Survival outcomes and failure patterns for oropharyngeal cancers treated with simultaneous integrated boost in intensity modulated radiotherapy (SIB-IMRT) and concurrent chemotherapy.

BACKGROUND: Intensity modulated radiotherapy (IMRT) has become a standard radiotherapy treatment delivery option owing to the advantages it offers in terms of target coverage and organ sparing. Furthermore, the ability to introduce different fractionation for different targets lets us deliver higher doses to the high-risk areas and lower doses to the elective volumes at the same sitting, referred to as simultaneous integrated boost (SIB). In the current study, we intended to retrospectively analyze the clinical outcomes and patterns of the failure of oropharyngeal cancers treated with SIB-IMRT and concurrent chemotherapy at our centre and analyze the factors contributing to poorer outcomes. MATERIAL AND METHODS: Data of oropharyngeal cancer patients treated with SIB-IMRT and concurrent chemotherapy were retrieved from the institutional database. Patient demographic details, histopathological features, staging, treatment details, failure patterns and outcomes were documented. All potential factors were evaluated for outcomes. Radiation was delivered by using the SIB-IMRT technique. High-risk planning target volume (PTV) received 66 Gy in 2.2 Gy/fraction, intermediate and low-risk PTV received 60 Gy and 54 Gy, respectively. Primary endpoint was to assess local control (LC), regional control (RC) and loco-regional control (LRC) rates and secondary end point was to evaluate the survival outcomes - overall survival (OS) and cancer-specific mortality. All survival analyzes were performed using the Kaplan-Meier method. RESULTS: A total of 169 cases were included in the final analysis. The median age was 55 years (range 20-78) with 95.3% males. The base of tongue was the most common primary site. Around 54% cases were node negative with 38% patients having stage IV disease. The local control rates for N0 vs. N+ cases were 74.1 vs. 62.3% (P = 0.046), respectively. Similarly, the 4-year RC rates for N0 vs. N+ cases were 94.4 vs. 83.5% (P = 0.024), respectively. On multivariate analysis, only 4-year RC rates showed significant difference between the two (P = 0.039). No differences were found between T stages in LRC and OS. The 4-year LRC rates for stages 1, 2 vs. 3, 4 were non-significant (69.2 vs. 66.3%; P = 0.178). The 4-year OS rate was 81.3%. The 4-year LC and LRC rates were 67.8 and 89.5%, respectively. There were 54 local and 17 regional failures. The median time to failure was 13 months (range 3.6-82.9). CONCLUSION: SIB-IMRT provides comparable outcomes for oropharyngeal cancers. OS and loco-regional recurrences were significantly worse for nodal positive disease.

A systematic analysis of read-across within REACH registration dossiers.

Read-across is a well-established data-gap filling technique used within analogue or category approaches. Acceptance remains an issue, mainly due to the difficulties of addressing residual uncertainties associated with a read-across prediction and because assessments are expert-driven. Frameworks to develop, assess and document read-across may help reduce variability in read-across results. Data-driven read-across approaches such as Generalised Read-Across (GenRA) include quantification of uncertainties and performance. GenRA also affords opportunities on how New Approach Method (NAM) data can be systematically incorporated to support the read-across hypothesis. Herein, a systematic investigation of differences in expert-driven read-across with data-driven approaches was pursued in terms of establishing scientific confidence in the use of read-across. A dataset of expert-driven read-across assessments that made use of registration data as disseminated in the public International Uniform Chemical Information Database (IUCLID) (version 6) of Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Study Results were compiled. A dataset of ~5000 read-across cases pertaining to repeated dose and developmental toxicity was extracted and mapped to content within EPA's Distributed Structure Searchable Toxicity database (DSSTox) to retrieve chemical name and structural identification information. Content could be mapped to ~3600 cases which when filtered for unique cases with curated quantitative structure-activity relationship-ready SMILES resulted in 389 target-source analogue pairs. The similarity between target and the source analogues on the basis of different contexts - from structural similarity using chemical fingerprints to metabolic similarity using predicted metabolic information was evaluated. An attempt was also made to quantify the relative contribution each similarity context played relative to the target-source analogue pairs by deriving a model which predicted known analogue pairs. Finally, point of departure values (PODs) were predicted using the GenRA approach underpinned by data extracted from the EPA's Toxicity Values Database (ToxValDB). The GenRA predicted PODs were compared with those reported within the REACH dossiers themselves. This study offers generalisable insights on how read-across is already applied for regulatory submissions and expectations on the levels of similarity necessary to make decisions.

SMaRT-PCR: sampling using masks and RT-PCR, a non-invasive diagnostic tool for paediatric pulmonary TB.

Key challenges in paediatric TB diagnosis are invasive sampling and poor sensitivity of standard methods. This study demonstrates the diagnostic potential of non-invasive sampling of bioaerosols from children using SMaRT-PCR, comprising mask sampling combined with reverse transcriptase-polymerase chain reaction (RT-PCR) for TB.Exhaled bioaerosols were captured on modified N-95 masks in a 10-min talk-cough-breathe process from 51 children (30 with TB confirmed using standard sampling methods and 21 without TB) aged 2-15 years. All mask samples were tested using in-house RT-PCR for 16s and rpoB RNA transcripts. Additional mask samples from children with TB were tested using Xpert® MTB/RIF (n = 3) and Xpert® MTB/RIF Ultra (n = 27).SMaRT-PCR sensitivity for detecting TB among treatment-naïve children was 96% if 16s or rpoB was present, and 75% if both genes were present, comparable to standard methods (71%) in the same cohort. Specificity was better for both genes, at 95%, than 85% for a single gene detection. Mask sampling with Xpert MTB/RIF or Ultra had a sensitivity of only 13%.This is the first study to provide evidence for testing bioaerosols as a promising alternative for detecting paediatric TB. Sampling is non-invasive and simple, with the potential for point-of-care applications. This pilot study also suggests that RNA transcript-based detection may improve TB diagnostic sensitivity in children; however, further investigation is required to establish its adaptability in clinical settings..

Association between Smartphone Addiction and Breathing Pattern in Sedentary Young College-Going Students - A Cross-Sectional Study.

BACKGROUND: The number of smartphone users has progressively increased worldwide. Altered biomechanics of the cervicothoracic spine and ribcage could limit the chest wall function that affects the respiratory muscles strength, reducing diaphragm function in smartphone users. This study aimed to compare breathing patterns between smartphone-addicted and -nonaddicted user groups. OBJECTIVE: To find the association between excessive smartphone use and breathing pattern in sedentary young college-going students. MATERIALS AND METHODS: This cross-sectional study includes 230 participants. The participants were screened for the inclusion and exclusion criteria and were asked to fill out a Smartphone Addiction Scale questionnaire. These breathing patterns were then assessed by self-evaluation of breathing questionnaire (SEBQ), manual assessment of respiratory motion (MARM), breath-holding test, and capnography. RESULTS: The correlation of smartphone-addicted and -nonaddicted groups with breathing patterns was performed by Spearman rank correlation. Results show no significant association between the smartphone-nonaddicted and -addicted users. CONCLUSION: This study concluded that excessive smartphone use and breathing patterns are not associated.

Assessment of attitude and hesitancy toward vaccine against COVID-19 in a Pakistani population: A mix methods survey.

Objective: The objective of this study was to assess the attitude and hesitancy toward vaccine against COVID-19 in a Pakistani Population. Materials and methods: A mix-method, prospective study was conducted and adults (aged ≥18 years) residing in Pakistan were invited to participate. The questionnaire was prepared, hosted in Google Forms and circulated through electronic platforms and was also available to be done in in-person. Data was compiled from 15th September to 30th November 2020. Results: The response rate was 80%. A total of 1003 participants were included in the final analysis. Of them, 75% completed survey questionnaire online, while remaining 25% responded in-person. The mean age of the participants was 29.62 ± 10.47 years. The majority of participants were females; 60.9% (n = 611). 57.02% (n = 572) of the participants were employed at the time of survey. Overall, 70.68% (n = 709) of the participants had previous experience of vaccines such as the flu vaccine Only 4.9% (n = 49) participants thought that they will be seriously ill from COVID-19 within six months and 39% (n = 392) participants were confident that they will get COVID-19. A total of 71.29% of the participants reported they would consider getting vaccinated once available. There was statistical association between gender and getting vaccinated (P < 0.001). Conclusion: This study demonstrated that majority of the participants showed positive attitude toward considering COVID-19 vaccine. However awareness with informed knowledge of efficacy, possible adverse effects and cost would be of added great value to increase the real response of Pakistani population toward COVID-19 vaccination.

Objetivo: El objetivo de este estudio fue evaluar la actitud y la renuencia hacia la vacuna frente a la COVID-19 en una población paquistaní. Materiales y métodos: Se realizó un estudio prospectivo de método mixto, invitándose a participar a personas adultas (edad ≥18 años) residentes en Paquistán. Se preparó el cuestionario, que se alojó en Google Forms y se hizo circular a través de plataformas electrónicas, pudiendo realizarse también de manera personal. Los datos se recopilaron desde el 15 de septiembre al 30 de noviembre de 2020. Resultados: La tasa de respuesta fue del 80%. El análisis final incluyó un total de 1.003 participantes, de los cuales el 75% completó el cuestionario-encuesta online, mientras que el 25% respondió en persona. La edad media de los participantes fue de 29,62 ± 10,47 años. La mayoría de los participantes eran mujeres: el 60,9% (n = 611). El 57,02% (n = 572) de los participantes tenía empleo en el momento de la encuesta. En general, el 70,68% (n = 709) de los participantes tenía experiencia previa sobre vacunas tales como la vacuna frente a la gripe. Solo el 4,9% (n = 49) de los participantes pensaba que padecerían la COVID-19 de forma grave en el plazo de seis meses, y el 39% (n = 392) de los participantes estaba seguro de que se contagiaría de dicha enfermedad. El 71,29% de los participantes reportó que consideraría recibir la vacuna una vez que se dispusiera de la misma. Existió una asociación estadística entre el sexo y el ser vacunado (P< 0,001). Conclusión: Este estudio demostró que la mayoría de los participantes mostró una actitud positiva hacia la consideración de la vacuna frente a la COVID-19. Sin embargo, la concienciación sobre el conocimiento informado de la vacuna, los posibles efectos adversos y el coste supondrían un gran valor añadido al incremento de la respuesta real de la población paquistaní hacia la vacuna frente a la COVID-19.

Evaluating structure-based activity in a high-throughput assay for steroid biosynthesis.

Data from a high-throughput human adrenocortical carcinoma assay (HT-H295R) for steroid hormone biosynthesis are available for >2000 chemicals in single concentration and 654 chemicals in multi-concentration (mc). Previously, a metric describing the effect size of a chemical on the biosynthesis of 11 hormones was derived using mc data referred to as the maximum mean Mahalanobis distance (maxmMd). However, mc HT-H295R assay data remain unavailable for many chemicals. This work leverages existing HT-H295R assay data by constructing structure-activity relationships to make predictions for data-poor chemicals, including: (1) identification of individual structural descriptors, known as ToxPrint chemotypes, associated with increased odds of affecting estrogen or androgen synthesis; (2) a random forest (RF) classifier using physicochemical property descriptors to predict HT-H295R maxmMd binary (positive or negative) outcomes; and, (3) a local approach to predict maxmMd binary outcomes using nearest neighbors (NNs) based on two types of chemical fingerprints (chemotype or Morgan). Individual chemotypes demonstrated high specificity (85-98%) for modulators of estrogen and androgen synthesis but with low sensitivity. The best RF model for maxmMd classification included 13 predicted physicochemical descriptors, yielding a balanced accuracy (BA) of 71% with only modest improvement when hundreds of structural features were added. The best two NN models for binary maxmMd prediction demonstrated BAs of 85 and 81% using chemotype and Morgan fingerprints, respectively. Using an external test set of 6302 chemicals (lacking HT-H295R data), 1241 were identified as putative estrogen and androgen modulators. Combined results across the three classification models (global RF model and two local NN models) predict that 1033 of the 6302 chemicals would be more likely to affect HT-H295R bioactivity. Together, these in silico approaches can efficiently prioritize thousands of untested chemicals for screening to further evaluate their effects on steroid biosynthesis.

The family planning "know-do" gap among married women of reproductive age in urban Pakistan.

OBJECTIVE: To examine the prevalence and predictors of family planning (FP) know-do gaps among married women of reproductive age (MWRA) in low socio-economic urban areas of Karachi, Pakistan. DESIGN: This was a cross-sectional survey of randomly selected 7288 MWRA (16-49 years) to identify predictors of the know-do gap in FP using a logistic regression model. RESULTS: More than one third (35.5%) of MWRA had FP know-do gap, i.e., despite having a knowledge of contraceptives and desire to limit or delay childbearing, they were not using contraceptives. Women were less likely to use FP if they were getting older (25-35 years: OR 1.45, 95% CI 1.09-1.94; >35 years: OR 3.02, 95% CI 1.90-4.80), from certain ethnicities (Sindhi: OR 1.64, 95% CI 1.11-2.42; Saraiki: OR 1.66, 95% CI 1.01-2.71; other minorities: OR 2.37, 95% CI 1.63-3.44); did not receive FP counselling: OR 1.43, 95% CI 1.13-1.80; and had not made a joint decision on FP: OR 1.44, 95% CI 1.06-1.98). Conversely, women were more likely to use contraceptives if they had >10 years of schooling (OR 0.66, 95% CI 0.46-0.94), with each increasing number of a living child (OR 0.68, 95% CI 0.62-0.75) and each increasing number of contraceptive method known (OR 0.93, 95% CI 0.88-0.98). CONCLUSION: The predictors associated with the FP know-do gap among MWRA should be considered when planning future strategies to improve the contraceptive prevalence rate in Pakistan.

OBJECTIF: Étudier la prévalence et les variables explicatives du fossé entre informations et actions en matière de planification familiale (FP) chez les femmes mariées en âge de procréer (MWRA) dans les quartiers urbains socio-économiquement défavorisés de Karachi, Pakistan. PLAN: Enquête transversale réalisée auprès de 7 288 MWRA (16­49 ans) sélectionnées de manière aléatoire visant à identifier les variables explicatives du fossé entre informations et actions en matière de FP en utilisant un modèle de régression logistique. RÉSULTATS: Un fossé entre informations et actions en matière de FP a été observé chez plus d'un tiers (35,5%) des MWRA, c.-à-d., qu'en dépit de connaissances sur les moyens de contraception et d'un souhait de limiter ou retarder les grossesses, ces femmes n'utilisaient aucun moyen de contraception. Les femmes étaient moins susceptibles d'avoir recours à la FP en vieillissant (25­35 ans : OR 1,45 ; IC 95% 1,09­1,94 ; >35 ans : OR 3,02 ; IC 95% 1,90­4,80), si elles appartenaient à certains groupes ethniques (Sindhi : OR 1,64 ; IC 95% 1,11­2,42 ; Saraiki : OR 1,66 ; IC 95% 1,01­2,71 ; autres minorités : OR 2,37 ; IC 95% 1,63­3,44), si elles ne bénéficiaient d'aucune aide en matière de FP (OR 1,43 ; IC 95% 1,13­1,80), et si la décision relative à la FP avait été prise unilatéralement (OR 1,44 ; IC 95% 1,06­1,98). À l'inverse, les femmes étaient plus susceptibles d'utiliser des contraceptifs si elles avaient été scolarisées pendant >10 ans (OR 0,66, ; IC 95% 0,46­0,94), à mesure que leur nombre d'enfants vivants augmentait (OR 0,68 ; IC 95% 0,62­0,75) et à mesure que le nombre de moyens contraceptifs qui leur étaient connus augmentait (OR 0,93 ; IC 95% 0,88­0,98). CONCLUSION: Les variables explicatives associées au fossé entre informations et actions en matière de FP chez les MWRA devraient être prises en compte lors de la planification de futures stratégies visant à améliorer le taux de prévalence des contraceptifs au Pakistan.

New TB drugs for the treatment of children and adolescents with rifampicin-resistant TB in Mumbai, India.

SETTING: Médecins Sans Frontières (MSF) clinic in Mumbai, India.OBJECTIVE: To determine the final treatment outcomes, culture conversion and adverse events (AEs) during treatment among children and adolescents (0-19 years) with rifampicin-resistant tuberculosis (RR-TB) who received ambulatory injectable-free treatment, including bedaquiline (BDQ) and/or delamanid (DLM) during September 2014-January 2020.DESIGN: This was a retrospective cohort study based on review of routinely collected programme data.RESULTS: Twenty-four patients were included; the median age was 15.5 years (min-max 3-19) and 15 (63%) were females. None were HIV-coinfected. All had fluoroquinolone resistance. Twelve received treatment, including BDQ and DLM, 11 received DLM and one BDQ. The median exposure to BDQ (n = 13) and DLM (n = 23) was 82 (IQR 80-93) and 82 (IQR 77-96) weeks, respectively. Seventeen (94%) patients with positive culture at baseline (n = 18) had negative culture during treatment; median time for culture-conversion was 7 weeks (IQR 5-11). Twenty-three (96%) had successful treatment outcomes: cured (n = 16) or completed treatment (n = 7); one died. Eleven (46%) had 17 episodes of AEs. Two of 12 serious AEs were associated with new drugs (QTcF >500 ms).CONCLUSION: Based on one of the largest global cohorts of children and adolescents to receive new TB drugs, this study has shown that injectable-free regimens containing BDQ and/or DLM on ambulatory basis were effective and well-tolerated among children and adolescents and should be made routinely accessible to these vulnerable groups.

Profile of osteoarticular tuberculosis in children.

OBJECTIVE: To determine clinical profile of osteoarticular tuberculosis (TB) in children. METHODS: Cross-sectional analysis from 2007 to 2013. All patients diagnosed with bone TB, spinal TB or TB abscesses were included. RESULTS: Out of 1318 children with TB, 39 (2.96%) had osteoarticular TB, of which 16 (42%) had osteomyelitis, 8 (20.5%) had spinal involvement, 7 (17.9%) had TB synovitis, 2 (5.1%) had psoas abscess and 6 (15.4%) had abscesses. The mean age of presentation was 7.1 ± 3.5 years (range 2-14 years). Of the 33 cases in which a culture was done, 25 (64%) showed a positive culture. Drug sensitivity tests were done in 21 patients of which 10 (47.6%) tested were drug resistant, of which 4 (36.4%) were multidrug resistant (MDR), 2 (18.2%) were extensively drug resistant (XDR), 3 were pre-XDR (27.3%) and 1 was polyresistant (9.1%). Nine (23.1%) patients had TB in the past with a treatment duration of 8.3 ± 5.3 months. Contact with a TB patient had occurred in 10 (25.6%) cases. Associated pulmonary TB were seen in 6 (15.39%) and TB meningitis were seen in 1 (2.6%) patients. Surgical intervention was needed in 11 (28.2%) patients of which 5 (45.5%) underwent curettage, drainage was done in 1 (9.1%), arthrotomy in 4 (36.4%) and spinal surgery in 1 (9.1%) patient. CONCLUSION: Drug resistant osteoarticular TB is an emerging problem in children.

Quantitative prediction of repeat dose toxicity values using GenRA.

Computational approaches have recently gained popularity in the field of read-across to automatically fill data-gaps for untested chemicals. Previously, we developed the generalized read-across (GenRA) tool, which utilizes in vitro bioactivity data in conjunction with chemical descriptor information to derive local validity domains to predict hazards observed in in vivo toxicity studies. Here, we modified GenRA to quantitatively predict point of departure (POD) values obtained from US EPA's Toxicity Reference Database (ToxRefDB) version 2.0. To evaluate GenRA predictions, we first aggregated oral Lowest Observed Adverse Effect Levels (LOAEL) for 1,014 chemicals by systemic, developmental, reproductive, and cholinesterase effects. The mean LOAEL values for each chemical were converted to log molar equivalents. Applying GenRA to all chemicals with a minimum Jaccard similarity threshold of 0.05 for Morgan fingerprints and a maximum of 10 nearest neighbors predicted systemic, developmental, reproductive, and cholinesterase inhibition min aggregated LOAEL values with R2 values of 0.23, 0.22, 0.14, and 0.43, respectively. However, when evaluating GenRA locally to clusters of structurally-similar chemicals (containing 2 to 362 chemicals), average R2 values for systemic, developmental, reproductive, and cholinesterase LOAEL predictions improved to 0.73, 0.66, 0.60 and 0.79, respectively. Our findings highlight the complexity of the chemical-toxicity landscape and the importance of identifying local domains where GenRA can be used most effectively for predicting PODs.

Pharmacokinetics of isoniazid in Indian children with tuberculosis on daily treatment.

OBJECTIVE: To assess the pharmacokinetics of isoniazid (INH) at 10 mg/kg/day among Indian children. METHODS: INH levels were estimated using liquid chromatography-tandem mass spectroscopy in 35 children aged 1-15 years on daily anti-tuberculosis treatment. Blood samples were collected 0, 1, 2, 3, 6 and 24 h after INH administration. The maximum concentration (Cmax) and area under the curve (AUC0-24) were determined. The normal therapeutic range for Cmax is 3-5 µg/ml. An AUC of <10.52 µg•h/ml for INH is low. RESULTS: The mean Cmax was 8.3 ± 4.28 µg/ml and was attained in 1.22 ± 0.5 h, with a median time to Cmax (Tmax) of 1 h. The mean AUC for INH was 46.23 ± 34.82 µg•h/ml. Children aged 1-4.9 years, 5-10 years and >10 years had a mean Cmax of respectively 9.87 ± 5.75 µg/ml, 7.62 ± 3.37 µg/ml and 7.21 ± 2.50 µg/ml (P = 0.08) and a mean AUC of respectively 60.97 ± 49.90 µg•h/ml, 38.95 ± 22.28 µg•h/ml and 36.09 ± 13.56 µg•h/ml (P = 0.29). The mean Cmax in children taking fixed-drug combinations and individual drugs was respectively 9.07 ± 4.67 µg/ml and 7.43 ± 3.71 µg/ml (P = 0.26); the mean AUC was respectively 50.48 ± 38.38 µg•h/ml and 41.20 ± 30.52 µg•h/ml (P = 0.44). Two children had hepatitis. CONCLUSION: Most Indian children had higher than normal INH AUC and Cmax values. It is necessary to determine the ideal dose of INH in Indian children using the genotypic acetylator status of the patients and pharmacokinetic toxicity analysis.

Genotypes of CYP1A1,†SULT1A1 and SULT1A2 and risk of squamous cell carcinoma of esophagus: outcome of a case-control study from Kashmir, India.

Studies on associations of various polymorphism in xenobiotic metabolizing genes with different cancers including esophageal squamous cell carcinoma (ESCC) are mixed and inconclusive. To evaluate the association of CYP1A1*4, SULT1A1*2 and SULT1A2*2 genotypes with ESCC risk and their modifying effects on different risk factors of ESCC, we conducted a case-control study in Kashmir, India, an area with relative high incidence of ESCC. We recruited 404 histopathologically confirmed ESCC cases, and equal number of controls, individually matched for sex, age and district of residence to respective case. Information was obtained on various dietary, lifestyle and environmental factors in face-to-face interviews, using a structured questionnaire, from each subject. Genotypes were analyzed by polymerase chain reaction, restriction fragment length polymorphism and direct sequencing. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). A higher risk was observed in the subjects who harbored variant genotype of CYP1A1*4 (OR = 2.06; 95% CI: 1.28-3.32); and the risk was further enhanced in ever smokers (OR = 3.47; 95% CI: 1.62-7.42), adobe dwellers (OR = 6.71; 95% CI: 3.02-14.89), and biomass fuel users (OR = 5.11; 95% CI: 1.34-19.50). We did not find any significant differences in the polymorphic variants of SULT1A1*2 and SULT1A2*2 between cases and controls. The study indicates that, unlike SULT1A1*2 and SULT1A2*2, the polymorphism of CYP1A1*4 is associated with ESCC risk. However, replicative studies with larger sample size are needed to substantiate our findings.

Family history of cancer and the risk of squamous cell carcinoma of oesophagus: a case-control study in Kashmir, India.

BACKGROUND: Only a few studies have examined the association between family history of cancer (FHC) and the risk of oesophageal squamous cell carcinoma (ESCC) in high incidence areas of ESCC. We conducted a case-control study to evaluate the relationship between FHC and ESCC risk in Kashmir, India, with analysis of detailed epidemiological data and information on multiple gene polymorphisms. METHODS: We collected detailed information on FHC and a number of socio-demographic and lifestyle factors, and also obtained blood samples for genetic analysis from 703 histopathologically confirmed ESCC cases and 1664 individually matched controls. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Participants who had FHC showed a strong association with ESCC risk, and the risk was stronger when first-degree relatives (FDRs) had FHC (OR=6.8; 95% CI=4.6-9.9). Having a sibling with a cancer showed the strongest association (OR=10.8; 95% CI=6.0-19.3), but having a child with a cancer was not associated with ESCC risk. A history of any cancer in the spouse was also associated with ESCC risk (OR=4.1; 95% CI=1.6-10.2). Those with two or more relatives with FHC were at a higher risk of ESCC. After restricting FHC to familial ESCC only, the above associations were strengthened, except when spouses were affected with ESCC (OR=2.5; 95% CI=0.7-8.9). When we examined the associations between several single-nucleotide polymorphisms and ESCC in those with and without FHC, the associations of variant genotypes in cytochrome P450 (CYP) 2C19 and CYP2D6 and the wild genotype of CYP2E1 with ESCC were much stronger in those with FHC. The FHC had an additive interaction with several risk factors of ESCC in this population. CONCLUSION: Our results showed that FHC was strongly associated with ESCC risk in Kashmir. It seems both genetic factors and shared environment are involved in this association.

Eosinophilic meningitis: a case series and review of literature of Angiostrongylus cantonensis and Gnathostoma spinigerum.

Eosinophilic meningitis is defined as the presence of >10 eosinophils/µL in cerebrospinal fluid (CSF) or at least 10% eosinophils in the total CSF leukocyte count. Eosinophilic meningitis has been reported in two case series and two case reports in India till date and has not been reported in children below 15 years of age. We present two children with eosinophilic meningitis with peripheral eosinophilia and the proposed etiologic agents based on the clinical setting and their response to antihelminthic agents.

Adolescent conduct problems and premature mortality: follow-up to age 65 years in a national birth cohort.

BACKGROUND: Severe youth antisocial behaviour has been associated with increased risk of premature mortality in high-risk samples for many years, and some evidence now points to similar effects in representative samples. We set out to assess the prospective association between adolescent conduct problems and premature mortality in a population-based sample of men and women followed to the age of 65 years. METHOD: A total of 4158 members of the Medical Research Council National Survey of Health and Development (the British 1946 birth cohort) were assessed for conduct problems at the ages of 13 and 15 years. Follow-up to the age of 65 years via the UK National Health Service Central Register provided data on date and cause of death. RESULTS: Dimensional measures of teacher-rated adolescent conduct problems were associated with increased hazards of death from cardiovascular disease by the age of 65 years in men [hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.04-1.32], and of all-cause and cancer mortality by the age of 65 years in women (all-cause HR 1.16, 95% CI 1.07-1.25). Adjustment for childhood cognition and family social class did little to attenuate these risks. Adolescent conduct problems were not associated with increased risks of unnatural/substance-related deaths in men or women in this representative sample. CONCLUSIONS: Whereas previous studies of high-risk delinquent or offender samples have highlighted increased risks of unnatural and alcohol- or substance abuse-related deaths in early adulthood, we found marked differences in mortality risk from other causes emerging later in the life course among women as well as men.

Poor oral hygiene and risk of esophageal squamous cell carcinoma in Kashmir.

BACKGROUND: Several studies have suggested an association between poor oral health and esophageal squamous cell carcinoma (ESCC). We conducted a case-control study in Kashmir, a region with relatively high incidence of ESCC in north India, to investigate the association between oral hygiene and ESCC risk. METHODS: We recruited 703 histologically confirmed ESCC cases, and 1664 controls individually matched to the cases for age, sex, and district of residence. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We found an inverse association between teeth cleaning and ESCC risk. As compared with never cleaning teeth, the OR (95% CI) was 0.41 (0.28-0.62) for cleaning less than daily and 0.44 (0.25-0.77) for cleaning at least once a day (P for trend=0.026) in models adjusted for multiple potential confounders, including several indicators of socioeconomic status. This association persisted after we limited our analyses to never tobacco users. The inverse association between cleaning teeth and ESCC was stronger with using brushes than with using sticks/fingers. We also found an association between the number of decayed, filled, and missing teeth and ESCC risk, but the trend of the associations was not statistically significant. Avoiding solid food and cold beverages because of teeth and oral problems were also associated with ESCC risk. CONCLUSION: We found an association between poor oral hygiene indicators and ESCC risk, supporting the previous studies that showed the same associations.

Effects of sleeve gastrectomy and ileal transposition, alone and in combination, on food intake, body weight, gut hormones, and glucose metabolism in rats.

Bariatric surgeries are hypothesized to produce weight loss and improve diabetes control by multiple mechanisms including gastric restriction and lower gut stimulation; the relative importance of these mechanisms remains poorly understood. We compared the effects of a typical foregut procedure, sleeve gastrectomy, (SG) with a primarily hindgut surgery, ileal transposition (IT), alone and together (SGIT), or sham manipulations, on food intake, body weight, gut hormones, glucose tolerance, and key markers of glucose homeostasis in peripheral tissues of adult male Sprague-Dawley rats (450-550 g, n = 7-9/group). SG, IT, and SGIT surgeries produced transient reduction in food intake and weight gain; the effects of SG and IT on intake and body weight were nonadditive. SG, IT, and SGIT surgeries resulted in increased tissue expression and plasma concentrations of the lower gut hormones glucagon-like peptide-1 and peptide YY and decreased plasma glucose-dependent insulinotropic peptide, insulin, and leptin concentrations. Despite transient effects on intake and weight gain, the SG, IT, and SGIT surgeries produced a significant improvement in glucose tolerance. In support of glycemic improvements, the protein abundance of key markers of glucose metabolism (e.g., GLUT4, PKA, IRS-1) in muscle and adipose tissue were increased, whereas the expression of key gluconeogenic enzyme in liver (G-6-Pase) were decreased following the surgeries. Therefore, our data suggest that enhanced lower gut stimulation following SG, IT, and SGIT surgeries leads to transient reduction in food intake and weight gain together with enhanced secretion of lower gut hormones and improved glucose clearance by peripheral tissues.

Using a birth cohort to study ageing: representativeness and response rates in the National Survey of Health and Development.

Britain's oldest birth cohort study, the MRC National Survey of Health and Development (NSHD) provides data to explore life time influences on ageing. The latest data collection was undertaken between 2006 and 2011 when study members were aged 60-64 and consisted of postal and pre-assessment questionnaires to eligible study members, followed by invitation to attend one of six clinical research facilities (CRFs) across the UK for clinical assessments, and dietary diaries and activity monitors in the days following the CRF visit. The option of a home visit for clinical assessments was provided if the study member refused or was unable to attend the CRF. We examined response and attrition, here describing rates overall and for postal and clinical assessment modes of data collection, identifying socioeconomic and health-related predictors of response, and assessing the continued representativeness of the sample. In total, 2,661 (84 % of the target sample) responded. Lower educational attainment, lower childhood cognition and lifelong smoking independently predicted lower likelihood of both overall response and CRF cooperation. At 53 years, not owning one's home and not being married predicted lower likelihood of overall response whereas manual social class and obesity predicted lower likelihood of CRF cooperation. Providing for collection of biomedical data in the home and use of assessment instruments and modes to retain study members with lower education attainment, lower cognition and poorer health behaviours should be priorities for helping reduce attrition amongst vulnerable ageing study members.

Change in heritability estimates due to half-sib family selection in the maize variety Pahari.

This research was carried out at the Agriculture Research Farm, Khyber Pakhtunkhwa Agricultural University, Peshawar, and the Cereal Crops Research Institute, Pirsabak, Nowshera, during 2009 and 2010. Half-sib families (HS) derived from the maize variety Pahari in spring crop seasons 2009 and 2010 were developed at the Cereal Crops Research Institute. All HS families were detasseled well before pollen shedding. At maturity, each family was harvested and shelled separately. During the summer crop of seasons 2009 and 2010, these HS families were evaluated in 12 x 12 and 11 x 11 partially balanced lattice square arrangements at the Khyber Pakhtunkhwa Agricultural University, Peshawar, for various flowering and yield traits, respectively. The data on days to mid-silking, anthesis, anthesis-silking interval, 100-grain weight, and grain yield were recorded. The results revealed significant differences among families for all traits in both cycles. High heritability (0.88) was observed for days to mid-silking in cycle 0 (C0), while moderate heritability (0.42) was recorded for 100-grain weight in C1. The selection differential was quite reasonable and varied according to the traits of interest. The observed response for grain yield in C0 (815.74 kg/ha) was greater than the expected response (681.76 kg/ha).