dataesr/scientific-paragraphs-categorization huggingface dataset:
Only NICU numbers and study numbers will be used to identify participants (i. e. the data kept at Copenhagen Trial Unit is pseudo-anonymised), while lists of study numbers and personal identifying information (e. g. to allow Good Clinical Practice, data cleansing, and later follow-up) will be kept at the NICUs. Six months after the acceptance of the publication that presents the primary outcome, the dataset will be transferred to the Danish data archive. Before transfer, subject study numbers will be removed, NICU numbers will be replaced, sex documentation removed, and birth weight and gestational age recoded into binary variables to minimise the risk of re-identification. Use by other researchers will depend on the permission of the steering group. The investigators permit trial-related monitoring, audits, and regulatory inspections by providing direct access to the source data and other relevant documents.
Therefore, we aim at a pragmatic trial, rather than doing a proof-of-concept trial first. Extremely preterm infants demonstrate stress reactions during routine manipulation. Positioning and repositioning of cerebral NIRS sensors can result in such reactions. There are, however, no data to support substantially more risk or discomfort compared with no intervention or compared with current routine care. All interventions proposed in the evidence-based treatment guideline are commonly used in this patient group  [21]. 'Treatment as usual', defined as treatment according to participating hospital's standard procedures, will be provided to the control group. Also, this will be the care provided to any participant that withdraws consent, in addition to infants who are not included in the trial. Multiple births will be randomised together and undergo allocation to the same study group.
Publication plan The trial protocol is registered at ClinicalTrials. gov (NCT03770741) and all versions are available at www. safeboosc. eu. Following trial completion, summary trial data will additionally be entered at www. clinicaltrials. gov. Further summary data of main outcomes will be entered after statistical analyses are conducted. Attempts will be made to publish all results, positive, neutral, as well as negative, in a peer-reviewed international journal. Authorship will be determined according to the International Committee of Medical Journal Editors. An additional requirement is one author per NICU completing at least 30 participants. Ancillary studies with results potentially affecting equipoise with regard to the value of NIRS shall not be published before the main publication of the SafeBoosC III trial.
The design of the SafeBoosC III trial strives to minimise the risks regarding the primary outcome. The pragmatic methodology of this trial also has some limitations. Cranial ultrasound-based diagnoses will be performed locally rather than centrally as was done in SafeBoosC II  [18]. This may potentially raise concerns in SafeBoosC III since discrepancies between local readers in different centres could be expected. However, when comparing local and central interpretations of cranial ultrasound images in preterm infants in previous clinical trials, the sensitivity and specificity for local interpretations of severe brain injury were quite robust  [39]. Furthermore, we have developed a web-based training program for staff members caring for trial participants. Among other topics, this web program includes a cranial ultrasound module for the purpose of decreasing interobserver variability and heightening data quality.
recruitment and intervention Patients included in the study are those referred for a diagnostic chest CT without contrast media injection. On the day of the CT scan, a radiologist checks the eligibility criteria for the study and informs the patient who signs a participation consent form if he accepts to join the study. The radiologist then collects the following parameters: height, weight, history of oncology, cardiorespiratory pathology and exposure to smoking. The patient then undergoes the standard diagnostic LD CT acquisition followed by the ULD acquisition. If, however, the dose of the LD acquisition is greater than 6. 65 mSv (French diagnostic reference level), the ULD acquisition is not performed, and the patient is excluded from the data analysis. The patient's participation in the study is completed once he leaves the examination room.
1. 0 (library MKmisc, function power. diagnostic. [27]  statistical analysis In this non-randomised study where each patient is his own control, the threshold o<0. 05 will be taken into account to define the significance of the statistical tests. Analyses will be carried out in accordance with good statistical analysis practices after freezing of the database and will be carried out with the software R (version ≥3. 10. 0). The normality of the dependent quantitative parameters will be determined by the Shapiro-Wilks test or by graphical verification of the symmetry of the distribution. When the normality of the distribution of such a parameter has been demonstrated, it will be described by its mean and its SD. Otherwise it will be described by its median, the 25th and the 75th percentile. The qualitative parameters will be expressed in number and percentage.
In order to maintain an overall threshold of 5% in the final analysis, the interim analysis will be carried out with a threshold of 0. 1%. 28 The results of the interim analysis will be taken into account by the steering committee to propose modifications to the analysis plan. For this interim analysis, data from the confrontation between the two radiologists will be used. limitations First limitation of our protocol is that we do not have a true screening population because there is no organised lung cancer screening programme in our country yet. Therefore, our study population corresponds to patients routinely referred for lung nodule check-up or follow-up instead of a risk factor-based population. Another limitation is that ULD CT is easily recognisable as the image noise is increased as compared with LD CT, as well as ULD 50 and ULD 100 are possible to distinguish for an experienced radiologist.
Ethics and dissemination This trial is registered on the ClinicalTrials. gov database (see online supplementary file 'trial registration data set'). The protocol version is N°1. 0-Date: 4 May 2017. All patients sign a consent form before being enrolled in the trial, in accordance with the Declaration of Helsinki II. Once the statistical report is finalised, we plan to publish our results in an international scientific journal and present them in national and international congresses.
Ad-hoc studies vs. studies on databases Pharmacoepidemiology studies can be performed by collecting specific information. They are called ad-hoc studies, since no ongoing system of information is available to perform such studies. They are descriptive or etiologic studies. For example, an ad-hoc study can be performed by a systematically approach of physicians who are likely to prescribe a specific drug. To evaluate a new drug indicated in multiple sclerosis, one could solicit via mail the cooperation of all neurologists of a geographic area. Ad-hoc studies can also be used to perform etiologic study. For example, we previously evaluated mortality related to antipsychotic drug use in elderly patients with Parkinson disease in nursing home (NH)  [21]. Data were provided by the IQUARE study (Impact d'une démarche QUAlité sur l'évolution des pratiques et le déclin fonctionnel des résidents en Etablissement d'Hébergement pour Personnes Agées Dépendantes), a non-randomized controlled multicentric study.
Data were collected at baseline and after an 18-month interval. Information about residents' characteristics and prescriptions was recorded by the coordinating physician or the coordinating nurse of each NH through direct completion of questionnaires on-line on a website developed specifically for the study. In addition, the coordinating physician sent to the research team all drug prescriptions for each resident participating in the study. As in North American and other European countries, French medico-administrative databases are increasingly used for pharmacoepidemiology studies  [22]. For this purpose, their accessibility to researchers is regularly improved. These databases offer preregistered data and can be used for dedicated studies or combined with other data sources. French health insurance databases are organized since 2003 into a huge digital data warehouse, the "système national d'information interrégimes de l'Assurance maladie" (SNIIR-AM).
It covers the entire French population (65 million inhabitants). In order to facilitate studies on more frequent conditions, a random sample of 1/97th of national health system beneficiaries has been built since 2005, called the "échantillon généraliste de bénéficiaires" (EGB). French health insurance databases include demographic, out-hospital reimbursement (including drug dispensing), medical (costly long-term diseases, occupational diseases, sick-leaves…), and in-hospital data. All these data are prospectively recorded, individualized, made anonymous and linkable. Consequently, the SNIIR-AM is a very useful data source for pharmacoepidemiological studies, particularly for rare events. Unlike SNIIRAM data, EGB data is available on a long-term basis. It is also appropriate for long-term research on more frequent diseases.
Principles of drug exposure measurement Quantitative data on drug use can be used to measure drug exposure. The usefulness of each type of measure depends on the purpose of the study. For descriptive studies, we can use the number of patients in a population who ingested a specific drug during a defined time frame. Data available are approximations of this, issued from ad-hoc studies (surveys), drugs sales or medico-administrative databases. They are usually expressed in terms of cost (total cost or unit cost) or volume (global or by unit volume sold). Number of tablets, capsules or doses is closer to the number of patients exposed than cost data, which can be influenced by price fluctuations. Number of prescriptions is a measure frequently used. To obtain the number of patients exposed from the number of prescriptions, we must divide it by the average number of prescriptions per patient.
Another volume unit is the number of defined daily doses (DDD). The DDD system has been developed by an independent scientific committee assisting the World health organisation (WHO) collaborating centre for drugs statistics methodology in order to measure and compare drug use at an international level  [24]. This unit is worldwide used and very useful for comparisons accross countries. Nevertheless, since DDD is based on a theoretical daily dosage, it does not necessarily reflect the recommended or prescribed daily dose. For etiologic studies, exposure data have to be related to the reasons for the drug use and to health events. Data on morbidity and mortality may be obtained from medico-administrative databases, from registries, from hospital or physician records, and from patient or household surveys.
Other methods can be helpful to quantify more precisely drug exposure: for example, timedependent drug exposures for drugs prescribed for varying time periods  [26, 27] , and drug exposures considered as exposure trajectories according to the KML method (K-averages for longitudinal data) corresponding to a classification of longitudinal data  [28]. Rational use of drug must be assessed by taking into account indication of drug, patient characteristics, drug dosage, concomitant diseases, and concomitant drugs. All this information is generally not available in a single data source.
Indicators of compliance (adherence and persistence) Observance concerns mainly chronic treatments. Adherence refers to whether a patient takes a prescribed drug. Persistence indicates if a patient stays on therapy (or time between initiation and discontinuation of the treatment). Increasing use of medico-administrative databases helps to approximate these two indicators. Different types of measures of adherence and persistence are commonly used: the medication possession ratio (MPR), the discontinuation or continuation of the drug (persistence), switching, and medication gaps  [29, 30]. The most frequently used indicator, the MPR, is defined as the proportion of days' supply obtained during a specific time period or over a period a refill interval. The refill interval is the interval between the first and the last delivery of a drug plus number of days considered as duration of the last box delivered  [31].
Indicators of misuse Indicators of misuse or drug abuse have been developed in medico-administrative databases in order to identify the relative abuse liability of several psychoactive drugs in real-life setting. One of them is the doctor shopping quantity (DSQ), defined by the quantity obtained by overlapping prescriptions from several prescribers. The doctor shopping indicator (DSI) is calculated by the DSQ divided by the total dispensed quantity and measures the proportion of the drug obtained by doctor shopping among the overall quantity of the drug reimbursed  [32]. A signal of abuse by doctor-shopping is considered meaningful when the DSI is superior to 1%. Below this value, one considers that there is no clear signal of abuse. This threshold of 1% is empirical: it is derived from different published studies  [32] [33] [34] , from other national surveys among patients from drug dependence centres  [35] , and from surveys related to falsified prescriptions by pharmacies  [36].
Main study designs and methods for controlling biases Throughout this section, the study designs and methods used in pharmacoepidemiology will be presented in the current context of drug evaluation in the population, a context in which a growing proportion of studies are carried out using medico-administrative data. In these databases, information on drug exposure and health events is present for large populations, with a follow-up now reaching up to 10-15 years in France, and sometimes several decades in other countries  [44]. The limits traditionally affecting the study designs are modified in this context, almost any design selected for the conduct of a study from these databases then deriving from a cohort in whom the information has been recorded prospectively and exhaustively.
The validity of these studies is conditioned by two types of elements: -the quality of exposure measurement: in this area, the limitations of field studies in terms of comprehensiveness of the collection of drug exposure, and database studies in terms of the reality of drug consumption for drugs identified as prescribed (or reimbursed) are well known; -the representativeness of the sample studied: the limit here is not specific to pharmacoepidemiology studies but to all observational studies. The objective is to describe a behaviour or a population, it is necessary to make sure that the sample is well representative of the population and use one aims at studying. For these studies, apart from the statistical methods traditionally used to carry out descriptions, it is worth mentioning the time series or time series analyses.
Cohort studies and cohort-related designs These studies, in which the follow-up of the subjects or patients starts with the exposure and advances forward in time towards the search for an event still constitutes the gold standard design for observational studies. Their implementation, difficult when conducted on the field and sometimes requiring very long follow-up periods, has been greatly simplified by the use of medicoadministrative databases. In the constraint context of regulatory needs in which time is always limited, these data sources make it possible to consider conducting cohort studies or analyses much more frequently for drug evaluation. While these databases also allow considering comprehensively a large number of concomitant drug exposures, they are often limited in terms of accuracy regarding the severity of co-morbidities presented by patients.
Moreover, with regard to the French bases in particular, they lack almost completely of indicators concerning patients' lifestyle and health behaviours, with the limits that this implies in terms of confusion bias. To overcome this limitation, the use of techniques to minimize, as far as possible, the confusion related to unmeasured variables became widespread in the conduct of studies from medico-administrative databases. The use of propensity scores (that reflect the estimated probability of a patient being exposed to treatment) and disease risk score (that reflects the estimated probability of a patient developing the event of interest) has thus widely spread in these studies, the high-dimension versions of these scores constituting the most performing tools  [48]. Several modalities exist for the use of these scores, from the simple adjustment to the individual matching.
The latter, however, leads to a selection of subjects that some people prefer to avoid by using the techniques of population standardizations based on the inverse propensity score weighting methods. Altogether, by allowing the use of these techniques, the large amount of information contained in the medico-administrative databases reinforces the validity of the results of observational cohort studies by limiting the risk of unmeasured confounding. The results obtained can therefore be comparable to results obtained in the presence of information, as was observed for instance for the study conducted in France SNIIRAM database concerning the risk of bladder cancer associated with the use of pioglitazone  [49]. Indeed, its results were fully consistent with those obtained from the clinical practice research datalink (CPRD)  [50] , despite the SNIIRAM lacked information on tobacco use, a major risk factor for bladder cancer (two hypotheses could actually be discussed here: either unmeasured confounding was very efficiently dealt in the SNIIRAM study, either tobacco use was not a confounder in these studies…).
Finally, the accuracy of the information contained in these databases also makes it possible to consider exposures and related risks in a time-dependent manner. In addition to the greater precision that this allows in the estimates, this approach is also essential to avoid obtaining results affected by immortal time bias, to which cohort studies are exposed when they study risks associated to cumulated exposures  [8, 9]. Cohorts conducted from medico-administrative databases, however, cannot be compared to field cohorts on at least one very important aspect. In field cohorts, the protocoled and standardized procedure for the screening / diagnosis of the event of interest guarantees that its discovery is done under conditions that do not depend on exposure. This important force is not encountered in the studies carried out from medico-administrative databases.
Case-control studies and related designs As explained in the preamble, the weaknesses usually attributed to case-control studies in comparison with cohort studies, which remain valid for field studies, are essentially corrected when carrying out studies from medico-administrative databases. The case-control studies performed within these are, in principle, studies to be considered as nested case-control studies, in which the recall bias is no longer a limit, and in which the detection bias is not different from that of the natural cohorts, i. e. cohorts without a standardized procedure for the screening or diagnosis of the event of interest. The principle here is inverted with respect to a cohort study: the reference point in time is the date of occurrence of the event (or the date of selection for the controls); the probability of exposure in one or several time period(s) preceding the reference date is then compared across the cases and controls groups in order to obtain the estimate of the association, namely the odds ratio in case-control studies.
In the case where such difference remains after matching on a propensity score or a disease score, a further adjustment of the analyses on the variables that do not fulfil the conditions of comparability is carried out. By allowing the selection of more likely cases-specific controls and eliminating the possibility of recall bias, the use of medico-administrative databases helps raising the level of evidence of case-controls studies in a way that is not currently taken into account in the scales used for the categorization of evidence levels. Actually, these sales now appear largely outdated and too simplistic in view of the developments performed in observational study schemes, statistical tools for the mitigation of biases, and of the diversification of the data sources of information used in pharmacoepidemiology.
Conclusion The methods that can be used for the pharmacoepidemiological evaluation at the drug in real life are numerous. Access to information from medico-administrative databases, which has been available for about 10 years in France, and over 30 years in other countries, has considerably modified the context for conducting these studies. The limitations usually encountered in terms of study power and duration, comprehensiveness of recorded information, or ability to eliminate biases to which any observational research is exposed have been considerably reduced. However, other limits remain, which fully justify maintaining the use of field studies: the French medico-administrative bases are limited for clinical aspects and do not contain information on the habits of life of patients. The current limits of pharmacoepidemiology in France, compared to other countries, lie in this lack of information (diagnosis associated with a prescription and indicating the severity of the disease, intra-hospital prescription data, test results biological or radiological, etc.
Intrinsic pathway mediated release of mitochondrial cytochrome-C switches on caspase9/apoptosome to activate effector caspase-3, which cleaves many of the major constituents of the cell cytoskeleton and is important for the programmed dismantling of vital cellular structures  27, 28. Considering, caspases are canonically pivotal mediators of apoptosis, we determined the expression level of caspase-9 in various treated groups. Results shown in Fig. 4  demonstrate significantly enhanced expression of caspase-9 in 5-FU NPs treated group as compared to the group that received microcrystals of free 5-FU drug only (p < 0. 01). There was relatively lower expression of caspase-9 in OJ (alone) as well as cream base only treated control groups. The data suggests that 5-FU NPs demonstrate remarkable efficacy in up-regulation of caspase-9 and facilitating apoptosis of fibrosarcoma in mouse model.
Differential scanning calorimetry (DSC). DSC study was carried out on dried samples of pure 5-FU (control) and formulation containing 5-FU. Briefly, 3-5 mg dried powder was placed in an aluminium pan. Empty aluminium pan was used as reference. The sample pan and reference pan were heated at constant flow rate of 10 o C/ min within the temperature range of 10-350 o C (Simultaneous Thermal Analyser (STA) 8000, Perkin Elmer, USA). Nitrogen gas was continuously purged (Flow rate = 20 ml/min) throughout the experiment. The data obtained was smoothened and corrected for baseline using Origin Pro (64 bit, Sr3, b275, OriginLab Corporation, Northampton, MA01060, USA)  19, 20. Evaluation of in-vitro Nano-drug release kinetics. Release kinetics of 5-FU NPs, was examined by dispensing multiple samples of the formulation into various micro vials following the protocol as standardized in our lab.