Distribution of chronic cough phenotypes in the general population: A cross-sectional analysis of the LEAD cohort in Austria.

RATIONALE: Recent guidelines consider chronic cough to be a unique clinical entity with different phenotypes. We aimed to investigate them in a general population and to describe prevalence, distribution, and characteristics of these phenotypes within the Austrian general population. METHODS: From the LEAD study, a longitudinal observational population-based cohort, data from questionnaires and spirometry of 10,057 adult participants was analysed. Chronic cough was defined as coughing nearly every day during the last 12 months for at least 3 months (>12 weeks). RESULTS: The prevalence of chronic cough was 9% and increased with age. We found no sex predominance but a female preponderance (68%) in never smokers. A presumable cause was identified in 85% of which more than half (53.9%) had two phenotypes, 36.9% belonged to one only and 9.2% to three or more. Regarding the distribution of phenotypes, 40.8% were current smokers, 32.6% had an ACE inhibitor intake, 18.2% GERD, 17.6% asthmatic cough, 9.7% UACS and 28.3% other diseases associated with chronic cough. 15% had unexplained chronic cough with no identifiable phenotype. Current smoking, low socioeconomic status, obesity, COPD and obstructive sleep apnea were associated factors with chronic cough. CONCLUSION: Chronic cough is common among adults in Austria and highly prevalent in the older population. Most participants can be phenotyped with simple questionnaire-based assessment and can therefore potentially receive specific treatment without intensive clinical workup.

Tolerance and microbiological efficacy of cefepime or piperacillin/tazobactam in combination with vancomycin as empirical antimicrobial therapy of prosthetic joint infection: a propensity-matched cohort study.

BACKGROUND: The use of piperacillin/tazobactam with vancomycin as empirical antimicrobial therapy (EAT) for prosthetic joint infection (PJI) has been associated with an increased risk of acute kidney injury (AKI), leading us to propose cefepime as an alternative since 2017 in our reference centre. OBJECTIVES: To compare microbiological efficacy and tolerance of these two EAT strategies. METHODS: All adult patients with PJI empirically treated with vancomycin+cefepime (n = 89) were enrolled in a prospective observational study and matched with vancomycin+piperacillin/tazobactam-treated historical controls (n = 89) according to a propensity score including age, baseline renal function and concomitant use of other nephrotoxic agents. The two groups were compared using Kaplan-Meier curve analysis, and non-parametric tests regarding the proportion of efficacious empirical regimen and the incidence of empirical therapy-related adverse events (AE). RESULTS: Among 146 (82.0%) documented infections, the EAT was considered efficacious in 77 (98.7%) and 65 (98.5%) of the piperacillin/tazobactam- and cefepime-treated patients, respectively (P = 1.000). The rate of AE, particularly AKI, was significantly higher in the vancomycin+piperacillin/tazobactam group [n = 27 (30.3%) for all AE and 23 (25.8%) for AKI] compared with the vancomycin+cefepime [n = 13 (14.6%) and 6 (6.7%)] group (P = 0.019 and <0.001, respectively), leading to premature EAT discontinuation in 20 (22.5%) and 5 (5.6%) patients (P = 0.002). The two groups were not significantly different regarding their comorbidities, and AKI incidence was not related to vancomycin plasma overexposure. CONCLUSIONS: Based on the susceptibility profile of bacterial isolates from included patients, microbiological efficacy of both strategies was expected to be similar, but vancomycin + cefepime was associated with a significantly lower incidence of AKI.

Comparison of the Chinese bamboo partridge and red Junglefowl genome sequences highlights the importance of demography in genome evolution.

BACKGROUND: Recent large-scale whole genome sequencing efforts in birds have elucidated broad patterns of avian phylogeny and genome evolution. However, despite the great interest in economically important phasianids like Gallus gallus (Red Junglefowl, the progenitor of the chicken), we know little about the genomes of closely related species. Gallus gallus is highly sexually dichromatic and polygynous, but its sister genus, Bambusicola, is smaller, sexually monomorphic, and monogamous with biparental care. We sequenced the genome of Bambusicola thoracicus (Chinese Bamboo Partridge) using a single insert library to test hypotheses about genome evolution in galliforms. Selection acting at the phenotypic level could result in more evidence of positive selection in the Gallus genome than in Bambusicola. However, the historical range size of Bambusicola was likely smaller than Gallus, and demographic effects could lead to higher rates of nonsynonymous substitution in Bambusicola than in Gallus. RESULTS: We generated a genome assembly suitable for evolutionary analyses. We examined the impact of selection on coding regions by examining shifts in the average nonsynonymous to synonymous rate ratio (dN/dS) and the proportion of sites subject to episodic positive selection. We observed elevated dN/dS in Bambusicola relative to Gallus, which is consistent with our hypothesis that demographic effects may be important drivers of genome evolution in Bambusicola. We also demonstrated that alignment error can greatly inflate estimates of the number of genes that experienced episodic positive selection and heterogeneity in dN/dS. However, overall patterns of molecular evolution were robust to alignment uncertainty. Bambusicola thoracicus has higher estimates of heterozygosity than Gallus gallus, possibly due to migration events over the past 100,000 years. CONCLUSIONS: Our results emphasized the importance of demographic processes in generating the patterns of variation between Bambusicola and Gallus. We also demonstrated that genome assemblies generated using a single library can provide valuable insights into avian evolutionary history and found that it is important to account for alignment uncertainty in evolutionary inferences from draft genomes.

Duration of viral shedding and factors associated with prolonged shedding among inpatients with influenza treated with oseltamivir: a prospective cohort study.

The purpose of this study was to determine the rate of decline in the diagnostic yield of influenza PCR assay after oseltamivir administration, and to identify risk factors for prolonged shedding. This was a prospective observational study. We included adult inpatients with clinical signs of influenza during the influenza seasons 2015 and 2016, who had positive influenza PCR tests and who were treated with oseltamivir. Clinical follow-up and repeat PCR testing were performed on days 2, 4 and 6 after the first positive test. We defined prolonged shedders as patients who still required hospitalization and had a positive PCR assay on day 4. Risk factors for prolonged shedding were assessed in univariate and multivariate analyses. A total of 215 patients were included in our study. The median age was 64 years and 49.3% were men. The main influenza type was H1N1 (50.1%). Rates of PCR positivity among evaluable patients on days 2, 4 and 6 were 142/215 (66%), 50/78 (64.1%) and 20/30 (66.6%), respectively. Independent risk factors for prolonged shedding (50 patients) included hypoxemia [odds ratio (OR) 2.55, 95% confidence interval (1.3-5.1)] and lower diastolic blood pressure [OR 0.94, 95% CI (0.92-0.97)] on admission. Negative PCR tests taken more than 48 h after initiation of treatment had low diagnostic yield. More severe disease, manifested by hypoxemia and lower blood pressure, is associated with prolonged shedding on oseltamivir treatment.

Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation.

Ibrutinib, a recently approved inhibitor of Bruton's tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cell-mediated cytokine levels (IL10 and TNFα) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT.

Abundant cytomegalovirus (CMV) reactive clonotypes in the CD8(+) T cell receptor alpha repertoire following allogeneic transplantation.

Allogeneic stem cell transplantation is potentially curative, but associated with post-transplantation complications, including cytomegalovirus (CMV) infections. An effective immune response requires T cells recognizing CMV epitopes via their T cell receptors (TCRs). Little is known about the TCR repertoire, in particular the TCR-α repertoire and its clinical relevance in patients following stem cell transplantation. Using next-generation sequencing we examined the TCR-α repertoire of CD8(+) T cells and CMV-specific CD8(+) T cells in four patients. Additionally, we performed single-cell TCR-αß sequencing of CMV-specific CD8(+) T cells. The TCR-α composition of human leucocyte antigen (HLA)-A*0201 CMVpp65- and CMVIE -specific T cells was oligoclonal and defined by few dominant clonotypes. Frequencies of single clonotypes reached up to 11% of all CD8(+) T cells and half of the total CD8(+) T cell repertoire was dominated by few CMV-reactive clonotypes. Some TCR-α clonotypes were shared between patients. Gene expression of the circulating CMV-specific CD8(+) T cells was consistent with chronically activated effector memory T cells. The CD8(+) T cell response to CMV reactivation resulted in an expansion of a few TCR-α clonotypes to dominate the CD8(+) repertoires. These results warrant further larger studies to define the ability of oligoclonally expanded T cell clones to achieve an effective anti-viral T cell response in this setting.

Management of emerging multidrug-resistant tuberculosis in a low-prevalence setting.

Multidrug-resistant (MDR) tuberculosis (TB) is an emerging concern in communities with a low TB prevalence and a high standard of public health. Twenty-three consecutive adult MDR TB patients who were treated at our institution between 2007 and 2013 were reviewed for demographic characteristics and anti-TB treatment management, which included surgical procedures and long-term patient follow-up. This report of our experience emphasizes the need for an individualized approach as MDR TB brings mycobacterial disease management to a higher level of expertise, and for a balance to be found between international current guidelines and patient-tailored treatment strategies.

Build better bones with exercise: protocol for a feasibility study of a multicenter randomized controlled trial of 12 months of home exercise in women with a vertebral fracture.

BACKGROUND: Our goal is to conduct a multicenter randomized controlled trial (RCT) to investigate whether exercise can reduce incident fractures compared with no intervention among women aged ≥65 years with a vertebral fracture. OBJECTIVES: This pilot study will determine the feasibility of recruitment, retention, and adherence for the proposed trial. DESIGN: The proposed RCT will be a pilot feasibility study with 1:1 randomization to exercise or attentional control groups. SETTING: Five Canadian sites (1 community hospital partnered with an academic center and 4 academic hospitals or centers affiliated with an academic center) and 2 Australian centers (1 academic hospital and 1 center for community primary care, geriatric, and rehabilitation services). PARTICIPANTS: One hundred sixty women aged ≥65 years with vertebral fracture at 5 Canadian and 2 Australian centers will be recruited. INTERVENTION: The Build Better Bones With Exercise (B3E) intervention includes exercise and behavioral counseling, delivered by a physical therapist in 6 home visits over 8 months, and monthly calls; participants are to exercise ≥3 times weekly. Controls will receive equal attention. MEASUREMENTS: Primary outcomes will include recruitment, retention, and adherence. Adherence to exercise will be assessed via calendar diary. Secondary outcomes will include physical function (lower extremity strength, mobility, and balance), posture, and falls. Additional secondary outcomes will include quality of life, pain, fall self-efficacy, behavior change variables, intervention cost, fractures, and adverse events. Analyses of feasibility objectives will be descriptive or based on estimates with 95% confidence intervals, where feasibility will be assessed relative to a priori criteria. Differences in secondary outcomes will be evaluated in intention-to-treat analyses via independent Student t tests, chi-square tests, or logistic regression. The Bonferroni method will be used to adjust the level of significance for secondary outcomes so the overall alpha level is .05. LIMITATIONS: No assessment of bone mineral density will be conducted. The proposed definitive trial will require a large sample size. CONCLUSIONS: The viability of a large-scale exercise trial in women with vertebral fractures will be evaluated, as well as the effects of a home exercise program on important secondary outcomes.

Predominance of Gram-negative bacilli among patients with catheter-related bloodstream infections.

We evaluated changes in the epidemiology of catheter-related bloodstream infections (CRBSIs) between 1996 and 2012 in a tertiary care centre in Israel. The cohort included 1754 episodes of CRBSI. The incidence of CRBSIs decreased throughout the study period, whereas 30-day mortality following bacteraemia increased. There was a linear shift toward predominance of Gram-negative bacilli throughout the study period (p for trend<0.001). In 1996, 68% (68/100) of CRBSIs were caused by Gram-positive cocci, whereas in 2012 77.8% (28/26) were caused by Gram-negative bacilli. The shift towards Gram-negative CRBSIs and the associated mortality mandates that empirical treatment for CRBSIs be directed by local epidemiology.

Epidemiology and clinical significance of non-tuberculous mycobacteria isolated from pulmonary specimens.

SETTING: A tertiary university medical centre in northern Israel. OBJECTIVE: To evaluate the clinical significance of non-tuberculous mycobacteria (NTM) isolated from pulmonary specimens. DESIGN: Clinical and microbiological data were collected from patient files. Cases were classified as definite, probable and possible NTM. RESULTS: Between 2004 and 2010, 215 cases with respiratory isolates of NTM were identified. Mycobacterium xenopi was the most common species (n = 84, 39.1%), followed by M. simiae (n = 52, 24.2%). A total of 170 (79.1%) cases were classified as possible and 24 (11.2%) as probable NTM. Only 21 (9.8%) cases were considered definite NTM, the majority of which were M. kansasii and M. avium complex. CONCLUSIONS: M. xenopi and M. simiae are the most prevalent species of NTM isolated from respiratory samples in northern Israel. However, most of these isolates represent colonisation. Of the relatively small number of clinically significant isolates, M. kansasii and M. avium complex were the most common.

Cholesterol granulomas of the petrous apex; endonasal endoscopic approach.

OBJECTIVE: Cholesterol granulomas are benign lesions that sometimes occur on the petrous apex (PA). We report our experience using an endoscopic endonasal approach to remove PA cholesterol granulomas. MATERIAL AND METHODS: A retrospective patient chart analysis was conducted at a tertiary care university hospital. RESULTS: Four patients (3 females, 1 male) were included in this study. Patients' ages ranged from 27 to 78 years. Computed tomography (CT) and magnetic resonance imaging (MRI) for diagnosis and computer-assisted navigation were performed. The most common symptom was abducens nerve palsy. The largest granuloma measured 5 x 2 cm and was located on the left side. An endoscopic endonasal approach was chosen and navigation was applied (3/4 patients) to identify the optimal area for opening the granuloma. No complications occurred, and patients were free from recurrence during the follow-up period. CONCLUSION: The endoscopic endonasal approach to PA cholesterol granulomas is feasible and safe. Intra-operative navigation is recommended to identify the position of the internal carotid artery and determine the safest area for opening the granuloma without damaging the artery. Another advantage of this approach is an easier follow-up through diagnostic nasal endoscopy.

Colorectal serrated adenocarcinoma shows a different profile of oncogene mutations, MSI status and DNA repair protein expression compared to conventional and sporadic MSI-H carcinomas.

Molecular characterization has been extensively studied in serrated polyps but very little is known in serrated adenocarcinomas (SACs). We analyzed the incidence of KRAS, BRAF and PIK3CA mutations, microsatellite instability (MSI) status and loss of the DNA repair proteins MLH1, MSH2, MSH6 and MGMT in a series of 89 SAC, 81 matched conventional carcinomas (CC) and 13 sporadic colorectal cancer showing histological and molecular features of high-level MSI (sMSI-H). Our results demonstrate that KRAS are more prevalent than BRAF mutations in SAC (42.7% vs. 25.8%; p = 0.011) being the KRAS-mutated cases even more abundant in SAC displaying adjacent serrated adenomas (51%). G12D and E545K are the most common KRAS and PIK3CA mutations found in SAC, respectively. SAC show higher frequency of MGMT loss compared to CC (50.6% vs. 25.3%; p = 0.001) especially in distal colon/rectum (60.0% vs. 21.6%; p = 0.0009). SAC differ from sMSI-H in terms of KRAS and BRAF mutation prevalence, MSI status and MLH1 expression (p = 0.0003, p < 0.0001, p < 0.0001, p < 0.001, respectively). SACs are more often KRAS-mutated and microsatellite stable and display different molecular and immunohistochemical characteristics compared to CC and sMSI-H.

Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two-part pharmacokinetic/pharmacodynamic phase I dose-escalation study.

BACKGROUND: This phase I dose-escalation study was designed to determine the maximum tolerated dose (MTD) and recommended dose of cetuximab administered on an every-second-week schedule to patients with metastatic colorectal cancer, on the basis of safety, pharmacokinetic and pharmacodynamic evaluation. PATIENTS AND METHODS: The study comprised two parts: a 6-week cetuximab monotherapy dose-escalation phase and a subsequent combination therapy phase, during which patients received cetuximab, at the same dose/schedule as in the monotherapy phase, followed by irinotecan plus infusional 5-fluorouracil/folinic acid (FOLFIRI). Patients in the control group received cetuximab as a 400 mg/m(2) initial dose, then 250 mg/m(2)/week and in the dose-escalation group, at 400-700 mg/m(2), every second week. RESULTS: Sixty-two patients were included in the study. The MTD of cetuximab administered on an every-second-week schedule was not reached. The safety profiles were similar across all groups. Response rates in the cetuximab monotherapy and combination therapy phases were 15% and 42%, respectively. Trough levels for the 500, 600 mg/m(2) and standard weekly regimens were comparable. CONCLUSION: Cetuximab can be safely administered once every second week at doses between 400 and 700 mg/m(2), with 500 mg/m(2) being the most convenient and feasible dose for future studies.

Aurora kinase inhibitors: a new class of drugs targeting the regulatory mitotic system

The present review gives a perspective on the Aurora kinase family members, their function in normal cells, their role in cancer progression as well as their potential as target for anticancer treatment. Mitosis has been an important target for anticancer therapy development, leading to some specific drugs mainly addressing Tubulines, as a key structure of the mitotic spindle. Vinca alkaloids, taxanes or epotilones are good examples of conventionally developed antimitotic agents. However, novel classes of antineoplastic drugs are being studied, targeting the regulatory system that controls functional aspects of mitosis, such as Aurora or Polo-like kinases or Kinespondin inhibitors. The specific role of the different Aurora kinase proteins as regulator enzymes of the mitotic process in normal cells is discussed. Some of the mechanisms that link Aurora overexpression with cancer are also considered. Thereafter, the clinical and preclinical development of the different Aurora kinase inhibitors is presented. This is nowadays a very active area of therapeutic research and at least, sixteen new compounds are being studied as potential antineoplastic drugs. Most of them are in a very early phase of clinical development. However, we summarized the most recently published findings related with these drugs: main characteristics, way of administration, dose limiting toxicities and recommended doses for further studies. Another important aspect in Aurora kinase inhibition is the study and validation of potential biomarkers to optimize the clinical development. Several studies included pharmacodynamic assessments in normal blood cells, skin or/and tumor biopsies. Several proposals included a higher mitotic index, a decreased number of mitosis with bipolar spindles or normal alignment of chromosomes and inhibition of histone H3 phosphorylation. Future strategies and challenges for trials with Aurora kinase inhibitors are also discussed (AU)

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From reptilian phylogenomics to reptilian genomes: analyses of c-Jun and DJ-1 proto-oncogenes.

Genome projects have revolutionized our understanding of both molecular biology and evolution, but there has been a limited collection of genomic data from reptiles. This is surprising given the pivotal position of reptiles in vertebrate phylogeny and the potential utility of information from reptiles for understanding a number of biological phenomena, such as sex determination. Although there are many potential uses for genomic data, one important and useful approach is phylogenomics. Here we report cDNA sequences for the c-Jun(JUN) and DJ-1(PARK7) proto-oncogenes from 3 reptiles (the American alligator, Nile crocodile, and Florida red-belly turtle), show that both genes are expressed in the alligator, and integrate them into analyses of their homologs from other organisms. With these taxa it was possible to conduct analyses that include all major vertebrate lineages. Analyses of c-Jun revealed an unexpected but well-supported frog-turtle clade while analyses of DJ-1 revealed a topology largely congruent with expectation based upon other data. The conflict between the c-Jun topology and expectation appears to reflect the overlap between c-Jun and a CpG island in most taxa, including crocodilians. This CpG island is absent in the frog and turtle, and convergence in base composition appears to be at least partially responsible for the signal uniting these taxa. Noise reduction approaches can eliminate the unexpected frog-turtle clade, demonstrating that multiple signals are present in the c-Jun alignment. We used phylogenetic methods to visualize these signals; we suggest that examining both historical and non-historical signals will prove important for phylogenomic analyses.

Outcome of atrial fibrillation ablation: assessment of success.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with a prevalence in the general population of approximately 1%. Catheter ablation has emerged from being a highly experimental procedure to one of the most common ablation performed in many electrophysiology laboratories throughout the world. The stability of sinus rhythm restored by catheter ablation is important not only for comparison of different ablation techniques, but also for guiding anticoagulation and possible antiarrhythmic drug treatment. It has been shown that asymptomatic AF after ablation is at least as common as before the ablation. Rhythm assessment is therefore a key component of post AF ablation follow-up. A variety of electrocardiogram (ECG) monitoring techniques is available. Besides of technical characteristics such as the number of recording leads and further signal processing, these techniques differ mainly in the duration of ECG recordings and the involvement of the patient. Intermittent rhythm monitoring techniques include standard 12-lead ECG, Holter-ECG of various duration, patient activated external loop ECG recorder as well as patient activated transtelephonic ECG monitor. Continuous ECG represents the gold standard for rhythm monitoring recording and can be achieved by means of a pacemaker, implan-table defibrillator or implantable cardiac ECG monitor.

Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial.

This is a phase II institutional exploratory trial of biweekly irinotecan and cetuximab administration regimen in metastatic colorectal cancer patients progressing to at least one previous chemotherapy line. A total of 40 patients were treated between November 2005 and November 2007 with irinotecan 180 mg m-2 and cetuximab 500 mg m-2 q2w (every 2 weeks), in every 21-day cycles, until unacceptable toxicity or progressive disease. An overall response rate of 22.5% was obtained (two complete and seven partial responses). The disease control rate was 60%. The time to progression was 3.4 months and the overall survival was 8 months. The toxicity compared very favourably to weekly cetuximab combination schedules. Grade 3/4 adverse effects were observed in 12 patients. Overall, our results turn up very similar both in terms of toxicity and efficacy to those obtained by weekly and biweekly administration regimens.