Prevalence of Salmonella in juvenile dogs affected with parvoviral enteritis

Salmonellosis is a disease of major zoonotic importance and canine parvovirus is a potentially fatal cause of canine enteritis with a world-wide distribution. Persistent isolation of Salmonella during routine environmental sampling surveys of a hospital ward, reserved for the treatment of dogs with canine parvovirus infection, prompted investigation into a possible source. We hypothesised that dogs affected by canine parvovirus would have a higher prevalence of faecal salmonellae compared to an apparently healthy cohort. Seventy-four client-owned dogs naturally infected with canine parvovirus and 42 apparently healthy client-owned dogs were included in the study. This prospective, longitudinal, observational study was conducted over an 18-month period. Fresh faecal samples were collected from dogs aged 6 weeks to 9 months diagnosed with canine parvovirus infection and admitted for treatment, and from apparently healthy dogs presented for vaccination or routine hospital procedures. Faeces were submitted for the isolation, antimicrobial susceptibility testing and serotyping of salmonellae. The prevalence of faecal Salmonella shedding was 22% and 31% for the affected and apparently healthy dogs, respectively, which was not statistically different. No significant associations between Salmonella status and possible risk factors or continuous variables such as age, body weight and duration of hospitalisation were identified. All the Salmonella isolates (n = 32) were resistant to penicillin G, lincomycin and tylosin. Salmonellae from nine different serotypes were identified. The prevalence of Salmonella shedding in both groups was higher than that commonly reported, yet similar to those in previous reports on young dogs, shelter dogs or dogs fed a raw meat diet

Multimodal therapy in an inpatient setting

Inpatient Multimodal Therapy (imt) is a residential treatment program, lasting a maximum of 36 weeks, for patients with severe neurotic symptoms. A group of 44 chronic obsessive-compulsive patients and a group of 40 chronic phobic patients were treated in order to assess the outcome and the process of treatment and to identify prognostic factors associated with the effect. At follow-up-on average, eight months after discharge-it was found that 60% had improved, 32% had remained the same, and 8% had deteriorated, indicating that, in general, the treatment was beneficial. That these effects were long-lasting is supported by the fact that, at follow-up, 78% of all patients were no longer receiving treatment, 18% were receiving outpatient or day treatment, and 4% were receiving inpatient treatment. Phobic patients appear to have gained more from the multimodal approach than did obsessive-compulsive patients, as indicated by the fact that the severity of symptoms decreased as they improved in rational thinking, assertiveness, and arousal. By contrast, obsessive-compulsive patients relapsed more than phobic patients did. This was attributed to the fact that the former gained less from the rational-emotive training, denied problems with assertiveness, and did not practice the acquired relaxation skills. It further appeared that a favorable outcome could be induced in patients who (1) expressed relatively mild symptoms in this otherwise severe group, (2) reported relatively few additional complaints, (3) could clearly indicate interpersonal problems, and (4) did not use psychotropic drugs. These prognostic factors are so widespread that not much weight can be ascribed to them. Yet they are useful for indication of imt until better predictors are found

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Genetic and genomic analysis of acute lymphoblastic leukaemia in older adults reveals a distinct profile of abnormalities: analysis of 210 patients from the UKALL14 and UKALL60+ clinical trials

Despite being predominantly a childhood disease, the incidence of ALL has a second peak in adults aged 60 years and over. These older adults fare extremely poorly with existing treatment strategies and very few studies have undertaken a comprehensive genetic and genomic characterisation to improve prognosis in this age group. We performed cytogenetic, single nucleotide polymorphism (SNP) array and next generation sequencing (NGS) analyses on samples from 210 patients aged ≥60 years from the UKALL14 and UKALL60+ clinical trials. BCR-ABL1 positive disease was present in 26% (55/210) of patients, followed by low hypodiploidy/near triploidy in 13% (28/210). Cytogenetically cryptic rearrangements in CRLF2, ZNF384 and MEF2D were detected in 5%, 1% and 1% of patients respectively. Copy number abnormalities were common and deletions in ALL driver genes were seen in 77% of cases. IKZF1 deletion was present in 51% (40/78) of samples tested and the IKZF1plus profile identified in over a third (28/77) of BCP-ALL cases. The genetic good risk abnormalities high hyperdiploidy (n=2), ETV6-RUNX1 (no cases) and ERG deletion (no cases) were exceptionally rare in this cohort. RAS pathway mutations were seen in 17% (4/23) of screened samples. KDM6A abnormalities, including biallelic deletions, were discovered in 5% (4/78) of SNP array and 9% (2/23) of NGS samples, and represent a novel, potentially therapeutically actionable lesions using EZH2 inhibitors. Outcome remained poor with five-year event-free (EFS) and overall survival (OS) rates of 17% and 24% respectively across the cohort indicating a need for novel therapeutic strategies

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

A search for the decay B+→K+ννˉB^+ \to K^+ \nu \bar{\nu}

We search for the rare flavor-changing neutral-current decay $B^+ \to K^+ \nu \bar{\nu}$ in a data sample of 82 fb$^{-1}$ collected with the {\sl BABAR} detector at the PEP-II B-factory. Signal events are selected by examining the properties of the system recoiling against either a reconstructed hadronic or semileptonic charged-B decay. Using these two independent samples we obtain a combined limit of ${\mathcal B}(B^+ \to K^+ \nu \bar{\nu})<5.2 \times 10^{-5}$ at the 90% confidence level. In addition, by selecting for pions rather than kaons, we obtain a limit of ${\mathcal B}(B^+ \to \pi^+ \nu \bar{\nu})<1.0 \times 10^{-4}$ using only the hadronic B reconstruction method.Comment: 7 pages, 8 postscript figures, submitted to Phys. Rev. Let

High-reflectivity broadband distributed Bragg reflector lattice matched to ZnTe

We report on the realization of a high quality distributed Bragg reflector with both high and low refractive index layers lattice matched to ZnTe. Our structure is grown by molecular beam epitaxy and is based on binary compounds only. The high refractive index layer is made of ZnTe, while the low index material is made of a short period triple superlattice containing MgSe, MgTe, and ZnTe. The high refractive index step of Delta_n=0.5 in the structure results in a broad stopband and the reflectivity coefficient exceeding 99% for only 15 Bragg pairs.Comment: 4 pages, 3 figure

Driver Fusions and Their Implications in the Development and Treatment of Human Cancers.

Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy