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Abstract Background Mycoplasma pneumoniae is a major cause of community-acquired pneumonia (CAP) in school-aged children. Macrolides are the first-line treatment for this infection. However, it is unclear whether macrolides are effective in treating M. pneumoniae CAP, mainly due to limitations in microbiological diagnosis of previous studies. The extensive global use of macrolides has led to increasing antimicrobial resistance. The overall objective of this trial is to produce efficacy data for macrolide treatment in children with M. pneumoniae CAP. Methods The MYTHIC Study is a randomized, double-blind, placebo-controlled, multicenter, non-inferiority trial in 13 Swiss pediatric centers. Previously healthy ambulatory and hospitalized children aged 3–17 years with clinically diagnosed CAP will be screened with a sensitive and commercially available M. pneumoniae-specific IgM lateral flow assay from capillary blood. Mycoplasma pneumoniae infection in screened patients will be verified retrospectively by respiratory PCR (reference test) and IgM antibody-secreting cell enzyme-linked immunospot (ELISpot) assay (confirmatory test for distinguishing between carriage and infection). Patients will be randomized 1:1 to receive a 5-day treatment of macrolides (azithromycin) or placebo. The co-primary endpoints are (1) time to normalization of all vital signs, including body temperature, respiratory rate, heart rate, and saturation of peripheral oxygen (efficacy), and (2) CAP-related change in patient care status (i.e., admission, re-admission, or intensive care unit transfer) within 28 days (safety). Secondary outcomes include adverse events (AEs), as well as antimicrobial and anti-inflammatory effects. For both co-primary endpoints, we aim to show non-inferiority of placebo compared to macrolide treatment. We expect no macrolide effect (hazard ratio of 1, absolute risk difference of 0) and set the corresponding non-inferiority margins to 0.7 and −7.5%. The “at least one” success criterion is used to handle multiplicity with the two co-primary endpoints. With a power of 80% to reject at least one null hypothesis at a one-sided significance level of 1.25%, 376 patients will be required. Discussion This trial will produce efficacy data for macrolide treatment in children with M. pneumoniae CAP that might help to reduce the prescription of antibiotics and therefore contribute to the global efforts toward reducing antimicrobial resistance. Trial registration ClinicalTrials.gov, NCT06325293. Registered on 24 April 2024

Abstract The FICUS trial is a cluster-randomized superiority trial to determine the effectiveness of a nurse-led, interprofessional family support intervention (FSI) on the quality of care, family management and individual mental health of family members of critically ill patients, compared to usual care. This paper describes the statistical analysis plan of the FICUS trial. The primary outcome is quality of family care, assessed by the Family Satisfaction in ICU Questionnaire (FS-ICU-24R) at patient discharge from the ICU. Several secondary outcomes are additionally assessed 3, 6, and 12 months thereafter. Sixteen clusters (ICUs) were randomly assigned 1:1 to FSI or usual care using minimization (8 per treatment). The target sample size is 56 patients per cluster (896 in total). Recruitment has been completed in January 2024. The follow-up of the last participant will be completed in early 2025. The primary and secondary outcomes will be analyzed by linear mixed-effects models (LMM). The main model for the primary outcome will include a random intercept per cluster with treatment (FSI vs. usual care) as the only explanatory variable due to the relatively small number of clusters. In addition, covariate-adjusted analyses will be conducted, including two cluster-level characteristics used in the minimization as well as participant-level characteristics. Moreover, a number of subgroup analyses by cluster- and participant-level characteristics are pre-specified. Trial registration ClinicalTrials.gov NCT05280691 . Registered on February 20, 2022.

Summary: Background: Lyme disease (LD) is caused by Borrelia burgdorferi and is the most common tickborne disease in the northern hemisphere. Although classical characteristics of LD are well-known, the diagnosis and treatment are often delayed. Laboratory diagnosis by serological testing is recommended for most LD manifestations. The objective of this study was to describe clinical characteristics and associated serological profiles in children with LD. Methods: This retrospective cohort study included children aged 0–18 years, diagnosed with LD according to current guidelines at University Children's Hospital Zurich between January 1, 2006 and December 31, 2020. Two-tier serological testing with the recomWell enzyme-linked immunosorbent assay and recomLine Western blot (MIKROGEN Diagnostik, MIKROGEN GmbH, Neuried, Germany) was performed at the Institute of Medical Microbiology, University of Zurich. Findings: In total, 469 children diagnosed with LD were included (median age, 7.9 years); 190 patients (40.5%) with Lyme neuroborreliosis (LNB), 171 (36.5%) patients with skin manifestations (erythema migrans, n = 121; multiple erythema migrans, n = 11; borrelial lymphocytoma, n = 37; and acrodermatitis chronica atrophicans, n = 2), and 108 (23.0%) patients with Lyme arthritis. We observed seasonal variations for patients with skin manifestations and LNB, with high prevalence in May–October, but not for patients with Lyme arthritis. Significant differences between LD manifestation groups were found for age, inflammatory parameters, and specificity and concentration of B. burgdorferi-specific serum antibody responses. We observed distinct patterns of pronounced serum antibody responses against B. burgdorferi antigens in LNB (IgM against VlsE, p41, and OspC) and Lyme arthritis (IgG against p100, VlsE, p58, p41, p39, and p18). Interpretation: Our study is one of the largest and most detailed for children with LD. We present unique findings regarding the differences in clinical characteristics and immune responses between various manifestations of LD in children. Funding: No specific funding to disclose for this study.

Abstract Background & aims With the increase in patients at risk of advanced liver disease due to the obesity epidemic, there will be a need for simple screening tools for advanced liver fibrosis. Soluble suppression of tumorigenicity 2 (sST2) is a serum biomarker for fibrotic processes. The aim of this study was to evaluate sST2 as marker for liver fibrosis in patients successfully treated for chronic hepatitis C. Methods 424 patients from the Swiss Hepatitis C Cohort Study were screened for inclusion in this post-hoc cohort study. Inclusion criteria were sustained virological response (SVR), available elastography (VCTE) and serum samples for biomarker analysis before and after treatment. For the validation of sST2, values were compared to VCTE, FIB-4 and APRI using Spearman’s correlation and AUROC analyses. Results Data of 164 subjects were finally analyzed. Median sST2 values slightly increased with VCTE-derived fibrosis stages and remained stable after reaching SVR within the respective fibrosis stage, suggesting that sST2 is not influenced by liver inflammation. However, correlation of sST2 pre- and post-treatment with VCTE was fair (Spearman’s rho = 0.39 and rho = 0.36). The area under the curve (AUROC) for sST2 in detecting VCTE-defined F4 fibrosis (vs. F0-F3) before therapy was 0.74 (95%CI 0.65–0.83), and 0.67(95%CI 0.56–0.78) for the discrimination of F3/F4 fibrosis vs. F0-F2. Adding sST2 to either APRI or FIB-4, respectively, increased diagnostic performance of both tests. Conclusions sST2 can potentially identify patients with advanced fibrosis as a single serum marker and in combination with APRI and FIB-4.

Abstract Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.

Abstract Simplified first-trimester abortion protocols are well established. However, data on the use of medical or surgical abortion protocols across Switzerland is lacking. We report protocol characteristics in abortion care for two different facility types, hospital vs private practices (office-based) in Switzerland. Furthermore, we investigate an association between protocol characteristics and the likelihood of following through with the abortion at the same facility. We also report abortion outcomes of an office-based cohort where doctors use simplified abortion protocols. This study consists of two parts. (i) Between April and July, 2019, we collected data regarding medical and surgical abortion protocols of institutions offering abortions, in a nationwide survey. We assessed whether the proportion of patients who followed through with the abortion (primary outcome) after first appointment was associated with predefined protocol characteristics, considered to complicate access to abortion services, using generalised estimating equations. (ii) We analysed abortion outcomes of six selected office-based facilities from January, 2008, to December, 2018, using simplified abortion protocols in accordance with the Worlds Health Organisation (WHO) guidelines. (i) We included a total of 39 institutions. Hospitals showed more protocol-based barriers to abortion access compared with office-based facilities. The odds of undergoing an abortion after the first appointment were increased using protocols with minimal barriers. Overall, office-based facilities applied higher gestational age limits, required fewer appointments, and administered mifepristone more often after the first visit than did hospitals. (ii) We included a total of 5274 patients with an incidence of complications requiring surgery of 2.5% in line with rates reported in published literature. Only a few hospitals provide abortion care with easy access to medical and surgical abortion, whereas most office-based facilities do. Access to abortion services is generally crucial, and should be provided in a single visit whenever clinically permissible.

Abstract Background The number of children and adolescents living with life-limiting conditions and potentially in need for specialised paediatric palliative care (SPPC) is rising. Ideally, a specialised multiprofessional team responds to the complex healthcare needs of children and their families. The questions of, how SPPC is beneficial, for whom, and under what circumstances, remain largely unanswered in the current literature. This study’s overall target is to evaluate the effectiveness of a SPPC programme in Switzerland with respect to its potential to improve patient-, family-, health professional-, and healthcare-related outcomes. Methods This comparative effectiveness study applies a quasi-experimental design exploring the effectiveness of SPPC as a complex intervention at one treatment site in comparison with routine care provided in a generalised PPC environment at three comparison sites. As the key goal of palliative care, quality of life - assessed at the level of the patient-, the family- and the healthcare professional - will be the main outcome of this comparative effectiveness research. Other clinical, service, and economic outcomes will include patient symptom severity and distress, parental grief processes, healthcare resource utilisation and costs, direct and indirect health-related expenditure, place of death, and introduction of SPPC. Data will be mainly collected through questionnaire surveys and chart analysis. Discussion The need for SPPC has been demonstrated through numerous epidemiological and observational studies. However, in a healthcare environment focused on curative treatment and struggling with limited resources, the lack of evidence contributes to a lack of acceptance and financing of SPPC which is a major barrier against its sustainability. This study will contribute to current knowledge by reporting individual and child level outcomes at the family level and by collecting detailed contextual information on healthcare provision. We hope that the results of this study can help guiding the expansion and sustainability of SPPC and improve the quality of care for children with life-limiting conditions and their families internationally. Trial registration Registered prospectively on ClinicalTrials.gov on January 22, 2020. NCT04236180 Protocol version Amendment 2, March 01, 2021.

Abstract Background Family members of critically ill patients face considerable uncertainty and distress during their close others’ intensive care unit (ICU) stay. About 20–60% of family members experience adverse mental health outcomes post-ICU, such as symptoms of anxiety, depression, and posttraumatic stress. Guidelines recommend structured family inclusion, communication, and support, but the existing evidence base around protocolized family support interventions is modest and requires substantiation. Methods To test the clinical effectiveness and explore the implementation of a multicomponent, nurse-led family support intervention in ICUs, we will undertake a parallel, cluster-randomized, controlled, multicenter superiority hybrid-type 1 trial. It will include eight clusters (ICUs) per study arm, with a projected total sample size of 896 family members of adult, critically ill patients treated in the German-speaking part of Switzerland. The trial targets family members of critically ill patients with an expected ICU stay of 48 h or longer. Families in the intervention arm will receive a family support intervention in addition to usual care. The intervention consists of specialist nurse support that is mapped to the patient pathway with follow-up care and includes psycho-educational and relationship-focused family interventions, and structured, interprofessional communication, and shared decision-making with families. Families in the control arm will receive usual care. The primary study endpoint is quality of family care, operationalized as family members’ satisfaction with ICU care at discharge. Secondary endpoints include quality of communication and nurse support, family management of critical illness (functioning, resilience), and family members’ mental health (well-being, psychological distress) measured at admission, discharge, and after 3, 6, and 12 months. Data of all participants, regardless of protocol adherence, will be analyzed using linear mixed-effects models, with the individual participant as the unit of inference. Discussion This trial will examine the effectiveness of the family support intervention and generate knowledge of its implementability. Both types of evidence are necessary to determine whether the intervention works as intended in clinical practice and could be scaled up to other ICUs. The study findings will make a significant contribution to the current body of knowledge on effective ICU care that promotes family participation and well-being. Trial registration ClinicalTrials.gov NCT05280691 . Prospectively registered on 20 February 2022.

Abstract Background With the goal of reducing the prevalence of early childhood caries, the city of Zurich, Switzerland, started a specific prevention programme in 2010. All 2-year-olds are invited to a free dental check-up at a local public dental health service before the first legally mandated yearly dental check-up for school children between 4 and 5 years of age (at kindergarten). However, for the success of this prevention programme, it is of particular importance that children at high risk of caries are reached. The objective of our study was to assess the effectiveness of the prevention programme in (1) reaching the children who needed it the most and (2) improving subsequent oral health. Methods This retrospective cohort study included all children born between July 1, 2013 and July 15, 2014 who had lived in Zurich between the ages of 23 and 36 months. Socio-economic data were extracted from official school records, and dental health data from public dental clinic records. Binomial and quasi-binomial generalised linear models were used to identify the socio-economic factors associated with toddler check-up attendance and to assess the associations between attendance and caries experience (dmft $$\ge$$ ≥ 1) as well as degree of treatment (proportion m+f out of dmft) at the kindergarten check-up, adjusting for socio-economic factors. Results From a total of 4376 children, 2360 (54%) attended the toddler check-up (mean age 2.4 years) and 3452 (79%) had a dental examination at kindergarten (mean age 5.3 years). Non-Swiss origin of the primary caretaker, presence of older siblings, low amount of savings and allocation to certain public dental clinics were associated with a lower odds of attendance. Factors associated with a higher odds of caries experience were similar to those associated with a lower odds of attendance at the toddler check-up, but additionally included low income. Attendance at the toddler check-up was non-significantly associated with a lower odds of caries experience at kindergarten (adjusted OR 0.84, 95% CI from 0.70 to 1.01), but was significantly associated with a higher degree of treatment at this stage (adjusted OR 2.41, 95% CI from 1.79 to 3.24). Conclusions Our study suggests that children with a high caries risk are less likely to attend the toddler check-up. Greater effort should be put into reaching these children.

Abstract Background Measures of the sonorheometry based Quantra® viscoelastic hemostatic analyzer (HemoSonics, LCC, Charlottesville, VA, USA) were compared with corresponding results of the ROTEM® sigma device (Instrumentation Laboratory, Bedford, MA, USA). Methods In thirty-eight patients scheduled for elective cardiac surgery between December 2018 and October 2019, blood samples were taken after induction of anesthesia (sample 1) and after heparin neutralization (sample 2) and measured on Quantra (QPlus® Cartridge) and ROTEM sigma (ROTEM® sigma complete + hep Cartridge). Clot times and clot stiffness values were recorded. Clot stiffness values of ROTEM amplitudes (A in mm) were converted to shear modulus (G) in hectoPascal (hPa): G (hPa) = (5 x A)/(100-A). Additionally, time-to-results was recorded. Spearman rank test correlation and Bland Altman analysis were performed. Results Clot stiffness parameters of the Quantra correlated strongly with corresponding measurements of the ROTEM with r = 0.93 and 0.94 for EXTEM A10 vs CS and r = 0.94 and 0.96 for FIBTEM A10 vs FCS for sample 1 and 2, respectively. Quantra clot time correlated strongly with ROTEM INTEM CT with r = 0.71 for sample 1 and r = 0.75 for sample 2. However, Bland Altman analysis showed no agreement in all compared assays of both methods. The median time to delivery of first and complete results was significantly shorter for Quantra (412 and 658 s) compared to ROTEM sigma (839 and 1290 s). Conclusions The Quantra showed a strong correlation with the ROTEM sigma for determining clot times and clot stiffness and the parameters assess similar aspects of clot development. However, these parameters are not directly interchangeable and implicate that separate cut-off values need to be established for users of the Quantra device. Word count: 278. Trial registration The study was retrospectively registered with ClinicalTrials.gov (ID: NCT04210830 ) at December 20th 2019.

Abstract Background Klebsiella spp. are opportunistic pathogens which can cause severe infections, are often multi-drug resistant and are a common cause of hospital-acquired infections. Multiple new Klebsiella species have recently been described, yet their clinical impact and antibiotic resistance profiles are largely unknown. We aimed to explore Klebsiella group- and species-specific clinical impact, antimicrobial resistance (AMR) and virulence. Methods We analysed whole-genome sequence data of a diverse selection of Klebsiella spp. isolates and identified resistance and virulence factors. Using the genomes of 3594 Klebsiella isolates, we predicted the masses of 56 ribosomal subunit proteins and identified species-specific marker masses. We then re-analysed over 22,000 Matrix-Assisted Laser Desorption Ionization - Time Of Flight (MALDI-TOF) mass spectra routinely acquired at eight healthcare institutions in four countries looking for these species-specific markers. Analyses of clinical and microbiological endpoints from a subset of 957 patients with infections from Klebsiella species were performed using generalized linear mixed-effects models. Results Our comparative genomic analysis shows group- and species-specific trends in accessory genome composition. With the identified species-specific marker masses, eight Klebsiella species can be distinguished using MALDI-TOF MS. We identified K. pneumoniae (71.2%; n = 12,523), K. quasipneumoniae (3.3%; n = 575), K. variicola (9.8%; n = 1717), “K. quasivariicola” (0.3%; n = 52), K. oxytoca (8.2%; n = 1445), K. michiganensis (4.8%; n = 836), K. grimontii (2.4%; n = 425) and K. huaxensis (0.1%; n = 12). Isolates belonging to the K. oxytoca group, which includes the species K. oxytoca, K. michiganensis and K. grimontii, were less often resistant to 4th-generation cephalosporins than isolates of the K. pneumoniae group, which includes the species K. pneumoniae, K. quasipneumoniae, K. variicola and “K. quasivariicola” (odds ratio = 0.17, p < 0.001, 95% confidence interval [0.09,0.28]). Within the K. pneumoniae group, isolates identified as K. pneumoniae were more often resistant to 4th-generation cephalosporins than K. variicola isolates (odds ratio = 2.61, p = 0.003, 95% confidence interval [1.38,5.06]). K. oxytoca group isolates were found to be more likely associated with invasive infection to primary sterile sites than K. pneumoniae group isolates (odds ratio = 2.39, p = 0.0044, 95% confidence interval [1.05,5.53]). Conclusions Currently misdiagnosed Klebsiella spp. can be distinguished using a ribosomal marker-based approach for MALDI-TOF MS. Klebsiella groups and species differed in AMR profiles, and in their association with invasive infection, highlighting the importance for species identification to enable effective treatment options.

Abstract Background Adverse responses to critical illness, such as symptoms of depression, anxiety or posttraumatic stress, are relatively common among family members. The role of risk factors, however, remains insufficiently understood, but may be important to target those family members most in need for support. We therefore examined the association of patient-, family member- and care-related factors with post-ICU psychological distress in family members in a general population of critical ill patients. Methods We conducted a prospective, single-centre observational study in a twelve-bed surgical ICU in a 900-bed University Hospital in Switzerland. Participants were family members of patients treated in ICU who completed the Family Satisfaction in ICU-24 Survey, the Hospital Anxiety Depression Scale, Impact of Event Scale-Revised-6, and a demographic form within the first 3 months after their close other’s ICU stay. Data were analysed using linear mixed-effects models, with depression, anxiety, and posttraumatic stress as outcome measures. Results A total of 214 family members (53% return rate) returned a completed questionnaire. We found that higher levels of satisfaction were significantly associated with lower levels of depression, anxiety and posttraumatic stress. There was no statistically significant association between family member characteristics and any measure of psychological distress. Among the included patient characteristics, younger patient age was associated with higher levels of depression, and patient death was associated with higher levels of depression and posttraumatic stress. Conclusions Our results suggest that satisfaction with ICU care is strongly associated with family well-being post-ICU. Family members of younger patients and of those who die seem to be most at risk for psychological distress, requiring specific support, whereas family member characteristics may have less relevance.

Background The reporting quality in medical research has recently been critically discussed. While reporting guidelines intend to maximize the value from funded research, and initiatives such as the EQUATOR network have been introduced to advance high quality reporting, the uptake of the guidelines by researchers could be improved. The aim of this study was to assess the contribution of a biostatistician to the reporting and methodological quality of health research, and to identify methodological knowledge gaps. Methods In a retrospective, single center, observational cohort study, two groups of publications were compared. The group of exposed publications had an academic biostatistician on the author list, whereas the group of non-exposed publications did not include a biostatistician of the evaluated group. Rating of reporting quality was done in blinded fashion and in duplicate. The primary outcome was a sum score based on six dimensions, ranging between 0 (worst) and 11 (best). The study protocol was reviewed and approved as a registered report. Results There were 131 publications in the exposed group published between 2017 and 2018. Of these, 95 were either RCTs, observational, or prediction / prognostic studies. Corresponding matches in the group of non-exposed publications were identified in a reproducible manner. Comparison of reporting quality overall revealed a 1.60 (95%CI from 0.92 to 2.28, p Conclusion Our study is the first to report an association of a higher reporting quality and methodological strength in health research publications with a biostatistician on the author list. The higher reporting quality persisted through subgroups of study types and dimensions. Methodological knowledge gaps were identified for prediction / prognostic studies, and for reporting on statistical methods in general and missing values, specifically.

BackgroundThe reporting quality in medical research has recently been critically discussed. While reporting guidelines intend to maximize the value from funded research, and initiatives such as the EQUATOR network have been introduced to advance high quality reporting, the uptake of the guidelines by researchers could be improved. The aim of this study was to assess the contribution of a biostatistician to the reporting and methodological quality of health research, and to identify methodological knowledge gaps.MethodsIn a retrospective, single center, observational cohort study, two groups of publications were compared. The group of exposed publications had an academic biostatistician on the author list, whereas the group of non-exposed publications did not include a biostatistician of the evaluated group. Rating of reporting quality was done in blinded fashion and in duplicate. The primary outcome was a sum score based on six dimensions, ranging between 0 (worst) and 11 (best). The study protocol was reviewed and approved as a registered report.ResultsThere were 131 publications in the exposed group published between 2017 and 2018. Of these, 95 were either RCTs, observational, or prediction / prognostic studies. Corresponding matches in the group of non-exposed publications were identified in a reproducible manner. Comparison of reporting quality overall revealed a 1.60 (95%CI from 0.92 to 2.28, p ConclusionOur study is the first to report an association of a higher reporting quality and methodological strength in health research publications with a biostatistician on the author list. The higher reporting quality persisted through subgroups of study types and dimensions. Methodological knowledge gaps were identified for prediction / prognostic studies, and for reporting on statistical methods in general and missing values, specifically.

BackgroundNeonatal mortality in Guinea accounts for about 30% of all fatalities in children younger than five years. Countrywide, specialized neonatal intensive care is provided in one single clinic with markedly limited resources. To implement targeted measures, prospective data on patient characteristics and factors of neonatal death are needed.ObjectiveTo determine the rates of morbidity and mortality, to describe clinical characteristics of admitted newborns requiring intensive care, to assess the quality of disease management, and to identify factors contributing to neonatal mortality.MethodsProspective observational cohort study of newborns admitted to the hospital between mid-February and mid-March 2019 after birth in other institutions. Data were collected on maternal/prenatal history, delivery, and in-hospital care via convenience sampling. Associations of patient characteristics with in-hospital death were assessed using cause-specific Cox proportional-hazards models.ResultsHalf of the 168 admitted newborns underwent postnatal cardiopulmonary resuscitation. Reasons for admission included respiratory distress (49.4%), poor postnatal adaptation (45.8%), prematurity (46.2%), and infections (37.1%). 101 newborns (61.2%) arrived in serious/critical general condition; 90 children (53.9%) showed clinical signs of neurological damage. Quality of care was poor: Only 59.4% of the 64 newborns admitted with hypothermia were externally heated; likewise, 57.1% of 45 jaundiced infants did not receive phototherapy. Death occurred in 56 children (33.3%) due to birth asphyxia (42.9%), prematurity (33.9%), and sepsis (12.5%). Newborns in serious/critical general condition at admission had about a fivefold higher hazard to die than those admitted in good condition (HR 5.21 95%-CI 2.42-11.25, p = ConclusionNeonatal mortality was strikingly high. Birth asphyxia, prematurity, and infection accounted for 89.3% of death, aggravated by poor quality of in-hospital care. Children with serious general condition at admission had poor chances of survival. The whole concept of perinatal care in Guinea requires reconsideration.

Introduction Delirium is frequently observed in the intensive care unit (ICU) population, in particular. Until today, there is no evidence for any reliable pharmacological intervention to treat delirium. The Basel BOMP-AID (Better Outcome with Melatonin compared to Placebo Administered to normalize sleep-wake cycle and treat hypoactive ICU Delirium) randomised trial targets improvement of hypoactive delirium therapy in critically ill patients and will be conducted as a counterpart to the Basel ProDex Study (Study Protocol, BMJ Open, July 2017) on hyperactive and mixed delirium. The aim of the BOMP-AID trial is to assess the superiority of melatonin to placebo for the treatment of hypoactive delirium in the ICU. The study hypothesis is based on the assumption that melatonin administered at night restores a normal circadian rhythm, and that restoration of a normal circadian rhythm will cure delirium.Methods and analysis The Basel BOMP-AID study is an investigator-initiated, single-centre, randomised controlled clinical trial for the treatment of hypoactive delirium with the once daily oral administration of melatonin 4 mg versus placebo in 190 critically ill patients. The primary outcome measure is delirium duration in 8-hour shifts. Secondary outcome measures include delirium-free days and death at 28 days after study inclusion, number of ventilator days, length of ICU and hospital stay, and sleep quality. Patients will be followed after 3 and 12 months for activities of daily living and mortality assessment. Sample size was calculated to demonstrate superiority of melatonin compared with placebo regarding the duration of delirium. Results will be presented using an intention-to-treat approach.Ethics and dissemination This study has been approved by the Ethics Committee of Northwestern and Central Switzerland and will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the International Conference on Harmonisation (ICH) of technical requirements for registration of pharmaceuticals for human use; Good Clinical Practice (GCP) or ISO EN 14155 (as far as applicable), as well as all national legal and regulatory requirements. Study results will be presented in international conferences and published in a peer-reviewed journal.Trial registration number NCT03438526.Protocol version Clinical Study Protocol Version 3, 10.03.2019.

BackgroundQuality in medical research has recently been criticized for being low, especially in observational research. Methodology is increasingly difficult, but collaboration between clinical researchers and biostatisticians may improve research and reporting quality. The aim of this study is to quantify the value of a biostatistician in the team of authors.MethodsSingle-center, retrospective observational study following the STROBE reporting guidelines. We will systematically review all medical publications with biostatisticians from our center as co-authors or authors and review corresponding papers without biostatisticians from our center during the same time range. We will compare aspects of reporting quality, overall and for the three study types observational, randomized trial, and prognostic separately.DiscussionWe anticipate that the results of the study will raise awareness of the importance of high methodological quality, as well as appropriate reporting quality in clinical research.ConclusionOur study will have a direct impact on our center by making each of us more aware of the reporting guidelines for various research designs. This in turn will enhance reporting quality in future research with our involvement. Our study will also raise awareness of the important role that biostatisticians play in the design and analysis of health research projects.

An amendment to this paper has been published and can be accessed via the original article.

Heinz Ellenberg's historically important work on changes in the abundances of a community of grass species growing along experimental gradients of water table depth has played an important role in helping to identify the hydrological niches of plant species in wet meadows. We present a previously unpublished complete version of Ellenberg's dataset from the 1950s together with the results of a series of modern statistical analyses testing for hypothesized overyielding of aboveground net primary production as a consequence of resource-based niche differentiation. Interactions of species with water table depth and soil type in the results of our analyses are qualitatively consistent with earlier interpretations of evidence for differences in the fundamental and realized niches of species. Arrhenatherum elatius tended to dominate communities and this effect was generally positively related to increasing water table depth. There was little overyielding of aboveground net primary production during the two repeats of the experiment conducted in successive single growing seasons. Examination of how the effects of biodiversity on ecosystem processes vary across environmental gradients is an underutilized approach--particularly where the gradient is thought to be an axis of niche differentiation as is the case with water availability. Furthermore, advances in ecology and statistics during the 60 years since Ellenberg's classic experiment was performed suggest that it may be worth repeating over a longer duration and with modern experimental design and methodologies.