Sofosbuvir plus ribavirin in treatment-naïve patients with chronic hepatitis C virus genotype 1 or 3 infection in India.

Until 2014, pegylated interferon plus ribavirin was the recommended standard of care for the treatment of chronic hepatitis C virus (HCV) infection in India. This open-label phase 3b study, conducted across 14 sites in India between 31 March 2014 and 30 November 2015, evaluated the efficacy and safety of sofosbuvir plus ribavirin therapy among treatment-naïve patients with chronic genotype 1 or 3 HCV infection. A total of 117 patients with genotype 1 or 3 HCV infection were randomized 1:1 to receive sofosbuvir 400 mg and weight-based ribavirin (1000 or 1200 mg) daily for 16 or 24 weeks. Among those with genotype 1 infection, the primary efficacy endpoint of sustained virologic response at 12 weeks post-treatment (SVR12) was reported in 90% (95% confidence intervals [CI], 73-98) and 96% (95% CI, 82-100) of patients following 16 and 24 weeks of treatment, respectively. For patients with genotype 3 infection, SVR12 rates were 100% (95% CI, 88-100) and 93% (95% CI, 78-99) after 16 and 24 weeks of therapy, respectively. Adverse events, most of which were mild or moderate in severity, occurred in 69% and 57% of patients receiving 16 and 24 weeks of treatment, respectively. The most common treatment-emergent adverse events were asthenia, headache and cough. Only one patient in the 24-week group discontinued treatment with sofosbuvir during this study. Overall, sofosbuvir plus ribavirin therapy achieved SVR12 rates ≥90% and was well tolerated among treatment-naïve patients with chronic genotype 1 or 3 HCV infection in India.

Preoperative assessment of retrorectal tumours.

BACKGROUND: Retrorectal tumours present diagnostic and surgical challenges. This study aimed to identify whether preoperative imaging and/or biopsy provide diagnostic accuracy. METHODS: A consecutive series of patients who had undergone excision of a retrorectal tumour were identified from a database (2002-2013). Details of patient demographics, preoperative presentation, imaging, biopsy, surgical procedure, and gross and microscopic pathology were reviewed. Preoperative imaging and/or biopsies were compared with eventual pathology findings. RESULTS: In total, 76 patients were identified, all of whom had undergone preoperative cross-sectional imaging whereas only 22 had preoperative biopsy. Imaging correctly discriminated benign from malignant tumours in 72 of the 76 patients (specificity 97 per cent, sensitivity 88 per cent, positive predictive value 88 per cent and negative predictive value 97 per cent). The corresponding values for preoperative biopsy (benign versus malignant) were 100, 83, 100 and 93 per cent. None of the four patients who were assessed incorrectly as having benign or malignant disease on imaging would have undergone an alternative procedure had this been known before surgery. Preoperative biopsy did not significantly influence patient management, and the absence of preoperative biopsy had no detrimental effect; a definitive preoperative histological diagnosis would not have influenced subsequent management. CONCLUSION: Preoperative imaging was accurate in the assessment of retrorectal tumours, whereas biopsy did not add to the surgical strategy.

One-year outcomes of rate versus rhythm control of atrial fibrillation in the Kerala-AF Registry.

Background: There is ongoing debate around rate versus rhythm control strategies for managing atrial fibrillation (AF), however, much of the data comes from Western cohorts. Kerala-AF represents the largest prospective AF cohort study from the Indian subcontinent. Objectives: To compare 12-month outcomes between rate and rhythm control strategies. Methods: Patients aged ≥18 years with non-transient AF were recruited from 53 hospitals across Kerala. Patients were stratified by rate or rhythm control. The primary outcome was a composite of all-cause mortality, arterial thromboembolism, acute coronary syndrome or hospitalization due to heart failure or arrhythmia at 12 months. Secondary outcomes included bleeding events and individual components of the primary. Predictors of the composite outcome were analysed by logistic regression. Results: A total of 2901 patients (mean age 64.6 years, 51% female) were included (2464 rate control, 437 rhythm control). Rates of the primary composite outcome did not differ between groups (29.7% vs 30.0%; p = .955), nor did any component of the primary. Bleeding outcomes were also similar (1.6% vs 1.9%; p = .848). Independent predictors of the primary composite outcome were older age (aOR 1.01; p = .013), BMI <18 (aOR 1.51; p = .025), permanent AF (aOR 0.78; p = .010), HFpEF (aOR 1.40; p = .023), HFrEF (aOR 1.39; p = .004), chronic kidney disease (aOR 1.36; p < .001), and prior thromboembolism (aOR 1.31; p = .014). Conclusion: In the Kerala-AF registry, 12-month outcomes did not differ between rate and rhythm control cohorts.

Partial anterior sacrectomy with nerve preservation to treat locally advanced rectal cancer.

AIM: Most studies that have reported outcomes after composite abdomino-sacral resection for locally advanced/recurrent rectal cancer have involved resections below the S2/3 disc space. Involvement of the sacrum above this level is uncommon and, until recently, was considered a contraindication to resection. METHOD: We report here a surgical technique to deal with high sacral involvement with an anterior approach and maintenance of sacropelvic stability. RESULTS: The operative findings confirmed a locally perforated rectal cancer with an associated abscess cavity and direct invasion into S2. Given the likelihood that a complete dislocation of the sacrum would cause significant neurological damage and pelvic instability without oncological benefit, we opted for a partial high anterior sacrectomy with nerve preservation. The patient made an uncomplicated recovery without neurological deficit and was able to walk with the aid of crutches from postoperative day 3. CONCLUSION: While a high sacral transection is appropriate for some patients with locally advanced/recurrent rectal cancer, operative decisions and options should be tailored to each individual.

Anal bulking agents for faecal incontinence.

The aim of this review was to assess and evaluate reports of studies on the efficacy of anal bulking agents used in the treatment of faecal incontinence. A systematic review of the literature was carried out to identify studies that have reported on the use of anal bulking agents. A variety of biomaterials have been employed for anal bulking. These include autologous fat, bovine glutaraldehyde cross-linked collagen, carbon-coated zirconium oxide beads, dextranomer microspheres in a gel, hydrogel cross-linked with polyacrylamide, polydimethylsiloxane elastomer in a gel, porcine dermal collagen and synthetic calcium hydroxylapatitie ceramic microspheres. Although the ideal site of injection (submucosal or intramuscular) and the mechanism of action remain the subject of debate, most published studies report a significant improvement in continence in at least 50% of subjects with mild to moderate symptoms with little or no associated morbidity.We concluded that anal bulking agents may be used to alleviate symptoms of faecal seepage and soilage.

Pulmonary Hypertension Registry of Kerala, India (PRO-KERALA): One-year outcomes.

BACKGROUND: Short term outcomes of patients with pulmonary hypertension are not available from low and middle-income countries including India. METHODS: We conducted a prospective study of 2003 patients with pulmonary hypertension, from 50 centres (PROKERALA) in Kerala, who were followed up for one year. Pulmonary hypertension (PH) was mainly diagnosed on the basis of Doppler echocardiography. The primary outcome was a composite end-point of all-cause death and hospital admission for heart failure. All cause hospitalisation events constituted the secondary outcome. RESULTS: Mean age of study population was 56 ± 16 years. Group 1 and Group 2 PH categories constituted 21.2% and 59% of the study population, respectively. Nearly two-thirds (65%) of the study participants had functional class II symptoms. 31% of Group 1 PH patients were on specific vasodilator drugs.In total, 83 patients (4.1%) died during the one-year follow-up period. Further, 1235 re-hospitalisation events (61.7%) were reported. In the multivariate model, baseline NYHA class III/IV (OR 1.87, 95% C.I. 1.35-2.56), use of calcium channel blockers (OR 0.18, 95% C.I. 0.04-0.77), vasodilator therapy (OR 0.5, 95% C.I. 0.28-0.87) and antiplatelet agents (OR 1.80, 95% C.I. 1.29-2.51) were associated with primary composite outcome at one-year (p < 0.05). CONCLUSION: In the PROKERALA registry, annual mortality rate was 4%. More than half of the patients reported re-hospitalisation events on follow up. Uptake of guideline directed therapies were suboptimal in the study population. Quality improvement programmes to improve guideline directed therapy may improve clinical outcomes of PH patients in India.

Enhanced protection of mice against Japanese encephalitis virus infection by combinations of monoclonal antibodies to glycoprotein E.

In the present study, the protective effect of various combinations of four monoclonal antibodies (MAbs) to glycoprotein E (gpE) of Japanese encephalitis virus (JEV) on the JEV-infected mice was studied. The MAbs were characterized as hemagglutination-inhibition-positive and JEV-specific (Hs). In the protective experiment, mice were first administered single MAbs or their combinations intraperitoneally (i.p.) and 24 hrs later infected with the virus intracerebrally (i.c.). The results showed that single MAbs protected the mice to the extent of 45-65%, while combinations of two or three MAbs gave 85-90% or 100% protection, respectively. The enhanced effect of combinations of several Hs MAbs might be due to the sharing of neutralization epitopes recognized by the Hs MAbs. These results suggested that a combination of at least three epitopes represented by the Hs MAbs should be included in an effective JEV vaccine.

Associations between preoperative anaemia and hospital costs following major abdominal surgery: cohort study.

BACKGROUND: Determining the cost-effectiveness and sustainability of patient blood management programmes relies on quantifying the economic burden of preoperative anaemia. This retrospective cohort study aimed to evaluate the hospital costs attributable to preoperative anaemia in patients undergoing major abdominal surgery. METHODS: Patients who underwent major abdominal surgery between 2010 and 2018 were included. The association between preoperative patient haemoglobin (Hb) concentration and hospital costs was evaluated by curve estimation based on the least-square method. The in-hospital cost of index admission was calculated using an activity-based costing methodology. Multivariable regression analysis and propensity score matching were used to estimate the effects of Hb concentration on variables related directly to hospital costs. RESULTS: A total of 1286 patients were included. The median overall cost was US $18 476 (i.q.r.13 784-27 880), and 568 patients (44.2 per cent) had a Hb level below 13.0 g/dl. Patients with a preoperative Hb level below 9.0 g/dl had total hospital costs that were 50.6 (95 per cent c.i. 14.1 to 98.9) per cent higher than those for patients with a preoperative Hb level of 9.0-13.0 g/dl (P < 0.001), 72.5 (30.6 to 128.0) per cent higher than costs for patients with a Hb concentration of 13.1-15.0 g/dl (P < 0.001), and 62.4 (21.8 to 116.7) per cent higher than those for patients with a Hb level greater than 15.0 g/dl (P < 0.001). Multivariable general linear modelling showed that packed red blood cell (PRBC) transfusions were a principal cost driver in patients with a Hb concentration below 9.0 g/dl. CONCLUSION: Patients with the lowest Hb concentration incurred the highest hospital costs, which were strongly associated with increased PRBC transfusions. Costs and possible complications may be decreased by treating preoperative anaemia, particularly more severe anaemia.

One-year clinical outcome of patients with nonvalvular atrial fibrillation: Insights from KERALA-AF registry.

BACKGROUND: We report patient characteristics, treatment pattern and one-year clinical outcome of nonvalvular atrial fibrillation (NVAF) from Kerala, India. This cohort forms part of Kerala Atrial Fibrillation (KERALA-AF) registry which is an ongoing large prospective study. METHODS: KERALA-AF registry collected data of adults with previously or newly diagnosed atrial fibrillation (AF) during April 2016 to April 2017. A total of 3421 patients were recruited from 53 hospitals across Kerala state. We analysed one-year follow-up outcome of 2507 patients with NVAF. RESULTS: Mean age at recruitment was 67.2 years (range 18-98) and 54.8% were males. Main co-morbidities were hypertension (61.2%), hyperlipidaemia (46.2%) and diabetes mellitus (37.2%). Major co-existing diseases were chronic kidney disease (42.1%), coronary artery disease (41.6%), and chronic heart failure (26.4%). Mean CHA2DS2-VASc score was 3.18 (SD ± 1.7) and HAS-BLED score, 1.84 (SD ± 1.3). At baseline, use of oral anticoagulants (OAC) was 38.6% and antiplatelets 32.7%. On one-month follow-up use of OAC increased to 65.8% and antiplatelets to 48.3%. One-year all-cause mortality was 16.48 and hospitalization 20.65 per 100 person years. The main causes of death were cardiovascular (75.0%), stroke (13.1%) and others (11.9%). The major causes of hospitalizations were acute coronary syndrome (35.0%), followed by arrhythmia (29.5%) and heart failure (8.4%). CONCLUSIONS: Despite high risk profile of patients in this registry, use of OAC was suboptimal, whereas antiplatelets were used in nearly half of patients. A relatively high rate of annual mortality and hospitalization was observed in patients with NVAF in Kerala AF Registry.

Early death of Japanese encephalitis virus-infected mice administered a neutralizing cross-reactive monoclonal antibody against glycoprotein E.

UNLABELLED: In the present study, the effect of two haemagglutination-inhibition (HAI)-negative auto-reactive (NHA-1 and NHA-2) monoclonal antibodies (MAbs) against glycoprotein E (gpE) of Japanese encephalitis virus (JEV) administered 1 day before or 2 days after intracerebral (i.c.) inoculation of JEV was studied in mice. Of the two MAbs that cross-reacted with West Nile virus (WNV) and histones, the first one (NHA-1) neutralized JEV, while the second one was non-neutralizing. NHA-1 MAb given intraperitoneally (i.p.) 1 day before virus infection induced early death by about 2 days in comparison to controls, whereas mice administered HAI-positive anti-gpE JEV specific MAbs (Hs-1 or Hs-4) were invariably protected. In contrast, MAb NHA-2 failed to produce any effect in mice. Since the similar virus titers were recorded in the brains of experimental and control infected mice, the present results indicated a modification of the biological activity of JEV by the pre-existing MAb NHA-1 that might be leading to an early death of mice. KEYWORDS: Japanese encephalitis virus; neutralizing cross-reactive monoclonal antibody.

Survival of mice immunized with monoclonal antibodies against glycoprotein E of Japanese encephalitis virus before or after infection with Japanese encephalitis, West Nile, and Dengue viruses.

In the present study, the effect of monoclonal antibodies (MAbs) against glycoprotein E (gE) of Japanese encephalitis virus (JEV) strain 733913 administered 1 day before or 2 days after intracerebral (i.c.) challenge with West Nile virus (WNV) strain 68856 or Dengue virus (DENV-2) strain P23085, was studied in mice. Furthermore, two JEV strains belonging to group II (strains 641686 and 691004) that have lost reactivity against virus-specific MAbs were also used in passive immunization experiments. MAbs as ascitic fluids were administered intraperitoneally (i.p.) in mice. Hemagglutination-inhibition- (HAI) positive JEV-specific (Hs-3) MAbs given 2 days after the virus infection showed reduced mortality along with increased survival of mice challenged with WNV or with DENV-2. Also the HAI-positive flavivirus cross-reactive (Hx) MAbs produced a marginal increase in the survival of mice challenged with both JEV strains 641686 and 691004 belonging to the group II. As the MAbs reacting with HAI-positive JEV-specific (Hs) and HAI-negative JEV-specific (NHs) epitopes were neutralizing and protective in mice against JEV strain 733913 challenge, the results indicated presence of the cross-protection phenomenon that might be occurring in some of the localities endemic for the three closely related flaviviruses.

Geographical variation in the clinical presentation of endomyocardial fibrosis in India?

OBJECTIVES: To compare the clinical presentation, clinical profile and survival of two groups of endomyocardial fibrosis patients. METHODS: The study was a prospective cohort study, or a prospective case series, comparing all consecutive echocardiographically proven patients with endomyocardial fibrosis seen in Medical College Trivandrum with the patients seen in Medical College Hospital, Alappuzha(Alleppey) (or TD Medical College). In all patients the clinical details like age, sex, type of endomyocardial fibrosis, the presence of anaemia, eosinophilia, neutrophilia and type of rhythm(Sinus or atrial fibrillation) etc were compared by both simple X2 and by Kaplan Meier survival curves. RESULTS: The mean age and the sex distribution was same in both places Briefly the incidence of biventricular endomyocardial fibrosis was more from Trivandrum than Alleppey, 64.9% vs 14.3% (p<0.0.001), the incidence of atrial fibrillation was more in Trivandrum 44.2% vs 16.3%. (p<0.001)The overall survival of Trivandrum patients was poorer (p<0.0001). The six year survival was 61% in the Trivandrum population whereas it was 91.5% in the Alleppey population. CONCLUSIONS: These differences may have been due to the better nutrition of the Alleppey patients due to a higher exposure to fish compared to the Trivandrum population. Better nutrition would protect against Magnesium deficiency and prevent the absorption of Cerium in the patients from Alleppey, compared to those from Trivandrum.

Angiographic predictors of success in antegrade approach of Chronic Total Occlusion interventions in a South Indian population in the contemporary era.

Chronic Total Occlusion (CTO) intervention is a challenging area in interventional cardiology. Presently about 70% of CTO interventions are successful. MATERIALS AND METHODS: This was a single center prospective study of a cohort of all patients undergoing percutaneous coronary intervention (PCI) as elective or adhoc procedure for CTO from August 2014 to June 2015. Only antegrade CTO interventions were included. In all patients the following data were recorded. RESULTS: A total of 210 (8.9% of total PCI (2353) during the study period) CTO patients were followed up. The mean age was 56.54±8.9. In the study sixty nine patients (32.9%) presented with chronic stable angina and rest of the patients had history of acute coronary syndrome of which 22.9% (n=48) had unstable angina (UA) or non ST elevation myocardial infarction (NSTEMI) and 44.2% (n=93) had ST Elevation Myocardial Infarction (STEMI). In those with history of ACS, 64.78% (n=92) had ACS during the previous year and remaining 35.22% (n=49) had ACS prior to that. Single vessel CTO was seen in 89.5% (n=188) and two vessel CTO in 10.5% (n=22). LAD was involved in 36.7% (n=77), RCA in 48.1% (n=101), and LCX in 15.2% (n=32). Procedural success in the first attempt was 68.1% (n=143), which increased to 71.42% (n=150) after the second attempt. CTO interventions were more frequently successful when the calcium was absent or minimal (p-0.05), CTO length was <10mm (p<0.01) and good distal reformation (p<0.01).

Pulmonary hypertension registry of Kerala, India (PRO-KERALA) - Clinical characteristics and practice patterns.

BACKGROUND: Epidemiological data on pulmonary hypertension (PH) are scarce from developing countries including India. METHODS: We established a multi-center registry of PH, the PRO-KERALA registry, in Kerala, India. Fifty hospitals enrolled consecutive adult (>18 years) patients for one year. Echocardiographic criteria (right ventricular systolic pressure - RVSP > 50 mmHg) or invasively obtained mean pulmonary artery pressure > 25 mmHg was the criteria for entry. RESULTS: There were 2003 patients (52% Women, mean age 56 ±â€¯16.1 years) enrolled. The mean RVSP was 68.2 (SD = 17.9) mmHg. Majority of the study participants (59%) belonged to group 2 of the WHO Nice Classification 2013 (PH secondary to left heart disease). One-fifth (21.2%) belonged to group 1, while 13.3%, 3.8% and 2.4% of the study population belonged to groups 3, 4 and 5 respectively. More than a quarter (27%) reported PH due to left heart disease with valvular disease etiology; while 20.7% had coronary artery disease. The other common etiological factors were chronic obstructive pulmonary disease (10.6%), congenital heart disease (14.6%), idiopathic pulmonary hypertension (5.8%), and chronic thromboembolic pulmonary hypertension (3.8%). Only one of two patients with pulmonary artery hypertension was receiving PH specific therapies. The use of combination therapy was negligible and PH-specific therapies were prescribed off-label to a small proportion of patients too. CONCLUSION: PRO-KERALA is the first PH registry from South Asia and the second largest globally. Left heart diseases attribute to three fifths of patients with PH. Utilization rates of PH specific drug therapies are remarkably lower than the Western population.

Blood coagulation factor XIa binds specifically to a site on activated human platelets distinct from that for factor XI.

Binding of 125I-Factor XIa to platelets required the presence of high molecular weight kininogen, was enhanced when platelets were stimulated with thrombin, and reached a plateau after 4-6 min of incubation at 37 degrees C. Factor XIa binding was specific: 50- to 100-fold molar excesses of unlabeled Factor XIa prevented binding, whereas Factor XI, prekallikrein, Factor XIIa, and prothrombin did not. When washed erythrocytes, added at concentrations calculated to provide an equivalent surface area to platelets, were incubated with Factor XIa, only a low level of nonspecific, nonsaturable binding was detected. Factor XIa binding to platelets was partially reversible and was saturable at concentrations of added Factor XIa of 0.2-0.4 microgram/ml (1.25-2.5 microM). The number of Factor XIa binding sites on activated platelets was estimated to be 225 per platelet (range, 110-450). We conclude that specific, high affinity, saturable binding sites for Factor XIa are present on activated platelets, are distinct from those previously demonstrated for Factor XI, and require the presence of high molecular weight kininogen.

Population access to reperfusion services for ST-segment elevation myocardial infarction in Kerala, India.

BACKGROUND: Population access to timely reperfusion is a decisive factor in determining the success and acceptability of any regional system of ST-segment elevation myocardial infarction (STEMI) care. We sought to determine the proportion of population of the southern Indian state of Kerala having timely access to STEMI reperfusion. METHODS: We identified the STEMI reperfusion facilities available at all acute-care hospitals, in Kerala, by conducting a cross-sectional survey. We mapped the geographical catchment areas of these hospitals using historical travel speeds and appropriate Geospatial Information Systems (GIS) analyses. Subsequently, using block level population data, we estimated the proportion of the population residing within these geographies. RESULTS: We estimated that 23.33 million people, forming 69.84% of the state population, resided in the green zone (within half-hour travel distance of a percutaneous coronary intervention [PCI]-capable hospital), which covered 47.94% of the geographical area of the state. Outside this green zone, 21.87% of the state population resided within 1hr travel distance of a thrombolysis-capable hospital. Finally, 8.28% of the state population resided in the red zone, where access to any reperfusion-capable hospital took >1hr, which covered 22.15% of the geographical area of the state. CONCLUSIONS: A majority of the population of Kerala had timely access to PCI-capable hospitals. GIS-based mapping of Indian states, in terms of access to STEMI reperfusion, may help devise protocols to achieve seamless transfer of patients to reperfusion-capable hospitals. Such regionalization of STEMI care would enhance organizational synergies to achieve better access to reperfusion, especially in remote areas.

Rheumatic Heart Disease in Kerala: A Vanishing Entity? An Echo Doppler Study in 5-15-Years-Old School Children.

Background. Early detection of subclinical rheumatic heart disease by use of echocardiography warrants timely implementation of secondary antibiotic prophylaxis and thereby prevents or retards its related complications. Objectives. The objective of this epidemiological study was to determine prevalence of RHD by echocardiography using World Heart Federation criteria in randomly selected school children of Trivandrum. Methods. This was a population-based cross-sectional screening study carried out in Trivandrum. A total of 2060 school children, 5-15 years, were randomly selected from five government and two private (aided) schools. All enrolled children were screened for RHD according to standard clinical and WHF criteria of echocardiography. Results. Echocardiographic examinations confirmed RHD in 5 children out of 146 clinically suspected cases. Thus, clinical prevalence was found to be 2.4 per 1000. According to WHF criteria of echocardiography, 12 children (12/2060) were diagnosed with RHD corresponding to echocardiographic prevalence of 5.83 cases per 1000. As per criteria, 6 children were diagnosed with definite RHD and 6 with borderline RHD. Conclusions. The results of the current study demonstrate that echocardiography is more sensitive and feasible in detecting clinically silent RHD. Our study, the largest school survey of south India till date, points towards declining prevalence of RHD (5.83/1000 cases) using WHF criteria in Kerala.