dataesr/scientific-paragraphs-categorization huggingface dataset:
11 At least 10 to 18 per group is usually recommended in the literature. 14, 15 No additional personal data to describe the characteristics of participants were collected to maintain anonymisation and depersonalisation of the results. Convenience sampling was employed. Clinicians were recruited through professional bodies (eg, national dental associations) or social media (Twitter). Academics were recruited through the Global Antibiotics Research in Dentistry early career researcher network,  16  Twitter, and authors of relevant publications. 17 Adult patients and parent/carer participants were recruited through patient-representative bodies, Twitter, and word of mouth.
Consensus process As described in the study protocol, consensus was sought using a 9-point Likert scale. 13 Participants rated the importance of each candidate outcome using the DelphiManager system. Two rounds of an online Delphi survey were undertaken, with participants invited to suggest additional outcomes. Any potential additions suggested by 2 or more participants in round 1 were included for rating by all participants in round 2 of the Delphi. Those who completed both Delphi rounds were invited to a final consensus meeting to review the results from the Delphi study and finalise the core outcome set. The meeting was held online and included deciding how to address missing data for outcomes and conflicts in the results between participant groups. Study steering group members were also invited to the final consensus meeting.
23 Some dental ABS studies have used routinely collected data from health care systems. 24 Ideally such systems would be linked between medicine and dentistry to enable collection of all outcome data for the COS, such as adverse outcomes requiring emergency medical care. Further research is required to precisely define the COS-DABS indicators to be used during clinical trials and to explore the feasibility of collecting these data directly from health care systems. Assessment of stewardship outcomes at an individual patient level, rather than the more common cluster level, has been previously recommended. 18 The patient-reported outcome included within the COS was derived from the standardised core set of outcomes for adult oral health. 25 Further work to operationalise this outcome for studies of dental AMS should take into account the SPIRIT-PRO guidance about including patient-reported outcomes in clinical trials.
| Identifying relevant papers We identified relevant papers from multiple sources, as recommended by Arksey and O'Malley. Sources included electronic databases, reference lists, and existing networks and relevant organizations. The electronic database search strategy, developed in collaboration with a research librarian (E. F. G. ), surveyed PubMed, Embase and the Cochrane library for literature published from 2003 to May 2018 (Appendix A). After de-duplication, citations were uploaded into Rayyan  20  for review. We added key publications through 2020 from peer-reviewed and gray literature sources by: (1) searching reference lists of full-text papers meeting initial selection criteria; and (2) accessing information from professional organizations and networks.
| Study selection Identified papers were screened by five teams of two independent reviewers in two phases: (1) title/abstract and (2) full text review (Figure  1 ). Disagreements between reviewers were resolved through discussion. Data were abstracted from papers meeting the eligibility criteria (Appendix B). Papers were categorized as (A) general guidances regarding off-label medicines use or (B) therapeutic areaspecific guidances for off-label use.
Practice"[Mesh] OR "policy"[Mesh] OR "clinical decision-making"[Mesh] OR guideline*[tiab] OR policy[tiab] OR policies [tiab] OR protocol*[tiab] OR law*[tiab] OR legislat*[tiab] OR regulat*[tiab] OR guidance[tiab] OR guide[tiab] OR standard*[tiab] OR legal*[tiab] OR best practice*[tiab] OR fda[tiab] OR european medicines agency[tiab] OR '/exp OR 'government regulation'/exp OR 'government'/exp OR 'clinical practice'/exp OR 'attitude to health'/exp OR 'food and drug administration'/exp OR 'policy'/exp OR 'drug industry'/exp OR 'postmarketing surveillance'/exp OR 'european medicines agency'/ exp OR 'decision making'/exp OR 'risk assessment'/exp OR 'risk evaluation and mitigation strategy'/exp OR 'risk management'/exp OR 'pharmacoepidemiology'/exp OR 'drug approval'/exp OR 'recom-mendations'/exp OR guideline*:ti,ab OR policy:ti,ab OR policies:ti,ab OR protocol*:ti,ab OR law*:ti,ab OR legislat*:ti,ab OR regulat*:ti,ab OR guidance:ti,ab OR guide:ti,ab OR standard*:ti,ab OR legal*:ti,ab OR 'best ,ab OR infan*:ti,ab OR adolescen*:ti,ab OR teen*:ti,ab OR youth*:ti,ab OR paediatric*:ti,ab OR baby:ti,ab OR babies:ti,ab OR juvenile*:ti,ab) Cochrane Library (WileyOnline; Cochrane Database of Systematic Reviews [2005-present], Database of Abstracts of Reviews of Effects [1994-present], Cochrane Central Register of Controlled Trials [1898-present], Health Technology Assessment Database [1989-present], Cochrane Methodology Register [1951-present], and NHS Economic Evaluation Database [1968-present])-107 references retrieved on 05/21/2018.
ACKNOWLEDGMENTS This manuscript is endorsed by the  International Society for Pharmacoepidemiology (ISPE). The authors thank  Dr. Stuart MacLeod  for providing input to early stages of concept development. Matthew Iozzio  and  Edward Nonnenmacher  provided administrative support for virtual meetings and voting for the modified Delphi process in 2022. Open access publishing facilitated by  University of New South Wales , as part of the  Wiley -University of New South Wales agreement via the Council of Australian University Librarians.
[using Search Manager]. 1. ("off label" or unlicensed or unlabeled or unapproved or "not approved" or "off license" or unlabelled or "extra label"):ti,ab,kw 2. (guideline* or policy or policies or protocol* or law* or legislat* or regulat* or guidance or guide or standard* or legal* or "best practice" or "best practices" or "food and drug administration" or fda or "european medicines agency" or ema or "health canada" or "therapeutic goods administration" or "decision making" or pharmacoepidemiolog* or recommend* or approval or government* or risk or "evidence based"):ti,ab,kw. development and REDcap database design. Emily F. Gorman led lit-APP E NDIX A: SEARCH STRATEGY FOR SCOPING REVIEW erature search strategy and provided title and abstract review sup- port with Rayyan. Analysis and interpretation of data: all authors.
The pace of development and implementation of novel medications in child and adolescent psychiatry has remained slow. We systematically searched https://clinicaltrials. gov/ and https://www. clinicaltrialsregister. eu/ (from 01/01/2010 to 08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia. We also included RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥1 primary outcome, 43 (19%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results.
Search strategy We searched https://clinicaltrials. gov/and and https://www. clinicaltrialsregister. eu/ from 01/01/2010 to 08/23/2022 using search terms related to the mental health conditions of interest for this review (see below). The search was conducted independently by two investigators  (KMG and SC). The time frame is similar to the one considered in a recent similar review on phase 2/3 RCTs of psychopharmacological agents in adults  (Correll, 2023). We also conducted an additional systematic targeted search in PubMed to check if identified RCTs for which results were not available in the clinical trials platforms had been published. The following filters were used for the search in clinicaltrials. gov: 1) study type: interventional studies (Clinical Trials); 2) recruitment: not yet recruiting/recruiting/enrolling by invitation/active, not recruiting/terminated/completed/unknown status; 3) age group: "Child" (birth-17); 4) phase: phase 2/phase 3 or 4; 5) study start: from 01/01/2010, which, as in the systematic review by  Correll et al.
(2023)  in adults, was deemed adequate to reflect recent developments in the field. We assumed that, if a trial initiated ≥12 years ago and its results had not been published or no additional studies were ongoing, this trial program had been discontinued. The following filters were used for the search in https://www. clinicaltrialsregister. eu/: 1) select trial status: completed/ongoing/restarted; 2) age range: children and adolescents; 3) J o u r n a l P r e -p r o o f select trial phase: phase two/phase three/phase four; and 4) select date range: 2010-01-01 (with the same reasoning for the cut-off date as mentioned for clinicaltrials. gov).
Available results show the following pharmacological agents were significantly better than placebo/control in terms of improvement of ADHD core symptom severity: dasotraline 4 mg [in one RCT -NCT02428088 (n=112 on dasotraline 2mg/day, n=115 on dasotraline 4mg/day, n= 116 on placebo) with a mean ES of 0. 48 (95% CI not reported) whereas for another RCT -NCT02734693 (n=20 on dasotraline 6mg/d; n=56 on dasotraline 4mg/d; n=56 on placebo) results only indicated superiority but ES was not reported] and 2 mg in one RCT (NCT03231800, n=47 on dasotraline 2mg/day; n=47 on placebo) but not in another one (NCT02428088)of note, the development program of dasotraline for ADHD was halted by the manufacturer in 2020; lisdexamfetamine dimesylate for 4-5-year-olds  (5, 10, 20, 30mg: n= 40, 37, 37 and 39, respectively; placebo: n=4 ; ES: 0.
J o u r n a l P r e -p r o o f As for tolerability, in one study of dasotraline (NCT02428088) discontinuation rates due to adverse events were higher in the dasotraline 4 mg/day arm (12. 2%) compared with the 2 mg/day arm (6. 3%) and placebo (1. 7%). There were no serious adverse events or clinically meaningful changes in blood pressure or heart rate with dasotraline and lisdexamfetamine was generally well tolerated. Furthermore, one study showed that coenzyme Q was effective when added to atomoxetine (decreasing total ADHD symptom severity on the Conners parent-rating scale by about 34%, vs. 18% in the atomoxetine only group, ES not reported). Finally, in another RCT, treatment with micronutrients improved one of the primary outcomes (the clinical Global Impression Scale-CGI, ES not reported) but not the other primary outcome as labelled by the authors (parents' rating of ADHD symptoms).
Autism Spectrum Disorder (ASD) We found 84 RCTs. About 86% were sponsored by universities/hospitals/NIMH, and the rest (14%) were funded by drug companies. Among RCTs of pharmaceutical agents (n=70), 81% and 19% were sponsored by university/hospitals and pharmaceutical companies, respectively. Thirty-one mechanisms of action were assessed, including 41 compounds. Mechanisms of action of the compounds assessed in RCTs in autism-spectrum disorders included: -Serotonin and norepinephrine reuptake inhibition: amitriptyline (n=1) -Selective serotonin reuptake inhibition: sertraline (n=2) -Histaminergic, noradrenergic, and serotonergic receptor antagonism: mirtazapine Regarding compounds for which results were available, in one RCT (NCT01078714), bumetanide was superior to placebo for the primary outcome [Childhood Autism Rating Scale (CARS) (p=0.
0028 -ES not reported) but not on the other primary outcome (expressive language). In one RCT (NCT01372449), memantine was not superior to placebo in the primary outcome (adaptive behavior, measured with the Vineland Adaptive Behavior scale). In a withdrawal RCT, memantine did not significantly separate from placebo in any outcome, including the primary one: Proportion of Patients Meeting the Criterion for Loss of Therapeutic Response. Oxytocin was not superior to placebo in two  RCTs (NCT01944046 and 2018-000769-35)  in any of the outcomes. In another RCT (NCT01624194), oxytocin was superior to placebo on the Total SRS score (primary outcome; p=0. 027) and was well tolerated. In terms of non-core symptoms of ASD, in one RCT, guanfacine XR was found better than placebo for the symptom "hyperactivity" in ASD, measured with the Aberrant Behavior Checklist Hyperactivity Subscale (rather than a formal diagnosis of ADHD for which it is approved).
Depressive disorders Nineteen RCTs, including one testing a diet compound, were retained. Overall, about 68% of the RCTs (72% of those testing pharmacological compounds) were funded by drug companies, and 32% sponsored by universities/hospitals. Six modes of action were assessed, Another RCT tested omega-3 fatty acids. In one proof-of-concept cross-over RCT (n=17 participants, 16 of which received both treatments) (NCT02579928,  Dwyer et al. , 2021) , a single ketamine infusion significantly reduced depressive symptoms after 24 hours compared to midazolam (ES: 0. 78, 95% CI not reported), measured on the Montgomery-Åsberg Depression Rating Scale (MADRS) (primary outcome) and improvements remained 14 days after treatment, but no significant differences were found on the Children's Depression Rating Scale-Revised at days 1 and 24.
However, first, several dopamine antagonists/partial agonists are already approved and available for adolescents with schizophrenia  (Pagsberg et al. , 2017). Moreover, we excluded a number of RCTs where adolescents were recruited alongside adults, following more recent guidance by the FDA that considers the option of extrapolation of more limited adolescent data embedded within a larger adult trial program under certain circumstances (FDA). Of note, we limited our focus to schizophrenia, rather than other psychoses, as their heterogeneous nature would hamper the consistency of findings across RCTs. Several reasons may explain why relatively few RCTs targeted certain mental health conditions in children and adolescents compared to programmes in adults  (Correll, 2023)  and only isolated trial programmes and agents yielded positive results.
Here, information from multiple informants may be helpful but also complicates the assessment process  (Kraemer et al. , 2003). Fourth, while rising placebo effects have plagued all of psychiatry  (Correll, 2022) , this problem may be enhanced in paediatric mental health RCTs, even more so in children than in adolescents  (Parellada et al. , 2012; Siafis et al. , 2020 )  (Faraone et al. , 2022). Our study also informs research governance and reporting practices in the field. We found that 28% of the included RCTs were completed, but their results were not reported. While it is plausible that the effects of the COVID-19 pandemic impacted on the reporting of RCTs, we also found some RCTs for which results were labelled as "not available" in clinicaltrials. gov had indeed been published in articles in peer-reviewed journals.
Therefore, we urge authors to promptly update the RCT record in clinicaltrials. gov. Additionally, for some RCTs, mean and standard deviation values for each arm were reported, but not the results of statistical significance tests. Importantly, in the majority of studies, only p values -which are dependent on sample sizewere reported, rather than standardized effect size. and their 95% confidence intervals. We would urge for more consistent reporting of ES in this field as this would facilitate comparison across RCTs of studied or already available treatment options. This would be more clinically meaningful than solely reporting p-values. Finally, discontinuation of clinical trial programmes and abandonment of compounds should be publicly communicated, alongside the rationale for this. Our study should be considered in light of some limitations.
First, we limited the search from 2010, so we might have missed relevant RCTs registered before this date. However, we J o u r n a l P r e -p r o o f deemed a 12-year period as appropriate to retrieve novel agents potentially available for regulatory approval and of interest in day-to-day clinical practice. Second, we may have included agents in this review whose further development has been discontinued by the sponsor without making this decision public. Third, we excluded RCTs recruiting both children/adolescents (until the age of 17) and adults, as separate results for children and adolescents are usually not reported in https://clinicaltrials. gov/ or https://www. clinicaltrialsregister. eu/. Fourth, while we covered a broad range of mental health conditions, our selection did not address all conditions that practitioners could be faced with.
Seventh, we limited the search to two databases (https://clinicaltrials. gov/and and https://www. clinicaltrialsregister. eu/) as we could not include every national database. Eighth, we endeavoured to identify RCTs funded and not funded by drug companies, but where the listed sponsor was a public body this does not automatically equate with a drug company not being involved. Finally, for a sizeable J o u r n a l P r e -p r o o f proportion of RCTs, results of statistical analyses on tolerability were not available so we could report only the % of participants in each study arm that experienced serious adverse events or who discontinued the trial due to adverse events. Despite these limitations, we believe that this review will inform researchers and funders of future priorities and opportunities in the field, and practitioners, patients and their families of possible future treatment options.
ACKNOWLEDGMENTS He has no other financial or material support, including expert testimony, patents, royalties. D Coghill served in an advisory or consultancy role for Medice, Novartis, Servier, and Shire/Takeda. He received conference support or speaker's fee from Medice, Servier, and Shire/Takeda. He received royalties from Cambridge University Press and Oxford University Press; He is not an employee of any of these companies, and not a stock shareholder of any of these companies and the present work is unrelated to these relationships. Efficacy: Change in YGTSS-TTS at week 3 vs. placebo 0. 5mg: p=0. 12 2mg: p=0. 0087 Tolerability: part 1: 0, 1 (4. 17%) and 0 participants in the AZD5213 0. 5 mg/day, 2 mg/day, and placebo, respectively, had serious AE; part 2: 0, 0, and 1 (4. 76%) in the in the AZD5213 0.
044, ES not reported). In one RCT (NCT01411774), D-cycloserine was not superior to placebo on the CGI-S (secondary outcome; results not reported for the primary outcome: CY-BOCS). In another RCT recruiting participants with Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections (PANDAS) and OCD, the difference in the mean decrease in the CY-BOCS score was not J o u r n a l P r e -p r o o f significant between the intravenous immunoglobulin Gamunex and the placebo group.
Arango has received funding from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), co-financed by the European Union, ERDF Funds from the European Commission, "A way of making Europe", financed by the European Union -NextGenerationEU (PMP21/00051), PI19/01024. CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program, European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project PRISM-2 (Grant agreement J o u r n a l P r e -p r o o f D Purper-Ouakil reports non-financial support from HAC Pharma and Lundbeck, honoraria and non-financial support from Medice in the last 3 years. She also collaborated in FP7 and Horizon 2020 projects and a Horizon 2020 SME project sponsored by Mensia without financial interests.
She has received several national public grants (DGOS-PHRC-N and equivalent). AM Persico's work is funded by the Italian Ministry of Health, the Fondazione di Modena & UNIMORE (Mission-oriented), and the Italian Autism Foundation. V Roessner has received funding from the Federal Ministry of Education and Research (01GL1741C), the Innovation Fund of the Federal Joint Committee (01NVF17046, 01VSF19027), the German Research Foundation (RO 3876/11-1, RO 3876/11-2, TE 280\18-1, FR 2069/8-1), MSE Pharma, and Takeda (IIR-DEU-002258) OF INTEREST S Cortese declares honoraria and reimbursement for travel and accommodation expenses for lectures from the following non-profit associations: Association for Child and Adolescent Central Health (ACAMH), Canadian ADHD Alliance Resource (CADDRA), British Association of Pharmacology (BAP), and from Healthcare Convention for educational activity on ADHD.
In the last 3 years, D. Purper-Ouakil reports honoraria/non-financial support from Medice and Shire/Takeda, non-financial support from HAC Pharma, and has worked as an unpaid scientific coordinator for Mensia, all outside the submitted work. In the last 2 years, B Vitiello was a paid consultant for Medice, Menarini, Angelini, and Alkermes Pharmaceuticals. ICKW reports research funding outside the submitted work from Amgen, Bristol Myers Squibb, Pfizer, Janssen, Bayer, GSK, Novartis, Takeda, the Hong Kong Research Grants Council, the Hong Kong Health and Medical Research Fund, the Hong Kong Innovation and Technology Commission, the NIHR, the European Commission, and the Australian National Health and Medical Research Council, and has also received expert testimony payment from the Hong Kong Court of Final Appeal in the previous 3 years and consultancy fee from IQVIA and World Health Organization.
C Arango has received funding from the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (ISCIII), co-financed by the European Union, ERDF Funds from the European Commission, "A way of making Europe", financed by the European Union -NextGenerationEU (PMP21/00051), PI19/01024. CIBERSAM, Madrid Regional Government (B2017/BMD-3740 AGES-CM-2), European Union Structural Funds, European Union Seventh Framework Program, European Union H2020 Program under the Innovative Medicines Initiative 2 Joint Undertaking: Project PRISM-2 (Grant agreement J o u r n a l P r e -p r o o f D Purper-Ouakil reports non-financial support from HAC Pharma and Lundbeck, honoraria and non-financial support from Medice in the last 3 years. She also collaborated in FP7 and Horizon 2020 projects and a Horizon 2020 SME project sponsored by Mensia without financial interests.
2174/187152732 0666211124093345 2 Place bo 330 6 to 12 42 Sunovio n 2-3 NCT02 428088 US A April 2015 Super ior (4 mg) Efficacy: Change from baseline in ADHD-RS-IV at week 6: ES (4mg/d vs. placebo): 0. 84 ES (2mg/d vs. placebo): 0. 03 Tolerability: 6. 3%, 12. 2% and 1. 7% participants discontinued due to treatment-emergent AE in the dasotraline 2 mg/day, dasotraline 4 mg/day and placebo arm, respectively Results reported in doi: 10. 1089/cap. 2018. 0 083 Efficacy: SKAMP-score at day 15 ES: 1. 04 Dasotrali ne 2 Place 6 to Sunovio NCT03 US July Super Tolerability: 0 serious AE in both mg/day Seroton in-norepin 2 bo 95 12 15 n 3 231800 A 2017 ior arms Efficacy: SKAMP-score at day 15: ephrine -dopami 4mg/d vs. Placebo p<0. 001 -ES not reported. 6mg/d-arm ne reuptak e discontinued. Tolerability: 0 Dasotrali ne 4 and inhibito r (SNDR Place 6 to Sunovio NCT02 US April Super ior (4 mg/da serious AE in both dasotraline arms; 1 serious AE (1.
795) 6mg/day I) 1 bo 132 12 15 n 3 734693 A 2016 y) in placebo arm Fasorace tam Glutam ate Place 6 to Aevi Genomi NCT03 265119 US Augu st No In children and adolescents with (AEVI- receptor 1 bo 69 17 42 c 2 Part A A 2017 effect ADHD and without Legend: ADHD-RS-IV=ADHD Rating Scale-IV; AE=Adverse event; CGI-I=Clinical Global Impression-Improvement; ES=Effect size; FDA=US Food and Drug Administration; mGluR=Metabotroic glutamate receptor; PARS=Pediatric Anxiety Rating Scale; RCT=Randomized Controlled Trial; SCARED=Screen for Child Anxiety Related Emotional Disorders; SKAMP=Swanson, Kotkin, Agler, M-Flynn, Pelham Rating Scale.