Changes in quality of life and functional capacity after lung transplantation: A single-center experience

Lung transplantation (LT) increases the life expectancy of patients affected by end stage pulmonary disease; specifically, its ultimate aims are to improve survival and health related quality of life (HRQoL). The aim of the present longitudinal study was to determine the HRQoL trajectory and changes in functional capacity from time of entry in the waiting list for LT to 2 year after LT. The study included sixty-nine outpatients enrolled in a single medical center when they entered the waiting list for LT and who subsequently received it. They were then followed up over 2 years after LT. HRQoL was assessed by the physical and mental component summary (PCS and MCS) scores of the 36-item Short Form Health Survey (SF-36) and Saint George's Respiratory Questionnaire (SGRQ). Psychological distress was evaluated with the General Health Questionnaire (GHQ), and functional capacity was investigated using the six-minute walk test (6MWT) and forced expiratory volume (FEV1). Patients showed low SF-36 PCS (30.5±7.8) and SGRQ total (61.8±17.5) scores at entry in the waiting list, but exhibited significant changes over time after LT (p<0.001). Furthermore, patients who showed an increase of at least 50% in SF36 PCS and SGRQ scores at 6 months survived longer. Both FEV1 and 6MWT distance as well as GHQ scores significantly changed over time, with improvements occurring in the first 6 months after LT but no major changes thereafter. Out of the 69 patients enrolled, 32 died over a median follow-up of 51 months. Although mortality tended to be slightly higher for patients with lower HRQoL at the baseline assessment, this difference was not statistically significant. HRQoL evaluations appear critical in the follow-up of LT candidates, in particularly SGRQ, because of its specificity in targeting respiratory symptoms and functional wellbeing

Outliers detection by fuzzy classification method for model building

International audienceOptical Proximity Correction (OPC) is used in lithography to increase the achievable resolution and pattern transfer fidelity for IC manufacturing. Nowadays, immersion lithography scanners are reaching the limits of optical resolution leading to more and more constraints on OPC models in terms of simulation reliability. The detection of outliers coming from SEM measurements is key in OPC [1]. Indeed, the model reliability is based in a large part on those measurements accuracy and reliability as they belong to the set of data used to calibrate the model. Many approaches were developed for outlier detection by studying the data and their residual errors, using linear or nonlinear regression and standard deviation as a metric [8]. In this paper, we will present a statistical approach for detection of outlier measurements. This approach consists of scanning Critical Dimension (CD) measurements by process conditions using a statistical method based on fuzzy CMean clustering and the used of a covariant distance for checking aberrant values cluster by cluster. We propose to use the Mahalanobis distance [2] in order to improve the discrimination of the outliers when quantifying the similarity within each cluster of the data set. This fuzzy classification method was applied on the SEM CD data collected for the Active layer of a 65 nm half pitch technology. The measurements were acquired through a process window of 25 (dose, defocus) conditions. We were able to detect automatically 15 potential outliers in a data distribution as large as 1500 different CD measurement. We will discuss about these results as well as the advantages and drawbacks of this technique as automatic outliers detection for large data distribution cleaning

Mapping Fashion in the \u27City by the Sea\u27: Shopping Districts in Newport, Rhode Island

Newport, Rhode Island is internationally recognized for both its prime location on Narragansett Bay and its storied history. Nicknamed the ‘City by the Sea,’ it is famous for its world-class sailing, colonial New England architecture, Gilded Age mansions, trendy restaurants and bars, and nearby beaches. Cultural tourism is a multi-million dollar business for Rhode Island, especially for Newport, where shopping is fourth on the list of revenue generators. The relationship of an American resort city’s geographical setting, built environment, and cultural heritage to its fashion retail sector has not been explored. Acknowledging that fashion contributes to a city’s image, the authors review Newport’s history, provide a profile of Newport today, map Newport’s nine shopping districts, and analyze Newport’s fashion retail sector on the various streets, squares, wharves, and piers. Such an analysis may prove useful to retailers in other resort cities—both small independent boutique owners and national chain stores—as well as city planners and tourism boards

Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.

BackgroundInternal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia.MethodsIn this phase 1-2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing.FindingsBetween Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3-4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (92 [37%] of 252]), anaemia (86 [34%]), fatigue (83 [33%]), elevated aspartate aminotransferase (65 [26%]), and increased alanine aminotransferase (47 [19%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (98 [39%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission INTERPRETATION: Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials.FundingAstellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro

Identifying structural brain markers of resilience to adversity in young people using voxel-based morphometry

There is increasing evidence that resilience in youth may have a neurobiological basis. However, the existing literature lacks a consistent way of operationalizing resilience, often relying on arbitrary judgments or narrow definitions (e.g., not developing PTSD) to classify individuals as resilient. Therefore, this study used data-driven, continuous resilience scores based on adversity and psychopathology to investigate associations between resilience and brain structure in youth. Structural MRI data from 298 youth aged 9–18 years (M$_{age}$ = 13.51; 51% female) who participated in the European multisite FemNAT-CD study were preprocessed using SPM12 and analyzed using voxel-based morphometry. Resilience scores were derived by regressing data on adversity exposure against current/lifetime psychopathology and quantifying each individual’s distance from the regression line. General linear models tested for associations between resilience and gray matter volume (GMV) and examined whether associations between resilience and GMV differed by sex. Resilience was positively correlated with GMV in the right inferior frontal and medial frontal gyri. Sex-by-resilience interactions were observed in the middle temporal and middle frontal gyri. These findings demonstrate that resilience in youth is associated with volume in brain regions implicated in executive functioning, emotion regulation, and attention. Our results also provide evidence for sex differences in the neurobiology of resilience

Identifying cortical structure markers of resilience to adversity in young people using surface-based morphometry

Previous research on the neurobiological bases of resilience in youth has largely used categorical definitions of resilience and voxel-based morphometry methods that assess gray matter volume. However, it is important to consider brain structure more broadly as different cortical properties have distinct developmental trajectories. To address these limitations, we used surface-based morphometry and data-driven, continuous resilience scores to examine associations between resilience and cortical structure. Structural MRI data from 286 youths (Mage = 13.6 years, 51% female) who took part in the European multi-site FemNAT-CD study were pre-processed and analyzed using surface-based morphometry. Continuous resilience scores were derived for each participant based on adversity exposure and levels of psychopathology using the residual regression method. Vertex-wise analyses assessed for correlations between resilience scores and cortical thickness, surface area, gyrification and volume. Resilience scores were positively associated with right lateral occipital surface area and right superior frontal gyrification and negatively correlated with left inferior temporal surface area. Moreover, sex-by-resilience interactions were observed for gyrification in frontal and temporal regions. Our findings extend previous research by revealing that resilience is related to surface area and gyrification in frontal, occipital and temporal regions that are implicated in emotion regulation and face or object recognition

Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia: final analysis of ALCANTARA study

Aim To evaluate long-term durability of blinatumomab, a BiTE® (bispecific T-cell engager) molecule, in adults with relapsed/refractory (R/R) Philadelphia chromosome–positive (Ph+) B-cell precursor acute lymphoblastic leukaemia (ALL). Methods In this final analysis of an open-label, single-arm, phase 2, multicentre ALCANTARA study (NCT02000427), adults (age ≥18 years) with Ph+ ALL who had relapsed or were refractory to at least one TKI were included. The primary endpoint was the proportion of patients who achieved complete remission (CR)/CR with partial haematologic recovery (CRh) during the first two cycles of blinatumomab treatment. Results The final analysis included 45 patients who completed the study between 3rd January 2014 and 6th January 2017, of which 16 (35.6%; 95% CI, 21.9%–51.2%) achieved CR/CRh within the first two blinatumomab cycles. After a median follow-up of 16.1 months, median relapse-free survival (RFS) was 6.8 (95% CI, 4.4–not estimable [NE]) months. Median overall survival (OS) was 9.0 (95% CI, 5.7–13.5) months with a median follow-up of 25.1 months. Median OS in patients with CR (19.8 [95% CI, 12.1–NE] months) was greater than in those without CR (6.0 [95% CI, 2.9–7.1] months). Of 16 patients with CR/CRh, 14 achieved complete minimal residual disease (MRD) response; the median duration of complete MRD response was 9.7 (95% CI, 5.2–NE) months. Treatment-related adverse events were consistent with those previously reported. Conclusion Long-term durability of responses to blinatumomab was demonstrated in patients with R/R Ph+ ALL