Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial.

BACKGROUND: Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved to treat locally advanced/metastatic urothelial carcinoma (mUC) in patients with susceptible FGFR3/2 alterations (FGFRalt) who progressed after platinum-containing chemotherapy. FGFR-altered tumours are enriched in luminal 1 subtype and may have limited clinical benefit from anti-programmed death-(ligand) 1 [PD-(L)1] treatment. This cohort in the randomized, open-label phase III THOR study assessed erdafitinib versus pembrolizumab in anti-PD-(L)1-naive patients with mUC. PATIENTS AND METHODS: Patients ≥18 years with unresectable advanced/mUC, with select FGFRalt, disease progression on one prior treatment, and who were anti-PD-(L)1-naive were randomized 1 : 1 to receive erdafitinib 8 mg once daily with pharmacodynamically guided uptitration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. RESULTS: The intent-to-treat population (median follow-up 33 months) comprised 175 and 176 patients in the erdafitinib and pembrolizumab arms, respectively. There was no statistically significant difference in OS between erdafitinib and pembrolizumab [median 10.9 versus 11.1 months, respectively; hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.92-1.51; P = 0.18]. Median PFS for erdafitinib and pembrolizumab was 4.4 and 2.7 months, respectively (HR 0.88; 95% CI 0.70-1.10). ORR was 40.0% and 21.6% (relative risk 1.85; 95% CI 1.32-2.59) and median duration of response was 4.3 and 14.4 months for erdafitinib and pembrolizumab, respectively. 64.7% and 50.9% of patients in the erdafitinib and pembrolizumab arms had ≥1 grade 3-4 adverse events (AEs); 5 (2.9%) and 12 (6.9%) patients, respectively, had AEs that led to death. CONCLUSIONS: Erdafitinib and pembrolizumab had similar median OS in this anti-PD-(L)1-naive, FGFR-altered mUC population. Outcomes with pembrolizumab were better than assumed and aligned with previous reports in non- FGFR-altered populations. Safety results were consistent with the known profiles for erdafitinib and pembrolizumab in this patient population.

Synthesis and Properties of Electron-Deficient and Electron-Rich Redox-Active Ionic π-Systems.

There is growing interest towards the design and synthesis of organic redox-active systems, which exist in ionic form. Multi- redox systems entail life-sustaining processes like photosynthesis and cellular respiration. The significant challenge for material scientists is to rationally design complex molecular materials that can store and transfer multiple electrons at low operational potentials and are stable under ambient conditions. Also, important are the designed ionic π-systems that combine efficient electron and ion transport. Here, we discuss the synthesis of ionic π-systems which exist in the closed-shell form. Firstly, different classes of ionic arylenediimides and viologens with different π-linkers are discussed from the synthetic, structural and redox perspective. These ionic π-systems are based on the electron deficient π-scaffolds, and are shown to accumulate upto six electrons. We then discuss electron-rich ionic arylenediimides which can exist in anionic form or zwitterionic form. The anionic electron donors have absorption extending to the near Infrared (NIR) region and can be stabilized in aqueous solution. We also discuss the effect of the electron accumulation on the aromaticity and non-aromaticity of the naphthalene and the imide rings of the naphthalenediimides. We finally discuss in brief, the applications related to the organic mixed ionic-electronic conductors.

Comprehensive assessment of holding urine as a behavioral risk factor for UTI in women and reasons for delayed voiding.

BACKGROUND: Women of reproductive age group have greater predilection to urinary tract infections (UTI). Various risk factors increase the prevalence in women. Emergence of multidrug resistant uropathogens make clinical management of UTI challenging. Here we assess holding of urine as risk factor of UTI in women and reasons for delayed voiding. We also investigate the relationship between frequency of UTIs and overall behavioural features, menstrual hygiene and attitude of women towards their own health issues. METHODS: A questionnaire based cross-sectional study was performed with 816 hostel residents with written consent. Self-reported data was statistically analysed using SPSS software. Urinalysis and urine culture were done for 50 women by random sampling to obtain the information on leading causative agents of UTI in the study population and their antimicrobial resistance profile. RESULTS: The prevalence of UTI among the participants without risk factors was found to be 27.5 (95% CI: 24.4-30.7). Attitude of women towards their own personal health issues and use of public toilets showed a correlation with prevalence of infection. Delay in urination on habitual basis was found to be associated with UTI. Uropathogens isolated by random sampling were resistant to multiple drugs that are generally used to treat UTI. CONCLUSIONS: Holding urine for long time had proven to be an important risk factor and amongst different reasons of holding urine, holding due to poor sanitary condition of public toilets was the most common. Higher frequency of self-reported UTIs is related to holding of urine, behavioural features and attitude of women.

The role of infrared dermal thermometry in the management of neuropathic diabetic foot ulcers.

AIM: This prospective observational study evaluated the role of infrared (IR) dermal thermometry in the management of diabetic foot ulcers. METHODS: Thirty participants with unilateral neuropathic diabetic foot ulcers of University of Texas grade 1 or 2 (stage A) were followed up monthly for 1 year. At each visit, skin temperatures were measured with an IR dermal thermometer at corresponding sites on both feet, using the contralateral feet without ulcers as controls. RESULTS: Average temperature and ulcer temperature in affected feet were significantly higher than in unaffected feet, with a mean difference of 1.2 °C [95% confidence interval (CI) 0.7 to 1.7] and 3.1 °C (95% CI 2.3 to 3.9), respectively. Although the gradient between average temperature of affected foot and that of unaffected foot normalized (mean difference 0.2 °C, 95% CI -0.2 to 0.7) at healing, the temperature gradient between the ulcer and a corresponding site on the unaffected foot decreased but did not normalize (mean difference 2.1 °C, 95% CI 1.2 to 3.1) even at healing, as documented by skin closure, and persisted for up to 1 month after skin closure. A gradient of ≥1 °C between average temperature of affected foot and that of unaffected foot at initial presentation or at any time during ulcer healing was found to predict impaired healing and should alert clinicians to ulcers requiring more attention. An incremental trend in temperature gradient (median difference 2.2 °C; range 0.1-6.3 °C) at a site on the foot was predictive of a recurrent ulcer involving the same site. CONCLUSIONS: IR dermal thermometry may have a role in predicting diabetic foot ulcer healing, in determining the completeness of healing and in guiding the duration of offloading. Serial monitoring of the temperature gradient may predict the development of recurrent diabetic foot ulcers.

High titres of IgM-bound circulating immune complexes and erythrocytic oxidative damage are indicators of dengue severity.

Global incidence of dengue has drastically increased in the last few years. Despite the global morbidity and mortality associated with dengue infection, mechanisms of immune control and viral pathogenesis are poorly explored. Pancytopenias, along with increased oxidative stress, are salient clinical findings in severe dengue patients. Previously, we demonstrated significant differences of circulating immune complexes (CICs) among severe and non-severe dengue patients. Accordingly, here we sought to determine the contributory role of affinity-purified antibody-bound CICs in dengue severity. To characterize intracellular oxidative stress induced by antibody-bound CICs, 5-(and-6)-chloromethyl-2'-7'-dichlorodihydrofluorescein diacetate (DCFDA) was measured by flow cytometry. At the same time, CICs sensitized healthy red blood cells (RBC) and patients' RBC morphology was determined by scanning electron microscopy and flow cytometry analysis. Erythrophagocytosis and ferritin levels were further determined in severe and non-severe dengue patients. Our results showed that the severe patients had high titres of immunoglobulin (Ig)M-bound CICs (P < 0·0001) in their sera, increased intracellular oxidative stress (P < 0·0001), high ferritin levels (P < 0·0001), altered morphology of RBC and finally enhanced erythrophagocytosis. This study shows for the first time that RBC morphology is altered in severe dengue patients. Taken together, this study suggests that the enhanced IgM-bound CICs could contribute to the increased oxidative stress and act directly on RBC destruction of severe dengue patients, and is an important pathophysiological determinant. Hence, IgM-bound CICs can serve as an important laboratory parameter to monitor dengue infection progression.

Mixed-methods assessment of surgical capacity in two regions in Ethiopia.

BACKGROUND: Surgery is among the most neglected parts of healthcare systems in low- and middle-income countries. Ethiopia has launched a national strategic plan to address challenges in the surgical system. This study aimed to assess surgical capacity in two Ethiopian regions to inform priority areas for improvement. METHODS: A mixed-methods study was conducted using two tools adapted from the Lancet Commission's Surgical Assessment Tools: a quantitative Hospital Assessment Tool and a qualitative semistructured interview tool. Fifteen hospitals selected by the Federal Ministry of Health were surveyed in the Tigray and Amhara regions to assess the surgical system across five domains: service delivery, infrastructure, workforce, information management and financing. RESULTS: Service delivery was low across hospitals with a mean(s.d.) of 5(6) surgical cases per week and a narrow range of procedures performed. Hospitals reported varying availability of basic infrastructure, including constant availability of electricity (9 of 15) and running water (5 of 15). Unavailable or broken diagnostic equipment was also common. The majority of surgical and anaesthesia services were provided by non-physician clinicians, with little continuing education available. All hospitals tracked patient-level data regularly and eight of 15 hospitals reported surgical volume data during the assessment, but research activities were limited. Hospital financing specified for surgery was rare and the majority of patients must pay out of pocket for care. CONCLUSION: Results from this study will inform programmes to simultaneously improve each of the health system domains in Ethiopia; this is required if better access to and quality of surgery, anaesthesia and obstetric services are to be achieved.

Individuals with filaggrin-related eczema and asthma have increased long-term medication and hospital admission costs.

BACKGROUND: Eczema and asthma are chronic diseases with onset usually before the age of 5 years. More than 50% of individuals with eczema will develop asthma and/or other allergic diseases. Several loss-of-function mutations in filaggrin (FLG) have been identified in patients with eczema. However, the association of FLG with healthcare use is unknown. OBJECTIVES: To determine whether FLG mutations are associated with increased prescribing for eczema and asthma and whether increased prescribing is associated with increased healthcare costs. METHODS: A secondary analysis of BREATHE, a cross-sectional study of gene-environment associations with asthma severity, was undertaken. BREATHE data was collected for 1100 participants with asthma, in Tayside and Fife, Scotland during the period 2003-2005. Through collaboration with the Health Informatics Centre in Dundee, BREATHE was linked to accident and emergency, community prescribing and Scottish morbidity records. The data linkage allowed longitudinal exploration of associations between genetic variation and prescribing. RESULTS: An association was found between FLG mutations and increased prescribing for mild and moderate eczema, asthma-reliever medicine and asthma exacerbations. A strong association was found between FLG mutations and prescribing of emollients [incidence rate ratio (IRR) 2·19, 95% confidence interval (CI) 1·36-3·52], treatment for severe eczema (IRR 2·18, 95% CI 1·22-3·91) and a combination of a long-acting ß2 -agonist and corticosteroids (IRR 3·29, 95% CI 1·68-6·43). CONCLUSIONS: The presence of FLG mutations in this cohort is associated with increased prescribing for eczema and asthma. Randomized controlled trials are required to determine if these individuals could benefit from management strategies to reduce morbidity and treatment costs.

Laparoscopic salpingectomy and removal of Essure hysteroscopic sterilisation device: a case series.

OBJECTIVES: Tubal sterilisation using Essure is a minimally invasive technique for permanent contraception, with high rates of patient satisfaction. However, some women subsequently choose removal of the inserts, due to side effects such as pelvic pain, abnormal bleeding, dyspareunia or allergic dermatitis. This case series presents the management of eight women who underwent laparoscopic removal of Essure inserts in conjunction with salpingectomy. We describe our surgical technique, its underlying principles and immediate surgical outcomes. METHODS: Eight patients were identified as having undergone removal of Essure inserts, via an electronic search of the surgical procedures database. A retrospective review of case records was undertaken. The primary outcome was safety and feasibility of the laparoscopic salpingectomy approach. Secondary outcome measures included implant fracture rate, operative time, blood loss and length of patient stay. RESULTS: All eight women were able to undergo laparoscopic salpingectomy and removal of the Essure inserts without the need for laparotomy or hysterectomy. There were no incidences of fracture or incomplete removal of the insert. Immediate postoperative recovery was uncomplicated in all eight women; the mean length of stay was 17 h. One patient had a small bowel serosal tear attributed to laparoscopic entry. CONCLUSION: This case series suggests that laparoscopic salpingectomy for removal of Essure inserts is safe and feasible. We acknowledge that the numbers were small. However, consistent use of a laparoscopic approach in these eight patients indicates that this procedure is a feasible and suitable alternative to hysterectomy.

Ethnic Variations of Blood Groups in a Medical College of Eastern Nepal.

Background Red blood cells contain antigens in its membrane which are inherited according to Mendelian law. ABO and Rhesus blood group systems are considered the most important blood group systems for clinical procedures, blood transfusion, organ transplantation, anthropological study and medico-legal purposes. Determination of ABO and Rhesus blood groups and its frequency distribution in a multiethnic country like Nepal is important for effective management of blood banks, safe blood transfusion services. The trend of blood groups and its ethnic distributions in the eastern part of Nepal is still unknown. Objective To find the distribution of blood groups among the subjects of different ethnic groups of eastern Nepal. Method A cross-sectional perspective study was carried out among the subjects visited in the laboratory of Nobel Medical College, Biratnagar, Nepal for a period of one year from August 1, 2015 to July 30, 2016. Result The 11,960 subjects were included in the present study, among which 5012 were males and 6948 were females. The study revealed that in ABO system, blood group distribution was 34.80% O, 28.66% A, 27.66% B and 6.89% AB. With regard to Rh blood group system, Rhesus +ve was 96.79% and Rhesus -ve was 3.21%. O blood group dominant ethnic groups were Brahmin, Bhujel, Biswakarma, Shah, Gurung, Marwari, Magar, Mahato, Mandal, Newar, Sanyasi, Tamang, Terai Brahmin and Yadav. Similarly, blood group A dominant ethnic groups were Chhetri, Dhimal, Limbu, Rai and Muslim. Howerver, blood group B was dominant in ethnic groups, namely Biswakarma, Rajput, Satar and Tharu. Conclusion The frequency distribution pattern of ABO blood group was observed as O > A> B > AB and in Rhesus system, Rhesus +ve > Rhesus -ve. Variation in blood groups distribution was observed in various ethnic groups.

Experimental Determination of η/s for Finite Nuclear Matter.

We present, for the first time, simultaneous determination of shear viscosity (η) and entropy density (s) and thus, η/s for equilibrated nuclear systems from A∼30 to A∼208 at different temperatures. At finite temperature, η is estimated by utilizing the γ decay of the isovector giant dipole resonance populated via fusion evaporation reaction, while s is evaluated from the nuclear level density parameter (a) and nuclear temperature (T), determined precisely by the simultaneous measurements of the evaporated neutron energy spectra and the compound nuclear angular momenta. The transport parameter η and the thermodynamic parameter s both increase with temperature, resulting in a mild decrease of η/s with temperature. The extracted η/s is also found to be independent of the neutron-proton asymmetry at a given temperature. Interestingly, the measured η/s values are comparable to that of the high-temperature quark-gluon plasma, pointing towards the fact that strong fluidity may be the universal feature of the strong interaction of many-body quantum systems.

On the microscopic mechanism behind the purely orientational disorder-disorder transition in the plastic phase of 1-chloroadamantane.

Globular molecules of 1-chloroadamantane form a plastic phase in which the molecules rotate in a restrained way, but with their centers of mass forming a crystalline ordered lattice. Plastic phases can be regarded as test cases for the study of disordered phases since, contrary to what happens in the liquid phase, there is a lack of stochastic translational degrees of freedom. When the temperature is increased, a hump in the specific heat curve is observed indicating a change in the energetic footprint of the dynamics of the molecules. This change takes place without a change in the symmetry of the crystalline lattice, i.e. no first-order transition is observed between temperatures below and above the calorimetric hump. This implies that subtle changes in the dynamics of the disordered plastic phase concerning purely orientational degrees of freedom should appear at the thermodynamic anomaly. Accordingly, we describe, for the first time, the microscopic mechanisms behind a disorder-disorder transition through the analysis of neutron diffraction and QENS experiments. The results evince a change in the molecular rotational dynamics accompanied by a continuous change in density.

Cytohistological correlation in pituitary tumor and immunological assessment with the help of Ki-67.

BACKGROUND: Tumors of the pituitary gland and sellar region represent approximately 10-15% of all brain tumors. Pituitary adenoma (PA), the most common pathology of the pituitary gland, can be effectively subclassified only with the help of immunohistochemistry (IHC). This is important and needed for individual patient management. AIMS AND OBJECTIVES: The objective of the study was to analyze the importance of intraoperative imprint smear cytology and correlating with final histopathological diagnosis. Furthermore, to classify the different types of PA with the help of IHC, prolactin (PRL), adrenocorticotropic hormone (ACTH), and growth hormone (GH) and to predict the benign, atypical, or malignant nature of the tumor with the help of prognostic marker Ki-67. MATERIALS AND METHODS: A prospective study was done in 34 cases. The patients whose pituitary gland samples are referred from the endocrine and the neurosurgery department to the pathology department for histopathological examinations were selected. We have studied the clinical features, radiology and touch imprint cytology, histopathology, and IHC with the help of PRL, ACTH, GH, and Ki-67 of PA over 2 years. RESULTS: In our study, we had 32 cases of PA of 34 cases over a span of 2 years. We have seen that there is a correlation between cytological and histological diagnosis of the subtypes of PA in 62% cases, and the Kappa statistics show a moderate extent of agreement (Kappa - 0.320, 95% confidence interval = 0.031-0.609). Ki-67 when compared to the radiological grading showed a high degree of comparability (Chi-square test: P < 0.001). All cases with invasion had a higher Ki-67. On using the Fisher's exact test, we found that the Ki-67 expression with GH-producing adenomas and ACTH-producing adenomas was comparable (P = 1.000) while in PRL-producing adenomas too this was not significant (P = 0.269). CONCLUSION: PA can be effectively classified with the help of IHC. Intraoperative cytology is important in diagnosing PA, but histopathology remains the gold standard in diagnosing and differentiating PA from other pathologies of the pituitary gland. The radiological grading together with immunological classification and the prognostic markers of Ki-67 is important in deciding the benign or atypical nature of the adenomas thus helping in better patient management.

ZpdN, a Plasmid-Encoded Sigma Factor Homolog, Induces pBS32-Dependent Cell Death in Bacillus subtilis.

The ancestral Bacillus subtilis strain 3610 contains an 84-kb plasmid called pBS32 that was lost during domestication of commonly used laboratory derivatives. Here we demonstrate that pBS32, normally present at 1 or 2 copies per cell, increases in copy number nearly 100-fold when cells are treated with the DNA-damaging agent mitomycin C. Mitomycin C treatment also caused cell lysis dependent on pBS32-borne prophage genes. ZpdN, a sigma factor homolog encoded by pBS32, was required for the plasmid response to DNA damage, and artificial expression of ZpdN was sufficient to induce pBS32 hyperreplication and cell death. Plasmid DNA released by cell death was protected by the capsid protein ZpbH, suggesting that the plasmid was packaged into a phagelike particle. The putative particles were further indicated by CsCl sedimentation but were not observed by electron microscopy and were incapable of killing B. subtilis cells extracellularly. We hypothesize that pBS32-mediated cell death releases a phagelike particle that is defective and unstable. IMPORTANCE: Prophages are phage genomes stably integrated into the host bacterium's chromosome and less frequently are maintained as extrachromosomal plasmids. Here we report that the extrachromosomal plasmid pBS32 of Bacillus subtilis encodes a prophage that, when activated, kills the host. pBS32 also encodes both the sigma factor homolog ZpdN that is necessary and sufficient for prophage induction and the protein ComI, which is a potent inhibitor of DNA uptake by natural transformation. We provide evidence that the entire pBS32 sequence may be part of the prophage and thus that competence inhibition may be linked to lysogeny.

Noncapped Alphavirus Genomic RNAs and Their Role during Infection.

UNLABELLED: Alphaviruses are enveloped positive-sense RNA viruses that exhibit a wide host range consisting of vertebrate and invertebrate species. Previously we have reported that the infectivity of Sindbis virus (SINV), the model alphavirus, was largely a function of the cell line producing the viral particles. Mammalian-cell-derived SINV particles, on average, exhibit a higher particle-to-PFU ratio than mosquito cell-derived SINV particles. Nevertheless, the outcome of nonproductive infection, the molecular traits that determine particle infectivity and the biological importance of noninfectious particles were, prior to this study, unknown. Here, we report that the incoming genomic RNAs of noninfectious SINV particles undergo rapid degradation following infection. Moreover, these studies have led to the identification of the absence of the 5' cap structure as a primary molecular determinant of particle infectivity. We show that the genomic RNAs of alphaviruses are not universally 5' capped, with a significant number of noncapped genomic RNA produced early in infection. The production of noncapped viral genomic RNAs is important to the establishment and maintenance of alphaviral infection. IMPORTANCE: This report is of importance to the field of virology for three reasons. First, these studies demonstrate that noncapped Sindbis virus particles are produced as a result of viral RNA synthesis. Second, this report is, to our knowledge, the first instance of the direct measurement of the half-life of an incoming genomic RNA from a positive-sense RNA virus. Third, these studies indicate that alphaviral infection is likely a concerted effort of infectious and noninfectious viral particles.

Pragmatic randomized controlled trial of an allergy intervention for children aged 6-16 with asthma and rhinitis in general practice.

BACKGROUND: It is widely believed that for allergic rhinitis and asthma, avoidance of specific triggers can improve symptom control. Whilst many children with asthma or rhinitis are sensitized to airborne allergens, primary care diagnostic and management decisions are often made without a detailed history of the allergic triggers or allergy testing. Thus, treatment decisions are empirical and allergen avoidance advice is either not given or, if given, not tailored to the child's sensitivities. OBJECTIVE: To ascertain whether allergy assessment and tailored advice in general practice enhances outcomes of children with asthma and rhinitis. METHOD: Pragmatic RCT of allergy intervention (structured allergy history, skin prick testing and appropriate allergy avoidance advice) vs. usual care in children with asthma and/or rhinoconjunctivitis. A blinded observer assessed outcomes at 12 months. Main outcome measures were symptom scores and disease-specific health-related QoL. Secondary outcomes were healthcare utilization, days unable to pursue usual activities and self-rated improvement. RESULTS: A total of 335 participants were randomized to formal allergy assessment or normal care. There were no differences in participants' demographic or clinical characteristics at baseline (all P > 0.05). At 12 months, participants receiving the allergy intervention had fewer rhinitis symptoms (MD - 3.14, 95% CI - 6.01, - 0.81) and an improvement in QoL (MD - 0.50, 95% CI 0.32, 0.68). There were no significant changes in asthma symptoms, healthcare utilization or number of days unable to pursue usual activities. CONCLUSION: Amongst children with known asthma and/or rhinitis in primary care, taking a structured allergy history with skin prick testing and tailored advice on allergy avoidance resulted in reduced symptoms of rhinitis and improved QoL.

Candidate Elastic Quantum Critical Point in LaCu_{6-x}Au_{x}.

The structural properties of LaCu_{6-x}Au_{x} are studied using neutron diffraction, x-ray diffraction, and heat capacity measurements. The continuous orthorhombic-monoclinic structural phase transition in LaCu_{6} is suppressed linearly with Au substitution until a complete suppression of the structural phase transition occurs at the critical composition x_{c}=0.3. Heat capacity measurements at low temperatures indicate residual structural instability at x_{c}. The instability is ferroelastic in nature, with density functional theory calculations showing negligible coupling to electronic states near the Fermi level. The data and calculations presented here are consistent with the zero temperature termination of a continuous structural phase transition suggesting that the LaCu_{6-x}Au_{x} series hosts an elastic quantum critical point.

Quasielastic neutron scattering measurements and ab initio MD-simulations on single ion motions in molten NaF.

The ionic stochastic motions in the molten alkali halide NaF are investigated by quasielastic neutron scattering and first principles molecular dynamics simulation. Quasielastic neutron scattering was employed to extract the diffusion behavior of the sodium ions in the melt. An extensive first principles based simulation on a box of up to 512 particles has been performed to complement the experimental data. From that large box, a smaller 64-particle box has then been simulated over a runtime of 60 ps. A good agreement between calculated and neutron data on the level of spectral shape has been obtained. The obtained sodium diffusion coefficients agree very well. The simulation predicts a fluorine diffusion coefficient similar to the sodium one. Applying the Nernst-Einstein equation, a remarkable large cross correlation between both ions can be deduced. The velocity cross correlations demonstrate a positive correlation between the ions over a period of 0.1 ps. That strong correlation is evidence that the unlike ions do not move completely statistically independent and have a strong association over a short period of time.

Clinical evaluation of purified Shilajit on testosterone levels in healthy volunteers.

Purified Shilajit, an Ayurvedic rasayana, was evaluated in healthy volunteers of age between 45 and 55 years for its effect on male androgenic hormone viz. testosterone in a randomised, double-blind, placebo-controlled clinical study at a dose of 250 mg twice a day. Treatment with Shilajit for consecutive 90 days revealed that it has significantly (P < 0.05) increased total testosterone, free testosterone and dehydroepiandrosterone (DHEAS) compared with placebo. Gonadotropic hormones (LH and FSH) levels were well maintained.

ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults.

BACKGROUND: The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS. METHODS: We performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed. RESULTS: Two SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively. CONCLUSION AND CLINICAL RELEVANCE: A novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.

Transverse wobbling in

A pair of transverse wobbling bands is observed in the nucleus ^{135}Pr. The wobbling is characterized by ΔI=1, E2 transitions between the bands, and a decrease in the wobbling energy confirms its transverse nature. Additionally, a transition from transverse wobbling to a three-quasiparticle band comprised of strong magnetic dipole transitions is observed. These observations conform well to results from calculations with the tilted axis cranking model and the quasiparticle rotor model.