Investigation of the Differences in the Pharmacokinetics of CYP2D6 Substrates, Desipramine, and Dextromethorphan in Healthy African Subjects Carrying the Allelic Variants CYP2D6*17 and CYP2D6*29, When Compared with Normal Metabolizers.

This study investigated the differences in the pharmacokinetics (PK) of dextromethorphan and desipramine in healthy African volunteers to understand the effect of allelic variants of the human cytochrome P450 2D6 (CYP2D6) enzyme, namely the diplotypes of CYP2D6*1/*2 (*1*1, *1*2, *2*2) and the genotypes of CYP2D6*17*17 and CYP2D6*29*29. Overall, 28 adults were included and split into 3 cohorts after genotype screening: CYP2D6*1/*2 (n = 12), CYP2D6*17*17 (n = 12), and CYP2D6*29*29 (n = 4). Each subject received a single oral dose of dextromethorphan 30 mg syrup on day 1 and desipramine 50 mg tablet on day 8. The PK parameters of area under the plasma concentration-time curve from time of dosing to time of last quantifiable concentration (AUClast ), and extrapolated to infinity (AUCinf ), and the maximum plasma concentration (Cmax ) were determined. For both dextromethorphan and desipramine, AUCinf and Cmax were higher in subjects of the CYP2D6*29*29 and CYP2D6*17*17 cohorts, as compared with subjects in the CYP2D6*1/*2 diplotype cohort and with normal metabolizers from the literature. All PK parameters, including AUCinf , Cmax , and the elimination half-life, followed a similar trend: CYP2D6*17*17 > CYP2D6*29*29 > CYP2D6*1/*2. The plasma and urinary drug/metabolite exposure ratios of both drugs were higher in subjects of the CYP2D6*17*17 and CYP2D6*29*29 cohorts, when compared with subjects in the CYP2D6*1/*2 diplotype cohort. All adverse events were mild, except in 1 subject with CYP2D6*17*17 who had moderately severe headache with desipramine. These results indicate that subjects with CYP2D6*17*17 and CYP2D6*29*29 genotypes were 5-10 times slower metabolizers than those with CYP2D6*1/*2 diplotypes. These findings suggest that dose optimization may be required when administering CYP2D6 substrate drugs in African patients. Larger studies can further validate these findings.

Environmental persistence, bioaccumulation, and hazards of chemicals in e-cigarette e-liquids: short-listing chemicals for risk assessments.

BACKGROUND/METHODS: Increased use and sales of e-cigarettes raises concerns about the potential environmental impacts throughout their life-cycle. However, few available research studies focus on the environmental impacts and ecotoxicity of e-cigarettes. In this study, we short-list e-liquid chemicals from published literature that should be considered in future environmental impact and risk assessments. We used a combination of available laboratory bioassays-based data and predictive methods (eg, Structure-Activity Relationships) to characterise the hazards of the e-liquid chemicals (environmental persistence, bioaccumulation, and aquatic toxicity including hazardous concentration values (concentration affecting specific proportion of species)) for short-listing. RESULTS: Of the 421 unique e-liquid chemicals compiled from literature, 35 are US Environmental Protection Agency's hazardous constituents, 42 are US Food and Drug Administration's harmful or potentially harmful constituents in tobacco products and smoke, and 20 are listed as both. Per hazard characteristics, we short-listed 81 chemicals that should be considered for future environmental impact and risk assessments, including tobacco-specific compounds (eg, nicotine, N'-nitrosonornicotine), polycyclic aromatic hydrocarbons (eg, chrysene), flavours (eg, (-)caryophyllene oxide), metals (eg, lead), phthalates (eg, di(2-ethylhexyl)phthalate) and flame retardants (eg, tris(4-methylphenyl)phosphate). IMPLICATIONS: Our findings documenting various hazardous chemicals in the e-liquids underscore the importance of awareness and education when handling or disposing of e-liquids/e-cigarettes and aim to inform strategies to prevent and reduce hazards from e-cigarettes. This includes any scenario where e-liquids can come into contact with people or the environment during e-liquid storage, manufacturing, use, and disposal practices. Overall, our study characterises the environmental hazards of e-liquid chemicals and provides regulators and researchers a readily available list for future ecological and health risk assessments.

Seeing Beyond the Smoke: Selecting Waterpipe Wastewater Chemicals for Risk Assessments.

Background: Increasing use prevalence of waterpipe tobacco smoking raises concerns about environmental impacts from waterpipe waste disposal. The U.S. Food and Drug Administration (FDA) is required to assess the environmental impact of its tobacco regulatory actions per the National Environmental Policy Act. This study builds on FDA's efforts characterizing the aquatic toxicity of waterpipe wastewater chemicals. Methods: We compiled a comprehensive list of waterpipe wastewater chemical concentrations from literature. We then selected chemicals for risk assessment by estimating persistence, bioaccumulation, and aquatic toxicity characteristics (PBT; U.S. Environmental Protection Agency), and hazardous concentration values (concentration affecting specific proportion of species). Results: Of 38 chemicals in waterpipe wastewater with concentration data, 20 are listed as harmful or potentially harmful constituents (HPHCs) in tobacco smoke and tobacco products by FDA, and 15 are hazardous waste per U. S. Environmental Protection Agency. Among metals, six (cadmium, chromium, lead, mercury, nickel and selenium) are included in both HPHC and hazardous waste lists and were selected for future risk assessments. Among non-metals, nicotine, and 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) were shortlisted, as they are classified as persistent and toxic. Further, N-nitrosonornicotine (NNN), with a low HC50 value for chronic aquatic toxicity, had high aquatic toxicity concern and is selected. Conclusions: The presence of multiple hazardous compounds in waterpipe wastewater highlights the importance of awareness on the proper disposal of waterpipe wastewater in residential and retail settings. Future studies can build on the hazard characterization provided in this study through fate and transport modeling, exposure characterization and risk assessments of waterpipe wastewater chemicals.

Challenges and gender-based differences for women in the Indian urological workforce: Results of a survey.

Introduction: Entry of women into urology has not kept pace with that in other surgical branches with only 1% of Urological Society of India (USI) members being female. The objective of this study was to explore the personal and professional challenges, practice barriers, and level of satisfaction among female urologists/urology trainees in India. Methods: A strictly confidential and anonymous 26-item questionnaire with respect to professional and personal challenges, workplace discrimination, and family satisfaction was circulated as a Google form through email and WhatsApp to all the female members of the USI (full and associate) and trainees (n = 48) based on identification from the USI directory. Results: Thirty-three out of 48 female urologists responded (68%). Among the respondents (n = 33), majority had <5 years of experience (60.6%), of which 30.3% were residents, which reflected a recent surge in women joining urology. Majority (57.7%) chose to subspecialize, commonly in "female urology". Many (72.7%) were encouraged to take this subspecialty. Gender discrimination at workplace was reported by 54.5%, commonly by patients and consultants. 68% of respondents had conceived either before or during residency, leading to additional domestic responsibilities. 9.1% suffered a pregnancy-related complication, which they believed was a direct consequence of their work environment. These obstacles led to 30.3% of women reporting that their personal life had compromised their careers. Professional dissatisfaction was reported by 60.1% of women, with common causes being less operative time than male counterparts and lack of mentorship. Despite these challenges given a chance, 78.7% would choose urology again, and 66.7% would encourage their daughter to pursue a career in urology. Conclusion: Professional and personal challenges as perceived by women responding to our survey include gender discrimination in training and work, lack of mentorship, pregnancy-related compilations, and compromised career due to family responsibilities. Despite these, most would choose this specialty again.

Radio antipodal number of honeycomb derived networks.

The communication in a wireless network mainly depends on the frequencies or channels assigned to them. The channels must be assigned to all the transmitters in the network without interference for effective communication. This problem is said to be a channel (frequency) assignment problem (CAP). With the limited availability of channels, CAP has become a challenging problem. This problem is modeled as a graph, where each transmitter is represented by a vertex, and two vertices are adjacent when their corresponding transmitters are close. The labelling technique in graph theory has played an important role in solving CAP, thereby the time and cost will be saved. In radio antipodal labeling, the channels were reused again for the antipodal vertices. It will reduce the usage of the number of channels, with minimum interference. Hence it is a better labeling compared to other labelings. It is a mapping [Formula: see text] from the vertex set of a graph T to the set of natural numbers such that the condition [Formula: see text], is satisfied. The span of the antipodal labeling [Formula: see text] is the maximum label allotted in a graph and is given by [Formula: see text]. The lowest value of all the spans of the antipodal labeling of graph T is said to be radio antipodal number. It is denoted by an(T). The value of the minimum span gives the bandwidth or spectrum of the channels. The honeycomb network plays an important role in communication engineering because of its structure. In this paper, the bounds of the antipodal number of honeycomb derived networks-triangular and rhombic honeycomb were obtained and represented graphically. These bounds give the optimum number of channels (bandwidth) needed for these honeycomb derived networks for effective communication without interference.

Comparison of Zirconia to Dentin Bonding Using Resin-Based Luting Cements and Resin-Modified Glass-Ionomer Cement: In vitro.

Introduction: The aim of this study was to compare the shear bond strengths of zirconia to dentin using two resin-based luting cements and a resin-modified glass-ionomer cement (RMGIC). Materials and Methods: Thirty six zirconia blocks of 2 mm × 3 mm × 5 mm were milled and luted to the exposed dentin surfaces and grouped into three according to the cement used for luting: Group I - luted with Panavia F2.0, Group II - luted with RelyX U200, and Group III - luted with FujiCEM. After thermocycling, specimens were subjected to shear bond testing in an Universal Testing Machine (UTM). Data analysis using Kruskal-Wallis ANOVA and post hoc Mann-Whitney U-test with P < 0.05 was done. Results: Mean bond strengths were of the order Panavia F2.0 (5.99 MPa)>RelyX U200 (4.79MPa)>FujiCEM (1.59 MPa). Maximum failures were at the zirconia-cement interface and were adhesive in nature. Conclusions: It can be concluded with the study that there is a better bonding of zirconia to dentin with resin-based luting cements than a RMGIC. The single-step resin-luting cement RelyX U200 produced comparable bond strength to that of a multistep Panavia F2.0.

The Co-occurrence of Specialty Vape Shops, Social Disadvantage, and Poor Air Quality in the United States: An Assessment of Cumulative Risks to Youth.

Introduction: We conducted a cumulative environmental health risk assessment of whether specialty vape shops and poor air quality are more likely to co-occur in socially disadvantaged neighborhoods where racial/ethnic minority youth live. Methods: We examined the population-adjusted incidence of specialty vape shops in relation to youth race/ethnicity, neighborhood socioeconomic status (SES), and air quality (nitrogen dioxide [NO2]) at the census tract level across the conterminous United States for 2018. Results: We did not find disparity in vape shop incidence related to minority youth race/ethnicity. Vape shop incidence was significantly negatively associated with all the youth race/ethnicities examined. The two lowest SES quintiles had nearly double the rate of specialty vape shop incidence compared with the highest SES quintile. Specialty vape shop incidence increased with NO2 concentration, with more vape shops in poor air quality neighborhoods. Conclusions: Specialty vape shops are disproportionately present in neighborhoods with poor air quality and where socially disadvantaged youth live. The increased incidence of vape shops in poor air quality neighborhoods, particularly in an urban context with increased traffic emissions, further points to potentially disproportionate impacts on disadvantaged populations due to cumulative social and environmental risks. This raises environmental justice and health equity concerns. Retailer-focused strategies aimed at limiting youth exposure to electronic cigarettes' labeling and advertising, preventing sales to minors, and limiting the number of retailers in low-SES neighborhoods may reduce initiation and help prevent tobacco-related health disparities among youth.

Aquatic toxicity of waterpipe wastewater chemicals.

INTRODUCTION: The recent increase in U.S. popularity and use prevalence of water pipe (WP) tobacco smoking raises concerns about the potential environmental impacts of WP waste disposal and the need for strategies to reduce such impacts. The U.S. Food and Drug Administration (FDA) is required to assess the environmental impacts of its tobacco regulatory actions per the U.S. National Environmental Policy Act (NEPA). The purpose of this study was to identify and quantify specific chemical constituents in WP wastewater and to determine their potential aquatic toxicity. METHODS: Using a modified Beirut smoking regimen, five different WP charcoal brands (n = 70) and ten WP tobacco brands (n = 35) were smoked separately using a WP smoking machine in which smoke was passed through the WP base water. We analyzed and quantified specific chemical constituents in the WP bowl wastewater through standardized U.S. Environmental Protection Agency's (EPA) Hazardous Waste Test Methods. We then characterized the ecological hazard for acute and chronic aquatic toxicity posed by the specific chemicals through compilations of Globally Harmonized System of Classification and Labelling of Chemicals (GHS) and hazardous concentration values (concentration affecting 50% of the species). RESULTS: Among the list of 31 specific chemicals analyzed, we detected 22 and 11 chemicals in wastewater from WP tobacco and WP charcoal smoking, respectively. Nearly half of the 22 WP wastewater chemicals were classified as "very toxic" or "toxic" for acute and chronic aquatic toxicity per GHS classification. The most hazardous compounds with acute and chronic toxicity in aquatic organisms include acrolein, acrylonitrile, and metals (cadmium, lead, chromium, nickel, cobalt) found in both WP tobacco and charcoal wastewater, and N-nitrosonornicotine, nicotine, crotonaldehyde and selenium were additionally found in WP tobacco wastewater. All the identified chemicals are considered harmful or potentially harmful constituents in tobacco products and tobacco smoke per FDA's list, and seventeen of them represent hazardous waste per EPA's list. CONCLUSION: Our study expands the identification and quantifies several WP wastewater chemical constituents. It characterizes the ecological hazard of these chemicals and identifies chemicals of concern, aiding our evaluation of the environmental impacts of WP waste products. Our results add to the existing evidence that WP wastewater is a source of toxins that could affect water quality and aquatic organisms, and bioaccumulate in the environment if disposed of into public sewers, on the ground, or in an onsite septic system. These findings highlight the importance of concerted efforts to raise awareness of appropriate WP waste disposal practices in both retail and residential settings, and applicable regulatory compliance requirements for WP retailer establishments, thereby limiting hazards from WP wastewater.

Is preoperative neutrophil-to-lymphocyte ratio a red flag which can predict high-risk pathological characteristics in renal cell carcinoma?

INTRODUCTION: Renal cell carcinoma (RCC) is known to invoke both immunological and inflammatory responses. While the neutrophils mediate the tumor-induced inflammatory response, the lymphocytes bring about the various immunological events associated with it. The neutrophil-to-lymphocyte ratio (NLR) is a simple indicator of this dual response. We investigated the association between preoperative NLR and histopathological prognostic variables of RCC intending to find out whether it can be of value as a red flag capable of alerting the clinician as to the biological character of the tumor under consideration. METHODS: Preoperative NLR and clinicopathological variables, namely histological subtype, nuclear grade, staging, lymphovascular invasion, capsular invasion, tumor necrosis, renal sinus invasion, and sarcomatoid differentiation of 60 patients who underwent radical or partial nephrectomy, were analyzed to detect the association between the two. RESULTS: We found that mean preoperative NLR was significantly higher in clear-cell carcinomas (3.25 ± 0.29) when compared with nonclear-cell carcinomas (2.25 ± 0.63). There was a linear trend of NLR rise as the stage of the disease advanced. A significant rise in preoperative NLR was noted in tumors with various high-risk histopathological features such as tumor size, capsular invasion, tumor necrosis, and sarcomatoid differentiation. CONCLUSION: Preoperative measurement of NLR is a simple test which may provide an early clue of high-risk pathological features of renal cell cancer.

No Butts on the Beach: Aquatic Toxicity of Cigarette Butt Leachate Chemicals.

OBJECTIVES: Toxic pollutants leaching from littered cigarette butts (CB) raise environmental impact concerns. The US Food and Drug Administration (FDA) is required to assess the environmental impacts of its tobacco regulatory actions per the US National Environmental Policy Act (NEPA). METHODS: We determined the chemical constituents in CB leachate through analyses of 109 field-collected CB and literature compilation and characterized their ecotoxicity to aquatic organisms. RESULTS: One-third of the 98 identified CB leachate chemicals were very toxic and 10% were toxic to aquatic organisms due to acute and chronic toxicity. Polycyclic aromatic hydrocarbons, metals, phthalates, nicotine and volatile organic compounds were the most hazardous CB leachate chemicals for aquatic organisms. Of the 98 CB leachate chemicals, 25 are included in FDA's list of harmful or potentially harmful constituents in tobacco products and tobacco smoke. CONCLUSIONS: Our study quantifies CB leachate constituents, characterizes their ecological hazard and identifies chemicals of concern. Thus, it aids in evaluating the environmental impacts of tobacco products per NEPA requirements. These results provide important information for strategies to prevent and reduce CB litter (eg, awareness programs, litter laws enforcement), thereby reducing environmental hazards from CB toxicants.

Clinical and therapeutic implications of sex steroid hormone receptor status in urothelial bladder cancer.

Studies on the clinical profile of urothelial bladder cancer (UBC) have shown significant gender differences, namely, higher occurrence in males (male-to-female ratio of 3.5:1) and an advanced stage of disease at the time of diagnosis with rapid progression of the disease after initial diagnosis seen more commonly in females. The relationship between gender and UBC is complex and probably influenced by biological and epidemiological factors. Potential contributory factors such as sex steroid hormone pathway, gender difference in environmental carcinogen exposure, metabolic enzyme activity, and disparities in the intensity of diagnostic evaluation could probably explain the demographic trends in UBC. This comprehensive review of Medline publications during the period 2009-2019 attempts to identify the possible role of sex hormone receptors in gender variation and sexual dimorphism in the occurrence and progression of UBC. The clinical implications of identifying sex steroid receptors on factors such as disease prognostication and the therapeutic role of anti-androgens in the prevention and progression of UBC are critically reviewed. There is now significant evidence in literature to suggest the possible role of sex steroid hormone receptor-mediated signals in the genesis and progression of UBC. These receptors include androgen receptors, estrogen receptors, progesterone receptors, and various other orphan receptors. Excessive or reduced expression of these receptors, as well as alterations in their upstream or downstream pathways, correlate well with the clinical and therapeutic outcomes of UBC.

Renal salvage, an achievable goal in patients with emphysematous pyelonephritis: Outcomes of an algorithmic renal preserving strategy.

INTRODUCTION: Emergency nephrectomy has been the time-honored treatment of choice for emphysematous pyelonephritis (EPN), a fatal gas-forming necrotizing infection. Recent years have seen a shift toward nonextirpative approach aimed to achieve higher rates of renal salvage, limiting the indications for nephrectomy to severe grades of the disease. This study aimed at analyzing the role of initial renal preserving measures algorithmically applied across grades of EPN. MATERIALS AND METHODS: We prospectively analyzed the clinical data and outcome of 36 consecutive patients of EPN in 5 years' study period, treated by renal preserving measures, which include aggressive resuscitation, parenteral antibiotics, effective drainage of infected fluid/gas, and relieving the urinary tract obstruction. Huang-Tseng computed tomography-based classification system was used to categorize the patients as well as to employ suitable treatment modality. RESULTS: The mean age of the patients was 57.5 ± 12 years with female preponderance (2:1). Diabetes mellitus (97%) was the most common associated factor. Escherichia coli was (72%) the most frequent causative organism found. Urinary tract obstruction was seen in 27 patients (75%) attributable to ureteric calculi, renal papillary necrosis, ureteric stricture, and fungal bezoar in the descending order of frequency. Only 2 (6%) out of 36 patients managed according to our hospital renal salvage protocol required salvage nephrectomy. The overall survival rate was 94%. CONCLUSION: Our hospital-based algorithmic renal preserving strategy not only improved the survival but also decreased the need for nephrectomy.

Can new, improvised Visual Prostate Symptom Score replace the International Prostate Symptom Score? Indian perspective.

INTRODUCTION: Visual Prostate Symptom Score (VPSS) was introduced to overcome the drawbacks of the International Prostate Symptom Score (IPSS). However, this score also has potential for improvement. MATERIALS AND METHODS: The primary objective of this study was to evaluate the utility of VPSS in patients with benign enlarged prostate (BEP) after uroflowmetric validation of the stream component. The secondary objective was to improve VPSS by adding a new severity grading and to assess if the "new upgraded VPSS" can replace IPSS in terms of ease of completion without assistance and the time taken. RESULTS: Of 115 patients, 42.60% of them were of the age group between 61-70 years; mean ± standard deviation age was 64.75 years ± 8.042 (range 48-90 years). Nineteen (16.52%) patients, who had education level ≥10th grade completed IPSS without assistance. One hundred and eight (93.91%) patients completed VPSS without assistance (P = 0.000). None of those (0/6) with no formal education (but able to read and write) could complete the IPSS without assistance, whereas 66.67% completed the VPSS without assistance. Six minutes and two minutes was the average time taken to complete IPSS (4-10 min) and VPSS (1-3 min), respectively. Responses to different variables of VPSS were statistically significant (P < 0.001) compared to the IPSS. Correlation between the severity grading of the two scores was statistically significant (P < 0.001), with a statistically significant positive correlation between VPSS and IPSS (r = +0.582, P < 0.001). The new severity grading system developed on par with the IPSS, improvising the existing VPSS, showed statistically significant positive correlation to the IPSS (r = +0.587, P < 0.001). CONCLUSIONS: VPSS correlated well with IPSS. The "new improvised VPSS" developed by incorporating severity grading is a potential tool that can replace IPSS by overcoming its limitations.

Influence of Landscape Factors and Abiotic Conditions on Dispersal Behavior and Overwintering Site Selection by Halyomorpha halys (Hemiptera: Pentatomidae).

Since the initial detection of the invasive Halyomorpha halys (Stål) in the United States in the late 1990s, this insect has emerged as a severe agricultural and nuisance pest. Nuisance problems are due to adult dispersal to overwintering sites in the fall at which time they alight onto and eventually settle within human-made structures in addition to natural harborage. This study examined how three factors, elevation, light, and moisture affected overwintering site selection by H. halys in the mid-Atlantic. Observational counts performed along elevational transects revealed elevation was significant predictor of H. halys abundance during both years of the study in 2014 and 2015 with more adults observed at higher elevations. Choice tests examining effects of moisture and light on settling behavior demonstrated H. halys settled within overwintering shelter boxes in significantly greater numbers when shelters were dry compared with those having moist conditions, and in darkened shelters compared with those augmented with LED lights. Our findings indicate that H. halys use cues at both landscape and very localized levels when seeking and selecting overwintering sites.

Socioeconomic Disparities in Vape Shop Density and Proximity to Public Schools in the Conterminous United States, 2018.

We conducted an environmental justice assessment examining the distribution of specialty vape shops in relation to where minority and low-income youth live and attend school. We collated and examined the density of vape shops in public school districts in 2018 throughout the conterminous United States using geographic information systems. We calculated the proximity of vape shops to public middle and high schools through nearest neighbor analysis in QGIS software. We examined the statistical relationships between the density of vape shops in school districts, and proximity to schools, with the proportion of racial/ethnic minorities and those living in poverty. We found that vape shops are more densely distributed, and are in closer proximity to schools, in school districts with higher proportions of Asian and Black or African American populations. However, vape shops were further away from schools in school districts with higher proportions of the population in poverty. The proximity and higher density of vape shops in relationship to schools in Asian and Black or African American communities may result in disproportionate health impacts due to greater access and exposure to vape products and advertisements. Our results may help school district administrators prioritize and target efforts to curb youth vaping (e.g., health education curricula) in these school districts with high density and closer proximity of vape shops to schools. Policy efforts, such as local ordinances restricting the promotion and sale of vaping products close to schools, could help prevent disproportionate human and environmental health impacts to minorities.

The resurgence of estrogens in the treatment of castration-resistant prostate cancer.

Use of exogenous estrogens in manipulating the androgenestrogen equilibrium was one of the earliest therapeutic strategies developed to treat prostate cancer which followed close on heels the discovery of hormone dependence of this tumor. Despite its well-documented benefit, estrogen therapy fell out of favor with the advent of other forms of androgen deprivation therapy (ADT) as the former registered a higher incidence of cardiovascular complications and poorer overall survival. Clearer understanding of the mechanism of action of estrogen coupled with the adoption of alternative routes of administration has triggered a renewed interest in estrogen therapy. Since then, many studies have not only proved the therapeutic benefit of estrogens but also explored the ways and means of minimizing the dreaded side effects deterring its use. Further, the fact that estrogen therapy offered a clear advantage of reduced cost of treatment over other treatments has led many countries to readopt it in the treatment of advanced prostatic cancer. We reviewed the published data on the use of estrogens in CRPC, which may affect its revival as an efficacious treatment option having minimal side effects, with modified dosage and route of administration. Estrogen therapy would be a less expensive option having equivalent or even better therapeutic effect than ADT in advanced carcinoma of prostate.

A Phase III open-label, randomized, active controlled clinical study to assess safety, immunogenicity and lot-to-lot consistency of a bovine-human reassortant pentavalent rotavirus vaccine in Indian infants.

BACKGROUND: A heat-stable bovine-human rotavirus reassortant pentavalent vaccine (BRV-PV, ROTASIIL®) was developed in India. In this study, the vaccine was tested for safety, immunogenicity and clinical lot-to-lot consistency. METHODS: This was a Phase III, open label, randomized, equivalence design study. The primary objective was to demonstrate lot-to-lot consistency of BRV-PV. Subjects were randomized into four arms, three arms received Lots A, B, and C of BRV-PV and the control arm, received Rotarix®. Three doses of BRV-PV or two doses of Rotarix® and one dose of placebo were given at 6, 10, and 14 weeks of age. Blood samples were collected four weeks after the third dose to assess rotavirus IgA antibody levels. The three lots of BRV-PV were equivalent if the 95% Confidence Intervals (CIs) of the geometric mean concentration (GMC) ratios were between 0.5 and 2. Solicited reactions were collected by using diary cards. RESULTS: The study was conducted in 1500 randomized infants, of which 1341 infants completed the study. The IgA GMC ratios among the three lots were around 1 (Lot A versus Lot B: 1.07; Lot A versus Lot C: 1.06; and Lot B versus Lot C: 0.99). The 95% CIs for the GMC ratios were between 0.78 and 1.36. The IgA GMCs were: BRV-PV group 19.16 (95% CI 17.37-21.14) and Rotarix® group 10.92 (95% CI 9.36-12.74) (GMC ratio 1.75; 90% CI 1.51-2.04). Seropositivity rates were 46.98% (95% CI 43.86-50.11) and 31.12% (95% CI 26.17-36.41). The incidence of solicited reactions was comparable across the four arms. No serious adverse events were associated with the study vaccines, except two gastroenteritis events in the BRV-PV groups. CONCLUSION: Lot-to-lot consistency of BRV-PV was demonstrated in terms of GMC ratios of IgA antibodies. The vaccine safety and immunogenicity profiles were similar to those of Rotarix®. Clinical Trials.Gov [NCT02584816] and Clinical Trial Registry of India [CTRI/2015/07/006034].

Non-interference of Bovine-Human reassortant pentavalent rotavirus vaccine ROTASIIL® with the immunogenicity of infant vaccines in comparison with a licensed rotavirus vaccine.

BACKGROUND: A newly developed bovine-human reassortant pentavalent vaccine (BRV-PV, ROTASIIL®) was tested for its potential effect on the immunogenicity of concomitantly administered EPI vaccines in infants in a randomized controlled study in India. METHODS: In this Phase III, multicenter, open label, randomized, controlled study, three doses of BRV-PV or two doses of Rotarix® and one dose of placebo were given to healthy infants at 6, 10, and 14 weeks of age. Subjects also received three doses of DTwP-HepB-Hib (diphtheria, tetanus, whole-cell pertussis, hepatitis B, and haemophilus influenzae type b conjugate - pentavalent vaccine) and oral polio vaccine concomitantly at 6, 10, and 14 weeks of age and a single dose of inactivated polio vaccine at 14 weeks of age. Blood samples were collected four weeks after the final vaccination to assess immune responses to all the vaccines administered. For diphtheria, tetanus, hepatitis B, Hib, polio type 1, and polio type 3 antibodies, non-interference was to be supported if the lower limit of the two-sided 90% confidence interval (CI) for the seroprotection rate difference for the BRV-PV group minus the Rotarix® group was >10.0%. For pertussis antibodies, non-interference was to be supported if the lower limit of the two-sided 90% CI for the ratio of geometric mean concentrations (GMCs) was >0.5. RESULTS: A total of 1500 infants were randomized to either BRV-PV (1125 infants) or Rotarix® (375 infants), of which 1341 completed the study as per the protocol. More than 97% of subjects achieved seroprotective antibody titres against diphtheria, tetanus, hepatitis B, Hib, polio type 1, and polio type 3 in both groups. The difference in seroprotection rates between the BRV-PV group and the Rotarix® group for all these antibodies was less than 1%. The ratio of GMCs of anti-pertussis IgG concentrations for the BRV-PV group versus Rotarix® was 1.04 [90% CI: 0.90; 1.19]. CONCLUSION: BRV-PV does not interfere with the immunogenicity of concomitantly administered routine infants vaccines.