Diabetes associated with immune checkpoint inhibition: presentation and management challenges.

BACKGROUND: In recent years, immune checkpoint blockade has become a standard therapy for a wide range of cancers. Adverse events including endocrinopathies result from the induction of autoimmunity. CASE REPORT: We report a case series of nine individuals who presented with immunotherapy-induced type 1 diabetes between 2015-2017. DISCUSSION: Onset of diabetes occurred within 12 weeks of commencing therapy. Anti- GAD antibodies were present in six people. Retrospective testing of islet antibodies in pre-treatment samples was possible in two people and this revealed anti-GAD seroconversion in the first and high anti-GAD titres pre and post-treatment in the second person. Six people had high risk HLA haplotypes. Clinical and genetic factors are described and compared with previously published cases. This article is protected by copyright. All rights reserved.

A Japanese Encephalitis Vaccine From India Induces Durable and Cross-protective Immunity Against Temporally and Spatially Wide-ranging Global Field Strains.

BACKGROUND: Japanese encephalitis (JE) is a vaccine-preventable acute disease. We report the results of a phase 2/3 trial of JENVAC, a Vero cell-derived vaccine developed using an Indian strain of JE virus (JEV). METHODS: JENVAC was administered in 2 doses 28 days apart, and immunogenicity was compared to that from a single dose of SA-14-14-2, the only approved JE vaccine and regimen at the time in India. RESULTS: After both the doses, seroconversion and seroprotection were >90% for JENVAC. For SA-14-14-2, seroconversion and seroprotection were 57.69% and 77.56%, respectively, on day 28 and 39.74% and 60.26%, respectively, on day 56. The geometric mean titers at day 28 and day 56 were 145.04 and 460.53, respectively, for JENVAC and 38.56 and 25.29, respectively, for SA-14-14-2. With a single dose of JENVAC, seroprotection titers lasted at least 12 months in >80% of the subjects. Following receipt of 2 doses, 61.17% of subjects retained seroprotection titers at 24 months, and immunogenicity criteria were higher than that for SA-14-14-2 at 12, 18, and 24 months each. Sera from JENVAC subjects neutralized JEV genotypes I, II, III, and IV equally well. Adverse events were not significantly different between the 2 vaccines. CONCLUSIONS: JENVAC elicits long-lasting, broadly protective immunity. CLINICAL TRIALS REGISTRATION: CTRI/2011/07/001855.

The National Accreditation Board for Hospital and Health Care Providers accreditation programme in India.

Quality in health care is important as it is directly linked with patient safety. Quality as we know is driven either by regulation or by market demand. Regulation in most developing countries has not been effective, as there is shortage of health care providers and governments have to be flexible. In such circumstances, quality has taken a back seat. Accreditation symbolizes the framework for quality governance of a hospital and is based on optimum standards. Not only is India establishing numerous state of the art hospitals, but they are also experiencing an increase in demand for quality as well as medical tourism. India launched its own accreditation system in 2006, conforming to standards accredited by ISQua. This article shows the journey to accreditation in India and describes the problems encountered by hospitals as well as the benefits it has generated for the industry and patients.

Impact of educational interventions on pharmacovigilance and adverse drug reaction reporting by resident doctors and faculty members: A prospective comparative study.

Purpose/Aim: Adverse drug reactions (ADRs) are significantly under-reported worldwide. The aim of this study was to assess the impact of educational interventions (EIs) on knowledge, attitude, and practice (KAP) of hospital resident doctors and faculty members and compare ADR reporting in EI (medical specialties) vs. non-EI (surgical specialties) in these two cadres of doctors. Materials and Methods: This study was a prospective comparative study conducted in two groups (EI and non-EI) in resident doctors and faculty members working at a tertiary care hospital. EI group (medical specialties) were provided with EI to increase awareness about ADR reporting, whereas in non-EI group (surgical specialties), no EI was provided and they served as control. Respondents were asked to fill a pretest questionnaire followed by interactive EI in EI group and posttest questionnaire in both groups. The impact of EI among respondents was evaluated by their response to questionnaire and number of ADRs reported after intervention. Results: Total (n = 202) respondents were enrolled in the study. The number of resident doctors and faculty members in each group were (n = 101 [50%]). Overall, (n = 100 [49.5%]) were from the medical and (n = 102 [50.5%]) from surgical specialty. Post-EI period, there was statistically significant improvement in KAP domains. Conclusion: Our study serves as credible evidence that through EI; statistically significant improvement in KAP of resident doctors and faculty members in both medical and surgical specialties toward ADR reporting and existing pharmacovigilance system can be achieved.

Granulocyte-Colony Stimulating Factor (G-CSF) accelerates healing of radiation induced moist desquamation of the skin.

DESIGN: Clinical evidence from a few experimental and randomized trials have implicated the possible benefit of cytokines in prevention and healing of radiation induced mucositis. This pilot study was undertaken to assess the effectiveness of Granulocyte-Colony Stimulating Factor (G-CSF) on healing of radiation induced moist desquamation of the skin. RATIONALE FOR THE STUDY: intervention with exogenous growth factors along with conventional treatment practices may stimulate faster skin healing and help the patient in resuming normalcy at the earliest. MATERIALS AND METHODS: Twenty three patients with established grade III moist desquamation of skin at the site of radiation and during the course of their radiotherapy were recruited for this study. Patients were administered a single dose of Granulocyte-Colony Stimulating Factor (G-CSF - Neupogen® (Filgrastim)) 300 µg subcutaneously at the periphery of the wound as a single session. The rate of skin healing was documented as a function of time from D1 (day of Filgastrim instillation) to the number of days required for complete healing/re-epithelization of the open skin wound. RESULTS: There was a rapid response and decreased severity of the grade III radiation skin reactions, which extrapolated to an early resumption of radiotherapy treatment. Twenty patients (86%) showed healing of their wounds within 10 days which was notably faster than the expected 2 to 3 weeks anticipated for the severity/grade of the skin reaction. Thirteen patients (56.5%) showed a remarkably rapid response of healing within 5 days. No significant side effects were experienced after the single dose was administered. The mean duration to resolution of moist desquamation was calculated as 6.65 ± 4.73 days. Among the associated parameters, only location of lesion and depth of skin reaction significantly affected the rate of healing. Superficial epidermal erosions showed excellent response with 4.53 ± 2.07 days of re-epithelization & healing (p < 0.001) compared to deep dermal exposure. The results are suggestive of a promising role of G-CSF in the management of Grade III radiation induced skin reaction (moist desquamation).This concept requires structured randomized trials to establish significance of benefit. CONCLUSION: G-CSF appears to promote wound healing; this cytokine has the potential to favorably modify the healing process of radiation induced moist desquamation of the skin. This study demonstrates that this dreaded side effect of radiotherapy can by managed in a very simple, convenient and cost effective way, without toxicity & intervention.

Investigating the efficacy of baricitinib in new onset type 1 diabetes mellitus (BANDIT)-study protocol for a phase 2, randomized, placebo controlled trial.

BACKGROUND: Type 1 diabetes (T1D) places an extraordinary burden on individuals and their families, as well as on the healthcare system. Despite recent advances in glucose sensors and insulin pump technology, only a minority of patients meet their glucose targets and face the risk of both acute and long-term complications, some of which are life-threatening. The JAK-STAT pathway is critical for the immune-mediated pancreatic beta cell destruction in T1D. Our pre-clinical data show that inhibitors of JAK1/JAK2 prevent diabetes and reverse newly diagnosed diabetes in the T1D non-obese diabetic mouse model. The goal of this study is to determine if the JAK1/JAK2 inhibitor baricitinib impairs type 1 diabetes autoimmunity and preserves beta cell function. METHODS: This will be as a multicentre, two-arm, double-blind, placebo-controlled randomized trial in individuals aged 10-30 years with recent-onset T1D. Eighty-three participants will be randomized in a 2:1 ratio within 100 days of diagnosis to receive either baricitinib 4mg/day or placebo for 48 weeks and then monitored for a further 48 weeks after stopping study drug. The primary outcome is the plasma C-peptide 2h area under the curve following ingestion of a mixed meal. Secondary outcomes include HbA1c, insulin dose, continuous glucose profile and adverse events. Mechanistic assessments will characterize general and diabetes-specific immune responses. DISCUSSION: This study will determine if baricitinib slows the progressive, immune-mediated loss of beta cell function that occurs after clinical presentation of T1D. Preservation of beta cell function would be expected to improve glucose control and prevent diabetes complications, and justify additional trials of baricitinib combined with other therapies and of its use in at-risk populations to prevent T1D. TRIAL REGISTRATION: ANZCTR ACTRN12620000239965 . Registered on 26 February 2020. CLINICALTRIALS: gov NCT04774224. Registered on 01 March 2021.

Mutations of TFAP2B in congenital heart disease patients in Mysore, South India.

BACKGROUND & OBJECTIVES: Cardiac malformations in the young constitute a major portion of clinically significant birth defects. Congenital heart disease (CHD) is a common congenital cardiac birth defect, affecting nearly 1 per cent of all live births. Patent ductus arteriosus (PDA) is clinically significant foetal circulation anomaly, second most common form of CHD which constitutes approximately 10 per cent of total CHDs. The study aimed to screen for TFAP2B mutations in CHD patients of Mysore. METHODS: With informed consent, 100 clinically diagnosed CHD patients and 50 healthy controls in Mysore, south India, were recruited for the analysis of screening of mutations. MassARRAY analysis of 5 prominent mutations of TFAP2B was performed. RESULTS: The analysis did not show any of the five mutations of TFAP2B screened by massARRAY in patients and controls, indicating that these mutations were not involved in the manifestation of CHD in the patients at Mysore, south India. INTERPRETATION & CONCLUSIONS: The findings suggest the lack of involvement of known mutations of TFAP2B with syndromic or nonsyndromic CHDs in Mysore patients.

Distinct T cell receptor signaling requirements for perforin- or FasL-mediated cytotoxicity.

A diverse array of signals are generated in a cytotoxic T lymphocyte (CTL) after the T cell receptor (TCR) engages the class I major histocompatibility complex (MHC) peptide complex. These signals result in a multitude of CTL effector functions, including cellular cytotoxicity, cell surface receptor expression, and cytokine secretion. We have examined signaling through the TCR in a wild type CD8+, MHC-restricted, antigen-specific CTL clone, 14-7, and its interleukin 2-dependent variant clone 14-7FD. We report here that 14-7FD is unable to kill via the perforin mechanism of killing, yet is able to kill via the Fas ligand/Fas mechanism and secrete interferon-gamma in an antigen-specific manner. 14-7FD has cytolytic granules that contain perforin and serine esterases, which are secreted after phorbol ester and Ca2+ ionophore treatment. Lastly, to investigate which TCR signaling requirements were operational in 14-7FD, we examined TCR-triggered intracellular Ca2+ mobilization in the two clones. After TCR engagement, 14-7FD failed to mobilize intracellular Ca2+, which may be the cause for its inability to trigger the perforin/granule exocytosis mechanism of killing. These results indicate that the signal transduction events that trigger perforin killing and the signaling requirements to induce FasL expression are distinct. We hypothesize that these two distinct TCR signal transduction requirements allow for separate activation of these two mechanisms of killing relating to their role in eradication of infected cells or regulation of immune responses.

Region-wise distribution of high-risk human papillomavirus types in squamous cell carcinomas of the cervix in India.

HYPOTHESIS: Assessment of the prevalence and type distribution of human papillomavirus (HPV) in squamous cell carcinomas (SCC) of the cervix across India was undertaken to estimate the impact of available prophylactic HPV-L1 vaccines in the country and to find out additional types that might be needed to be incorporated in second-generation vaccines. METHODS: High-risk (HR) HPVs were genotyped from 667 histopathologically confirmed cases of SCC from 6 different centers representing 4 regions across India: Advanced Centre for Treatment, Research and Education in Cancer, Mumbai; All India Institute of Medical Sciences, New Delhi; Cancer Foundation of India, Kolkata; Christian Medical College, Vellore; Kidwai Memorial Institute of Oncology, Bangalore; and Regional Cancer Center, Thiruvananthapuram. Human papillomaviruses in tumor biopsies were analyzed by Xcytonscreen HPV based on PGMY09/11 multiplex polymerase chain reaction and reverse dot blot assay. RESULTS: Overall viral prevalence across India was not different; 92.1% of 667 cases harbored HPV; 8% were negative. Infection with single HR type was seen in 86.8%: predominant types being HPV-16 followed by HPV-18, -45, -73, -31, -56, -52, -58, -59, -33, -68, -51, -35, -26, and -39. Human papillomavirus types 16/18-positive fraction formed 79.6%; other types comprised 12.4%. CONCLUSIONS: Prophylactic HPV-16/18-L1 vaccines would provide greater than 75% protection against SCC in India. Ranking and frequencies of non-16/18 types were different from earlier reports. Hence, considering the possibility of promotion of persistence of nonvaccine types in the vaccinees due to original antigenic sin and the lack of organized screening programs in India, a broad-based vaccine approach would be appropriate.

Immunogenicity and safety of a liquid Pentavalent (DTwP-Hb-Hib) combination vaccine manufactured by Human Biologicals Institute in 6-8 weeks old healthy infants: A phase III, randomized, single blind, non-inferiority study.

BACKGROUND: A liquid Pentavalent (DTwP-Hb-Hib) combination vaccine, developed by Human Biologicals Institute, underwent a Phase III clinical study in India. In this randomized, single blind, non-inferiority study, the immunogenicity and safety of this Investigational vaccine was compared with Pentavac SD® vaccine in 6-8 weeks old healthy infants. METHODS: A total of 405 healthy infants aged 6-8 weeks old were randomized in 2:1 ratio to receive three doses of either the Investigational liquid Pentavalent (DTwP-Hb-Hib) combination vaccine or Pentavac SD® vaccine at four to six weeks interval. Immunogenicity was compared by estimation of antibody titers before the first dose and 4-6 weeks after the third dose of vaccination. Safety of each vaccine was assessed and compared by collection of data on solicited and unsolicited adverse events throughout the study period. RESULTS: Out of a total of 405 enrolled subjects, 387 subjects completed the study. The seroconversion rates, seroprotection rates and geometric mean titres of the Investigational liquid Pentavalent (DTwP-Hb-Hib) combination vaccine group were found to be comparable and non-inferior to the Pentavac SD® vaccine group at 4-6 weeks after the third dose of vaccination. Pain, erythema and swelling at the site of injection were found to be the most common local adverse events whereas fever, irritability and unusual crying were found to be the most common systemic adverse events in both the vaccine groups. No vaccine related serious adverse event was reported. In this study, both the Investigational vaccine as well as the Comparator vaccine were found to be immunogenic and well tolerated. CONCLUSION: After assessment of the results of the study it was concluded that the Investigational liquid Pentavalent (DTwP-Hb-Hib) combination vaccine developed by Human Biologicals Institute was immunogenic and safe when administered to infants aged 6-8 weeks and was non-inferior in immunogenicity and safety to Pentavac SD® vaccine. Clinical Trial Registry of India Identifier: CTRI/2016/01/006541.

Operative complications and economic outcomes of cholecystectomy for acute cholecystitis.

BACKGROUND: Recent management of acute cholecystitis favors same admission (SA) or emergent cholecystectomy based on overall shorter hospital stay and therefore cost savings. We adopted the practice of SA cholecystectomy for the treatment of acute cholecystitis at our tertiary care center and wanted to evaluate the economic benefit of this practice. We hypothesized that the existence of complications, particularly among patients with a higher degree of disease severity, during SA cholecystectomy could negate the cost savings. AIM: To compare complication rates and hospital costs between SA vs delayed cholecystectomy among patients admitted emergently for acute cholecystitis. METHODS: Under an IRB-approved protocol, complications and charges for were obtained for SA, later after conservative management (Delayed), or elective cholecystectomies over an 8.5-year period. Patients were identified using the acute care surgery registry and billing database. Data was retrieved via EMR, operative logs, and Revenue Cycle Operations. The severity of acute cholecystitis was graded according to the Tokyo Guidelines. TG18 categorizes acute cholecystitis by Grades 1, 2, and 3 representing mild, moderate, and severe, respectively. Comparisons were analyzed with χ 2, Fisher's exact test, ANOVA, t-tests, and logistic regression; significance was set at P < 0.05. RESULTS: Four hundred eighty-six (87.7%) underwent a SA while 68 patients (12.3%) received Delayed cholecystectomy. Complication rates were increased after SA compared to Delayed cholecystectomy (18.5% vs 4.4%, P = 0.004). The complication rates of patients undergoing delayed cholecystectomy was similar to the rate for elective cholecystectomy (7.4%, P = 0.35). Mortality rates were 0.6% vs 0% for SA vs Delayed. Patients with moderate disease (Tokyo 2) suffered more complications among SA while none who were delayed experienced a complication (16.1% vs 0.0%, P < 0.001). Total hospital charges for SA cholecystectomy were increased compared to a Delayed approach ($44500 ± $59000 vs $35300 ± $16700, P = 0.019). The relative risk of developing a complication was 4.2x [95% confidence interval (CI): 1.4-12.9] in the SA vs Delayed groups. Among eight patients (95%CI: 5.0-12.3) with acute cholecystitis undergoing SA cholecystectomy, one patient will suffer a complication. CONCLUSION: Patients with Tokyo Grade 2 acute cholecystitis had more complications and increased hospital charges when undergoing SA cholecystectomy. This data supports a selective approach to SA cholecystectomy for acute cholecystitis.

Self abortion of attacks in patients with Hot Water Epilepsy.

A cross sectional hospital based study was undertaken to find out the various clinical aspects and management of Hot Water Epilepsy (HWE) in children. Of the 71 cases analysed, 67.6% had onset of seizures in the first decade of life. Seizures occurred frequently towards the end of head bath (71.8%). In 14.1% cases, seizures were precipitated with cold-water head bath also. Complex partial seizures (60.6%) and generalized atonic seizures (21.1%) were common. Spontaneous non-reflex epilepsy was seen in 47.9% cases. Self-induction and self-abortion of seizures were seen in 16.9% and 12.7% patients respectively. Family history was available in 32.4% of cases. Majority had good response to continuous prophylactic treatment with antiepileptic drugs. We conclude that high incidence of spontaneous seizures and generalized atonic seizures seem to be peculiar to our geographical area. "Self abortion of attacks"may be of immense help in controlling the attacks.

Aortoiliac reconstruction in the setting of in-stent restenosis.

Complex iliac artery obstructions, particularly bilateral stenosis or total iliac artery occlusions, are usually treated with aortofemoral or aortobifemoral graft surgery. However, surgical treatment is associated with 3% mortality rate and significant morbidity such as intestinal ischemia, spinal cord injury, and ureteral damage. Percutaneous interventions of aortic bifurcation offer a promising alternative to surgery with potentially lower morbidity and mortality risk. We report a case of peripheral artery disease who had underwent right transfemoral iliac angioplasty with femoropopliteal bypass presented again with bilateral lower limb ischemia, who was successfully treated with stent implantation with the kissing balloon technique.

Neglected Recurrent Scalp Sinus: Calvarial Tuberculosis with Intracranial and Extracranial Extension.

BACKGROUND: Calvarial tuberculosis (TB) with intracranial tuberculoma and skin involvement is rare condition even in endemic regions. CASE PRESENTATION: A 43-year-old man presented with a generalized seizure, altered mental state, scalp swelling, and pus-discharging sinus over the scalp. Magnetic resonance imaging of the brain indicated a conflicting diagnosis of anaplastic meningiomas and chronic osteomyelitis with intracranial extension. Débridement and drainage of intracranial pus was performed. Histopathologic examination revealed TB. After surgery, the patient's general condition improved, and he was started on antitubercular drugs. CONCLUSIONS: Calvarial TB manifests with various clinical features, and strong clinical suspicion is needed to diagnose and treat it. Only a few cases of calvarial TB with either skin involvement or intracranial extension have been reported in the literature. The present case was challenging to diagnose with a rare presentation involving both intracranial and extracranial extension.

Segregation of cytoplasmic incompatibility properties in Culex pipiens fatigans.

Maternally inherited variants, which arose within a laboratory colony of Culex pipiens fatigans, have been studied by rearing cultures from single egg rafts. Segregation, i.e, variation of cytoplasmic incompatibility properties between the male progeny of individual females, was demonstrated. Also, from the daughters of individual females, sub-lines were derived within which all the males showed the same incompatibility or compatibility properties. Among the descendants of tetracycline-treated individuals were lines which superficially simulated these phenomena, but theses lines ultimately reverted to the cytoplasmic compatibility type of the strain which was submitted to the treatment. The types of variation s in cytoplasmic incompatibility properties that have been studied are discussed.

Transection of common bile duct following blunt injury to abdomen.

Isolated complete transection of the common bile duct due to blunt abdominal trauma is rare. We report such a case following an assault.

Soft tissue reconstruction after hemimandibulectomy in oral malignancies: a retrospective study.

AIMS: The present study was under taken to evaluate the efficacy of various local and regional soft tissue flaps used for reconstruction after excision of various malignant lesions of the mouth and also to evaluate complications with length of hospital stay after the reconstruction. MATERIALS AND METHODS: The study was a record based retrospective analysis of 127 patients who were histologically proven squamous cell carcinoma of the oral cavity for which excision of the lesion along with segmental mandibulectomy and primary reconstruction with local or regional flaps was the treatment modality. RESULTS: The male:female mean age is 48.27:48.79. The Z-proportionality test for intra oral reconstruction showed 5% level of significance (P < 0.05) between pectoralis major myocutaneous flap (PMMC) and other flaps. Difference between deltopectoral (DP) and PMMC, PMMC and primary closure at 1% level of significance, i.e. P < 0.01 was found for extra oral defects. The mean stay was found to be 31.31 days. Recurrence rate of 11% was reported. CONCLUSION: A total of 127 patients formed the study group. In the absence of bone reconstruction PMMC still continues to be the "work horse" of reconstruction following wide excision and hemimandibulectomy.

Impact of metabolic syndrome on re-stenosis development: role of drug-eluting stents.

Metabolic syndrome (MetS) is defined as a cluster of numerous cardiovascular risk factors, which encompasses obesity, dyslipidaemia, insulin resistance and hypertension. Patients with MetS are more prone to developing cardiovascular events than other patients. To date, several approaches such as physical exercise, dietary control and invasive and non-invasive therapeutic interventions for dyslipidaemia, hypertension and insulin resistance have been used to manage MetS. However, there is a progressive elevation in the incidence of fatal and non-fatal cardiovascular events due to the increased prevalence of obesity and diabetes. Percutaneous coronary intervention has emerged over the last few years as an effective revascularisation strategy for those with coronary artery disease, in parallel with the development of effective anti-platelet medications and newer drug-eluting stents. In recent years, considerable research efforts have been undertaken to elucidate the pathophysiology of re-stenosis and develop strategies to prevent re-stenosis following percutaneous transluminal coronary angioplasty and stent implantation. Although the rate of stent re-stenosis and target-lesion revascularisation has been reduced, there is little information in the literature on the outcome of MetS in the pathophysiology of re-stenosis. In this review article, we summarise the recent development and progress on re-stenosis and the role of drug-eluting stents, particularly in MetS.

Single-nucleotide polymorphisms of NKX2.5 found in congenital heart disease patients of Mysore, South India.

Congenital heart disease (CHD) is a common congenital birth defect, affecting nearly 1% of all live births, and is the most common cause of infant death. NKX2.5 is an important transcription factor expressed during vertebrate heart development and involved in the regulation of septation during cardiac morphogenesis and in the maturation and maintenance of the atrioventricular node throughout life. There are many reports on association of single-nucleotide polymorphisms (SNPs) of NKX2.5 with CHD but none have been reported from Mysore, South India. With informed consent, 150 clinically diagnosed CHD patients and 70 unrelated healthy controls in Mysore, South India, were recruited. In the first phase the DNAs of 50 CHD patients and 20 controls were subjected to polymerase chain reaction amplification of coding regions of NKX2.5 and further sequenced for SNP genotyping. Additionally, mass array analysis of SNPs was performed for 100 CHD and 50 controls. Analysis revealed the occurrence of six SNPs in different types of CHDs. Two were synonymous SNPs, the most common c.239A>G (p.E21E) and newly identified c.896C>A (p.A240A), as well as three nonsynonymous SNPs, c.608A>G (p.E203G), c.646C>T (p.R216C), and c.852G>A (p.N226D). The sixth SNP 1212G>T in the 3'UTR was observed in 40% of the CHD cases. The SNPs c.646C>T and c.608A>G were shown to cause changes in their secondary structure. Ventricular septal defect was the more prominent CHD observed in our study population. The SNPs c.608A>G (p.E203G) and c.852G>A (p.N226D) were present only in CHD patients, indicating their association with CHDs.