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Laser interstitial thermal therapy (LITT) is a minimally invasive neurosurgical technique used to ablate intra-axial brain tumors. The impact of LITT on the tumor microenvironment is scarcely reported. Nonablative LITT-induced hyperthermia (33-43˚C) increases intra-tumoral mutational burden and neoantigen production, promoting immunogenic cell death. To understand the local immune response post-LITT, we performed longitudinal molecular profiling in a newly diagnosed glioblastoma and conducted a systematic review of anti-tumoral immune responses after LITT. A 51-year-old male presented after a fall with progressive dizziness, ataxia, and worsening headaches with a small, frontal ring-enhancing lesion. After clinical and radiographic progression, the patient underwent stereotactic needle biopsy, confirming an IDH-WT World Health Organization Grade IV Glioblastoma, followed by LITT. The patient was subsequently started on adjuvant temozolomide, and 60 Gy fractionated radiotherapy to the post-LITT tumor volume. After 3 months, surgical debulking was conducted due to perilesional vasogenic edema and cognitive decline, with H&E staining demonstrating perivascular lymphocytic infiltration. Postoperative serial imaging over 3 years showed no evidence of tumor recurrence. The patient is currently alive 9 years after diagnosis. Multiplex immunofluorescence imaging of pre-LITT and post-LITT biopsies showed increased CD8 and activated macrophage infiltration and programmed death ligand 1 expression. This is the first depiction of the in-situ immune response to LITT and the first human clinical presentation of increased CD8 infiltration and programmed death ligand 1 expression in post-LITT tissue. Our findings point to LITT as a treatment approach with the potential for long-term delay of recurrence and improving response to immunotherapy., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

All cells employ a combination of endo- and exoribonucleases to degrade long RNA polymers to fragments 2-5 nucleotides in length. These short RNA fragments are processed to monoribonucleotides by nanoRNases. Genetic depletion of nanoRNases has been shown to increase abundance of short RNAs. This deleteriously affects viability, virulence, and fitness, indicating that short RNAs are a metabolic burden. Previously, we provided evidence that NrnA is the housekeeping nanoRNase for Bacillus subtilis. Herein, we investigate the biological and biochemical functions of the evolutionarily related protein, B. subtilis NrnB (NrnBBs). These experiments show that NrnB is surprisingly different from NrnA. While NrnA acts at the 5' terminus of RNA substrates, NrnB acts at the 3' terminus. Additionally, NrnA is expressed constitutively under standard growth conditions, yet NrnB is selectively expressed during endospore formation. Furthermore, NrnA processes only short RNAs, while NrnB unexpectedly processes both short RNAs and longer RNAs. Indeed, inducible expression of NrnB can even complement the loss of the known global 3'-5' exoribonucleases, indicating that it acts as a general exonuclease. Together, these data demonstrate that NrnB proteins, which are widely found in Firmicutes, Epsilonproteobacteria and Archaea, are fundamentally different than NrnA proteins and may be used for specialized purposes., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Introduction: Herpes Simplex Virus-1 (HSV-1) is a neurotropic DNA virus with neural latency and stereotypic viral encephalitis. It has been reported to conceal underlying glioblastoma (GBM) due to similar radiographic imaging and clinical presentation. Limited data exist on the co-occurrence of GBM and HSV-1. To better describe the pathophysiology of HSV-1 superinfections in GBM, we performed a comprehensive review of GBM cases with superimposed HSV-1., Methods: A comprehensive literature search of six electronic databases with apriori search criteria was performed to identify eligible cases of GBM with HSV-1. Relevant clinic-radiographic data were collected, Kaplan-Meier estimates, Fisher's exact test, and logistic regression analyses were used., Results: We identified 20 cases of HSE in GBM with an overall survival (OS) of 8.0 months. The median age of presentation was 63 years (range: 24-78 years) and the median interval between GBM or HSE diagnosis was 2 months (range: 0.05-25 months). HSE diagnosis before GBM diagnosis was a predictor for improved survival (HR: 0.06; 95% CI: [0.01-0.54]; p < 0.01). There is a significant reduction in OS in patients with concomitant HSE and GBM compared to the cancer genome atlas (TCGA) cohort (median OS: 8 months vs. 14.2 months; p < 0.05). Finally, HSV does not directly infect GBM cells but indirectly activates a local immune response in the tumor microenvironment., Conclusions: Superimposed HSE in GBM may contribute to a significant reduction in OS compared to uninfected controls, potentially activating proto-oncogenes during active infection and latency. Preoperative HSE may induce an antiviral immune response, which may serve as a positive prognostic factor. Prompt antiviral treatment upon co-occurrence is necessary., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Children with complex care needs are a growing proportion of the sick children seen in all healthcare settings in the UK. Complex care needs place demands on parents and professionals who often require many different healthcare teams to work together. Care can be both materially and logistically difficult to manage, causing friction with parents. These difficulties may be reduced if common best practice standards and approaches can be developed in this area., Objective: To develop a consensus approach to the management of complexity among healthcare professionals, we used a modified Delphi process. The process consisted of a meeting of clinical leaders to develop candidate statements, followed by two survey rounds open to all professionals in a UK children's hospital to measure and establish consensus recommendations., Results: Ninety-nine professionals completed both rounds of the survey, 69 statements were agreed. These pertained to seven thematic areas: standardised approaches to communicating with families; processes for interprofessional communication; processes for shared decision-making in the child's best interests; role of the multidisciplinary team; managing professional-parental disagreement and conflict; the role of clinical psychologists; and staff support. Overall, the level of consensus was high, ranging from agreement to strong agreement., Conclusions: These statements provide a consensus basis that can inform standardised approaches to the management of complexity. Such approaches may decrease friction between parents, children and healthcare professionals., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The Bacillus subtilis genome is predicted to encode numerous ribonucleases, including four 3' exoribonucleases that have been characterized to some extent. A strain containing gene knockouts of all four known 3' exoribonucleases is viable, suggesting that one or more additional RNases remain to be discovered. A protein extract from the quadruple RNase mutant strain was fractionated and RNase activity was followed, resulting in the identification of an enzyme activity catalyzed by the YloC protein. YloC is an endoribonuclease and is a member of the highly conserved "YicC family" of proteins that is widespread in bacteria. YloC is a metal-dependent enzyme that catalyzes the cleavage of single-stranded RNA, preferentially at U residues, and exists in an oligomeric form, most likely a hexamer. As such, YloC shares some characteristics with the SARS-CoV Nsp15 endoribonuclease. While the in vivo function of YloC in B. subtilis is yet to be determined, YloC was found to act similarly to YicC in an Escherichia coli in vivo assay that assesses decay of the small RNA, RyhB. Thus, YloC may play a role in small RNA regulation., (© 2022 Ingle et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.)

Nanostructured electrocatalysts for microbial fuel cell air-cathodes were obtained via use of conductive carbon blacks for the synthesis of high performing 3D conductive networks. We used two commercially available nanocarbons, Black Pearls 2000 and multiwalled carbon nanotubes, as conductive scaffolds for the synthesis of nanocomposite electrodes by combining: a hydrothermally carbonized resin, a sacrificial polymeric template, a nitrogenated organic precursor and iron centers. The resulting materials are micro-mesoporous, possess high specific surface area and display N-sites (N/C of 3-5 at%) and Fe-centers (Fe/C < 1.5at.%) at the carbon surface as evidenced from characterization methods. Voltammetry studies of oxygen reduction reaction activity were carried out at neutral pH, which is relevant to microbial fuel cell applications, and activity trends are discussed in light of catalyst morphology and composition. Tests of the electrocatalyst using microbial fuel cell devices indicate that optimization of the nanocarbon scaffold for the Pt-free carbon-based electrocatalysts results in maximum power densities that are 25% better than those of Pt/C cathodes, at a fraction of the materials costs. Therefore, the proposed Fe/N-carbon catalysts are promising and sustainable high-performance cathodic materials for microbial fuel cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Recent research demonstrated that obesity and high dietary sodium intake, the two established risk factors for hypertension, were associated with each other. The objective was to investigate the potential indirect effect of sodium intake on blood pressure via body mass index (BMI)., Methods and Results: Using ten years data from US NHANES (2007-2016), the study included adult participants (>20 years old) who were not taking antihypertensive medications and without baseline diseases (n = 12,262). BMI was modelled as the mediator of sodium intake on systolic and diastolic blood pressure, adjusted for age, sex, socioeconomic status, smoking, drinking, physical activity, calorie intake, fluid intake and potassium intake. Mediation analysis was performed to evaluate total effect, direct effect and indirect effect via BMI. Subgroup analyses based on three age subgroups (20-40, 41-60 and ≥61 years old) were performed. The mean age was 39.29 (13.4) years and 53.1 (0.45) % were males. The mean BMI was 27.8 (6.20) kg/m 2 . Overall, 1 g/d increase in sodium intake was associated with an increased systolic blood pressure by 0.36 (95% confidence interval 0.14 to 0.58) mmHg, with a direct effect (0.14 (0.09-0.19)) and an indirect effect via BMI (0.23 (0.02-0.44)). The indirect effect was mainly observed in participants ≤60 years old., Conclusion: Sodium intake showed both direct effect and indirect effect (via BMI) on systolic blood pressure in US NHANES. The findings provide evidence for combining sodium restriction and weight reduction measures for prevention of hypertension. Cautions should be taken when generalizing the findings to other populations with lower average BMI., Competing Interests: Conflicts of interest All authors have non conflict of interest to declare., (Copyright © 2021. Published by Elsevier B.V.)

Objective: To implement and evaluate the use of the conflict management framework (CMF) in four tertiary UK paediatric services., Design: Mixed methods multisite evaluation including prospective pre and post intervention collection of conflict data alongside semistructured interviews., Setting: Eight inpatient or day care wards across four tertiary UK paediatric services., Interventions: The two-stage CMF was used in daily huddles to prompt the recognition and management of conflict., Results: Conflicts were recorded for a total of 67 weeks before and 141 weeks after implementation of the CMF across the four sites. 1000 episodes of conflict involving 324 patients/families across the four sites were recorded. After implementation of the CMF, time spent managing episodes of conflict around the care of a patient was decreased by 24% (p<0.001) (from 73 min to 55 min) and the estimated cost of this staff time decreased by 20% (p<0.02) (from £26 to £21 sterling per episode of conflict). This reduction occurred despite conflict episodes after implementation of the CMF having similar severity to those before implementation. Semistructured interviews highlighted the importance of broad multidisciplinary leadership and training to embed a culture of proactive and collaborative conflict management., Conclusions: The CMF offers an effective adjunct to conflict management training, reducing time spent managing conflict and the associated staff costs., Competing Interests: Competing interests: SB is a director of the Medical Mediation Foundation (MMF), an organisation that provides conflict management training and mediation to resolve disagreement/conflict between patients, families and healthcare professionals. EM is an associate of the MMF., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Polynucleotide phosphorylase (PNPase), a 3' exoribonuclease that degrades RNA in the 3'-to-5' direction, is the major mRNA decay activity in Bacillus subtilis . PNPase is known to be inhibited in vitro by strong RNA secondary structure, and rapid mRNA turnover in vivo is thought to require an RNA helicase activity working in conjunction with PNPase. The most abundant RNA helicase in B. subtilis is CshA. We found for three small, monocistronic mRNAs that, for some RNA sequences, PNPase processivity was unimpeded even without CshA, whereas others required CshA for efficient degradation. A novel colour screen for decay of mRNA in B. subtilis was created, using mRNA encoded by the slrA gene, which is degraded from its 3' end by PNPase. A significant correlation between the predicted strength of a stem-loop structure, located in the body of the message, and PNPase processivity was observed. Northern blot analysis confirmed that PNPase processivity was greatly hindered by the internal RNA structure, and even more so in the absence of CshA. Three other B. subtilis RNA helicases did not appear to be involved in mRNA decay during vegetative growth. The results confirm the hypothesis that efficient 3' exonucleolytic decay of B. subtilis RNA depends on the combined activity of PNPase and CshA.

Streptomyces sp. strain S-9 was studied for its effect in inducing systemic resistance in Pigeon pea against the plant pathogen Fusarium udum causing wilt. The 16S rRNA gene sequencing and phylogenetic analysis indicated that S-9 is closely related to genus Streptomyces for which it was referred to as Streptomyces sp. S-9. Streptomyces sp. S-9 caused 85% inhibition of the pathogen and showed various attributes of plant growth-promoting such as the production of IAA, P-solubilization, and β -1, 3-Glucanase activity. Proline and malondialdehyde (MDA) content was significantly higher whereas the chlorophyll content decreased in the pathogen-infected plant when compared to S-9 treated Pigeon pea plants. The anatomical research assisted the biocontrol-mediated stress tolerance findings in the Pigeon pea plant through increased root epidermis and enhanced stress-related xylem tissues. Fungus inoculation elevated the antioxidative enzymatic activities of superoxide dismutase (SOD; 78%) and catalase (CAT; 56%). Marked reductions in antioxidant enzymes were associated with the antagonistic effects of the different treatments. Conclusions showed that S-9 bioinocula applied as a seed coating enhanced soil availability of nitrogen (N), phosphate (P), and potassium (K), indicating their suitability for direct application invigorating plant growth and persuade resistance in the plant Pigeon pea against Fusarium wilt., Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-021-02989-0., Competing Interests: Conflict of interestThe authors declare no conflicts of interest., (© King Abdulaziz City for Science and Technology 2021.)

Rabies is a highly fatal viral infection of the central nervous system affecting all warm-blooded animals including humans. To implement the preventive and control measures, it is important to decide the status of anti-rabies antibodies in dogs. Out of 120 serum samples, 47 (39.2 %) serum samples, showed an antibody titre equal to or above the cut off value of 0.5 IU/ml. The maximum number of dogs showed anti-rabies antibody titres equal to or above the cut-off value of 0.5 IU/ml after <1 month pre-exposure to the rabies vaccine. In 15 serum samples of pet dogs, we observed 13 (86.66 %) dogs with protective anti-rabies antibody titre. Statistical analysis suggests that the age of the animal had no significant effect on anti-rabies antibody titre in vaccinated pet dogs. The overall low seroprevalence of anti-rabies antibody in stray dogs indicates their susceptibility to rabies infection and thus posing a risk of rabies to other animals and humans., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Nearly 1.7 million cases of dog bites are reported every year in India and many cases of animal rabies are left unattended and undiagnosed. Therefore, a mere diagnosis of rabies is not sufficient to understand the epidemiology and the spread of the rabies virus (RV) in animals. There is a paucity of information about the evolutionary dynamics of RV in dogs and its biodiversity patterns in India. In total, 50 dog-brain samples suspected of rabies were screened by the nucleoprotein- (N) and glycoprotein- (G) gene PCR. The N and G genes were subsequently sequenced to understand the molecular evolution in these genes. The phylogenetic analysis of the N gene revealed that six isolates in the Mumbai region belonged to a single Arctic lineage. Time-scaled phylogeny by Bayesian coalescent analysis of the partial N gene revealed that the time to the most recent common ancestor (TMRCA) for the sequences belonged to the cluster from 2006.68 with a highest posterior density of 95 % betweeen 2005-2008, which is assigned to Indian lineage I. Migration pattern revealed a strong Bayes factor between Mumbai to Delhi, Panji to Hyderabad, Delhi to Chennai, and Chennai to Chandigarh. Phylogenetic analysis of the G gene revealed that the RVs circulating in the Mumbai region are divided into three lineages. Time-scaled phylogeny by the Bayesian coalescent analysis method estimated that the TMRCA for sequences under study was from 1993 and Indian clusters was from 1962. In conclusion, the phylogenetic analysis of the N gene revealed that six isolates belonged to single Arctic lineages along with other Indian isolates and they were clustered into a single lineage but divided into three clades based on the G-gene sequences. The present study highlights and enhances the current molecular epidemiology and evolution of RV and revealed strong location bias and geographical clustering within Indian isolates on the basis of N and G genes.

In the present research article we explore the synthesis method and adsorption capability of ZnFe oxides nanocomposites by using Pb as dopant. A conventional and simple batch adsorption method is selected and optimized. Pb@ZnFe 2 O 4 NCs were fabricated by facile method i.e. co-precipitation method and characterized by FESEM, XRD, IR, EDX. The removal of dye has monitored by UV method. An outstanding result is obtained as adsorption efficiency of 1042 mg g -1 shows more significant performance than currently available bench-mark adsorbents. The optimized parameters pH 7.1, Adsorbent Mass: 50 mg, Initial Dye Concentration: 150 mg/l and Agitation Time: 90 min results in 96.49 % removal of CR (Congo red) dye. A CCD (central composite design) is applied to evaluate the role of adsorption variables. Based on its excellent performance, cost effectiveness, facile fabrication and large surface area, the Pb@ZnFe 2 O 4 has considerable potential for the manufacture of cost effective and efficient adsorbents for environmental applications., (© 2019 The Author(s).)

Background: This study was designed to review the methodology and reporting of gastric cancer prognostic models and identify potential problems in model development., Methods: This systematic review was conducted following the CHARMS checklist. MEDLINE and EMBASE were searched. Information on patient characteristics, methodological details, and models' performance was extracted. Descriptive statistics was used to summarize the methodological and reporting quality., Results: In total, 101 model developments and 32 external validations were included. The median (range) of training sample size, number of death, and number of final predictors were 360 (29 to 15320), 193 (14 to 9560), and 5 (2 to 53), respectively. Ninety-one models were developed from routine clinical data. Statistical assumptions were reported to be checked in only nine models. Most model developments (94/101) used complete-case analysis. Discrimination and calibration were not reported in 33 and 55 models, respectively. The majority of models (81/101) have never been externally validated. None of the models have been evaluated regarding clinical impact., Conclusions: Many prognostic models have been developed, but their usefulness in clinical practice remains uncertain due to methodological shortcomings, insufficient reporting, and lack of external validation and impact studies., Impact: Future research should improve methodological and reporting quality and emphasize more on external validation and impact assessment., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Qi Feng et al.)

Background: Three-fifths of total deaths in India are attributed to noncommunicable diseases, and coronary heart disease (CHD) is one of the dominant causes. There are only few studies available in India to find confirmed CHD by pragmatic approach. This study aims to find prevalence of confirmed CHD and its risk factors in rural community of central India., Materials and Methods: This was a community-based cross-sectional study during 2013-2014 involving adults ≥60 years from 13 villages in rural central India. We screened CHD on the basis of history and standard 12-lead ECG. Apart from the past documentation of CHD, we diagnosed confirmed CHD in symptomatic patients or with resting ECG changes by means of echocardiography, exercise ECG test or coronary angiography whenever needed., Results: We screened 1190 of 1415 individuals ≥60 years for CHD. Five hundred eighty were men and 610 were women. Diagnosis of CHD was confirmed in 61 individuals (29 men and 32 women). The prevalence of CHD in individuals older than 60 years was 51.3 per 1000 population. Hypertension was the only independent risk factor associated with CHD, whereas association of diabetes mellitus, obesity, socioeconomic status and smoking with CHD was not significant., Conclusion: Prevalence of confirmed CHD has increased in agrarian rural community in central India, which requires further studies to find out causative factors., (Copyright © 2019 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Purpose: Describe the duration of symptoms, proportion of parents seeking primary care consultations, and costs for respiratory tract infections (RTIs) of children in the community., Methods: Community-based, online, prospective inception cohort study. General practitioners from socioeconomically diverse practices posted study invitations to parents of 10,310 children aged ≥3 months and <15 years., Results: One parent of 485 (4.7%) children in 331 families consented, completed baseline data and symptom diaries, and agreed to medical record review. Compared with nonresponders, responding parent's children were younger (aged 4 vs 6 years) and less socioeconomically deprived. Between February and July 2016, 206 parents reported 346 new RTIs in 259 children. Among the 197 first RTIs reported per family, it took 23 days for 90% (95% CI, 85%-94%) of children to recover. Median symptom duration was longer: in children with primary care consultations (9 days) vs those without consultations (6 days, P = 0.06); children aged <3 years (11 days) vs >3 years (7 days, P <.01); and among children with reported lower RTI symptoms (12 days) vs those with only upper RTI symptoms (8 days, P <.001). Sixteen (8.1%; 95% CI, 4.7%-12.8%) of 197 children had primary care consultations at least once (total 19 consultations), and a similar proportion had time off school or nursery. Sixty of 188 (32%; 95% CI, 25%-39%) parents reported paying for medications for their child's illness., Conclusions: Parents can be advised that RTI symptoms last up to 3 weeks. Policy makers should be aware that parents may seek primary care support in at least 1 in 12 illnesses., (© 2019 Annals of Family Medicine, Inc.)

Background: There is a need to reduce unnecessary general practitioner (GP) consultations and improve antibiotic stewardship in primary care. Respiratory tract infections (RTIs) in children are the most common reason for consulting and prescribing. Most RTI research is conducted at the point of consultation, leaving a knowledge gap regarding the population burden of RTIs., Methods: Community-based, online prospective inception cohort study with nested qualitative study, to evaluate the feasibility and acceptability of collecting RTI symptom and microbiological data from children recruited prior to RTI onset., Results: Parents of 10,310 children were invited. Three hundred thirty-one parents of 485 (4.7%) children responded and completed baseline data. Respondents were less socioeconomically deprived ( p  < 0.001) with younger (median ages 4 vs. 6 years, p  < 0.001) children than non-respondents. The same parents reported 346 RTI episodes in 259 children, and 305 RTIs (in 225 children) were retained to parent-reported symptom resolution. Restricting analyses to the first RTI episode per family (to account for clustering effects), parents fully completed symptom diaries for 180 (87%) of 192 first illness episodes. Research nurses conducted home visits for 199 RTI episodes, collecting complete (symptomatic) swab sets in 195 (98%). Parents collected 194 (98% of 199 possible) symptomatic (during the nurse visit) and 282 (92% of 305 possible) asymptomatic swab sets (on symptom resolution, no nurse present). Interviews with 30 mothers and 11 children indicated study acceptability., Conclusions: Invitation response rates were in the expected range. The high retention and qualitative evidence suggest that community-based paediatric syndromic and microbiological surveillance research is feasible., Competing Interests: Ethics and dissemination: The South West Frenchay Bristol Research Ethics Committee approved the study (reference: 15/SW/0264), including the consent processes and documentation used for participant recruitment.This manuscript contains no individual person’s data in any form.PM received funding, in the past 5 years from medical diagnostics companies who are active in developing or marketing in vitro diagnostic devices for diagnosis of respiratory tract infections, including Nanosphere Inc. and Hologic Inc. The other authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Aim: To examine the risk to heroin users of also using gabapentin or pregabalin (gabapentoids)., Design: Multi-disciplinary study: we (a) examined trends in drug-related deaths and gabapentoid prescription data in England and Wales to test for evidence that any increase in deaths mentioning gabapentin or pregabalin is associated with trends in gabapentoid prescribing and is concomitant with opioid use; (b) interviewed people with a history of heroin use about their polydrug use involving gabapentin and pregabalin; and (c) studied the respiratory depressant effects of pregabalin in the absence and presence of morphine in mice to determine whether concomitant exposure increased the degree of respiratory depression observed., Setting: England and Wales., Participants: Interviews were conducted with 30 participants (19 males, 11 female)., Measurements: (a) Office of National Statistics drug-related deaths from 1 January 2004 to 31 December 2015 that mention both an opioid and pregabalin or gabapentin; (b) subjective views on the availability, use, interactions and effects of polydrug use involving pregabalin and gabapentin; and (c) rate and depth of respiration., Results: Pregabalin and gabapentin prescriptions increased approximately 24% per year from 1 million in 2004 to 10.5 million in 2015. The number of deaths involving gabapentoids increased from fewer than one per year prior to 2009 to 137 in 2015; 79% of these deaths also involved opioids. The increase in deaths was correlated highly with the increase in prescribing (correlation coefficient 0.94; 5% increase in deaths per 100 000 increase in prescriptions). Heroin users described pregabalin as easy to obtain. They suggested that the combination of heroin and pregabalin reinforced the effects of heroin but were concerned it induced 'blackouts' and increased the risk of overdose. In mice, a low dose of S-pregabalin (20 mg/kg) that did not itself depress respiration reversed tolerance to morphine depression of respiration (resulting in 35% depression of respiration, P < 0.05), whereas a high dose of S-pregabalin (200 mg/kg) alone depressed respiration and this effect summated with that of morphine., Conclusions: For heroin users, the combination of opioids with gabapentin or pregabalin potentially increases the risk of acute overdose death through either reversal of tolerance or an additive effect of the drugs to depress respiration., (© 2017 Society for the Study of Addiction.)

Objectives: To estimate mortality rates and prognostic factors in HIV-positive patients who started combination antiretroviral therapy between 1996-1999 and survived for more than ten years., Methods: We used data from 18 European and North American HIV cohort studies contributing to the Antiretroviral Therapy Cohort Collaboration. We followed up patients from ten years after start of combination antiretroviral therapy. We estimated overall and cause-specific mortality rate ratios for age, sex, transmission through injection drug use, AIDS, CD4 count and HIV-1 RNA., Results: During 50,593 person years 656/13,011 (5%) patients died. Older age, male sex, injecting drug use transmission, AIDS, and low CD4 count and detectable viral replication ten years after starting combination antiretroviral therapy were associated with higher subsequent mortality. CD4 count at ART start did not predict mortality in models adjusted for patient characteristics ten years after start of antiretroviral therapy. The most frequent causes of death (among 340 classified) were non-AIDS cancer, AIDS, cardiovascular, and liver-related disease. Older age was strongly associated with cardiovascular mortality, injecting drug use transmission with non-AIDS infection and liver-related mortality, and low CD4 and detectable viral replication ten years after starting antiretroviral therapy with AIDS mortality. Five-year mortality risk was <5% in 60% of all patients, and in 30% of those aged over 60 years., Conclusions: Viral replication, lower CD4 count, prior AIDS, and transmission via injecting drug use continue to predict higher all-cause and AIDS-related mortality in patients treated with combination antiretroviral therapy for over a decade. Deaths from AIDS and non-AIDS infection are less frequent than deaths from other non-AIDS causes.

Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores (adjusted p-value = 0.06). Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy (adjusted p-value = 0.48). These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment.

Background: CD4 count at start of combination antiretroviral therapy (ART) is strongly associated with short-term survival, but its association with longer-term survival is less well characterized., Methods: We estimated mortality rates (MRs) by time since start of ART (<0.5, 0.5-0.9, 1-2.9, 3-4.9, 5-9.9, and ≥10 years) among patients from 18 European and North American cohorts who started ART during 1996-2001. Piecewise exponential models stratified by cohort were used to estimate crude and adjusted (for sex, age, transmission risk, period of starting ART [1996-1997, 1998-1999, 2000-2001], and AIDS and human immunodeficiency virus type 1 RNA at baseline) mortality rate ratios (MRRs) by CD4 count at start of ART (0-49, 50-99, 100-199, 200-349, 350-499, ≥500 cells/µL) overall and separately according to time since start of ART., Results: A total of 6344 of 37 496 patients died during 359 219 years of follow-up. The MR per 1000 person-years was 32.8 (95% confidence interval [CI], 30.2-35.5) during the first 6 months, declining to 16.0 (95% CI, 15.4-16.8) during 5-9.9 years and 14.2 (95% CI, 13.3-15.1) after 10 years' duration of ART. During the first year of ART, there was a strong inverse association of CD4 count at start of ART with mortality. This diminished over the next 4 years. The adjusted MRR per CD4 group was 0.97 (95% CI, .94-1.00; P = .054) and 1.02 (95% CI, .98-1.07; P = .32) among patients followed for 5-9.9 and ≥10 years, respectively., Conclusions: After surviving 5 years of ART, the mortality of patients who started ART with low baseline CD4 count converged with mortality of patients with intermediate and high baseline CD4 counts., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The relationship between chemotherapy-related toxicities and prognosis is unclear. Previous studies have examined the association of myelosuppression parameters or neuropathy with survival and reported conflicting results. This study aims to investigate 13 common chemotherapy toxicities and their association with relapse-free survival and breast cancer-specific survival., Methods: Chemotherapy-related toxicities were collected prospectively for 6,248 women with early-stage breast cancer from four randomised controlled trials (NEAT; BR9601; tAnGo; Neo-tAnGo). Cox proportional-hazards modelling was used to analyse the association between chemotherapy-related toxicities and both breast cancer-specific survival and relapse-free survival. Models included important prognostic factors and stratified by variables violating the proportional hazards assumption., Results: Multivariable analysis identified severe neutropenia (grades ≥3) as an independent predictor of relapse-free survival (hazard ratio (HR) = 0.86; 95% confidence interval (CI), 0.76-0.97; P = 0.02). A similar trend was seen for breast cancer-specific survival (HR = 0.87; 95% CI, 0.75-1.01; P = 0.06). Normal/low BMI patients experienced more severe neutropenia (P = 0.008) than patients with higher BMI. Patients with fatigue (grades ≥3) showed a trend towards reduced survival (breast cancer-specific survival: HR = 1.17; 95% CI, 0.99-1.37; P = 0.06). In the NEAT/BR9601 sub-group analysis by treatment component, this effect was statistically significant (HR = 1.61; 95% CI, 1.13-2.30; P = 0.009)., Conclusions: This large study shows a significant association between chemotherapy-induced neutropenia and increased survival. It also identifies a strong relationship between low/normal BMI and increased incidence of severe neutropenia. It provides evidence to support the development of neutropenia-adapted clinical trials to investigate optimal dose calculation and its impact on clinical outcome. This is important in populations where obesity may lead to sub-optimal chemotherapy doses.

Background: Migraine is a highly disabling disease affecting a significant proportion of the Australian population. The methylenetetrahydrofolate reductase (MTHFR) C677T variant has been associated with increased levels of homocysteine and risk of migraine with aura (MA). Folic acid (FA), vitamin B6 , and B12 supplementation has been previously shown to reduce increased levels of homocysteine and decrease migraine symptoms. However, the influence of dietary folate intake on migraine has been unclear. The aim of the current study was to analyze the association of dietary folate intake in the form of dietary folate equivalent, FA, and total food folate (TFF) on migraine frequency, severity, and disability., Methods: A cohort of 141 adult females of Caucasian descent with MA was genotyped for the MTHFR C677T variant using restriction enzyme digestion. Dietary folate information was collected from all participants and analyzed using the "FoodWorks" 2009 package. Folate consumption was compared with migraine frequency, severity, and disability using linear regression., Results: A significant inverse relation was observed between dietary folate equivalent (R(2)  = 0.201, B = -0.002, P = .045, 95% confidence interval [CI] [-0.004, -0.001]) and FA (R(2)  = 0.255, B = -0.005, P = .036, 95% CI [-0.009, -0.002]) consumption and migraine frequency. It was also observed that in individuals with the CC genotype for the MTHFR C677T variant, migraine frequency was significantly linked to FA consumption (R(2)  = 0.106, B = -0.004, P = .029, 95% CI [-0.007, -0.004])., Conclusions: The results from this study indicate that folate intake in the form of FA may influence migraine frequency in female MA sufferers., (© 2015 American Headache Society.)

Background: The goal of antiretroviral therapy (ART) is to reduce HIV-related morbidity and mortality by suppressing HIV replication. The prognostic value of persistent low-level viremia (LLV), particularly for clinical outcomes, is unknown., Objective: Assess the association of different levels of LLV with virological failure, AIDS event, and death among HIV-infected patients receiving combination ART., Methods: We analyzed data from 18 cohorts in Europe and North America, contributing to the ART Cohort Collaboration. Eligible patients achieved viral load below 50  copies/ml within 3-9 months after ART initiation. LLV50-199 was defined as two consecutive viral loads between 50 and 199  copies/ml and LLV200-499 as two consecutive viral loads between 50 and 499  copies/ml, with at least one between 200 and 499  copies/ml. We used Cox models to estimate the association of LLV with virological failure (two consecutive viral loads at least 500  copies/ml or one viral load at least 500 copies/ml, followed by a modification of ART) and AIDS event/death., Results: Among 17 902 patients, 624 (3.5%) experienced LLV50-199 and 482 (2.7%) LLV200-499. Median follow-up was 2.3 and 3.1 years for virological and clinical outcomes, respectively. There were 1903 virological failure, 532 AIDS events and 480 deaths. LLV200-499 was strongly associated with virological failure [adjusted hazard ratio (aHR) 3.97, 95% confidence interval (CI) 3.05-5.17]. LLV50-199 was weakly associated with virological failure (aHR 1.38, 95% CI 0.96-2.00). LLV50-199 and LLV200-499 were not associated with AIDS event/death (aHR 1.13, 95% CI 0.81-1.68; and aHR 0.95, 95% CI 0.62-1.48, [corrected] respectively)., Conclusion: LLV200-499 was strongly associated with virological failure, but not with AIDS event/death. Our results support the US guidelines, which define virological failure as a confirmed viral load above 200  copies/ml.

While hydroxyl radical cleavage is widely used to map RNA tertiary structure, lack of mechanistic understanding of strand break formation limits the degree of structural insight that can be obtained from this experiment. Here, we determine how individual ribose hydrogens of sarcin/ricin loop RNA participate in strand cleavage. We find that substituting deuterium for hydrogen at a ribose 5'-carbon produces a kinetic isotope effect on cleavage; the major cleavage product is an RNA strand terminated by a 5'-aldehyde. We conclude that hydroxyl radical abstracts a 5'-hydrogen atom, leading to RNA strand cleavage. We used this approach to obtain structural information for a GUA base triple, a common tertiary structural feature of RNA. Cleavage at U exhibits a large 5' deuterium kinetic isotope effect, a potential signature of a base triple. Others had noted a ribose-phosphate hydrogen bond involving the G 2'-OH and the U phosphate of the GUA triple, and suggested that this hydrogen bond contributes to backbone rigidity. Substituting deoxyguanosine for G, to eliminate this hydrogen bond, results in a substantial decrease in cleavage at G and U of the triple. We conclude that this hydrogen bond is a linchpin of backbone structure around the triple., (© The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Control and eradication of malaria is hindered by the acquisition of drug resistance by Plasmodium species. This has necessitated a persistent search for novel drugs and more efficient targets. Plasmodium species specific lactate dehydrogenase is one of the potential therapeutic and diagnostic targets, because of its indispensable role in endoerythrocytic stage of the parasite. A target molecule that is highly conserved in the parasite population can be more effectively used in diagnostics and therapeutics, hence, in the present study polymorphism in PfLDH (Plasmodiumfalciparum specific LDH) and PvLDH (Plasmodiumvivax specific LDH) genes was analyzed using PCR-single strand confirmation polymorphism (PCR-SSCP) and sequencing. Forty-six P. falciparum and thirty-five P. vivax samples were screened from different states of India. Our findings have revealed presence of a single PfLDH genotype and six PvLDH genotypes among the studied samples. Interestingly, along with synonymous substitutions, nonsynonymous substitutions were reported to be present for the first time in the PvLDH genotypes. Further, through amino acid sequence alignment and homology modeling studies we observed that the catalytic residues were conserved in all PvLDH genotypes and the nonsynonymous substitutions have not altered the enzyme structure significantly. Evolutionary genetics studies have confirmed that PfLDH and PvLDH loci are under strong purifying selection. Phylogenetic analysis of the pLDH gene sequences revealed that P. falciparum compared to P. vivax, has recent origin. The study therefore supports PfLDH and PvLDH as suitable therapeutic and diagnostic targets as well as phylogenetic markers to understand the genealogy of malaria species., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: Associations between taxane-related sensory neuropathy (TRSN) and single-nucleotide polymorphisms (SNP) have previously been reported, but few have been replicated in large, independent validation studies. This study evaluates the association between previously investigated SNPs and TRSN, using genotype data from a study of chemotherapy-related toxicity in patients with breast cancer., Experimental Design: We investigated 73 SNPs in 50 genes for their contribution to TRSN risk, using genotype data from 1,303 European patients. TRSN was assessed using National Cancer Institute common toxicity criteria for adverse events classification. Unconditional logistic regression evaluated the association between each SNP and TRSN risk (primary analysis). Cox regression analysis assessed the association between each SNP and cumulative taxane dose causing the first reported moderate/severe TRSN (secondary analysis). The admixture likelihood (AML) test, which considers all SNPs with a prior probability of association with TRSN together, tested the hypothesis that certain SNPs are truly associated., Results: The AML test provided strong evidence for the association of some SNPs with TRSN (P = 0.023). The two most significantly associated SNPs were rs3213619(ABCB1) [OR = 0.47; 95% confidence interval (CI), 0.28-0.79; P = 0.004] and rs9501929(TUBB2A) (OR = 1.80; 95% CI, 1.20-2.72; P = 0.005). A further 9 SNPs were significant at P-value ≤ 0.05., Conclusion: This is currently the largest study investigating SNPs associated with TRSN. We found strong evidence that SNPs within genes in taxane pharmacokinetic and pharmacodynamic pathways contribute to TRSN risk. However, a large proportion of the inter-individual variability in TRSN remains unexplained. Further validated results from GWAS will help to identify new pathways, genes, and SNPs involved in TRSN susceptibility., (©2014 AACR.)

Background: HIV cohort collaborations, which pool data from diverse patient cohorts, have provided key insights into outcomes of antiretroviral therapy (ART). However, the extent of, and reasons for, between-cohort heterogeneity in rates of AIDS and mortality are unclear., Methods: We obtained data on adult HIV-positive patients who started ART from 1998 without a previous AIDS diagnosis from 17 cohorts in North America and Europe. Patients were followed up from 1 month to 2 years after starting ART. We examined between-cohort heterogeneity in crude and adjusted (age, sex, HIV transmission risk, year, CD4 count and HIV-1 RNA at start of ART) rates of AIDS and mortality using random-effects meta-analysis and meta-regression., Results: During 61 520 person-years, 754/38 706 (1.9%) patients died and 1890 (4.9%) progressed to AIDS. Between-cohort variance in mortality rates was reduced from 0.84 to 0.24 (0.73 to 0.28 for AIDS rates) after adjustment for patient characteristics. Adjusted mortality rates were inversely associated with cohorts' estimated completeness of death ascertainment [excellent: 96-100%, good: 90-95%, average: 75-89%; mortality rate ratio 0.66 (95% confidence interval 0.46-0.94) per category]. Mortality rate ratios comparing Europe with North America were 0.42 (0.31-0.57) before and 0.47 (0.30-0.73) after adjusting for completeness of ascertainment., Conclusions: Heterogeneity between settings in outcomes of HIV treatment has implications for collaborative analyses, policy and clinical care. Estimated mortality rates may require adjustment for completeness of ascertainment. Higher mortality rate in North American, compared with European, cohorts was not fully explained by completeness of ascertainment and may be because of the inclusion of more socially marginalized patients with higher mortality risk.

Ethnopharmacological Relevance: Medicinal plants traditionally used to treat malaria can provide quality leads towards identifying novel anti-malarial drugs. Here we combined this approach with target based drug discovery and explored Plasmodium specific lactate dehydrogenase (LDH) inhibitory activity of 8 Indian plants which are ethnically used to treat malaria., Methods: LDH from Indian Plasmodium falciparum and Plasmodium vivax strains, were cloned and expressed in Escherichia coli, followed by purification of recombinant enzymes (rPfLDH and rPvLDH respectively). Extracts of 8 plants in different organic and aqueous solvents, were screened for their inhibitory activity on rPfLDH, rPvLDH and mammalian LDHs. Phyllanthus amarus aqueous extract was further tested for in vitro parasiticidal activity., Results: Aqueous extract of Phyllanthus amarus Schum. and Thonn. and chloroform extract of Murraya koenigii (L.) Spreng. exhibited profound and exclusive inhibitory effect on Plasmodium falciparum LDH (IC(50)=11.2 μg/ml ± 0.4) and Plasmodium vivax LDH (IC(50)=6.0 μg/ml ± 0.6) respectively. Moreover, Phyllanthus amarus aqueous extract also demonstrated antiplasmodial activity in vitro, on Chloroquine sensitive and resistant strains of Plasmodium falciparum (IC(50)=7.1 μg/ml ± 0.5 and 6.9 μg/ml ± 0.7 respectively)., Conclusion: Target specific screening of traditional herbs used in malaria treatment has proffered Phyllanthus amarus and Murraya koenigii extracts as hits which can optimistically provide novel antimalarial drugs., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Allyl isothiocyanate (AITC), which has the potential to be used as flavoring, antibacterial, antifungal, antifermentative and antibrowning agent in food industry, was extracted from the pretreated MM by distillation technique. The mustard meal was analyzed for the proximate composition and the metals Fe, Mg and Zn. At the optimum pretreatment conditions of temperature 60 °C, time 120 min and pH 4.5, the effect of fractional distillation, mesh size and different additives was studied. Considerable effect of mesh size was observed, as the mesh size was decreased from 1,690 to 400 μm, the allyl isothiocyanate content was increased from 99.15 to 337.11 mg/100 ml. Addition of magnesium chloride (0.05 g/l to 0.2 g/l) and L-ascorbic acid (1 g/l to 5 g/l) increased allyl isothiocyanate from 257.79 to 317.28 mg/100 ml and 316.77 to 396.60 mg/100 ml respectively whereas the addition of the magnesium chloride and L-ascorbic acid in combination did not affect the AITC extraction rate as compare to their addition in single effect.

Background: The increasing trend for incorporation of biological sample collection within clinical trials requires sample collection procedures which are convenient and acceptable for both patients and clinicians. This study investigated the feasibility of using saliva-extracted DNA in comparison to blood-derived DNA, across two genotyping platforms: Applied Biosystems Taqman™ and Illumina Beadchip™ genome-wide arrays., Method: Patients were recruited from the Pharmacogenetics of Breast Cancer Chemotherapy (PGSNPS) study. Paired blood and saliva samples were collected from 79 study participants. The Oragene DNA Self-Collection kit (DNAgenotek®) was used to collect and extract DNA from saliva. DNA from EDTA blood samples (median volume 8 ml) was extracted by Gen-Probe, Livingstone, UK. DNA yields, standard measures of DNA quality, genotype call rates and genotype concordance between paired, duplicated samples were assessed., Results: Total DNA yields were lower from saliva (mean 24 μg, range 0.2-52 μg) than from blood (mean 210 μg, range 58-577 μg) and a 2-fold difference remained after adjusting for the volume of biological material collected. Protein contamination and DNA fragmentation measures were greater in saliva DNA. 78/79 saliva samples yielded sufficient DNA for use on Illumina Beadchip arrays and using Taqman assays. Four samples were randomly selected for genotyping in duplicate on the Illumina Beadchip arrays. All samples were genotyped using Taqman assays. DNA quality, as assessed by genotype call rates and genotype concordance between matched pairs of DNA was high (>97%) for each measure in both blood and saliva-derived DNA., Conclusion: We conclude that DNA from saliva and blood samples is comparable when genotyping using either Taqman assays or genome-wide chip arrays. Saliva sampling has the potential to increase participant recruitment within clinical trials, as well as reducing the resources and organisation required for multicentre sample collection.

Background: The low incidence of colorectal cancer in India, coupled with absence of specialized units, contribute to lack of relevant data arising from the subcontinent. We evaluated the data of the senior author to better define the requirements that would enable development of specialized units in a country where colorectal cancer burden is increasing., Methods: We retrospectively analyzed data of 401 consecutive colorectal resections from a prospective database of the senior author. In addition to patient demographics and types of resections, perioperative data like intraoperative blood loss, duration of surgery, complications, re-operation rates and hospital stay were recorded and analyzed., Results: The median age was 52 years (10-86 years). 279 were males and 122 were females. The average duration of surgery was 220.32 minutes (range 50-480 min). The overall complication rate was 12.2% (49/401) with a 1.2% (5/401) mortality rate. The patients having complications had an increase in their median hospital stay (from 10.5 days to 23.4 days) and the re-operation rate in them was 51%. The major complications were anastomotic leaks (2.5%) and stoma related complications (2.7%)., Conclusions: This largest ever series from India compares favorably with global standards. In a nation where colorectal cancer is on the rise, it is imperative that high volume centers develop specialized units to train future specialist colorectal surgeons. This would ensure improved quality assurance and delivery of health care even to outreach, low volume centers.

Background: The ideal treatment of patients with "borderline resectable pancreatic tumors (BRTs)" needs to be established. Current protocols advise neoadjuvant chemo(radio)therapy, although some patients may appear to have BRT on preoperative imaging and a complete resection may be achieved without the need for vascular resection. The aim of the present study was to identify specific findings on preoperative imaging that could help predict in which patients with BRT a complete resection, with or without vascular resection (VR), could be achieved., Methods: Twelve patients with BRTs were identified. Tumor location, maximum degree of circumferential contact (CC), length of contact of the tumor with major vessels (LC), and luminal narrowing of vessels at the point of contact with the tumor (venous deformity, VD) were graded on preoperatively acquired multidetector computed tomography (MDCT) images and then compared with the intraoperative findings and need for VR., Results: A complete resection (R0) was achieved in 10 patients with 2 having microscopic positive margins (R1) on histopathology at the uncinate margin. Four of the 10 patients required VR (40%). In 3 of the 4 patients whose tumors required VRs, CC was ≥grade III and VD was grade 2. LC did not influence the need for VR., Conclusions: It is possible to achieve a complete resection at the first instance in patients found to have BRTs on preoperative imaging. Preoperative MDCT-based grading systems and our proposed criteria may help identify such patients, thus avoiding any delay in curative resections in such patients.

Introduction: Tamoxifen is one of the most effective adjuvant breast cancer therapies available. Its metabolism involves the phase I enzyme, cytochrome P4502D6 (CYP2D6), encoded by the highly polymorphic CYP2D6 gene. CYP2D6 variants resulting in poor metabolism of tamoxifen are hypothesised to reduce its efficacy. An FDA-approved pre-treatment CYP2D6 gene testing assay is available. However, evidence from published studies evaluating CYP2D6 variants as predictive factors of tamoxifen efficacy and clinical outcome are conflicting, querying the clinical utility of CYP2D6 testing. We investigated the association of CYP2D6 variants with breast cancer specific survival (BCSS) in breast cancer patients receiving tamoxifen., Methods: This was a population based case-cohort study. We genotyped known functional variants (n = 7; minor allele frequency (MAF) > 0.01) and single nucleotide polymorphisms (SNPs) (n = 5; MAF > 0.05) tagging all known common variants (tagSNPs), in CYP2D6 in 6640 DNA samples from patients with invasive breast cancer from SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity); 3155 cases had received tamoxifen therapy. There were 312 deaths from breast cancer, in the tamoxifen treated patients, with over 18000 years of cumulative follow-up. The association between genotype and BCSS was evaluated using Cox proportional hazards regression analysis., Results: In tamoxifen treated patients, there was weak evidence that the poor-metaboliser variant, CYP2D6*6 (MAF = 0.01), was associated with decreased BCSS (P = 0.02; HR = 1.95; 95% CI = 1.12-3.40). No other variants, including CYP2D6*4 (MAF = 0.20), previously reported to be associated with poorer clinical outcomes, were associated with differences in BCSS, in either the tamoxifen or non-tamoxifen groups., Conclusions: CYP2D6*6 may affect BCSS in tamoxifen-treated patients. However, the absence of an association with survival in more frequent variants, including CYP2D6*4, questions the validity of the reported association between CYP2D6 genotype and treatment response in breast cancer. Until larger, prospective studies confirming any associations are available, routine CYP2D6 genetic testing should not be used in the clinical setting.

Early enteral nutrition (EN) after major digestive surgery has been receiving increasing attention. Supporting evidence has not been clear. This evidence-based review traces the development of early EN and analyses whether it is indeed an advance. We performed a PubMed search in October 2009 with the key words enteral nutrition, early feeding, and gastrointestinal surgery. Our emphasis was on earliest studies documenting the benefits or adverse effects of EN, comparative studies, documenting the benefits or adverse effects of EN, comparative studies, and randomized controlled trials. Thirty-one results were returned from which 17 were included for evaluation (1979-2009). Fifteen papers concluded that early EN was beneficial. In general, patients put on early EN and immunonutrition postoperatively seemed to have decreased hospital stay, decreased complication rates, decreased treatment and hospital costs, and even decreased morbidity and mortality; however, judicious use has been suggested. One study did not recommend early enteral feeding in well-nourished patients at low risk of nutrition-related complications and another suggested that immunonutrition is not beneficial and should not be used routinely. Early EN has been safely given after major digestive surgery since 1979. It benefits patients undergoing major gastrointestinal (GI) surgeries, with reduction in perioperative infection, better maintainance of nitrogen balance, and shorter hospital stay. Early EN may be superior to total parenteral nutrition (TPN). However, TPN is perhaps better tolerated in the immediate postoperative period. Early enteral immunonutrition should be used only in malnourished and in transfused patients. Early EN after major digestive surgery is an old advance that is now in fashion.

Perianal lesions are exceedingly common in Crohn's disease and many patients have more than one type of lesion. Skin tags, fissures and haemorrhoids may persist over time and are usually managed expectantly or with topical therapy. Perianal and rectovaginal fistulas and associated abscesses often require both local and systemic therapy, and recurrence is common. In general, the clinical course of Crohn's disease is more aggressive in patients with perianal involvement. Established risk factors for perianal disease include colonic disease and young age at disease onset. Classification schema now recognize perianal fistulas as distinct from other forms of penetrating Crohn's disease. Genetic susceptibility factors for perianal disease may exist, but they remain incompletely delineated at present. There is hope that immunosuppressive and biotechnology medications will influence the natural history of perianal disease by preventing invasive surgeries, disease complications and recurrence, but this needs to be confirmed. Cancer, a rare complication of perianal disease, must be suspected when lesions persist despite therapy.

Background: Previous studies have been unable to characterise the association between physical activity and obesity, possibly because most relied on inaccurate measures of physical activity and obesity., Methods and Findings: We carried out a cross sectional analysis on 5,500 12-year-old children enrolled in the Avon Longitudinal Study of Parents and Children. Total physical activity and minutes of moderate and vigorous physical activity (MVPA) were measured using the Actigraph accelerometer. Fat mass and obesity (defined as the top decile of fat mass) were measured using the Lunar Prodigy dual x-ray emission absorptiometry scanner. We found strong negative associations between MVPA and fat mass that were unaltered after adjustment for total physical activity. We found a strong negative dose-response association between MVPA and obesity. The odds ratio for obesity in adjusted models between top and the bottom quintiles of minutes of MVPA was 0.03 (95% confidence interval [CI] 0.01-0.13, p-value for trend <0.0001) in boys and 0.36 (95% CI 0.17-0.74, p-value for trend = 0.006) in girls., Conclusions: We demonstrated a strong graded inverse association between physical activity and obesity that was stronger in boys. Our data suggest that higher intensity physical activity may be more important than total activity.

Sampling an intact sequence of oceanic crust through lavas, dikes, and gabbros is necessary to advance the understanding of the formation and evolution of crust formed at mid-ocean ridges, but it has been an elusive goal of scientific ocean drilling for decades. Recent drilling in the eastern Pacific Ocean in Hole 1256D reached gabbro within seismic layer 2, 1157 meters into crust formed at a superfast spreading rate. The gabbros are the crystallized melt lenses that formed beneath a mid-ocean ridge. The depth at which gabbro was reached confirms predictions extrapolated from seismic experiments at modern mid-ocean ridges: Melt lenses occur at shallower depths at faster spreading rates. The gabbros intrude metamorphosed sheeted dikes and have compositions similar to the overlying lavas, precluding formation of the cumulate lower oceanic crust from melt lenses so far penetrated by Hole 1256D.

Experiments on air and biomonitoring were conducted to evaluate pollution impact on the vegetation along the road in Jalgaon City, Maharashtra. The plantation along the roads and mainly includes neem (Aadirachta indica), peepal (Ficus religiosa), banyan (Ficus benghalensis), almond (Terminalia catapa). For biomonitoring, leaf area, total chlorophyll, plant protein were analyzed to study the impact of air pollutants. It was observed that vegetation at roadside with heavy traffic and markets was much affected by vehicular emission. Significant decrease in total chlorophyll and protein content was observed with reduced leaf area. It is concluded that plants can be used as indicators for urban air pollution, and there is need to protect the roadside plants from air pollution.

The Hawaiian-Emperor volcanic island and seamount chain is usually attributed to a hot mantle plume, located beneath the Pacific lithosphere, that delivers material sourced from deep in the mantle to the surface. The shield volcanoes of the Hawaiian islands are distributed in two curvilinear, parallel trends (termed 'Kea' and 'Loa'), whose rocks are characterized by general geochemical differences. This has led to the proposition that Hawaiian volcanoes sample compositionally distinct, concentrically zoned, regions of the underlying mantle plume. Melt inclusions, or samples of local magma 'frozen' in olivine phenocrysts during crystallization, may record complexities of mantle sources, thereby providing better insight into the chemical structure of plumes. Here we report the discovery of both Kea- and Loa-like major and trace element compositions in olivine-hosted melt inclusions in individual, shield-stage Hawaiian volcanoes--even within single rock samples. We infer from these data that one mantle source component may dominate a single lava flow, but that the two mantle source components are consistently represented to some extent in all lavas, regardless of the specific geographic location of the volcano. We therefore suggest that the Hawaiian mantle plume is unlikely to be compositionally concentrically zoned. Instead, the observed chemical variation is probably controlled by the thermal structure of the plume.

Enlarged thyroid with retrosternal extension presenting as anterior mediastinal mass is known. Superior vena cava (SVC) syndrome due to direct invasion from a primary thyroid malignancy is a rare phenomenon. We present a unique case of papillary carcinoma of thyroid extending into the posterior mediastinum with superior vena cava syndrome along with internal jugular and azygous vein thrombosis.

A case of a 21 years male patient with type 3 glycogen storage disorder diagnosed at necropsy, who died suddenly with hypovolemic shock following a massive upper gastrointestinal bleeding due to hepatocellular failure is reported. Salient features of GSD type 3 are briefly discussed.

Spongilla lacustris were exposed to sub lethal concentrations of pesticides, rogar and endosulfan for one month period. Metabolites like carbohydrates, protein and enzymes like those that peroxidase and carbonic anhydrase were estimated in the experimental and control animals. The results show, depletion of carbohydrates while protein elevated as the days progressed. Similarly an enzyme activity found to be decreased in exposed Spongilla lacustris.

Brush border membrane vesicles (BBMVs) were prepared from the 2nd instar larvae of Helicoverpa armigera. Binding of the activated Cry1Ac of Bacillus thuringiensis (Bt) toxin was shown by immunoblot. A 120-kDa protein was identified as a receptor for the Cry1Ac type delta-endotoxin. The aminopeptidase-N activity of BBMVs was measured as the hydrolysis of L-leucine p-nitroanilide. The specific activity was 35 units/mg protein. The BBMV preparation also showed low level of alkaline phosphatase activity. Zn++ chelating agents 2,2'-dipyridyl and 1,10-phenanthroline inhibited aminopeptidase activity at 10 mM concentration, indicating the presence of zinc-dependent aminopeptidase in the brush border of H. armigera. The aminopeptidase activity was increased with increasing concentration of delta-endotoxin. The purified 120-kDa binding protein was N-terminally sequenced. The first 10-amino-acid sequence showed 60-77% similarity with human cysteine-rich secretory protein-1 precursor, inhibin alpha chain precursor. Salmonella flagellar hook protein and yeast carboxypeptidase S.