dataesr/scientific-paragraphs-categorization huggingface dataset:
INMA study ( phthalate) BOSCH DE BASEA et al. [4]  investigated the associations between phthalate exposure during pregnancy and lung function during childhood. The authors used data from the Sabadell and Gipuzkoa cohorts within the Spanish INMA study (INfancia y Medio Ambiente -Environment and Childhood). Lung function parameters were measured by spirometry at ages 4, 7, 9 and/or 11 years, with pre-bronchodilator measurements for forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV 1 ), based on which the FEV 1 to FVC ratio (FEV 1 /FVC) was subsequently derived. Nine phthalate metabolites (mono-ethyl phthalate (MEP), mono-iso-butyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-2-carboxymethyl hexyl phthalate (MCMHP; only measured in the Gipuzkoa cohort), mono-benzyl phthalate (MBzP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), and mono-(2-ethyl-hexyl) phthalate (MEHP)) were measured in urine samples collected in both the first and third trimesters of pregnancy from the participating women.
Multivariable linear regression models were used to assess the association between phthalates and each lung function marker at each visit, whilst linear mixed regression with the participant as a random intercept was used to assess the association across all visits. WQS regression, an approach that is designed to estimate the effect of correlated chemical mixtures on health outcomes  [8] , was used to assess the effect of the phthalate metabolites mixture on the children's lung function at each study visit. RHINESSA study (air pollution and greenness) NORDEIDE KUIPER et al. [5]  investigated the associations between air pollution and greenness and respiratory health during different exposure windows. The authors used data from the Respiratory Health in Northern Europe, Spain and Australia (RHINESSA) study.
25 mm i. d. , 0. 25 µm, 5% phenyl-methylpolysiloxane; Agilent J&W). Helium was used as the carrier gas at a flow rate of 1 mL/min. The column temperature was initially programmed at 60 • C and then increased to 180 • C at 12 • C/min and held for 2 min. The injector and detector temperatures were 220 • C and 230 • C, respectively. The ionization energy was 70 eV. The compounds were identified based on a comparison of their mass spectra using the data in NIST 14 (National Institute of Standards and Technologies, Mass Spectra Libraries).
Acknowledgments In addition to the centres: ASST  Niguarda -Milano  and  Ospedale Maggiore Policlinico -Milano  we would like to convey our appreciation for the transplant teams at the following Italian centres for contributing with their data: ASST  Papa Giovanni XXIII -Bergamo :  Stefania Camagni ,  Michele Colledan ,  ISMETT -Palermo :  Duilio Pagano ,  Salvatore Gruttadauria ,  Istituto Nazionale dei Tumori -Milano :  Marco Angelo Bongini ,  Vincenzo Mazzaferro ,  AOU di Padova :  Enrico Gringeri ,  Umberto Cillo ,  AOU Pisana -Pisa :  Davide Ghinolfi ,  Francesco Torri ,  Paolo De Simone ,  AOU Città della Salute -Torino :  Damiano Patrono ,  Renato Romagnoli ,  Policlinico Sant'Orsola-Malpighi -Bologna :  Matteo Ravaioli ,  Giuliana Germinario ,  Matteo Cescon ,  AOU di Modena :  Tiziana Olivieri ,  Paolo Magistri ,  Fabrizio Di Benedetto.
The primary objective of this study was to assess the safety and tolerability of mocravimod in patients undergoing allo-HSCT for hematologic malignancies. Secondary objectives were to determine the pharmacokinetic profiles of mocravimod and its active metabolite mocravimodphosphate in this patient group, as well as to assess GVHD-free, relapse free survival at 6 months after the last treatment. In this 2-part, single-and 2-arm randomized, open-label trial, we evaluated the safety, tolerability, and pharmacokinetics of mocravimod in allo-HSCT recipients (ClinicalTrials. gov identifier NCT01830010). Patients received either 1 mg or 3 mg mocravimod per day on top of standard of care GVHD prophylaxis with either cyclosporine A/methotrexate or tacrolimus/methotrexate. We found that mocravimod can be safely added to standard treatment regimens in patients with hematologic malignancies requiring allo-HSCT.
Study Design and Patient Population CKRP203A2105 (ClinicalTrials. gov identifier NCT01830010) is a multicenter, phase Ib study of mocravimod in intermediate-risk to high-risk patients undergoing allo-HSCT for hematologic malignancies (Figure  1 ). Part 1 was a single-arm open-label study to investigate the safety of 3 mg/day orally administered mocravimod added to SoC GVHD prophylaxis with cyclosporine A (CsA)/methotrexate (MTX) (Mo3CsA) in 10 patients. Part 2 was a randomized 2-arm open-label study to assess the safety, pharmacokinetics, and preliminary efficacy of 1 mg/day mocravimod in combination with CsA/ MTX (Mo1CsA) or 3 mg/day mocravimod in combination with tacrolimus/ MTX (Mo3Tac). Study drug dose adjustments were permitted according to the study protocol, and drug interruptions were allowed based on the judgment of the investigator.
Statistical Analysis All patients who received at least 1 dose of mocravimod were included in the analyses. Descriptive analysis was performed for safety and pharmacokinetic and pharmacodynamic data by treatment and time point. Descriptive visualization of pharmacokinetic data presents the arithmetic mean with error bars representing the standard deviation (SD), and visualization of pharmacodynamic data presents the arithmetic mean with error bars representing the standard error (SE). Where consolidated descriptive visualizations are presented, the errors for both pharmacokinetic and pharmacodynamic data are in terms of SD. Efficacy (time-to-event) data are presented using Kaplan-Meier curves, and where the median time to event is described, it is obtained from Kaplan-Meier estimates. For descriptive summaries of pharmacokinetic parameters, unless stated otherwise, these parameters were summarized using geometric means, except for T max and T lag , which were summarized using the median.
The relationship between mocravimod-P and ALC also was analyzed using a sigmoid E max model with a random effect to adjust for patient variability, ALC ij ¼ E 0 À E max þ Conc ij EC 50 þ Conc ij þ s i þ e ij where ALC ij is the ALC of patient i at observation j, Conc ij is the corresponding metabolite concentration, E max is the maximum decrease, EC 50 is the metabolite concentration at which the expected benefit is one-half the maximum, and E 0 is the effect at zero metabolite concentration. Safety data were summarized using standard descriptive methods. All statistical analyses were performed using SAS software (SAS Institute, Cary, NC). Analysis of endpoints that may be affected by a competing risk of death were analyzed using cumulative incidence function estimates, unless no effect by competing risks was observed, in which case Kaplan-Meier estimates were used instead.
Liver Safety Mildly elevated liver function test (LFT) results are typical with most S1PR modulators, and increased levels are frequently observed in allo-HSCT recipients [12À16]. Therefore, LFTs were closely monitored in this study (Figure  2 ). No consistent increase in LFTs beyond the expected range was observed during mocravimod treatment. One noticeable increase in LFTs post-mocravimod treatment was caused by cGVHD. Except for 1 patient in the Mo3Tac arm, total bilirubin remained normal. Importantly, no increases in LFTs were observed on diagnosis of aGVHD. Linear increases of AST and ALT, as observed with increasing doses of fingolimod in multiple sclerosis patients [17À20], did not occur in our allo-HSCT recipients treated with mocravimod. Overall, within the limitations of this small dataset, there is no evidence for mocravimod-induced liver toxicity.
DISCUSSION This is the first reported study investigating the effect of an S1PR modulator in patients with hematologic malignancies undergoing allo-HSCT. The primary objective of the study was to evaluate the safety, tolerability, and pharmacokinetics of mocravimod as an adjunctive and maintenance treatment for allo-HSCT. Patients with a broad variety of malignancies were included in this trial. The data suggest that administration of mocravimod in a prophylactic mode from 10 days pretransplantation and then as maintenance therapy to 100 days posttransplantation, along with a broad range of SoC is safe and well tolerated. As reported previously in autoimmune indications, mocravimod treatment caused first dose, transient bradycardia in 2 patients of mild severity with no clinical concern. Because S1PR signaling is suggested to be involved in the homing and engraftment of hematopoietic stem cells to bone marrow  [24] , the first patient in our series received nonmyeloablative conditioning (Mini-Seattle) to mitigate the risk of engraftment failure.
It is important to note, however, that the number and heterogeneity of patients in this study are not suitable for drawing final conclusions on GVHD outcomes. Of note, ATG was not used as part of GVHD prophylaxis. Patients in the Mo3Tac arm performed slightly worse than those in the other arms in terms of efficacy outcomes (RFS and GRFS). The pharmacokinetics of mocravimod and mocravimod-P were similar in the Mo3Tac and Mo1CsA arms, and thus no difference between these arms would be expected based on pharmacokinetics. Relapse rates were slightly better in mocravimod-treated patients compared with a similar patient cohort from the Center for International Blood and Marrow Transplant Research database. Hematologic malignancies were heterogenic with different relapse risks, impeding our ability to draw final conclusions.
Eteplirsen is FDA-approved for the treatment of Duchenne muscular dystrophy (DMD) in exon 51 skipamenable patients. Previous studies in boys > 4 years of age indicate eteplirsen is well tolerated and attenuates pulmonary and ambulatory decline compared with matched natural history cohorts. Here the safety, tolerability and pharmacokinetics of eteplirsen in boys aged 6-48 months is evaluated. In this open-label, multicenter, dose-escalation study (NCT03218995), boys with a confirmed mutation of the DMD gene amenable to exon 51 skipping (Cohort 1: aged 24-48 months, n = 9; Cohort 2: aged 6 to < 24 months, n = 6) received ascending doses (2, 4, 10, 20, 30 mg/kg) of once-weekly eteplirsen intravenously over 10 weeks, continuing at 30 mg/kg up to 96 weeks. Endpoints included safety (primary) and pharmacokinetics (secondary).
Pre-clinical and clinical evaluations of PMOs have demonstrated favorable, consistent and predictable safety profiles  [ 9 , 16 , 19 , 20 ]. Eteplirsen is a PMO treatment designed to skip exon 51 of the DMD gene  [21]  and is currently approved in the United States for boys with DMD who have a confirmed genetic mutation amenable to exon 51 skipping  [ 9 , 19 , 22 ]. Previous studies of eteplirsen in boys > 4 years of age indicate that it is well tolerated, has a well characterized pharmacokinetic profile and attenuates pulmonary and ambulatory decline compared with mutation-matched natural history cohorts  [ 9 , 19 , 23-27 ]. Study 4658-102 (NCT03218995) is a phase 2, multicenter, open-label, dose-escalation clinical trial designed to assess safety, tolerability and pharmacokinetics of eteplirsen in boys with mutations amenable to exon 51 skipping who are 6-48 months of age.
Study design This phase 2, multicenter, open-label, dose-escalation study was conducted across 5 sites in the European Union and the United Kingdom (NCT03218995). An institutional review board or independent ethics committee at each site approved the study protocol and informed consent form prior to enrollment. This study was conducted in accordance with the ethical principles of Good Clinical Practice and the Declaration of Helsinki. Written informed consent was obtained for each participant from the parent/legal guardian(s) before beginning any study-related procedures.
Treatment cohorts Participants were enrolled into 2 cohorts based on their age. Boys 24-48 months comprised Cohort 1 and those 6 to < 24 months comprised Cohort 2. Cohort 2 was enrolled only after the first 3 participants in Cohort 1 completed at least 12 intravenous (IV) infusions of eteplirsen and all available safety data were reviewed. An external Data Monitoring Committee reviewed safety data at least weekly through the first 12 weeks of dosing for the first 3 participants of each cohort and then at least quarterly thereafter. Eligible boys received a weekly IV infusion of eteplirsen for up to 96 weeks ( Fig. 1  ). Dose titration lasted 10 weeks overall (1 infusion/week) to slowly achieve the target dose of 30 mg/kg. Eteplirsen dosing began at 2 mg/kg for 2 weeks and was escalated to 4 mg/kg, 10 mg/kg, 20 mg/kg and 30 mg/kg.
Statistical analyses There was no formal sample size calculation. The sample size was based on qualitative considerations and was sufficient to allow evaluation of safety and the estimation of PK parameters for eteplirsen in the studied population. The study was not powered to evaluate efficacy in this population. AEs, vital signs, height/length, weight, clinical chemistry, hematology, renal function, coagulation, urinalysis and ECGs were analyzed using descriptive statistics. ECG parameters, including left ventricular ejection fraction (LVEF) and change from baseline in LVEF to each visit, were summarized by visit for each age cohort and overall. PK parameters   for eteplirsen were calculated from plasma and urine concentration data using non-compartmental analysis, as appropriate. For all hypothesis testing, 2-sided significance level was 0.
Funding Study  4658-102  (  NCT03218995  ) was funded by  Sarepta Therapeutics , Inc. Medical writing and editorial support was provided by  Katherine Alfond ,  PharmD, RPh , of  Sarepta Therapeutics, Inc. , and  Paraskevi Briassouli, PhD , of  Eloquent Scientific Solutions , and was funded by  Sarepta Therapeutics , Inc.
Study variables and data collection The screening and extraction of data and the study of the files were performed using the Résurgences ® software. The data were subsequently compiled into a Microsoft Excel. An agreement was set up between the two sites in order to allow a combined analysis in compliance with regulations concerning data privacy. We studied different patient characteristics, patient pathologies and the management of the two consultations. Patient data included gender, age and baseline comorbidities that we measured using the Charlson Comorbidity Index (CCI) (Table  1 ). Characteristics of the first visit included how they arrived [by their own means or by medical transport such as an ambulance or an Véhicule de Secours et d' Assistance aux Victimes (VSAV)] if they were sent to the ED on the recommendation of a HCP or by a social establishment such as a retirement home or assisted living facility (known as the EHPAD in France), the date and time of the first consultation (working hours from 8:30 a.
05. In order to avoid a possible recruitment bias, the models were adjusted on the center. The odds-ratio (OR) and 95% confidence interval (CI) were obtained from the model. The performance of the models was examined in terms of calibration using the Hosmer-Lemeshow test and calibration by calculating the c-statistic. Statistical tests were performed at the 0. 05 significance level. The data was analyzed using SAS software Version 9. 4 (SAS Institute, Cary, NC, United States).
PET Imaging Experiments Imaging studies were performed on a Inveon µPET/CT scanner (Siemens Healthcare Molecular Imaging). The respiratory rate was monitored during imaging sessions. Listmode PET data were acquired for 60 min, and this was initiated as soon as the formulated [ 18 F]1 (~5. 6 MBq/100 µL) was injected. The PET images were reconstructed using an iterative OSEM3D/MAP algorithm. Dead-time, random, scatter, as well as attenuation correction (based on CT) were applied. The image analysis was performed with P-Mod 3. 7 software (P-MOD Technologies). Briefly, the PET and CT images were co-registered. Volumes of interest (VOIs) were semi-automatically delimitated for the following organs: bladder, bone, brain, heart, kidney, liver, lung, and muscle, if available. Time-activity curves (TACs) were extracted from PET images, with the data expressed as standardized uptake value (SUVMean).
Purpose The reliability of magnetic resonance imaging (MRI) as a local and nodal staging tool in radio-recurrent prostate cancer (PCa) is still unclear. The present study aims at evaluating the predictive value of MRI in the detection of extracapsular extension (ECE), seminal vesical invasion (SVI) and nodal involvement (LNI) in patients after primary radio (EBRT) and/ or brachytherapy (BT) before salvage radical prostatectomy (SRP). Methods This systematic review and meta-analysis were performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Pubmed, Scopus, and Web of Science databases were systemically reviewed to extract the data on diagnostic performance of MRI in radio-recurrent PCa. Results Four studies comprising 94 radio-recurrent PCa patients were included.
Search strategy The study was registered with the International prospective register of systematic reviews PROSPERO (ID: CRD42022359818). A systemic literature review was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. We queried Medline (Pubmed), Scopus and Web of Science databases on September 2022. The search terms included the following: "MRI", "magnetic resonance imaging", "prostate cancer", "radiotherapy" and "salvage prostatectomy". Two investigators (PZ and AŚ) performed an independent initial screening based on the titles and abstracts. The causes of the exclusion of ineligible reports were noted. Full texts were retrieved and evaluated for eligibility. In case of discrepancies, disagreements were solved by the authors' consensus.
Methods Study Design and Patients Consecutive patients with symptomatic severe AS  13  who underwent TAVR were enrolled in a prospective registry at our institution (Nouvel Hôpital Civil, Université de Strasbourg, Strasbourg, France) between February 2012 and May 2019. For the purpose of the present analysis, absence of CT-ADP assays and patients with missing AF data were excluded (►Fig. 1). Indications for TAVR and procedural approaches were assessed by the local heart team. The balloon-expandable Edwards SAPIEN XT or S3 prosthesis (Edwards Lifesciences, Irvine, California, United States), the self-expandable CoreValve, Evolut-R, or Evolut-PRO (Medtronic, Irvine, California, United States), and ACURATE neo (Boston Scientific, Natick, Massachusetts, United States) were used. All patients signed informed consent before the procedure and agreed to the anonymous processing of their data (France 2 and France TAVI Registries).
Clinical Events Bleeding complications were assessed according to the Valve Academic Research Consortium-2 (VARC-2) definitions and were classified as follows: life-threatening bleeding, major bleeding, and minor bleeding. Major adverse cardiac and cerebrovascular events (MACCEs) were defined as a composite of all-cause death, myocardial infarction, stroke, and heart failure hospitalization. In-hospital events were collected by careful reviewing of the patient electronic medical records. Patients' follow-up data were obtained through telephone interviews from the patients or their family, the cardiologist, the family physician, or by hospital records. The primary endpoint of the present analysis was major/life-threatening bleeding complications (MLBCs) at 1 year after TAVR. Secondary endpoint was MACCE at 1 year.
Study Limitations We acknowledge the following limitations: first, the analyses were performed on the basis of a single center data set with uncertain generalizability. Second, CT-ADP prolongation could be influenced by the presence of low Hb levels, low platelet count, and P2Y 12 inhibitors. Nevertheless, the noxious impact of CT-ADP >180 seconds on bleeding events was confirmed by adjusting the Hb levels and platelet count in the multivariate analysis and the sensitivity analysis with and without clopidogrel at discharge. Third, assessments of CT-ADP were only performed 24 hours after TAVR and were not repeated during the follow-up. Forth, since the majority of patients received dual antithrombotic therapy at discharge (90%) (►Supplementary Table  S9 ), we were not able to investigate the relationship between the number of antithrombotic therapies and bleeding events.
Data Collection All data were prospectively collected. They comprised details on ICU admission, demographic characteristics, chronic disease, relevant comorbidities, and baseline severity indices, including SAPS II and SOFA score. Treatments on admission were recorded, including corticosteroids, IL-6 or IL-1 receptor antagonists, and previous antibiotic treatments. Several variables were recorded throughout the ICU stay, including clinical and biological parameters; requirements for non-invasive ventilatory support and invasive mechanical ventilation (IMV); prone position; the presence of a pulmonary embolism; other organ support (vasopressors, renal replacement therapy (RRT), and ECMO); and antimicrobial therapy. Biological analyses were performed as clinically indicated. The presence of glomerular hyperfiltration was usually evaluated but not always available (defined by a glomerular filtration rate above 130 mL/min/m 2 ).
The random forest analysis was conducted using the package randomForest (CRAN; version 4. 6-14) in R (CRAN; version 3. 6. 3). The ranking of the first 20 preselected factors was then used as the order in which the factors were added to the survival model using a forward variable selection based on the Bayesian information criterion (BIC). The factors identified as important during the forward variable selection were then further explored using a backward selection survival model, in order to determine their association with 60-day mortality. All terms with a p-value of <0. 05 remained in the backward selection survival model. A hazard ratio (HR) >1 indicated an increased risk of death. The proportionality of hazard risks for the covariates was assessed using the marginal residuals. Second, subgroup analyses among the patients with VAP were conducted to assess the impact of relapse, superinfection, and treatment failure on 60-day mortality, using similarly selected covariates.
Third, the risk of treatment failure (relapse, superinfection, or death, depending on which event occurred first) at Day 60 was computed using a univariate and a multivariate survival model and covariate selection using the random forest method. In order to identify the risk factors for relapse, superinfection, and treatment failure among the patients with VAP, we performed multivariable Fine and Gray sub-distribution competing risk models. ICU death and extubation were considered competing events. The variables associated with these events with a p-value of <0. 2 were introduced in the multivariate model. A backward selection was performed to select the final covariates. All models were stratified by center. For all tests, a two-sided α of 0. 05 was considered significant. Missing baseline variables were handled through multiple imputation with only one dataset.
Ethics The methods for data collection and the quality of the database have been described previously. In accordance with French laws, the OutcomeRea TM database has been ap-proved by the French Advisory Committee for Data Processing in Health Research (CCTIRS) and the French Informatics and Liberty Commission (CNIL, registration no. 8999262). The database protocol was submitted to the Institutional Review Board of the Clermont-Ferrand University Hospital (Clermont-Ferrand, France), who waived the need for informed consent (IRB no. 5891). The analysis of the risk factors and the outcome associated with VAP relapse was approved by the ethical committee of the French Society of Intensive Care (# SRLF 21-76).