dataesr/scientific-paragraphs-categorization huggingface dataset:
1 million persons in 2030. 14 cently, our group highlighted significant associations between AF reporting and 19 anticancer drugs (abiraterone, aldesleukin, azacitidine, bortezomib, cisplatin, clofarabine, dacarbazine, daunorubicin, docetaxel, ibrutinib, idarubicin, ipilimumab, lenalidomide, midostaurin, nilotinib, obinutuzumab, pomalidomide, ponatinib, and rituximab) in the World Health Organization spontaneous reporting pharmacovigilance database VigiBase,  15  however, the incidence of AF associated with these therapies remains unknown. 16 The aim of this study was to estimate the annualized incidence rate of AF reporting associated with exposure to 1 of 19 anticancer drugs used as monotherapy in clinical trials, using a safety meta-analysis of cancer clinical trials. to post results at ClinicalTrials.
gov within 1 year of trial completion. 18 It was previously showed that trial results, particularly safety results, were more comprehensively reported at ClinicalTrials. gov than in journal publications. 19, 20 The ClinicalTrials. gov registry thus provides a unique opportunity to study safety outcomes. The extraction and analysis of the ClinicalTrials. gov results database was previously described and validated to estimate the risk and incidence of adverse events (AEs). 21, 22   follow-up time frame (months), year of the study, and the type of the control drug (placebo or other anticancer drug) in presence of control groups. Among the trials included in our safety meta-analysis, we also extracted all AF cases in control arms treated by placebo or a monotherapy anticancer drug not belonging to the list of the 19 anticancer drugs of interest.
METHODS RISK OF BIAS AND QUALITY ASSESSMENT. Two authors (P. -M. M. and J. A. ) evaluated the risk of bias in individual studies using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist tool specially designed to assess bias in safety meta-analyses. 23 A final summary risk of bias assessment was asked for the whole study, and judgments could be low, high, or unclear. Bias domains that could not be completed owing to insufficient data were classified as "unclear risk. " In case of disagreements, a third author (C. D. ) was consulted. Publication bias was assessed graphically by constructing a funnel plot based on the standard error of logit transformed proportion against the logit transformed proportion. OUTCOMES. The primary outcome was the annualized incidence rate of AF reporting associated with exposure to 1 of 19 anticancer drugs  15  used as monotherapy in clinical trials.
We also report the annualized incidence rate of AF reported in the placebo arms of these trials. In addition, we performed post hoc subgroup analyses according to cancer site. Because September 2009 was the mandatory date of AE registration in ClinicalTrials. gov, we performed a post hoc subgroup analysis based on this date. STATISTICAL ANALYSIS. We conducted a randomeffects meta-analysis to compute the summary annualized incidence rate with its 95% CI. The summary annualized incidence rate of AF reporting per 100 observations associated with anticancer drugs was computed using the log transformation and inverse variance weighting. The person-time estimator was defined as the mean/median time frame multiplied by the number of patients, at study level, because it was assumed the follow-up for AF was identical to the study follow-up in most cases.
We assessed between-study heterogeneity using the inconsistency index I 2 , t 2 , and Cochran's Q test. Substantial between-study heterogeneity was defined by an I 2 value >50%, and significant heterogeneity was defined by a P value <0. 10 for Cochran's Q test. The t 2 statistic was used to measure the variance of true effect sizes across studies. 24 Time frames were expressed as mean/median [range]. Post hoc subgroup analyses on cancer site and the mandatory date of AE registration in ClinicalTrials. gov were performed using Z-test. Data management and meta-analysis of proportions and incidence rates were performed with R v4. 2. 1 (R Core Team) and the R package meta and presented as forest plots. 25  were included in the main analysis after application of selection criteria, of which 2 were eligible for 2 anticancer drugs (Supplemental Tables  3  and 4 ).
DISCUSSION Using the ClinicalTrials. gov registry, we performed a meta-analysis of 191 studies accruing 26,604 patients, and we determined the summary annualized 1. 78-3. 12) per 100 person-years. These results indicate that in oncological trials, AF reporting is not a rare event, even though these results are probably underestimated compared with the "real-life" incidence, as supported by the funnel plots. In oncological trials reporting CVAEs, AE rates were markedly lower than those observed among real-life populations. 11 These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants, and AF reporting is expected to be particularly affected. Cardiac rhythm abnormalities, particularly subclinical and/or paroxysmal AF, still represent a diagnostic challenge, although they may be frequent in specific populations.
7, 33 In chronic lymphocytic leukemia patients, using the National Inpatient Sample database, AF was associated with an increased risk of allcause mortality (6. 06%; OR: 1. 39; 95% CI:  Abbreviations as in Table  1. cancer, incident AF occurring within 30 days after breast cancer diagnosis was associated with a significant increase in both all-cause (aHR: 2. 15; 95% CI: 1. 32-3. 48) and cardiovascular (aHR: 3. 00; 95% CI: 1. 28-7. 00) mortality at 1 year compared with the no-AF patients. 7 In addition to an increased risk of allcause and cardiovascular mortality, cancer also increased major bleeding risk in AF patients. 34   included by combination. We excluded 2,069 studies (80. 8%) because patients were treated only with combinations of anticancer drugs; these exclusions may have resulted in a selection bias, thus altering the annualized incidence rates of AF reporting or even precluded estimation for some drugs.
DATA SOURCE. ClinicalTrials. gov is the largest clinical trial registry website, holding registrations from over 353,000 trials from 209 countries since 1997. ClinicalTrials. gov provides easy access to data on publicly and privately supported clinical studies on a wide range of diseases and conditions. It contains information about publicly and privately funded clinical trials, the purpose of each experimental drug, subject eligibility criteria to participate in the clinical trial, the location of clinical trial sites being used for a study, and a point of contact for patients interested in enrolling in the trial. The 2007 U. S. Food and Drug Administration (FDA) Amendments Act required clinical trials of all FDA-approved drugs and biologics.
Results are generally submitted to the website by the responsible party (sponsor or principal investigator) soon after the completion of the study, and results can be updated over time. Once submitted, the results go through a quality assurance process and are reviewed by a ClinicalTrials. gov staff member who focuses on internal consistency and logic. In the ClinicalTrials. gov results database, all AEs are classified according to the Cancer Therapy Evaluation Program Adverse Event Reporting System definition (CTEP-AERS, U. S. National Institutes of Health). SEARCH STRATEGY. For each of the 19 anticancer drugs of interest in monotherapy, 15 we searched ClinicalTrials. gov up to September 18, 2020, for A B B R E V I A T I O N S A N D A C R O N Y M S AE = adverse event AF = atrial fibrillation CVAE = cardiovascular adverse event ECG = electrocardiogram FDA = Food and Drug Administration J A C C : C A R D I O O N C O L O G Y , V O L.
A C C : C A R D I O O N C O L O G Y , V O L. 5 , N O. 2 , 2 0 2 3increased risk of AF, 5  should consider implementation of a standardized AF detection strategy based, not only on 12-lead ECGs performed only in cases of AF-related symptoms, but also on longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AF. 29, 30 This lack of systematic and standardized rhythm monitoring in oncological trials associated with an underreporting of cardiac AEs 11 is also problematic to clearly define which anticancer drugs are significantly associated with AF reporting. In our previous work using the international pharmacovigilance database, we found that 19 anticancer drugs were associated with AF reporting, 15  whereas only 3 exhibited an AF reporting annualized incidence rate not overlapping with the calculated AF reporting annualized incidence rates of the placebo arms in the present work.
The discrepancy for this is unclear. However, it may be related to underreporting. Although also prone to postmarketing AE underreporting, pharmacovigilance databases are valuable due to the large number of reports available (11,757 vs 551 AF cases in the present study) and the possibility to more easily analyze a combination of several anticancer drugs. In our view, they represent a suitable complementary approach to oncological trial meta-analyses. We were able to compare annualized incidence rates reported before or after September 2009, the date of the legal obligation to report AEs. The overall trend was toward a higher estimate of the summary annualized incidence rates of AF reporting for studies registered after 2009 than before even though AF detection strategies were similar and based on 12-lead ECGs only.
This suggests that AF underreporting was significant for older studies and that the Clinical-Trials. gov requirement was useful in increasing the AF reporting and allows for a more comprehensive approach to the true incidence. Therefore, caution should be exercised in our estimation of the summary annualized incidence rate of AF reporting for midostaurin and clofarabine, which have no studies registered after September 2009. Moreover, although the ClinicalTrials. gov requirement was useful in increasing the AF reporting, CVAEs and especially AF remained underreported AEs mainly due to the lack of systematic cardiovascular monitoring in oncological trials. 11.
J A C C : C A R D I O O N C O L O G Y , V O L. 5 , N O. 2 , 2 0 2 3increased risk of AF, 5  should consider implementation of a standardized AF detection strategy based, not only on 12-lead ECGs performed only in cases of AF-related symptoms, but also on longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AF. 29, 30 This lack of systematic and standardized rhythm monitoring in oncological trials associated with an underreporting of cardiac AEs 11 is also problematic to clearly define which anticancer drugs are significantly associated with AF reporting. In our previous work using the international pharmacovigilance database, we found that 19 anticancer drugs were associated with AF reporting, 15  whereas only 3 exhibited an AF reporting annualized incidence rate not overlapping with the calculated AF reporting annualized incidence rates of the placebo arms in the present work.
Statistics For ELISA and QRT-PCR, each experiment of cell incubation with bacteria and secretome was carried out at least three times in independent experiments and all quantifications were performed in triplicate. Results are presented as means ± standard deviations (SDs) and were analyzed by Welsh's test. Differences in values were considered significant at p < 0. 05. For ELISAs, the data were the means ± SDs of triplicate values and were representative of three independent experiments. For qRT-PCR, the values were normalized to the negative control (medium alone) for each experiment and shown as the fold change or Log Fold change of the control's value. The means ± SDs of triplicate values were compared between stimulated and unstimulated cells and are representative of three independent experiments.
Acknowledgments These studies were funded by the  French Office for Biodiversity (OFB). The authors thank the  GRAIE (Research, Technical Coordination and Information on Water Group)  for managing the RISMEAU project (Risks linked to drug residues, biocides and anti-bioresistance of human and veterinary origin in the water resources of the Arve catchment area), the Provademse platform for its technical support and laboratories that analyzed the different pollutants present in this study ( Myriam Hammada , LEHNA laboratory;  Marjolaine Deschamps ,  Ghislaine Delarue ,  Erell Naslain  and  Françoise Poiroux ECOSYS  laboratory;  Philippe Marchand , Residues and  Contaminants in Food Analysis Laboratory ). RISMEAU is a research program supported by  Bellecombe  site ( SIPIBEL ), a field observatory  on hospital effluents  and urban sewage treatment plan.
A candidate AS01-adjuvanted vaccine containing four surface proteins from non-typable Haemophilus influenzae and Moraxella catarrhalis (NTHi-Mcat) has been developed to help prevent exacerbations of chronic obstructive pulmonary disease (COPD). Sequential administration of different vaccines containing the same AS01-adjuvant system could lead to immune interference. We compared administration of NTHi-Mcat following AS01adjuvanted recombinant zoster vaccine (RZV) versus NTHi-Mcat alone. This phase 2a, openlabel trial (NCT03894969) randomized healthy current or former smokers (50-80 years) without COPD to administration of NTHi-Mcat at 1, 3, or 6 months after RZV or to NTHi-Mcat alone (2-dose for both vaccines). Primary outcome was non-inferiority of the humoral immune response to NTHi-Mcat administered 1 month after RZV versus NTHi-Mcat alone, evaluated by specific antibody geometric mean concentration (GMC) ratio with 95% confidence intervals (CIs).
Results The first participant was enrolled on 23 April 2019 and the last study visit took place on 13 August 2021. A total of 541 participants were enrolled and randomized, all of whom received at least one dose of NTHi-Mcat vaccine or RZV; 16 participants received only RZV and were excluded from the safety set which therefore comprized 525 participants (Figure  2 ). The PPS included 411 participants (Figure  2 ). Baseline demographic characteristics were similar between study groups. In the safety set, mean age was approximately 60 years, approximately three-quarters were aged ≤64 years, there were similar proportions of men and women and similar proportions of current and former smokers (Table  1 ). Most participants were White. Participant baseline characteristics in the PPS were similar across the four vaccine groups (data not shown).
Results: 692 out of 1246 surgical patients met our inclusion criteria. 153 smokers were matched with 153 non-smokers according to age, BMI, number of fused levels and global tilt. After PSM both groups were homogeneous regarding baseline parameters, surgical data and complications (MC and infection excluded). Smokers had worse baseline results for SRS-total, SRS-pain COMI-back, NRS-Back pain/leg pain and ODI; smokers also showed worse 2-year outcomes for SRS-total, SRS-function, SRS-pain, SRS-image and ODI (table). However, no differences between the two groups were found in the improvement from baseline to two-year FU or in the timing of this improvement (MMRM). The proportion of patients reaching the minimal clinically important difference (MCID) after surgery was similar in the two groups, but the proportion of patients reaching patient acceptable symptom state (PASS) was significantly lower in smokers for SRS-Subtotal, SRS-function and SRS-image.
Data sources 7] [38]  The relative size of each KP and clients of FSW varied across simulations to reflect heterogeneities in available country-specific studies but was constant over time within simulations (Table  S1a , Figures  S3c, S4c, S5c ). 3] [44] [45]  The sizes of the client population were estimated by triangulating the estimated sizes of the FSW population, the number of sex acts paid by clients and paid for by FSW. As no client data was available for Mali, we used estimates of the number of sex acts paid by clients in Côte d'Ivoire. Sexual behaviours, trends in condom use and HIV prevalence of KP were based on local surveys in the three countries (Tables  S1, S2 ). Importantly, the annual HIV testing rates and fractions of PLHIV ever tested was mostly sourced from secondary analysis of local population-based and KP surveys by age, sex, and HIV status when available (Tables  S2a-c ).
This work was supported by  Unitaid  (Grant Number: 2018-23 ATLAS) through a collaborative agreement with Solthis. RS and MCB acknowledge funding from the  MRC Centre for Global Infectious Disease Analysis  (reference  MR/R015600/1 ), jointly funded by the  UK Medical Research Council (MRC)  and the  UK Foreign, Commonwealth & Development Office (FCDO) , under the  MRC/FCDO  Concordat agreement and is also part of the EDCTP2 programme supported by the  European Union. PV, MCB and MMG acknowledge funding from the  Wellcome Trust  ( WT 226619/Z/22/Z ). MMG research program is supported Tier 2  Canada Research Chairs. For the purpose of open access, the author has applied a  Creative Commons Attribution (CC BY) license  to.
Background: The aim of this study was to analyze whether prescriptions of antiepileptic drugs (AEDs) are significantly associated with an increased incidence of Parkinson's disease (PD) in the German population. Methods: This study used data from German primary care practices found in the Disease Analyzer database (IQVIA) and included all patients aged ≥18 years who were diagnosed with PD between January 2010 and December 2021 (index date). The controls were patients without PD matched (1:1) by age, sex, and pre-diagnostic observation time in years. Associations between AED prescriptions (any AED as well as separate evaluations for carbamazepine, lamotrigine, levetiracetam, sodium valproate, gabapentin, and pregabalin) and subsequent diagnosis of PD were examined using a logistic regression model adjusted for epilepsy, restless legs syndrome, and neuropathy diagnoses.
Database This study used data from German primary care practices found in the Disease Analyzer database (IQVIA). Details of the methodology behind this database have been published previously  [6]. In brief, the Disease Analyzer database contains data on demographic variables, diagnoses, and prescriptions from general and specialized practices in Germany. The quality of the data is assessed every month based on several criteria (e. g. , completeness of documentation and linkage between diagnoses and prescriptions). Practices included in the database are selected based on the yearly statistics published by the German Medical Association, which include information on physician's age, specialty group, community size category, and German federal state. Prior research has shown that the Disease Analyzer database is representative of all practices in Germany  [7].
Study Population The study population included all patients aged ≥18 years with a diagnosis of PD (ICD-10 code: G20) made between January 2010 and December 2021 (index date) who had been registered in the database for at least one year prior to the index date. This latter inclusion criterion was chosen to ensure that no patients recently registered in the database who had an existing diagnosis of PD were included. Controls were patients without PD who were matched (1:1) by age, sex, and their pre-diagnostic observation time in years. For individuals without PD, the index date was a randomly selected visit date between January 2010 and December 2021. A flow diagram of study participants is shown in Figure  1.
In addition, we have expanded the findings by adding new associations for further AEDs and examining the differential contribution of underlying diagnoses and AED prescription. While it is well known that parkinsonism is induced by sodium valproate, it is less commonly described as an adverse effect of other AEDs  [9, 10]. Pacheco-Paez et al. reported a significant association between gabapentin and pregabalin and parkinsonism: among 5,653,547 case safety reports from the World Health Organization individual case safety report database, 4925 parkinsonism reports were found for patients taking pregabalin and 4881 for those receiving gabapentin  [11]. In rare cases, parkinsonism cases were also reported in patients treated with lamotrigine  [12]. No parkinsonism cases have yet been reported among patients treated with levetiracetam  [13].
However, the study is also subject to several limitations. First, as we used electronic medical records from primary care practices, we did not have information on how the PD cases were diagnosed (i. e. , diagnostic criteria or assessment tools). The diagnosis of PD relied on ICD-10 codes alone, and no data were available on symptoms (e. g. , tremor, bradykinesia, muscle stiffness, and others). Second, both epilepsy and PD may have been diagnosed and treated in specialized practices and hospitals, and some of the related data could have been undocumented in the electronic medical records of general practitioners in the Disease Analyzer database. Third, no data were available on smoking status and alcohol use that would allow these variables to be taken into consideration as PD risk factors.
Introduction From 2018 single inhaler triple therapy (SITT) became available in France to treat moderate-to-severe chronic obstructive pulmonary disease (COPD). Given its simplified inhaler use compared with multiple inhaler triple therapy (MITT), this therapeutic option has the potential to offer benefit in terms of improved persistence and adherence. Given the lack of real-world evidence of the effectiveness of triple therapy, this study was designed to evaluate the use of MITT and SITT in France and compare persistence. Methods A retrospective cohort study was performed. Patients with COPD who initiated triple therapy between 1 July 2017 and 31 December 2019 were included from The Health Improvement Network, a large electronic medical database in France, which includes pharmacy data. A 60-day treatment gap defined discontinuation and thereby persistence.
MATERIAL AND METHODS Patients were included in this retrospective cohort study from The Health Improvement Network (THIN) in France, a Cegedim database. The Cegedim databases are anonymised in compliance with currently applicable data protection laws, regulations and policies. THIN is an unobtrusive medical data collection scheme that collects anonymised patient data from its members, that is, electronic health records of GPs and specialists. This includes information about people's health such as their diseases, test results and medication, but not their name, address or other information that could directly identify them-the study was a retrospective analysis of secondary anonymised patient data only. Data cannot be shared publicly because of legal restrictions. For the THIN database in France, several audits were conducted by Commission Nationale de l'Informatique et des Libertés-the French authority responsible for the protection of personal data and is approved for research purposes and does not require patient consent for specific studies.
Data are available from the GERS SAS for researchers who meet the criteria for access to confidential data. THIN France is collected from a pool of 2000 general practitioners and 1000 specialists including 65 pulmonologists (private practice exclusively) and is representative of the French population in terms of age, sex and geography. The study period was from 1 July 2017 to the end of data collection for this study (20 September 2021). Patients were eligible for this study if they initiated a new triple therapy regimen (LABA, LAMA and ICS) in the study inclusion period comprising 1 July 2017 until 31 December 2019 and had a diagnosis of COPD or chronic bronchitis at or prior to the initiation of their triple therapy. ] [27]  Other respiratory comorbidities such as asthma or bronchiectasis when associated with COPD or chronic bronchitis were not excluded as they are common COPD comorbidities.