Control of infectious mortality due to carbapenemase-producing Klebsiella pneumoniae in hematopoietic stem cell transplantation.

Carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infections are an emerging cause of death after hematopoietic stem cell transplantation (HSCT). In allogeneic transplants, mortality rate may rise up to 60%. We retrospectively evaluated 540 patients receiving a transplant from an auto- or an allogeneic source between January 2011 and October 2015. After an Institutional increase in the prevalence of KPC-Kp bloodstream infections (BSI) in June 2012, from July 2012, 366 consecutive patients received the following preventive measures: (i) weekly rectal swabs for surveillance; (ii) contact precautions in carriers (iii) early-targeted therapy in neutropenic febrile carriers. Molecular typing identified KPC-Kp clone ST512 as the main clone responsible for colonization, BSI and outbreaks. After the introduction of these preventive measures, the cumulative incidence of KPC-Kp BSI (P=0.01) and septic shocks (P=0.01) at 1 year after HSCT was significantly reduced. KPC-Kp infection-mortality dropped from 62.5% (pre-intervention) to 16.6% (post-intervention). Day 100 transplant-related mortality and KPC-Kp infection-related mortality after allogeneic HSCT were reduced from 22% to 10% (P=0.001) and from 4% to 1% (P=0.04), respectively. None of the pre-HSCT carriers was excluded from transplant. These results suggest that active surveillance, contact precautions and early-targeted therapies, may efficiently control KPC-Kp spread and related mortality even after allogeneic HSCT.

Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients.

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.

High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists.

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors.

Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.

Early molecular diagnosis of aspergillosis in a patient with acute myeloid leukaemia.

Diagnosis of invasive fungal infection remains challenging. Here we report a case of early diagnosis of invasive aspergillosis in a neutropenic patient affected by acute myeloid leukaemia, achieved through the detection of Aspergillus fumigatus species-specific ribonucleic acid sequences by a sensitive multiplex real-time polymerase chain reaction-based molecular assay. Thanks to the early diagnosis, targeted therapy was promptly established and the severe fungal infection controlled, allowing the patient to subsequently receive allogeneic hematopoietic stem cell transplantation from a haploidentical donor, her only curative option. Also in this instance, targeted secondary antifungal prophylaxis with voriconazole avoided any other fungal infection afterwards. This report suggests how the implementation of molecular assays in combination with routine diagnostic procedures, can improve microbiological diagnosis in sepsis, particularly in case of fungal infection, difficult to detect with standard microbiological culture methods.

Two algorithms for fitting constrained marginal models.

The two main algorithms that have been considered for fitting constrained marginal models to discrete data, one based on Lagrange multipliers and the other on a regression model, are studied in detail. It is shown that the updates produced by the two methods are identical, but that the Lagrangian method is more efficient in the case of identically distributed observations. A generalization is given of the regression algorithm for modelling the effect of exogenous individual-level covariates, a context in which the use of the Lagrangian algorithm would be infeasible for even moderate sample sizes. An extension of the method to likelihood-based estimation under L1-penalties is also considered.

Predicting the Clinical Outcome of Allogeneic Hematopoietic Stem Cell Transplantation: The Long and Winding Road toward Validated Immune Biomarkers.

The clinical outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is strongly influenced from the potential complications arising during the delicate phase of post-transplant immune restoration. The quantitative aspects of immune-cell repopulation after HSCT and the qualitative features their functional restitution have been extensively reported. Nevertheless, measurable immune biomarkers predicting the clinical outcome of HSCT await formal validation. The aim of this review is an appraisal of most studies published so far on the predictive value of different T and NK-cell biomarkers after HSCT with emphasis on defined thresholds endorsed by multivariate analysis.

Have the prevalence and incidence of occupational asthma and rhinitis because of laboratory animals declined in the last 25 years?

BACKGROUND: Data for time trends in the prevalence of occupational asthma (OA) and rhinitis (OR) are not known. OBJECTIVE: To investigate the prevalence and incidence of OA and OR over time. METHODS: We chose to review studies on the prevalence and incidence of OA and OR due to laboratory animals (LA) as a marker of changing OA and OR patterns over time and analysed 15 cross-sectional and 4 longitudinal studies published from 1980 to 2006. RESULTS: The estimated prevalence of OA, defined as work-related chest symptoms (WRCS), declined from 8.2% in 1976 to 4.2% in 2001 (P < 0.005). When defined by WRCS and positive skin prick test (SPT) to LA, the estimated prevalence of OA was 6.7% in 1977 and 2.9% in 1999 (P < 0.02). The prevalence of OR, defined by WRNS or WRNS and SPT to LA, was not related to study date but was inversely associated with mean exposure duration. In four longitudinal studies no clear trend emerged over time. CONCLUSIONS: This review suggests a trend toward a progressive decline in the prevalence of occupational asthma due to laboratory animals, which may be due to the reduction of exposure since the early 1980s. A further reduction of exposure is needed to prevent the onset of occupational rhinitis.

Analysis of capture-recapture data with a Rasch-type model allowing for conditional dependence and multidimensionality.

In this article, we show that, if subjects are assumed to be homogeneous within a finite set of latent classes, the basic restrictions of the Rasch model (conditional independence and unidimensionality) can be relaxed in a flexible way by simply adding appropriate columns to a basic design matrix. When discrete covariates are available so that subjects may be classified into strata, we show how a joint modeling approach can achieve greater parsimony. Parameter estimates may be obtained by maximizing the conditional likelihood (given the total number of captures) with a combined use of the EM and Fisher scoring algorithms. We also discuss a technique for obtaining confidence intervals for the size of the population under study based on the profile likelihood.

Dyspnoea is associated with pulmonary function impairment in exposed workers.

This study aimed to evaluate the prevalence of dysponea and its predictors in studies on several working male groups in British Columbia (BC), Canada (cedar sawmill, grain elevator, pulpmill, and aluminum smelter workers), and Tuscany (T), Italy, (shoe and furniture makers, millers, bakers, and pharmaceutical workers). We performed cross-sectional health studies (interviews and pulmonary function tests) for 2498 BC and 1474 T workers exposed to air contaminants, and 1110 BC and 243 T controls. Similar questionnaires and the same definitions were used in BC and in T. Pulmonary function tests were also performed. The participation rates were >92% in BC workers and 82% in T workers. The overall prevalence of moderate dyspnoea was not different in exposed BC and T workers in comparison with controls. Slight dyspnoea was significantly more frequent in BC workers, but not in T workers, with respect to controls. After adjusting for age, body mass index (BMI), smoking, current asthma, and chronic bronchitis, forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were found to be significantly associated with slight and moderate dyspnoea in BC workers, and slight dyspnoea in T workers. Isolated dyspnoea is associated with reduction in FEV1 and FVC in working populations, after adjusting for potentially confounding variables.

Modelling balanced longitudinal data: maximum likelihood estimation and analysis of variance.

For linear models, assuming a within-experimental-units covariance structure that incorporates errors of measurement, serial correlation, and variation between units, results on explicit estimation of regression parameters are used to simplify maximum likelihood estimation of covariance parameters. The use of an analysis of variance table as a simpler alternative to likelihood inference is illustrated with two examples.

Monitoring of peak expiratory flow rates during occupational asthma treatment.

The purpose of this study was to evaluate the effect of anti-inflammatory drug treatment on respiratory symptoms and lung function in twelve subjects with occupational asthma while at work. PEFR was monitored for four weeks and antiasthmatic drugs (salbutamol, chromolyn sodium and beclomethasone dipropionate) were administered for three weeks, starting after the first week of PEFR monitoring, in an unchanged working environment. After treatment five subjects became asymptomatic, six improved and one continued to have unchanged work-related asthmatic symptoms. There were only minor increases in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and mean forced expiratory flow during the middle half of FVC (FEF25-75). Bronchial reactivity was studied in eleven subjects: six worsened and five improved. PEFR at 0600 h increased by 9.4% in nine responders and decreased by 5.8% in three non-responders. After treatment diurnal variation (DV) in PEFR decreased by 28.4% in responders and 30.8% in non-responders, even if at the fourth week it was 1.75 higher in non-responders compared to responders. In conclusion, in this study a continuous treatment of occupational asthma with anti-inflammatory drugs minimized respiratory symptoms, slightly increased PEFR and greatly reduced DV in PEFR.

An 11-year longitudinal study of the occupational dust exposure and lung function of polyvinyl chloride, cement and asbestos cement factory workers.

Standardized questionnaires and lung function tests were administered in 1973, 1980, and 1984 to 126 workers occupationally exposed to polyvinyl chloride (PVC) dust, to cement dust, or to asbestos cement dust until 1974-1978 and to PVC thereafter. The workers in the last group were assigned to two asbestos exposure categories (heavy and slight). The decline in forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1.0) was analyzed with regard to the length of time since the data of first employment. After adjustment for age, height, and smoking status at the date of first employment, the decline in FVC and FEV1.0 among the nonsmokers-light smokers was slightly accelerated with length of employment in the PVC and slight asbestos exposure groups and markedly accelerated with time since first employment in the heavy asbestos exposure group. The heavy smokers in all the exposure groups had FVC and FEV1.0 predicted values that were lower than those of the nonsmokers-light smokers; these differences remained constant with length of employment. Cessation of asbestos exposure for about 10 years did not seem to change lung function decline.