (18.2%) women developed ARDS and seven (15.9%) women required ventilatory support; four (9.1%) women developed acute liver failure. 18 (40.9%) women had evidence of shock. Seven (15.9%) women died and another seven (15.9%) were classified as WHO maternal near-miss cases. Two (4.5%) pregnancies suffered from miscarriages, four (9%) from still births and two (4.5%) from neonatal deaths. Preterm babies were delivered in 15 (34.1%) and low birth weight babies in 13 (29.5%). CONCLUSIONS: Dengue in pregnancy adversely affects maternal and fetal outcomes with high maternal mortality of 15.9%. Prematurity and postpartum haemorrhage are significant risks to mother and baby. Vector control strategies should be implemented with vigour in affected areas.

Prognostic Value of Serum Procalcitonin Levels in Patients With Febrile Neutropenia Presenting to the Emergency Department.

BACKGROUND: Various risk-stratification scores have been developed to identify low-risk febrile neutropenia (FN). The Multinational Association of Supportive Care in Cancer (MASCC) score is a commonly used validated scoring system, although its performance varies due to its subjectivity. Biomarkers like procalcitonin (PCT) are being used in patients with FN to detect bacteremia and additional complications. OBJECTIVE: Our objective was to compare the performance of MASCC score with PCT in predicting adverse outcomes in patients with FN. METHODS: This was a prospective observational study that included chemotherapy-induced FN in hematologic or solid malignancy. The MASCC score, PCT levels, and blood cultures were taken at the first point of contact, and patient treatment was managed according to routine institutional protocol. The primary outcome was mortality at 30 days. RESULTS: A total of 100 patients were recruited, of which 92 had hematologic malignancy and 8 had solid malignancy. Forty-six patients were classified as low risk by MASCC score (≥21). The PCT threshold, 1.42 ng/mL, was taken as a cutoff value, with area under the receiver operating characteristic curve (AUROC) of 0.664 (95% confidence interval [CI] -0.55 to 0.77) for predicting mortality. AUROC for MASCC was 0.586 (95% CI 0.462 to 0.711). CONCLUSIONS: PCT is a useful marker with better prognostic efficacy than MASCC score in patients with FN and can be used as an adjunct to the score in risk-stratifying patients with FN.

CISNE versus MASCC: Identifying low risk febrile neutropenic patients.

OBJECTIVE: Febrile neutropenia though a dreaded complication of chemotherapy, not all patients need inpatient treatment. Risk score indices like MASCC and CISNE have been developed to identify low risk patients eligible for outpatient management. We undertook this study to compare the performances of MASCC and CISNE. METHODS: This was a prospective observational study conducted in a tertiary care centre from August 2017 to April 2019 where patients with chemotherapy induced febrile neutropenia were included. Basic demographic data and primary site of cancer were collected with characteristics required to calculate both MASCC and CISNE scores. The primary outcome measure was 30-day mortality. Apart from the 3 group risk stratification of CISNE, apriori it was decided that two-tier CISNE score will be calculated with 0 or 1 score as low risk and ≥2 as high risk. Descriptive statistics are reported and predictive performance of each score was analysed. RESULTS: Total of 129 patients were recruited. The performance of three-tier CISNE score was more specific (90.6%, 95% CI 76.9-96.9) but sensitivity (25.1%, 95% CI 17.0-36.3) was low compared to that of MASCC score (sensitivity 58.1%, 95% CI 47.0-68.5; specificity 65.1, 95% CI 49.0-78.5%). However, analysis with two-tier CISNE score demonstrated a better sensitivity (56.9%, 95%CI 45.8-67.4). Kappa for agreement between the two scores was 0.520 (95% CI 0.373-0.667, p < 0.001). CONCLUSION: CISNE and MASCC have fair discriminatory power in identifying low risk febrile neutropenia cases. Two group stratification on CISNE scoring will help in better decision making in emergency department.

Neisseria mucosa: A not so Benign Culprit of urinary tract infection: A case report.

Neisseria mucosa is saprophytic human commensal but reported as a causative agent in a couple of urinary tract infections [UTI] in susceptible individuals. In the present case, a young girl with long standing neurological problems presented with bladder outlet obstruction and fever. Her urine culture yielded Neisseria mucosa which was susceptible to broad spectrum penicillins, aminoglycosides, cephalosporins, ciprofloxacin, and azithromycin. She recovered with suitable dosage of amoxicillin clavulanic acid and was discharged. Isolation of N. mucosa here becomes clinically significant as this girl had various ureteric and lower limb weaknesses in past and was symptomatic for UTI with this infection.