Persistence of immunity and impact of third dose of inactivated COVID-19 vaccine against emerging variants.

This is a comprehensive report on immunogenicity of COVAXIN® booster dose against ancestral and Variants of Concern (VOCs) up to 12 months. It is well known that neutralizing antibodies induced by COVID-19 vaccines wane within 6 months of vaccination leading to questions on the effectiveness of two-dose vaccination against breakthrough infections. Therefore, we assessed the persistence of immunogenicity up to 6 months after a two or three-dose with BBV152 and the safety of a booster dose in an ongoing phase 2, double-blind, randomized controlled trial (ClinicalTrials.gov: NCT04471519). We report persistence of humoral and cell mediated immunity up to 12 months of vaccination, despite decline in the magnitude of antibody titers. Administration of a third dose of BBV152 increased neutralization titers against both homologous (D614G) and heterologous strains (Alpha, Beta, Delta, Delta Plus and Omicron) with a slight increase in B cell memory responses. Thus, seronversion rate remain high in boosted recipients compared to non-booster, even after 6 months, post third dose against variants. No serious adverse events observed, except pain at the injection site, itching and redness. Hence, these results indicate that a booster dose of BBV152 is safe and necessary to ensure persistent immunity to minimize breakthrough infections of COVID-19, due to newly emerging variants.Trial registration: Registered with the Clinical Trials Registry (India) No. CTRI/2021/04/032942, dated 19/04/2021 and on Clinicaltrials.gov: NCT04471519.

Immunogenicity and reactogenicity of an inactivated SARS-CoV-2 vaccine (BBV152) in children aged 2-18 years: interim data from an open-label, non-randomised, age de-escalation phase 2/3 study.

BACKGROUND: Despite having milder symptoms than adults, children are still susceptible to and can transmit SARS-CoV-2. Vaccination across all age groups is therefore necessary to curtail the pandemic. Among the available COVID-19 vaccine platforms, an inactivated vaccine platform has the advantage of excellent safety profile across all age groups; hence, we conducted an age de-escalation study to assess the safety, reactogenicity, and immunogenicity of an inactivated COVID-19 vaccine, BBV152 (COVAXIN; Bharat Biotech International, Hyderabad, India), in children aged 2-18 years. METHODS: In this phase 2/3 open-label, non-randomised, multicentre study done in six hospitals in India, healthy children (male or female) aged 2-18 years were eligible for inclusion into the study. Children who had positive SARS-CoV-2 nucleic acid and serology tests at baseline, or any history of previous SARS-CoV-2 infection, or with known immunosuppressive condition were excluded. Children were sequentially enrolled into one of three groups (>12 to ≤18 years [group 1], >6 to 12 years [group 2], or ≥2 to 6 years [group 3]) and administered with adult formulation of BBV152 as two 0·5 mL intramuscular doses on days 0 and 28. Co-primary endpoints were solicited adverse events for 7 days post-vaccination and neutralising antibody titres on day 56, 28 days after the second dose. Immunogenicity endpoints were compared with Biodefense and Emerging Infections, Research Resources Repository (BEI) reference serum samples and from adults who received two doses of BBV152 in the same schedule in a previously reported phase 2 study. The trial is registered with the Clinical Trials Registry, India (CTRI/2021/05/033752) and ClinicalTrials.gov (NCT04918797). FINDINGS: From May 27, 2021, to July 10, 2021, we enrolled 526 children sequentially into groups 1 (n=176), 2 (n=175), and 3 (n=175). Vaccination was well tolerated, with no differences in reactogenicity between the three age groups, and no serious adverse events, deaths, or withdrawals due to an adverse event. Local reactions mainly consisted of mild injection site pain in 46 (26%) of 176 participants in group 1, 61 (35%) of 175 in group 2, and 39 (22%) of 175 in group 3 after dose 1; and 39 (22%) of 176 in group 1, 43 of 175 (25%) in group 2, and 14 of 175 (8%) in group 3 after dose 2; there were no cases of severe pain and few reports of other local reactions. After dose 1, the most frequent solicited systemic adverse event was mild-to-moderate fever, reported in eight (5%) of 176 participants in group 1, 17 (10%) of 175 in group 2, and 22 (13%) of 175 in group 3. No case of severe fever was reported, and rates of all fever were all 4% or less after dose 2. Geometric mean titres (GMTs) of microneutralisation antibodies at day 56 in groups 1 (138·8 [95% CI 111·0-173·6]), 2 (137·4 [99·1-167·5]), and 3 (197·6 [176·4-221·4]) were similar to titres in vaccinated adults (160·1 [135·8-188·8]) and with BEI reference serum samples (103·3 [50·3-202·1]). Similar results were obtained using the plaque reduction neutralisation test (PRNT), in which 166 (95%) of 175 participants in group 1, 165 (98%) of 168 in group 2, and 169 (98%) of 172 in group 3 seroconverted at day 56. The GMT ratio of PRNT titres in children and adults was 1·76 (95% CI 1·32-2·33), indicating a superior response in children compared with adults. INTERPRETATION: BBV152 was well tolerated in children aged 2-18 years, and induced higher neutralising antibody responses than those observed in adults, in whom the efficacy (ie, the prevention or decrease in the severity of COVID-19 infection) has been demonstrated. FUNDING: Bharat Biotech International.

A multi-centre, post-marketing surveillance study of Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar TCV®) in India.

A typhoid Vi capsular-polysaccharide tetanus toxoid conjugate vaccine (Typbar-TCV®) was recommended by the World Health Organization for use in children >6 months of age. The present post-marketing surveillance study was intended to assess the clinical safety of approximately 11 million doses of TCV sold till 2019 in a diverse age range Indian population. Both active and passive post-marketing surveillance studies were conducted at multiple centers. Active surveillance was performed in two periods, Period-I: February to October 2016, Period-II: April 2017 to October 2018. In Period-II, the Brighton Collaboration Criteria adverse event case definitions were used. Passive surveillance was performed from February 2016 to December 2019 through voluntary reporting by pediatricians across India. During the active surveillance, 1147 adverse events were reported among 4,991 (23.0%) subjects in Period-I, and 596 adverse events among 3898 (21.3%) subjects in Period-II. The most frequent adverse events were fever (9.2% and 12.02%in Periods I and II, respectively), pain at the injection site (8.3% and 7.33%), and swelling (4.0% and 1.93%). No serious adverse events (SAEs) were reported during either Period. Passive surveillance revealed 235 adverse events, including 25 SAEs requiring hospitalization, of which two were due to typhoid fever. All the events mentioned above occurred within one week of vaccination, and all the subjects have recovered from AEs with medications. All reported adverse events resolved with no clinical sequelae. Observations in this study are consistent with the pre-licensure studies with no additional safety signals detected, confirming that Typbar-TCV® is safe.Abbreviations: AE: Adverse event; LMIC: low- and middle-income countries; PMS: Post-marketing surveillance; SAE: Serious adverse event; TCV: Vi-polysaccharide tetanus -toxoid conjugate vaccine (Typbar-TCV®).

Persisting antibody responses to Vi polysaccharide-tetanus toxoid conjugate (Typbar TCV®) vaccine up to 7 years following primary vaccination of children < 2 years of age with, or without, a booster vaccination.

BACKGROUND: Serum IgG anti-Vi titers attained by 327 children 6-23 months of age immunized with Vi polysaccharide-tetanus toxoid conjugate vaccine (Typbar TCV®), of whom 193/327 received a booster dose 2 years post-primary vaccination, were previously reported. METHODS: Anti-Vi IgG in boosted and unboosted children 3, 5, and 7 years post-primary immunization were monitored using three different enzyme-linked immunosorbent assays (ELISAs): Vacczyme™ kit ELISA (all specimens); "Szu" ELISA (all specimens), and National Institute of Biological Standards NIBSC ELISA (subset). Endpoints analyzed included: persisting seroconversion (titer remaining ≥ 4-fold above baseline), geometric mean titer (GMT), geometric mean-fold rise post-vaccination, and percent exhibiting putative protective anti-Vi level (≥2 µgSzu/ml) using Szu method and National Institutes of Health IgG reference standard. In assessing the persistence of elevated anti-Vi titers stimulated by Typbar-TCV®, four subgroups were compared based on whether or not the initially enrolled children were boosted on day 720 and whether they provided serum on all key timepoints, or if they missed one or more timepoints: i) Among boosted participants, an "All Specimens Cohort" (ASC) comprised 86 children who provided sera on days 42, 720 (booster), 762 (42 days post-booster), 1095, 1825 and 2555, to define kinetics of the Vi antibody response in a fully compliant cohort of boosted children monitored over seven years; ii) Among non-boosted subjects, a compliant All Specimens Cohort of 25 children provided sera on days 0, 42, 720, 1095, 1825, and 2555; iii) Among boosted children, an "Any Available Specimen" (AAS) subgroup consisted of boosted children who provided sera on days 0, 42, and 720 days and also on one or more of days 762, 1095, 1825, or 2555 but not on all those time points; iv) Among the non-boosted subjects, there was also an Any Available Specimen subgroup of 47 children who provided sera on days 0 and 42, of whom 41 subsequently contributed sera on one or more of days 1095, 1825 and 2555. RESULTS: Vacczyme™ GMTs among boosted ASC children (N = 86) increased significantly on day 762, and remained 32-fold, 14-fold, and 10-fold over baseline at 3, 5 and 7 years; among unboosted ASC children (N = 25), GMTs remained 21-fold, 8-fold and 5-fold over baseline, respectively. Post-primary vaccination, 72% and 44% of unboosted ASC subjects (N = 25) exhibited persisting seroconversion by Vacczyme™ at 5 and 7 years, respectively; the corresponding numbers for ASC boosted subjects were 84% and 71%. Amongst the four sub-groups, boosted subjects showed higher prevalence of persisting seroconversion at most time points with the gap widening by 7th year, though not statistically significant (except 3rd year). Tested by Szu and also NIBSC ELISAs, 92-100% of unboosted ASC children showed persisting seroconversion at 7 years with 100% also exceeding the Szu protective threshold. CONCLUSION: To extend protection, administering a booster of Typbar TCV® to children ∼5 years after their primary dose, i.e., coinciding with school entry, may be advisable. Typbar TCV® is presently the only WHO pre-qualified Vi conjugate vaccine with reported efficacy, effectiveness, and long-term immunogenicity findings.

Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: interim results from a double-blind, randomised, multicentre, phase 2 trial, and 3-month follow-up of a double-blind, randomised phase 1 trial.

BACKGROUND: BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine (3 µg or 6 µg) formulated with a toll-like receptor 7/8 agonist molecule (IMDG) adsorbed to alum (Algel). We previously reported findings from a double-blind, multicentre, randomised, controlled phase 1 trial on the safety and immunogenicity of three different formulations of BBV152 (3 µg with Algel-IMDG, 6 µg with Algel-IMDG, or 6 µg with Algel) and one Algel-only control (no antigen), with the first dose administered on day 0 and the second dose on day 14. The 3 µg and 6 µg with Algel-IMDG formulations were selected for this phase 2 study. Herein, we report interim findings of the phase 2 trial on the immunogenicity and safety of BBV152, with the first dose administered on day 0 and the second dose on day 28. METHODS: We did a double-blind, randomised, multicentre, phase 2 clinical trial to evaluate the immunogenicity and safety of BBV152 in healthy adults and adolescents (aged 12-65 years) at nine hospitals in India. Participants with positive SARS-CoV-2 nucleic acid and serology tests were excluded. Participants were randomly assigned (1:1) to receive either 3 µg with Algel-IMDG or 6 µg with Algel-IMDG. Block randomisation was done by use of an interactive web response system. Participants, investigators, study coordinators, study-related personnel, and the sponsor were masked to treatment group allocation. Two intramuscular doses of vaccine were administered on day 0 and day 28. The primary outcome was SARS-CoV-2 wild-type neutralising antibody titres and seroconversion rates (defined as a post-vaccination titre that was at least four-fold higher than the baseline titre) at 4 weeks after the second dose (day 56), measured by use of the plaque-reduction neutralisation test (PRNT50) and the microneutralisation test (MNT50). The primary outcome was assessed in all participants who had received both doses of the vaccine. Cell-mediated responses were a secondary outcome and were assessed by T-helper-1 (Th1)/Th2 profiling at 2 weeks after the second dose (day 42). Safety was assessed in all participants who received at least one dose of the vaccine. In addition, we report immunogenicity results from a follow-up blood draw collected from phase 1 trial participants at 3 months after they received the second dose (day 104). This trial is registered at ClinicalTrials.gov, NCT04471519. FINDINGS: Between Sept 5 and 12, 2020, 921 participants were screened, of whom 380 were enrolled and randomly assigned to the 3 µg with Algel-IMDG group (n=190) or 6 µg with Algel-IMDG group (n=190). Geometric mean titres (GMTs; PRNT50) at day 56 were significantly higher in the 6 µg with Algel-IMDG group (197·0 [95% CI 155·6-249·4]) than the 3 µg with Algel-IMDG group (100·9 [74·1-137·4]; p=0·0041). Seroconversion based on PRNT50 at day 56 was reported in 171 (92·9% [95% CI 88·2-96·2] of 184 participants in the 3 µg with Algel-IMDG group and 174 (98·3% [95·1-99·6]) of 177 participants in the 6 µg with Algel-IMDG group. GMTs (MNT50) at day 56 were 92·5 (95% CI 77·7-110·2) in the 3 µg with Algel-IMDG group and 160·1 (135·8-188·8) in the 6 µg with Algel-IMDG group. Seroconversion based on MNT50 at day 56 was reported in 162 (88·0% [95% CI 82·4-92·3]) of 184 participants in the 3 µg with Algel-IMDG group and 171 (96·6% [92·8-98·8]) of 177 participants in the 6 µg with Algel-IMDG group. The 3 µg with Algel-IMDG and 6 µg with Algel-IMDG formulations elicited T-cell responses that were biased to a Th1 phenotype at day 42. No significant difference in the proportion of participants who had a solicited local or systemic adverse reaction in the 3 µg with Algel-IMDG group (38 [20·0%; 95% CI 14·7-26·5] of 190) and the 6 µg with Algel-IMDG group (40 [21·1%; 15·5-27·5] of 190) was observed on days 0-7 and days 28-35; no serious adverse events were reported in the study. From the phase 1 trial, 3-month post-second-dose GMTs (MNT50) were 39·9 (95% CI 32·0-49·9) in the 3µg with Algel-IMDG group, 69·5 (53·7-89·9) in the 6 µg with Algel-IMDG group, 53·3 (40·1-71·0) in the 6 µg with Algel group, and 20·7 (14·5-29·5) in the Algel alone group. INTERPRETATION: In the phase 1 trial, BBV152 induced high neutralising antibody responses that remained elevated in all participants at 3 months after the second vaccination. In the phase 2 trial, BBV152 showed better reactogenicity and safety outcomes, and enhanced humoral and cell-mediated immune responses compared with the phase 1 trial. The 6 µg with Algel-IMDG formulation has been selected for the phase 3 efficacy trial. FUNDING: Bharat Biotech International. TRANSLATION: For the Hindi translation of the abstract see Supplementary Materials section.

Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial.

BACKGROUND: To mitigate the effects of COVID-19, a vaccine is urgently needed. BBV152 is a whole-virion inactivated SARS-CoV-2 vaccine formulated with a toll-like receptor 7/8 agonist molecule adsorbed to alum (Algel-IMDG) or alum (Algel). METHODS: We did a double-blind, multicentre, randomised, controlled phase 1 trial to assess the safety and immunogenicity of BBV152 at 11 hospitals across India. Healthy adults aged 18-55 years who were deemed healthy by the investigator were eligible. Individuals with positive SARS-CoV-2 nucleic acid and/or serology tests were excluded. Participants were randomly assigned to receive either one of three vaccine formulations (3 µg with Algel-IMDG, 6 µg with Algel-IMDG, or 6 µg with Algel) or an Algel only control vaccine group. Block randomisation was done with a web response platform. Participants and investigators were masked to treatment group allocation. Two intramuscular doses of vaccines were administered on day 0 (the day of randomisation) and day 14. Primary outcomes were solicited local and systemic reactogenicity events at 2 h and 7 days after vaccination and throughout the full study duration, including serious adverse events. Secondary outcome was seroconversion (at least four-fold increase from baseline) based on wild-type virus neutralisation. Cell-mediated responses were evaluated by intracellular staining and ELISpot. The trial is registered at ClinicalTrials.gov (NCT04471519). FINDINGS: Between July 13 and 30, 2020, 827 participants were screened, of whom 375 were enrolled. Among the enrolled participants, 100 each were randomly assigned to the three vaccine groups, and 75 were randomly assigned to the control group (Algel only). After both doses, solicited local and systemic adverse reactions were reported by 17 (17%; 95% CI 10·5-26·1) participants in the 3 µg with Algel-IMDG group, 21 (21%; 13·8-30·5) in the 6 µg with Algel-IMDG group, 14 (14%; 8·1-22·7) in the 6 µg with Algel group, and ten (10%; 6·9-23·6) in the Algel-only group. The most common solicited adverse events were injection site pain (17 [5%] of 375 participants), headache (13 [3%]), fatigue (11 [3%]), fever (nine [2%]), and nausea or vomiting (seven [2%]). All solicited adverse events were mild (43 [69%] of 62) or moderate (19 [31%]) and were more frequent after the first dose. One serious adverse event of viral pneumonitis was reported in the 6 µg with Algel group, unrelated to the vaccine. Seroconversion rates (%) were 87·9, 91·9, and 82·8 in the 3 µg with Algel-IMDG, 6 µg with Algel-IMDG, and 6 µg with Algel groups, respectively. CD4+ and CD8+ T-cell responses were detected in a subset of 16 participants from both Algel-IMDG groups. INTERPRETATION: BBV152 led to tolerable safety outcomes and enhanced immune responses. Both Algel-IMDG formulations were selected for phase 2 immunogenicity trials. Further efficacy trials are warranted. FUNDING: Bharat Biotech International.

Risk factors for stillbirths: how much can a responsive health system prevent?

BACKGROUND: The stillbirth rate is an indicator of quality of care during pregnancy and delivery. Good quality care is supported by a functional heath system. The objective of this study was to explore the risk factors for stillbirths, particularly those related to a health system. METHODS: This case-control study was conducted in two districts of Bihar, India. Information on cases (stillbirths) were obtained from facilities as reported by Health Management Information System; controls were consecutive live births from the same population as cases. Data were collected from 400 cases and 800 controls. The risk factors were compared using a hierarchical approach and expressed as odds ratio, attributable fractions and population attributable fractions. RESULTS: Of all the factors studied, 22 risk factors were independently associated with stillbirths. Health system-related factors were: administration of two or more doses of oxytocics to augment labour before reaching the facilities (OR 1.6; 95% CI 1.2-2.1), any complications during labour (OR 2.3;1.7-3.1), >30 min to reach a facility from home (OR 1.4;1.05-1.8), >10 min to attend to the pregnant woman after reaching the facility (OR 2.8;1.7-4.5). In the final regression model, modifiable health system-related risk factors included: >10 min taken to attend to women after they reach the facilities (AOR 3.6; 95% CI 2.5-5.1), untreated hypertension during pregnancy (AOR 2.9; 95% CI 1.5-5.6) and presence of any complication during labour, warranting treatment (AOR 1.7; 95% CI 1.2-2.4). Among mothers who reported complications during labour, time taken to reach the facility was significantly different between stillbirths and live births (2nd delay; 33.5 min v/s 25 min; p < 0.001). Attributable fraction for any complication during labour was 0.56 (95% CI 0.42-0.67), >30 min to reach the facility 0.48 (95% CI 0.31-0.60) and institution of management 10 min after reaching the facility 0.68 (95% CI 0.58-0.75). Reaching a facility within 30 min, initiation of management within 10 min of reaching the facility and timely management of complications during labour could have prevented 17%, 37% and 20% of stillbirths respectively. CONCLUSION: A pro-active health system with accessible, timely and quality obstetric services can prevent a considerable proportion of stillbirths in low and middle income countries.

An assessment of bicycle intervention to improve service delivery by accredited social health activists in selected blocks of West Champaran district of Bihar.

BACKGROUND: Several programmatic and logistic issues affect the overall performance of Accredited Social Health Activists (ASHAs). Bihar Government provided bicycles to ASHAs in West Champaran district for increasing coverage of services by improving their mobility. OBJECTIVE: To assess the use of bicycles by ASHAs and it's effect on service delivery. It also captures the perspectives of ASHAs in terms of its utilization for performing tasks. METHODS: A community-based quasi-experimental study was undertaken during March-May 2016. Proportion of newborn babies visited within 24 h of birth was the primary outcome. Data were collected from two intervention blocks (West Champaran district) and a control block from the neighboring East Champaran district. A total of 323 (177 from intervention blocks and 146 from control block) mothers having children <3 years of age and who had delivered at home were interviewed. Besides, 88 ASHAs working in intervention blocks were also interviewed. RESULTS: Significantly higher proportion of mothers and newborn babies (44%) received postnatal care within 24 h of delivery in intervention blocks as compared to the control block (16%, P < 0.001). Nearly 73.1% of ASHAs were using the bicycle themselves. ASHAs were twice more likely to visit a newborn on the day of delivery if she was provided with mobility support. However, the likelihood of continuing visits after the 1st day was not statistically significant. CONCLUSION: The intervention demonstrated the potential of ASHAs to improve their functioning at the grass-root level. The scale-up of bicycle intervention should be supplemented with reforms in financial incentives disbursement and better system support.

Assessment of newborn care corners in selected public health facilities in Bihar.

BACKGROUND: A functional newborn care corner (NBCC) is critical to provide immediate care to newborns including resuscitation, warmth, and initial care to sick newborns. NBCC provides an acceptable environment for all infants at birth, and it is mandatory for all delivery points at all levels in the health system including operation theaters. OBJECTIVE: The objective of this study was to find the status of availability of NBCCs and service provision in selected public health facilities of Bihar. METHODS: A total of 57 NBCCs, having high delivery load (>100 deliveries/month), across 25 high-priority districts in Bihar, were selected purposively in consultation with the State Health Society, Bihar, for the assessment. These facilities were assessed for the availability and/or functioning of infrastructure, equipment maintenance, human resource, supply of drugs and consumables, adherence to protocols, and record keeping. RESULTS: Only 22.8% of the NBCCs were found to be fully functional, majority (68.4%) were partially functional, and 9% were nonfunctional. Thirty-seven (64.9%) NBCCs were located inside the labor room premises. Approximately, one-third of the neonates delivered were kept in NBCCs. Equipment though available lacked the provision of annual maintenance contract. Essential drugs such as adrenaline (24.6%) and Vitamin K injection (42.1%) were not available in many facilities. Only 6.2% of the newborns had low birth weight, indicating underreporting. Majority of the health-care staff available were trained but possessed poor skills. Data recording and reporting was also suboptimal. CONCLUSION: The network of NBCCs needs to be strengthened across the state and linked with higher facilities to achieve the desired reduction in neonatal morbidity and mortality.

Rollout of quality assurance interventions in labor room in two districts of Bihar, India.

BACKGROUND: Quality of care at the facilities during childbirth remains a major concern. Improved quality could have the greatest dividend in saving maternal and newborn lives. OBJECTIVE: The objective of this study was to implement quality assurance measures in the labor rooms of select public health facilities in two districts of Bihar. METHODS: The labor room quality assurance intervention was implemented in two districts, Gaya and Purnea in Bihar. Health facilities having >200 deliveries/month were assessed using labor room quality assurance checklist developed by the Ministry of Health and Family Welfare. The critical gaps affecting service delivery were identified, and a list of priority actions for quality improvement was developed. An intervention model was rolled out in consultation with the district authorities focusing on the building blocks of the health system. The interventions were implemented from August 2014 to March 2016 in selected facilities after which an assessment was conducted. RESULTS: Initial assessment of labor room was conducted in 24 facilities. After 2 years of intervention, there was a definite improvement in quality assurance scores in most facilities. The infection control scores increased by 20 points in Gaya (from 40 to 59.9) and 10 points in Purnea (from 57.6 to 67.1). The highest gain in scores was observed in quality management component in Gaya (from 6.2 to 58.2). The model attempted to incorporate all the elements of the health system to ensure scalability and sustainability. CONCLUSION: It is possible to have an implementable quality assurance mechanism within public health system with sustained efforts and commitment.

Impact of Statin Use After Heart Transplantation: A Meta-Analysis.

BACKGROUND: Although various studies revealed the beneficial effects of statins in post-cardiac transplant patients, these were relatively small and low-powered studies. We performed a meta-analysis of published studies to evaluate the role of statins in post-cardiac transplant patients, specifically examining the effects on hemodynamically significant/fatal graft rejection, coronary vasculopathy, terminal cancer, and overall survival. METHODS AND RESULTS: We searched PubMed, Cochran CENTRAL, and Web of Science databases using the search terms "cardiac transplant" or "heart transplant," and "statin" for a literature search. A random-effects model with Mantel-Haenszel method was used to pool the data. We identified 10 studies, 4 randomized controlled trials, and 6 nonrandomized studies, which compared outcomes in heart transplant recipients undergoing statin therapy to statin-naive patients. A pooled analysis of 9 studies reporting mortality revealed that the use of statins was associated with significant reduction in all-cause mortality (odds ratio, 0.26; 95% confidence interval, 0.20-0.35; P<0.0001). Statins also decreased the odds of hemodynamically significant/fatal rejection (odds ratio, 0.37; 95% confidence interval, 0.21-0.65; P=0.0005), incidence of coronary vasculopathy (odds ratio, 0.33; 95% confidence interval, 0.16-0.68; P=0.003), and terminal cancer (odds ratio, 0.30; 95% confidence interval, 0.15-0.63; P=0.002). CONCLUSIONS: The evidence from a pooled analysis suggests that statins improve survival in heart transplant recipients. Statins may prevent fatal rejection episodes, decrease terminal cancer risk, and reduce the incidence of coronary vasculopathy. Additional prospective studies are needed to further investigate and explain this association.

Study on the proportion and determinants of polycystic ovarian syndrome among health sciences students in South India.

INTRODUCTION: Polycystic ovarian syndrome (PCOS) constitutes most cases of endocrine disorder among females. OBJECTIVES: This study was done to assess the proportion of university students with PCOS and to study its risk factors. MATERIALS AND METHODS: Data were collected from students of a private medical, dental, and nursing college using a self-administered questionnaire. Height and weight of all participants were recorded by standard procedures. RESULTS: The mean age of students was 20.4 ΁ 1.5 years. Of the 480 participants, 39 (8.1%) were already diagnosed with PCOS. Out of the remaining 441 participants, 40 (9.1%) were at high risk, and 401 (90.9%) were at low risk for PCOS. Greater proportion of PCOS cases was seen in the age group 23-25 years (P = 0.026), among those with family history of PCOS (P = 0.002), among those who were permanent residents of urban areas (P = 0.048), and among those who were overweight or obese (P = 0.004). About 90% of PCOS cases and those at high risk for PCOS, each had difficulty in controlling excess weight or were experiencing difficulty in maintaining ideal weight. About 36 (92.3%) of PCOS cases and all those at high risk had emotional problems such as feeling moody or experiencing fatigability over the previous 2 weeks. CONCLUSION: PCOS is a common disorder among young women in this settings and this warrants periodic screening activities. A multidisciplinary approach is required to bring about lifestyle modification and help those with emotional problems due to this endocrine disorder.

Induction of adaptive response in human blood lymphocytes exposed to 900 MHz radiofrequency fields: influence of cell cycle.

PURPOSE: To investigate the influence of cell cycle on the adaptive response (AR) induced by the exposure of human blood lymphocytes to radiofrequency fields (RF). MATERIALS AND METHODS: Human peripheral blood lymphocytes in G(0)-, G(1)- or S-phase of the cell cycle were exposed for 20 hours to an adaptive dose (AD) of 900 MHz RF at an average specific absorption rate of 1.25 W/kg and then treated with a challenge dose (CD) of 100 ng/ml mitomycin C (MMC). Un-exposed and sham-exposed controls as well as cells treated with MMC alone were included in the study. The incidence of micronuclei (MN) was evaluated to determine the induction of AR. RESULTS: The results indicated that the cells which were exposed to AD of RF in G(0)- and G(1)-phase of the cell cycle did not exhibit AR while such a response was observed when the cells were exposed to AD of RF in S-phase of the cell cycle. CONCLUSIONS: These results confirmed the observations reported in our previous investigation where AR was observed in human blood lymphocytes exposed to AD of RF in S-phase of the cell cycle and further suggested that the timing of AD exposure of RF is important to elicit AR.

Micronuclei in the blood and bone marrow cells of mice exposed to specific complex time-varying pulsed magnetic fields.

For 8 weeks, adult CD-1 male mice were continuously exposed to complex time-varying pulsed magnetic fields (PMF) generated in the horizontal direction by a set of square Helmholtz coils. The PMF were <1000 Hz and delivered at a peak flux density of 1 mT. Sham-exposed mice were kept in a similar exposure system without a PMF. Positive control animals exposed to 1 Gy gamma radiation were also included in the study. Blood samples were collected before (time 0) and at 2, 4, 6, and 8 weeks. All mice were euthanized at the end of 8 weeks and their bone marrow was collected. From each blood and bone marrow sample, smears were prepared on microscope slides, fixed in absolute methanol, air-dried, and stained with acridine orange. All slides were coded and examined using a fluorescence microscope. The extent of genotoxicity and cytotoxicity was assessed from the incidence of micronuclei (MN) and percent polychromatic erythrocytes (PCE) in the blood and bone marrow, respectively. The data indicated that both indices in PMF-exposed mice were not significantly different from those observed in sham-exposed animals. In contrast, positive control mice exhibited significantly increased MN, and decreased percentages of PCE in both tissues. Thus, the overall data suggested that 8 weeks of continuous exposure to PMF did not induce significantly increased genotoxicity and cytotoxicity in experimental mice. Further investigations are underway using other genotoxicity assays (comet assay, gamma-H2AX foci, and chromosomal aberrations) to assess genotoxicity following PMF exposure.

Induction of adaptive response in human blood lymphocytes exposed to radiofrequency radiation.

The incidence of micronuclei was evaluated to assess the induction of an adaptive response to non-ionizing radiofrequency (RF) radiation in peripheral blood lymphocytes collected from five different human volunteers. After stimulation with phytohemagglutinin for 24 h, the cells were exposed to an adaptive dose of 900 MHz RF radiation used for mobile communications (at a peak specific absorption rate of 10 W/kg) for 20 h and then challenged with a single genotoxic dose of mitomycin C (100 ng/ml) at 48 h. Lymphocytes were collected at 72 h to examine the frequency of micronuclei in cytokinesis-blocked binucleated cells. Cells collected from four donors exhibited the induction of adaptive response (i.e., responders). Lymphocytes that were pre-exposed to 900 MHz RF radiation had a significantly decreased incidence of micronuclei induced by the challenge dose of mitomycin C compared to those that were not pre-exposed to 900 MHz RF radiation. These preliminary results suggested that the adaptive response can be induced in cells exposed to non-ionizing radiation. A similar phenomenon has been reported in cells as well as in animals exposed to ionizing radiation in several earlier studies. However, induction of adaptive response was not observed in the remaining donor (i.e., non-responder). The incidence of micronuclei induced by the challenge dose of mitomycin C was not significantly different between the cells that were pre-exposed and unexposed to 900 MHz RF radiation. Thus the overall data indicated the existence of heterogeneity in the induction of an adaptive response between individuals exposed to RF radiation and showed that the less time-consuming micronucleus assay can be used to determine whether an individual is a responder or non-responder.

Absence of genotoxic potential of 902 MHz (GSM) and 1747 MHz (DCS) wireless communication signals: In vivo two-year bioassay in B6C3F1 mice.

PURPOSE: The aim of the present investigation was to determine the incidence of micronuclei in peripheral blood erythrocytes of B6C3F1 mice that had been chronically exposed to radiofrequencies (RF) used for mobile communication. MATERIALS AND METHODS: 'Ferris wheels' were used to expose tube-restrained male and female mice to simulated environmental RF signals of the Global System for Mobile Communications (GSM, 902 MHz) or Digital Cellular System (DCS, 1747 MHz). RF signals were applied to the mice for 2 hours/day on 5 days/week for two years, at maximal whole-body-averaged specific absorption rates of 0.4, 1.3, and 4.0 W/kg body weight. Concurrent sham-exposed mice, cage controls, and positive controls injected with mitomycin C were included in this investigation. At necropsy, peripheral blood smears were prepared, and coded slides were stained using May-Grunwald-Giemsa or acridine orange. The incidence of micronuclei was recorded for each mouse in 2000 polychromatic and 2000 normochromatic erythrocytes. RESULTS: There were no significant differences in the frequency of micronuclei between RF-exposed, sham-exposed, and cage control mice, irrespective of the staining/counting method used. Micronuclei were, however, significantly increased in polychromatic erythrocytes of the positive control mice. CONCLUSIONS: In conclusion, the data did not indicate RF-induced genotoxicity in mice after two years of exposure.