The scientific chaos phase of the great pandemic: A longitudinal analysis and systematic review of the first surge of clinical research concerning COVID-19.

BACKGROUND: Early stages of catastrophes like COVID-19 are often led by chaos and panic. To characterize the initial chaos phase of clinical research in such situations, we analyzed the first surge of more than 1000 clinical trials about the new disease at baseline and after two years follow-up. Our 3 main objectives were: (1) Assessment of spatial and temporal evolution of clinical research of COVID-19 across the globe, (2) Assessment of transparency and quality-trial registration, (3) Assessment of research waste and redundancies. METHODS: By entering the keyword "COVID-19" we screened the International Clinical Trials Registry Platform of the WHO and downloaded the search output when our goal of 1000 trials was reached on the 1st of April 2020. Additionally, we verified the integrity of the downloaded data from the meta registry by comparing the data with each individual registration record on their source register. Also, we conducted a follow-up after two years to track their progress. RESULTS: (1) The spatial evolution followed the geographical spread of the disease as expected, however, the temporal development suggested that panic was the main driver for clinical research activities. (2) Trial registrations and registers showed a huge lack of transparency by allowing retrospective registrations and not keeping their registration records up to date. Quality of trial registration seems to have improved over the last decade, yet crucial information still was missing. (3) Research waste and redundancies were present as suggested by discontinuation of trials, preventable flaws in study design, and similar but uncoordinated research topics operationally fragmented in isolated silo-structures. CONCLUSION: The scientific response mechanism across the globe was intact during the chaos phase. However, supervision, leadership, and accountability are urgently needed to prevent research waste, to ensure effective structure, quality, and validity to ultimately break the "panic-then-forget" cycle in future catastrophes.

Missing trial results: analysis of the current publication rate of studies in pediatric dialysis from 2003 to 2020.

BACKGROUND: Decision-making in the field of pediatric dialysis requires evidence from clinical trials, but, similar to other fields of pediatric medicine, might be affected by a low trial publication rate. METHODS: We analyzed the current publication rate, the time to publication, and factors that might be associated with both rate of and time to publication in pediatric dialysis studies registered as completed on ClinicalTrials.gov from 2003 until November 2020. RESULTS: Fifty-three respective studies were identified. These enrolled 7287 patients in total. 28 of 53 studies (52.8%) had results available. We identified a median time to publication of 20.5 months (range, 3-67). Studies published after the FDA Amendments Act establishment in 2007 were published faster (P = 0.025). There was no trend toward a higher publication rate of studies completed more recently (P = 0.431). 26 of 53 studies (49.1%) focused on medication and control of secondary complications of kidney failure. 12 of 53 studies (22.6%) enrolled only children, were published faster (P = 0.029) and had a higher 5-year publication rate (P = 0.038) than studies enrolling both children and adults. 25 of 53 studies (47.1%) were co-funded by industry. These were published faster (P = 0.025). CONCLUSIONS: Currently, only 52.8% of all investigated studies in pediatric dialysis have available results, and the overall median time to publication did not meet FDA requirements. This might introduce a publication bias into the field, and it might negatively impact clinical decision-making in this critical subspecialty of pediatric medicine. A higher resolution version of the Graphical abstract is available as Supplementary information.

Quantitative longitudinal natural history of 8 gangliosidoses-conceptual framework and baseline data of the German 8-in-1 disease registry. A cross-sectional analysis.

PURPOSE: Gangliosidoses are a group of inherited neurogenetic autosomal recessive lysosomal storage disorders usually presenting with progressive macrocephaly, developmental delay, and regression, leading to significant morbidity and premature death. A quantitative definition of the natural history would support and enable clinical development of specific therapies. METHODS: Single disease registry of 8 gangliosidoses (NCT04624789). Cross-sectional analysis of baseline data in N = 26 patients. Primary end point: disease severity assessed by the 8-in-1 score. Secondary end points: first neurologic sign or symptom observed (1) by parents and (2) by physicians, diagnostic delay, as well as phenotypical characterization. Tertiary end points: neurologic outcomes (development, ataxia, dexterity) and disability. RESULTS: The 8-in-1 score quantitatively captured severity of disease. Parents recognized initial manifestations (startle reactions) earlier than physicians (motor developmental delay and hypotonia). Median diagnostic delay was 3.16 (interquartile range 0.69-6.25) years. In total, 8 patients presented with late-infantile phenotypes. CONCLUSION: Data in this registry raise awareness of these rare and fatal conditions to accelerate diagnosis, inform counseling of afflicted families, define quantitative end points for clinical trials, and can serve as historical controls for future therapeutic studies. We provide further insight into the rare late-infantile phenotype for GM2-gangliosidosis. Longitudinal follow up is planned.

Global key concepts of civil-military cooperation for disaster management in the COVID-19 pandemic-A qualitative phenomenological scoping review.

Background: In the context of a holistic and comprehensive disaster response effort to the COVID-19 pandemic, many countries across the globe mobilized their military forces in order to cope with sudden and exponential surges of critically ill patients with COVID-19 in stretched healthcare systems. Objective: The purpose of this work is to identify, map, and render world-wide key concepts of civil-military cooperation (CIMIC) in disaster management during the COVID-19 crisis visible. Material and methods: Literature was systematically searched in three databases (PubMed, Web of Science, Cochrane Library) on 26 January 2022, and analyzed with qualitative, mixed narrative-phenomenological methods in compliance with PRISM-ScR and SRQR. Results: Forty-five publications were included in the analysis; pertinent authors were from 22 countries covering five continents. We identified three key thematic clusters in the published literature: Cluster (1) Medico-scientific contributions with the participation of military medical personnel or institutions: members of the military acted as subject matter experts, clinical and experimental (co-) investigators as well as co-founders for enabling COVID-19 relevant research. Areas covered were relevant to the COVID-19 patient's clinical journey from prevention, exposure, diagnostics, and treatment and included pertinent fields such as digital health and telemedicine, global and public health, critical care, emergency and disaster medicine, radiology, neurology, as well as other medical specialties, i.e., respiratory care, pulmonology, burn medicine, and transfusion medicine, in addition to environmental and occupational sciences as well as materials science. Cluster (2) CIMIC field experiences or analyses included areas such as political framework, strategy, structure, nature of civil-military interaction, and concrete mission reports in selected countries. Themes covered a broad spectrum of pandemic disaster management subjects such as capacity and surge capacity building, medical and pharmaceutical logistics, patient care under austere circumstances, SARS-CoV-2 testing support, intelligent and innovative information management, vaccination support, and disaster communication. Cluster (3) The military as a role model for crisis management. Conclusion: Civil-military cooperation made a significant contribution to the level of resilience in crisis management on a global scale, positively impacting a broad spectrum of core abilities during the COVID-19 pandemic.

Orphan drug development in alpha-1 antitypsin deficiency.

Alpha-1 antitrypsin deficiency (AATD, OMIM #613490) is a rare metabolic disorder affecting lungs and liver. The purpose of this study is to assess the impact of the US orphan drug act on AATD by providing a quantitative clinical-regulatory insight into the status of FDA orphan drug approvals and designations for compounds intended to treat AATD. This is across-sectional analysis of the FDA database for orphan drug designations. Primary endpoint: orphan drug approvals. Secondary endpoint: orphan drug designations by the FDA. Close of database was 16 July 2021. STROBE criteria were respected. Primary outcome: one compound, alpha-1-proteinase inhibitor (human) was approved as an orphan drug in 1987 with market exclusivity until 1994. Secondary outcome: sixteen compounds received FDA orphan drug designation including protein, anti-inflammatory, mucolytic, gene, or cell therapy. Drug development activities in AATD were comparable to other rare conditions and led to the FDA-approval of one compound, based on a relatively simple technological platform. The current unmet medical need to be addressed are extrapulmonary manifestations, in this case the AATD-associated liver disease. Orphan drug development is actually focusing on (1) diversified recombinant AAT production platforms, and (2) innovative gene therapies, which may encompass a more holistic therapeutic approach.

Publication rate and research topics of studies in pediatric kidney transplantation.

BACKGROUND: The quality of medical care for pediatric kidney transplant recipients depends on sound evidence from published clinical trials. METHODS: We examined the publication rate, time to publication, and factors associated with publication of studies in pediatric kidney transplantation registered on ClinicalTrials.gov from 1999 to 2020. RESULTS: We identified 136 studies with an overall enrollment of 36255 study participants, of which only 58.8% have been published yet. Unpublished studies included data from 14 350 participants. The median time to publication was 25 months (range, 0-117) with a significantly shorter time to publication in more recent years. The most frequently investigated research topic was immunosuppressants (49.3%), followed by perioperative management (11.0%) and infectiology (10.3%). The percentage of published studies was highest for the topic steroid withdrawal (87.5%), followed by infectiology (78.6%), and nutrition, sports and quality of life (71.4%). Studies, which were co-funded by industry, showed a significantly higher 5-year publication rate (p = 0.019). CONCLUSIONS: In conclusion, nearly half of all studies in pediatric kidney transplantation remain unpublished. Non-publication of studies might lead to a publication bias with a negative impact on clinical decision-making.

Adalimumab Decorated Nanoparticles Enhance Antibody Stability and Therapeutic Outcome in Epithelial Colitis Targeting.

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Although a deeper understanding of the underlying mechanisms of IBD has led to new therapeutic approaches, treatment options are still limited. Severe adverse events in conventional drug therapy and poor drug targeting are the main cause of early therapy failure. Nanoparticle-based targeting approaches can selectively deliver drugs to the site of inflammation and reduce the risk of side effects by decreasing systemic availability. Here, we developed a nanoparticulate platform for the delivery of the anti-TNF-α antibody adalimumab (ADA) by covalent crosslinking to the particle surface. ADA binding to nanoparticles improved the stability of ADA against proteolytic degradation in vitro and led to a significantly better therapeutic outcome in a murine colitis model. Moreover, immobilization of ADA reduced systemic exposure, which can lead to enhanced therapeutic safety. Thus, nanoparticle protein decoration constitutes a platform through which epithelial delivery of any biological of interest to the inflamed gut and hence a local treatment can be achieved.

Quantitative retrospective natural history modeling of WDR45-related developmental and epileptic encephalopathy - a systematic cross-sectional analysis of 160 published cases.

WDR45-related neurodevelopmental disorder (NDD) is a clinically-heterogenous congenital disorder of macroautophagy/autophagy. The natural history of this ultra-orphan disease remains incompletely understood, leading to delays in diagnosis and lack of quantifiable outcome measures. In this cross-sectional study, we model quantitative natural history data for WDR45-related NDD using a standardized analysis of 160 published cases, representing the largest cohort to date. The primary outcome of this study was survival. Age at disease onset, diagnostic delay and geographic distribution were quantified as secondary endpoints. Our tertiary aim was to explore and quantify the spectrum of WDR45-related phenotypes. Survival estimations showed low mortality until 39 years of age. Median age at onset was 10 months, with a median diagnostic delay of 6.2 years. Geographic distribution appeared worldwide with clusters in North America, East Asia, Western Europe and the Middle East. The clinical spectrum was highly variable with a bi-phasic evolution characterized by early-onset developmental and epileptic encephalopathy during childhood followed by a progressive dystonia-parkinsonism syndrome along with cognitive decline during early adulthood. Female individuals showed milder disease severity. The majority of pathogenic WDR45 variants were predicted to result in a loss of WDR45 expression, without clear genotype-phenotype associations. Our results provide clinical and epidemiological data that may facilitate an earlier diagnosis, enable anticipatory guidance and counseling of affected families and provide the foundation for endpoints for future interventional trials.Abbreviations: BPAN: beta-propeller protein-associated neurodegeneration; CNS: central nervous system; DEE: developmental and epileptic encephalopathy; MRI: magnetic resonance imaging; NBIA: neurodegeneration with brain iron accumulation; NDD: neurodevelopmental disorder; NGS: next-generation sequencing; WDR45/WIPI4: WD repeat domain 45.

Spectrum of Clinical Research in Juvenile Idiopathic Arthritis: A Cross-Sectional Analysis of Registered Studies in Clinicaltrials.gov and Clinicaltrialsregister.eu.

The management of juvenile idiopathic arthritis (JIA) has improved tremendously in recent years due to the introduction of new drug therapies but remains complex in terms of non-pharmaceutical issues. In order to determine the direction of scientific progress by characterizing the current spectrum of ongoing clinical research in JIA, we analyzed all ongoing studies in the field of JIA-registered in clinicaltrials.gov and clinicaltrialsregister.eu-concerning sponsoring, enrollment, duration, localization, and particularly objectives. The close of the database was 7 January 2021. After identifying double-registered studies, n = 72 went into further analysis. Of these, 61.1% were academia-sponsored and 37.5% were sponsored by the pharma industry. The majority of the studies was of the interventional type (77.8%), while others (22.2%) were observational. The median planned enrollments were 100 participants (interventional studies) and 175 participants (observational studies), respectively. The duration differed remarkably from one month to more than 15 years, with a median of 42.5 months. A total of 61.1% of studies were located in a single country, and 38.9% were in several. Europe and North America clearly dominated the study localizations. The study objectives were DMARDs (56.9%), followed by diagnostics and disease activity measurement (18.1%), and medication other than DMARD (12.5%), besides others. Studies on DMARDs were mainly sponsored by industry, predominantly interventional studies on established and novel biologics, with several on specific issues such as systemic JIA and others. The spectrum of registered studies is currently centered on drug therapy and diagnostics, while other issues in JIA play a subordinated role in current research. Drug development was transferred from adult rheumatology into the JIA population with little innovation for children. Future research should take specific pediatric needs better into account.

Public Health Leadership in a VUCA World Environment: Lessons Learned during the Regional Emergency Rollout of SARS-CoV-2 Vaccinations in Heidelberg, Germany, during the COVID-19 Pandemic.

The purpose of this work is to share methods used and lessons learned during a comprehensive inter-institutional pandemic disaster response in Heidelberg, Germany, conveying experiences of the regional SARS-CoV-2 vaccination rollout campaign for up to 1,000,000 vaccines in the year 2020. In this volatile, uncertain, complex, and ambiguous (VUCA) environment, the following five strategic elements were pertinent for institutional arrangements so that specific contributions of the various project partners would be available fast without the necessity of extensive negotiations or information exchange: (1) robust mandate, (2) use of established networks, (3) fast onboarding and securing of commitment of project partners, (4) informed planning of supply capacity, and (5) securing the availability of critical items. Planning tools included analyses through a VUCA lens, analyses of stakeholders and their management, possible failures, and management of main risks including mitigation strategies. The method of the present analysis (VUCA factors combined with analyses of possible failures, and management of stakeholders and risks) can theoretically be adjusted to any public health care emergency anywhere across the globe. Lessons learned include ten tactical leadership priorities and ten major pitfalls.

The drug development pipeline for glioblastoma-A cross sectional assessment of the FDA Orphan Drug Product designation database.

BACKGROUND: Glioblastoma (GBM) is the most common malignant brain tumour among adult patients and represents an almost universally fatal disease. Novel therapies for GBM are being developed under the orphan drug legislation and the knowledge on the molecular makeup of this disease has been increasing rapidly. However, the clinical outcomes in GBM patients with currently available therapies are still dismal. An insight into the current drug development pipeline for GBM is therefore of particular interest. OBJECTIVES: To provide a quantitative clinical-regulatory insight into the status of FDA orphan drug designations for compounds intended to treat GBM. METHODS: Quantitative cross-sectional analysis of the U.S. Food and Drug Administration Orphan Drug Product database between 1983 and 2020. STROBE criteria were respected. RESULTS: Four orphan drugs out of 161 (2,4%) orphan drug designations were approved for the treatment for GBM by the FDA between 1983 and 2020. Fourteen orphan drug designations were subsequently withdrawn for unknown reasons. The number of orphan drug designations per year shows a growing trend. In the last decade, the therapeutic mechanism of action of designated compounds intended to treat glioblastoma shifted from cytotoxic drugs (median year of designation 2008) to immunotherapeutic approaches and small molecules (median year of designation 2014 and 2015 respectively) suggesting an increased focus on precision in the therapeutic mechanism of action for compounds the development pipeline. CONCLUSION: Despite the fact that current pharmacological treatment options in GBM are sparse, the drug development pipeline is steadily growing. In particular, the surge of designated immunotherapies detected in the last years raises the hope that elaborate combination possibilities between classical therapeutic backbones (radiotherapy and chemotherapy) and novel, currently experimental therapeutics may help to provide better therapies for this deadly disease in the future.

Patterns of extreme temperature-related catastrophic events in Europe including the Russian Federation: a cross-sectional analysis of the Emergency Events Database.

OBJECTIVE: To investigate reported extreme temperature-related catastrophic events and associated mortality on the European continent including the Russian Federation. DESIGN: Cross-sectional respecting Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria. SETTINGS: Data source: Emergency Events Database (EM-DAT). PARTICIPANTS: Search criteria: location-European continent including Russian Federation, time-years 1988 until 2019 (close of database 12 July 2019), catastrophic events-extreme temperatures. PRIMARY OUTCOME MEASURES: Numbers of heat waves, cold waves, severe winter conditions and associated number of deaths, overall, and per country and year, respecting STROBE criteria. RESULTS: The most frequent type of the 243 events recorded in EM-DAT were cold waves (54.7%). However, cold waves and severe winter conditions only accounted for 6460 deaths (4.5%), while heat waves were associated with 137 533 deaths (95.5%). The five most severe heat waves in 2003, 2006, 2010, 2013 and 2015 were associated with a total of 135 089 deaths. The most severe heat waves were geographically distributed over the Russian Federation (2010), as well as France, Italy, Spain and Germany, each in 2003. CONCLUSION: Although cold waves are more frequently reported in EM-DAT, heat waves are the major cause for temperature-related deaths. In order to better protect the public, it is important to address resiliency and vulnerability of populations at risk and age groups.

Experimental demonstration of the mechanism of steady-state microbunching.

The use of particle accelerators as photon sources has enabled advances in science and technology1. Currently the workhorses of such sources are storage-ring-based synchrotron radiation facilities2-4 and linear-accelerator-based free-electron lasers5-14. Synchrotron radiation facilities deliver photons with high repetition rates but relatively low power, owing to their temporally incoherent nature. Free-electron lasers produce radiation with high peak brightness, but their repetition rate is limited by the driving sources. The steady-state microbunching15-22 (SSMB) mechanism has been proposed to generate high-repetition, high-power radiation at wavelengths ranging from the terahertz scale to the extreme ultraviolet. This is accomplished by using microbunching-enabled multiparticle coherent enhancement of the radiation in an electron storage ring on a steady-state turn-by-turn basis. A crucial step in unveiling the potential of SSMB as a future photon source is the demonstration of its mechanism in a real machine. Here we report an experimental demonstration of the SSMB mechanism. We show that electron bunches stored in a quasi-isochronous ring can yield sub-micrometre microbunching and coherent radiation, one complete revolution after energy modulation induced by a 1,064-nanometre-wavelength laser. Our results verify that the optical phases of electrons can be correlated turn by turn at a precision of sub-laser wavelengths. On the basis of this phase correlation, we expect that SSMB will be realized by applying a phase-locked laser that interacts with the electrons turn by turn. This demonstration represents a milestone towards the implementation of an SSMB-based high-repetition, high-power photon source.

Beam halo measurements for special bunches in a storage ring by using a coronagraph.

We demonstrate an experimental methodology for measuring the halo distribution of special bunches in a storage ring using a synchrotron radiation coronagraph composed of the objective lens and a re-diffraction system. The optimum parameters for the coronagraph were investigated within several boundary conditions by applying a paraxial Fourier transformation sequentially from one plane to the next plane. In addition, the effect of Mie-scattering was estimated for different polishing-quality lenses and it shows that a high-quality lens is capable of achieving a dynamic range of the monitor of about 104. The capability of the halo monitor has been demonstrated by measuring the horizontal particle distribution of special bunches in beam experiments at the BESSY II storage ring. This monitor offers a new opportunity for continuous monitoring of special bunches in the storage ring such as transverse resonance island buckets and pulse-picking by resonant excitation, which open new horizons for storage rings that are capable of sophisticated experiments using a single bunch signal as well as serving high-flux users simultaneously.

Cross-sectional quantitative analysis of the natural history of TUBA1A and TUBB2B tubulinopathies.

PURPOSE: TUBA1A and TUBB2B tubulinopathies are rare neurodevelopmental disorders characterized by cortical and extracortical malformations and heterogenic phenotypes. There is a need for quantitative clinical endpoints that will be beneficial for future diagnostic and therapeutic trials. METHODS: Quantitative natural history modeling of individuals with TUBA1A and TUBB2B tubulinopathies from clinical reports and database entries of DECIPHER and ClinVar. Main outcome measures were age at disease onset, survival, and diagnostic delay. Phenotypical, neuroradiological, and histopathological features were descriptively illustrated. RESULTS: Mean age at disease onset was 4 (TUBA1A) and 6 months (TUBB2B), respectively. Mortality was equally estimated with 7% at 3.2 (TUBA1A) and 8.0 years (TUBB2B). Diagnostic delay was significantly higher in TUBB2B (12.3 years) compared with TUBA1A tubulinopathy (4.2 years). We delineated the isotype-dependent clinical, neuroradiological, and histopathological phenotype of affected individuals and present brain malformations associated with epilepsy and an unfavorable course of disease. CONCLUSION: The natural history of tubulinopathies is defined by the genotype and associated brain malformations. Defined data on estimated survival, diagnostic delay, and disease characteristics of TUBA1A and TUBB2B tubulinopathy will help to raise disease awareness and encourage future clinical trials to optimize genetic testing, family counseling, and supportive care.

Quantitative retrospective natural history modeling for orphan drug development.

The natural history of most rare diseases is incompletely understood and usually relies on studies with low level of evidence. Consistent with the goals for future research of rare disease research set by the International Rare Diseases Research Consortium in 2017, the purpose of this paper is to review the recently developed method of quantitative retrospective natural history modeling (QUARNAM) and to illustrate its usefulness through didactically selected analyses examples in an overall population of 849 patients worldwide with seven (ultra-) rare neurogenetic disorders. A quantitative understanding of the natural history of the disease is fundamental for the development of specific interventions and counseling afflicted families. QUARNAM has a similar relationship to a published case study as a meta-analysis has to an individual published study. QUARNAM relies on sophisticated statistical analyses of published case reports focusing on four research questions: How long does it take to make the diagnosis? How long do patients live? Which factors predict disease severity (eg, genotypes, signs/symptoms, biomarkers)? Where can patients be recruited for studies? Useful statistical techniques include Kaplan-Meier estimates, cluster analysis, regression techniques, binary decisions trees, word clouds, and geographic mapping. In comparison to other natural history study methods (prospective studies or retrospective studies such as chart reviews), QUARNAM can provide fast information on hard clinical endpoints (ie, survival, diagnostic delay) with a lower effort. The choice of method for a particular drug development program may be driven by the research question and may encompass combinatory approaches.

De novo variants in CELF2 that disrupt the nuclear localization signal cause developmental and epileptic encephalopathy.

We report heterozygous CELF2 (NM_006561.3) variants in five unrelated individuals: Individuals 1-4 exhibited developmental and epileptic encephalopathy (DEE) and Individual 5 had intellectual disability and autistic features. CELF2 encodes a nucleocytoplasmic shuttling RNA-binding protein that has multiple roles in RNA processing and is involved in the embryonic development of the central nervous system and heart. Whole-exome sequencing identified the following CELF2 variants: two missense variants [c.1558C>T:p.(Pro520Ser) in unrelated Individuals 1 and 2, and c.1516C>G:p.(Arg506Gly) in Individual 3], one frameshift variant in Individual 4 that removed the last amino acid of CELF2 c.1562dup:p.(Tyr521Ter), possibly resulting in escape from nonsense-mediated mRNA decay (NMD), and one canonical splice site variant, c.272-1G>C in Individual 5, also probably leading to NMD. The identified variants in Individuals 1, 2, 4, and 5 were de novo, while the variant in Individual 3 was inherited from her mosaic mother. Notably, all identified variants, except for c.272-1G>C, were clustered within 20 amino acid residues of the C-terminus, which might be a nuclear localization signal. We demonstrated the extranuclear mislocalization of mutant CELF2 protein in cells transfected with mutant CELF2 complementary DNA plasmids. Our findings indicate that CELF2 variants that disrupt its nuclear localization are associated with DEE.

Publication bias in pediatric emergence delirium: a cross-sectional analysis of ClinicalTrials.gov and ClinicalTrialsRegister.eu.

OBJECTIVES: Emergence delirium (ED) is a frequent and potentially serious complication of general anaesthesia in children. Although there are various treatment strategies, no general management recommendations can be made. Selective reporting of study results may impair clinical decision-making. We, therefore, analysed whether the results of completed registered clinical studies in patients with paediatric ED are publicly available or remain unpublished. DESIGN: Cross-sectional analysis. SETTING: ClinicalTrials.gov and ClinicalTrialsRegister.eu. PARTICIPANTS AND OUTCOME MEASURES: We determined the proportion of published and unpublished studies registered at ClinicalTrials.gov and ClinicalTrialsRegister.eu that were marked as completed by 1st September 2018. The major trial and literature databases were used to search for publications. In addition, the study investigators were contacted directly. For published trials, time to publication was calculated as the difference in months between study completion date and publication date. RESULTS: Of the 44 registered studies on paediatric ED, only 24 (54%) were published by September 2019. Published trials contained data from n=2556 patients, whereas n=1644 patients were enrolled in unpublished trials. Median time to publication was 19 months. Studies completed in recent years were published faster, but still only 9 of 24 trials were published within 12 months of completion. CONCLUSION: There is a distinct publication gap in clinical research in paediatric ED that may have an impact on meta-analyses and clinical practice.

Challenging behavior in mucopolysaccharidoses types I-III and day-to-day coping strategies: a cross sectional explorative study.

BACKGROUND: Challenging behavior represents a core symptom in neuropathological mucopolysaccharidoses (MPS) and puts major strain on affected families. Although multimodal approaches including behavioral strategies to treatment could be valuable, there is lack of research to the effectiveness of specific measures. This explorative, cross-sectional study is aimed at the collection of parental experiences regarding effective day-to-day measures against challenging behavior in MPS and focuses on 4 major research questions: First: What is challenging behavior in MPS? Second: Which strategies are helpful in the day-to-day coping with challenging behavior? Third: How strong is parental acceptance of illness and the disorder's impact on family relationships? Fourth: What are beneficial personal and interfamilial strategies for generally coping with the disorder? METHODS: A semi structured questionnaire was designed de novo in cooperation with affected families. 37/268 questionnaires were returned (rate: 13.8%), of which 34 (MPS I: n = 8, MPS II: n = 8; MPS III: n = 18) could be included in data analysis in accordance with inclusion criteria. Assessment of challenging symptoms was based on perceived frequency, parent- and child stress. Exploration of possible coping strategies for challenging behavior and general illness-related strain included the evaluation of perceived effectiveness. Questionnaires were completed by patient's relatives and analyzed for strategies to cope with challenging behavior and the disorder's impact. STROBE criteria were respected. RESULTS: MPS I was reported to show lower frequency and better perceived manageability of challenging behavior than MPS II and -III. Sleep disturbance, hyperactivity, agitation, aggression and orality seemed relevant symptoms regarding frequency and/or parent stress. Reported measures were manifold, worthwhile approaches against challenging behavior appeared to be aiming at distraction, relief and environmental changes. Medication and non-medication approaches were rated similarly effective. Social exchange, private space and networking with other affected families seemed highly important for personal and interfamilial well-being. CONCLUSIONS: Multimodal mentoring for affected families could be based on the following equivalent pillars: (1) Medication therapy for challenging behavior including evaluation of cost and benefit (2) Guided implementation and re-evaluation of specific behavioral measures against challenging behavior. (3) Psychosocial support of MPS-families, including options for strengthening parental well-being and family functioning. Trial registration This study was registered at clinicaltrials.gov prior to study start (NCT-Number: NCT03161171, Date: 2017/05/19).

Decision-making in acute viral bronchiolitis: A universal guideline and a publication gap.

BACKGROUND: Acute viral bronchiolitis is very common in infants and children up to 2 years. Some patients develop serious respiratory symptoms and need to be hospitalized. In 2014, the American Academy of Pediatrics (AAP) published a guideline on acute bronchiolitis which has gained global acceptance. We hypothesized that a publication gap, which is increasingly perceived in clinical medicine, might have also affected these universal recommendations. METHODS: We determined the proportion of published and unpublished studies registered at ClinicalTrials.gov that were marked as completed by October 1st 2018. The major trial and literature databases were used to search for publications. In addition, the study investigators were contacted directly. RESULTS: Of the 69 registered studies on the treatment of acute viral bronchiolitis, only 50 (72%) have been published by November 2019. Published trials contained data from n = 9403 patients, whereas n = 4687 patients were enrolled in unpublished trials. Median time to publication was 20 months, and only 8 of 50 trials were published within 12 months after completion. Only 40% of the clinical trials that were completed after the release of the AAP guideline were subsequently published as compared to 80% before 2014. CONCLUSION: There is a significant publication gap regarding therapy of acute viral bronchiolitis that may have influenced certain recommendations of the AAP guideline. In turn, recommendations of the guideline might have discouraged investigators to publish their results after its release.