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BackgroundWhile the effectiveness of patient-reported outcome measures (PROMs) as an intervention to impact patient pathways has been established for cancer care, it is unknown for other indications. We assessed the cost-effectiveness of a PROM-based monitoring and alert intervention for early detection of critical recovery paths following hip and knee replacement.Methods and findingsThe cost-effectiveness analysis (CEA) is based on a multicentre randomised controlled trial encompassing 3,697 patients with hip replacement and 3,110 patients with knee replacement enrolled from 2019 to 2020 in 9 German hospitals. The analysis was conducted with a subset of 546 hip and 492 knee replacement cases with longitudinal cost data from 24 statutory health insurances. Patients were randomised 1:1 to a PROM-based remote monitoring and alert intervention or to a standard care group. All patients were assessed at 12-months post-surgery via digitally collected PROMs. Patients within the intervention group were additionally assessed at 1-, 3-, and 6-months post-surgery to be contacted in case of critical recovery paths. For the effect evaluation, a PROM-based composite measure (PRO-CM) was developed, combining changes across various PROMs in a single index ranging from 0 to 100. The PRO-CM included 6 PROMs focused on quality of life and various aspects of physical and mental health. The primary outcome was the incremental cost-effectiveness ratio (ICER). The intervention group showed incremental outcomes of 2.54 units PRO-CM (95% confidence interval (CI) [0.93, 4.14]; p = 0.002) for patients with hip and 0.87 (95% CI [-0.94, 2.67]; p = 0.347) for patients with knee replacement. Within the 12-months post-surgery period the intervention group had less costs of 376.43€ (95% CI [-639.74, -113.12]; p = 0.005) in patients with hip, and 375.50€ (95% CI [-767.40, 16.39]; p = 0.060) in patients with knee replacement, revealing a dominant ICER for both procedures. However, it remains unclear which step of the multistage intervention contributes most to the positive effect.ConclusionsThe intervention significantly improved patient outcomes at lower costs in patients with hip replacements when compared with standard care. Further it showed a nonsignificant cost reduction in knee replacement patients. This reinforces the notion that PROMs can be utilised as a cost-effective instrument for remote monitoring in standard care settings.Trial registrationRegistration: German Register for Clinical Studies (DRKS) under DRKS00019916.

BackgroundPoor representation of pregnant and lactating women and people in clinical trials has marginalised their health concerns and denied the maternal-fetal/infant dyad benefits of innovation in therapeutic research and development. This mixed-methods systematic review synthesised factors affecting the participation of pregnant and lactating women in clinical trials, across all levels of the research ecosystem.Methods and findingsWe searched 8 databases from inception to 14 February 2024 to identify qualitative, quantitative, and mixed-methods studies that described factors affecting participation of pregnant and lactating women in vaccine and therapeutic clinical trials in any setting. We used thematic synthesis to analyse the qualitative literature and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. We compared quantitative data against the thematic synthesis findings to assess areas of convergence or divergence. We mapped review findings to the Theoretical Domains Framework (TDF) and Capability, Opportunity, and Motivation Model of Behaviour (COM-B) to inform future development of behaviour change strategies. We included 60 papers from 27 countries. We grouped 24 review findings under 5 overarching themes: (a) interplay between perceived risks and benefits of participation in women's decision-making; (b) engagement between women and the medical and research ecosystems; (c) gender norms and decision-making autonomy; (d) factors affecting clinical trial recruitment; and (e) upstream factors in the research ecosystem. Women's willingness to participate in trials was affected by: perceived risk of the health condition weighed against an intervention's risks and benefits, therapeutic optimism, intervention acceptability, expectations of receiving higher quality care in a trial, altruistic motivations, intimate relationship dynamics, and power and trust in medicine and research. Health workers supported women's participation in trials when they perceived clinical equipoise, had hope for novel therapeutic applications, and were convinced an intervention was safe. For research staff, developing reciprocal relationships with health workers, having access to resources for trial implementation, ensuring the trial was visible to potential participants and health workers, implementing a woman-centred approach when communicating with potential participants, and emotional orientations towards the trial were factors perceived to affect recruitment. For study investigators and ethics committees, the complexities and subjectivities in risk assessments and trial design, and limited funding of such trials contributed to their reluctance in leading and approving such trials. All included studies focused on factors affecting participation of cisgender pregnant women in clinical trials; future research should consider other pregnancy-capable populations, including transgender and nonbinary people.ConclusionsThis systematic review highlights diverse factors across multiple levels and stakeholders affecting the participation of pregnant and lactating women in clinical trials. By linking identified factors to frameworks of behaviour change, we have developed theoretically informed strategies that can help optimise pregnant and lactating women's engagement, participation, and trust in such trials.

Long terminal repeat retrotransposons (LTR-RTs) are powerful mutagens regarded as a major source of genetic novelty and important drivers of evolution. Yet, the uncontrolled and potentially selfish proliferation of LTR-RTs can lead to deleterious mutations and genome instability, with large fitness costs for their host. While population genomics data suggest that an ongoing LTR-RT mobility is common in many species, the understanding of their dual role in evolution is limited. Here, we harness the genetic diversity of 320 sequenced natural accessions of the Mediterranean grass Brachypodium distachyon to characterize how genetic and environmental factors influence plant LTR-RT dynamics in the wild. When combining a coverage-based approach to estimate global LTR-RT copy number variations with mobilome-sequencing of nine accessions exposed to eight different stresses, we find little evidence for a major role of environmental factors in LTR-RT accumulations in B. distachyon natural accessions. Instead, we show that loss of RNA polymerase IV (Pol IV), which mediates RNA-directed DNA methylation in plants, results in high transcriptional and transpositional activities of RLC_BdisC024 (HOPPLA) LTR-RT family elements, and that these effects are not stress-specific. This work supports findings indicating an ongoing mobility in B. distachyon and reveals that host RNA-directed DNA methylation rather than environmental factors controls their mobility in this wild grass model.

Cancer treatment often creates logistic conflicts with everyday life priorities; however, these challenges and how they are subjectively experienced have been largely unaddressed in cancer care. Our goal was to describe time and logistic requirements of cancer care and whether and how they interfered with daily life and well-being. We conducted interviews with 20 adults receiving cancer-directed treatment at a single academic cancer center. We focused on participants' perception of the time, effort, and energy-intensiveness of cancer care activities, organization of care requirements, and preferences in how to manage the logistic burdens of their cancer care. Participant interview transcripts were analyzed using an inductive thematic analysis approach. Burdens related to travel, appointment schedules, healthcare system navigation, and consequences for relationships had roots both at the system-level (e.g. labs that were chronically delayed, protocol-centered rather than patient-centered bureaucratic requirements) and in individual circumstances (e.g. greater stressors among those working and/or have young children versus those who are retired) that determined subjective burdensomeness, which was highest among patients who experienced multiple sources of burdens simultaneously. Our study illustrates how objective burdens of cancer care translate into subjective burden depending on patient circumstances, emphasizing that to study burdens of care, an exclusive focus on objective measures does not capture the complexity of these issues. The complex interplay between healthcare system factors and individual circumstances points to clinical opportunities, for example helping patients to find ways to meet work and childcare requirements while receiving care.

Determining if a sequence of numbers is ordered or not is one of the fundamental aspects of numerical processing linked to concurrent and future arithmetic skills. While some studies have explored the neural underpinnings of order processing using functional magnetic resonance imaging, our understanding of electrophysiological correlates is comparatively limited. To address this gap, we used a three-item symbolic numerical order verification task (with Arabic numerals from 1 to 9) to study event-related potentials (ERPs) in 73 adult participants in an exploratory approach. We presented three-item sequences and manipulated their order (ordered vs. unordered) as well as their inter-item numerical distance (one vs. two). Participants had to determine if a presented sequence was ordered or not. They also completed a speeded arithmetic fluency test, which measured their arithmetic skills. Our results revealed a significant mean amplitude difference in the grand average ERP waveform between ordered and unordered sequences in a time window of 500-750 ms at left anterior-frontal, left parietal, and central electrodes. We also identified distance-related amplitude differences for both ordered and unordered sequences. While unordered sequences showed an effect in the time window of 500-750 ms at electrode clusters around anterior-frontal and right-frontal regions, ordered sequences differed in an earlier time window (190-275 ms) in frontal and right parieto-occipital regions. Only the mean amplitude difference between ordered and unordered sequences showed an association with arithmetic fluency at the left anterior-frontal electrode. While the earlier time window for ordered sequences is consistent with a more automated and efficient processing of ordered sequential items, distance-related differences in unordered sequences occur later in time.

The quality of medicines for the prevention and management of hypertensive disorders of pregnancy globally is a critical challenge in the reduction of maternal mortality rate. We aimed to conduct a systematic review of available studies on the quality of the eight medicines recommended globally for the prevention and management of hypertensive disorders of pregnancy. We searched five electronic databases- Ovid MEDLINE, EMBASE, CINAHL, ProQuest and Cochrane Library, and also grey literature, without year or language limitations. Any study assessing the quality parameters (Active Pharmaceutical Ingredients, pH, sterility, solubility, impurities) of medicines by using any valid laboratory methods was eligible. Two reviewers independently screened the studies, extracted data and applied Medicine Quality Assessment Reporting Guidelines tool for quality assessment. Results were narratively reported and stratified by the drug types. Of 5669 citations screened, 33 studies from 27 countries were included. Five studies reported on the quality of magnesium sulphate-two (Nigeria and USA) found substandard medicine due to failing API specification and contaminants, respectively. Another study from Nigeria and a multi-country study (10 lower-middle- and low-income countries) found poor-quality due to failing the pH criteria. Seven of eight studies evaluating aspirin found quality issues, including degraded medicines in five studies (Brazil, USA, Yugoslavia and Pakistan). Five studies of calcium supplements found quality issues, particularly heavy metal contamination. Of 15 antihypertensives quality studies, 12 found substandard medicines and one study identified counterfeit medicines. This systematic review identified pervasive issues of poor-quality medicines across all recommended medicines used to prevent or treat hypertensive disorders of pregnancy, raising concerns regarding their safety and effectiveness.

SLC30A9 encodes a ubiquitously zinc transporter (ZnT9) and has been consistently suggested as a candidate for positive selection in humans. However, no direct adaptive molecular phenotype has been demonstrated. Our results provide evidence for directional selection operating in two major complementary haplotypes in Africa and East Asia. These haplotypes are associated with differential gene expression but also differ in the Met50Val substitution (rs1047626) in ZnT9, which we show is found in homozygosis in the Denisovan genome and displays accompanying signatures suggestive of archaic introgression. Although we found no significant differences in systemic zinc content between individuals with different rs1047626 genotypes, we demonstrate that the expression of the derived isoform (ZnT9 50Val) in HEK293 cells shows a gain of function when compared with the ancestral (ZnT9 50Met) variant. Notably, the ZnT9 50Val variant was found associated with differences in zinc handling by the mitochondria and endoplasmic reticulum, with an impact on mitochondrial metabolism. Given the essential role of the mitochondria in skeletal muscle and since the derived allele at rs1047626 is known to be associated with greater susceptibility to several neuropsychiatric traits, we propose that adaptation to cold may have driven this selection event, while also impacting predisposition to neuropsychiatric disorders in modern humans.

Current mitochondrial DNA (mtDNA) haplogroup classification tools map reads to a single reference genome and perform inference based on the detected mutations to this reference. This approach biases haplogroup assignments towards the reference and prohibits accurate calculations of the uncertainty in assignment. We present HaploCart, a probabilistic mtDNA haplogroup classifier which uses a pangenomic reference graph framework together with principles of Bayesian inference. We demonstrate that our approach significantly outperforms available tools by being more robust to lower coverage or incomplete consensus sequences and producing phylogenetically-aware confidence scores that are unbiased towards any haplogroup. HaploCart is available both as a command-line tool and through a user-friendly web interface. The C++ program accepts as input consensus FASTA, FASTQ, or GAM files, and outputs a text file with the haplogroup assignments of the samples along with the level of confidence in the assignments. Our work considerably reduces the amount of data required to obtain a confident mitochondrial haplogroup assignment.

Daylength sensing in many plants is critical for coordinating the timing of flowering with the appropriate season. Temperate climate-adapted grasses such as Brachypodium distachyon flower during the spring when days are becoming longer. The photoreceptor PHYTOCHROME C is essential for long-day (LD) flowering in B. distachyon. PHYC is required for the LD activation of a suite of genes in the photoperiod pathway including PHOTOPERIOD1 (PPD1) that, in turn, result in the activation of FLOWERING LOCUS T (FT1)/FLORIGEN, which causes flowering. Thus, B. distachyon phyC mutants are extremely delayed in flowering. Here we show that PHYC-mediated activation of PPD1 occurs via EARLY FLOWERING 3 (ELF3), a component of the evening complex in the circadian clock. The extreme delay of flowering of the phyC mutant disappears when combined with an elf3 loss-of-function mutation. Moreover, the dampened PPD1 expression in phyC mutant plants is elevated in phyC/elf3 mutant plants consistent with the rapid flowering of the double mutant. We show that loss of PPD1 function also results in reduced FT1 expression and extremely delayed flowering consistent with results from wheat and barley. Additionally, elf3 mutant plants have elevated expression levels of PPD1, and we show that overexpression of ELF3 results in delayed flowering associated with a reduction of PPD1 and FT1 expression, indicating that ELF3 represses PPD1 transcription consistent with previous studies showing that ELF3 binds to the PPD1 promoter. Indeed, PPD1 is the main target of ELF3-mediated flowering as elf3/ppd1 double mutant plants are delayed flowering. Our results indicate that ELF3 operates downstream from PHYC and acts as a repressor of PPD1 in the photoperiod flowering pathway of B. distachyon.

BackgroundRoutine anthropometry of children, including length/height measurement, is an essential component of paediatric clinical assessments. UNICEF has called for the accelerated development of novel, digital height/length measurement devices to improve child nutrition and growth surveillance programs. This scoping review aimed to identify all digital, portable height/length measurement devices in the literature or otherwise available internationally. We also assessed identified devices against the UNICEF Target Product Profile (TPP) to identify those of highest potential for clinical and public health use.MethodWe searched four databases (Medline, Embase, CINAHL and Global Health) and the grey literature between 1st January 1992 and 2nd February 2023. We looked for studies or reports on portable, digital devices for height or length measurement in children up to 18 years old. Citations were screened independently by two reviewers, with data extraction and quality assessment performed in duplicate and disagreements resolved. Devices were evaluated and scored against the 34 criteria of the UNICEF TPP.ResultsTwenty studies describing twelve height/length measurement devices were identified, most of which used prospective validation designs. Additional devices were found in the grey literature, but these did not report key performance data so were not included. Across the twelve devices, only 10 of 34 UNICEF criteria on average could be fully assessed. Six met UNICEF's ideal accuracy standard and one device met the minimum accuracy standard. The Leica DistoD2 device scored highest (41%), followed by Autoanthro in a controlled environment (33%) and GLM30 (32%). These devices may be high potential for further assessment and development, though further research is required.ConclusionWhile 12 portable, digital devices exist for child height/length measurement, insufficient data are available to fully assess whether they meet the industry's needs. Although some devices show promise, further research is needed to test the validity of these devices in varying contexts, and continued development and commercialization will be important to improve reliability and precision of these devices for widespread use.

ObjectiveThe overall goal of this work is to produce a set of recommendations (SoNHR-Social Networks in Health Research) that will improve the reporting and dissemination of social network concepts, methods, data, and analytic results within health sciences research.MethodsThis study used a modified-Delphi approach for recommendation development consistent with best practices suggested by the EQUATOR health sciences reporting guidelines network. An initial set of 28 reporting recommendations was developed by the author team. A group of 67 (of 147 surveyed) experienced network and health scientists participated in an online feedback survey. They rated the clarity and importance of the individual recommendations, and provided qualitative feedback on the coverage, usability, and dissemination opportunities of the full set of recommendations. After examining the feedback, a final set of 18 recommendations was produced.ResultsThe final SoNHR reporting guidelines are comprised of 18 recommendations organized within five domains: conceptualization (how study research questions are linked to network conceptions or theories), operationalization (how network science portions of the study are defined and operationalized), data collection & management (how network data are collected and managed), analyses & results (how network results are analyzed, visualized, and reported), and ethics & equity (how network-specific human subjects, equity, and social justice concerns are reported). We also present a set of exemplar published network studies which can be helpful for seeing how to apply the SoNHR recommendations in research papers. Finally, we discuss how different audiences can use these reporting guidelines.ConclusionsThese are the first set of formal reporting recommendations of network methods in the health sciences. Consistent with EQUATOR goals, these network reporting recommendations may in time improve the quality, consistency, and replicability of network science across a wide variety of important health research areas.

BackgroundHeight is a key component of nutrition assessments in children from limited-resource settings. This study aimed to assess whether handheld digital ultrasound devices for measuring children's height provide comparable accuracy to traditional measurement boards, which are bulky and difficult to transport.MethodsWe trained 12 health workers to measure the standing height of 222 children aged 2-5 years in rural Lao People's Democratic Republic using both the ultrasound device and measurement board. The Bland-Altman method was used to depict limits of agreement and potential bias. We reported the technical error of measurement (TEM) for precision and accuracy, then assessed these results against the Standardized Monitoring and Assessment for Relief and Transition (SMART) Manual 2.0 and the WHO Multicentre Growth Reference Study (MGRS).ResultsThe average difference between the ultrasound and board measurements was 0.096 cm (95% limits-of-agreement: 0.041cm, 0.61cm) with a systematic bias of 0.1cm (95% confidence interval: 0.067cm, 0.134cm), suggesting the ultrasound measurements were slightly higher than those from the board. The ultrasound and board TEMs for precision were 0.157cm and 0.091cm respectively. The accuracy TEM was 0.205cm. All TEMs were within SMART and WHO MGRS limits.ConclusionThe ultrasound device is comparable to the measurement board among standing Lao children aged 2-5 years for precision and accuracy TEMs but showed a bias of 0.1cm. Further studies are required to assess whether calibration can minimise this bias and determine the ultrasound's accuracy on recumbent length for infants and younger children.

PurposeTo improve automated lung segmentation on 2D lung MR images using balanced augmentation and artificially-generated consolidations for training of a convolutional neural network (CNN).Materials and methodsFrom 233 healthy volunteers and 100 patients, 1891 coronal MR images were acquired. Of these, 1666 images without consolidations were used to build a binary semantic CNN for lung segmentation and 225 images (187 without consolidations, 38 with consolidations) were used for testing. To increase CNN performance of segmenting lung parenchyma with consolidations, balanced augmentation was performed and artificially-generated consolidations were added to all training images. The proposed CNN (CNNBal/Cons) was compared to two other CNNs: CNNUnbal/NoCons-without balanced augmentation and artificially-generated consolidations and CNNBal/NoCons-with balanced augmentation but without artificially-generated consolidations. Segmentation results were assessed using Sørensen-Dice coefficient (SDC) and Hausdorff distance coefficient.ResultsRegarding the 187 MR test images without consolidations, the mean SDC of CNNUnbal/NoCons (92.1 ± 6% (mean ± standard deviation)) was significantly lower compared to CNNBal/NoCons (94.0 ± 5.3%, P = 0.0013) and CNNBal/Cons (94.3 ± 4.1%, P = 0.0001). No significant difference was found between SDC of CNNBal/Cons and CNNBal/NoCons (P = 0.54). For the 38 MR test images with consolidations, SDC of CNNUnbal/NoCons (89.0 ± 7.1%) was not significantly different compared to CNNBal/NoCons (90.2 ± 9.4%, P = 0.53). SDC of CNNBal/Cons (94.3 ± 3.7%) was significantly higher compared to CNNBal/NoCons (P = 0.0146) and CNNUnbal/NoCons (P = 0.001).ConclusionsExpanding training datasets via balanced augmentation and artificially-generated consolidations improved the accuracy of CNNBal/Cons, especially in datasets with parenchymal consolidations. This is an important step towards a robust automated postprocessing of lung MRI datasets in clinical routine.

The tactical cooperation for the optimal interaction of team members is an essential performance-determining variable in sports games. The underlying cognitive memory structures of cooperative tactical actions have so far been little researched. Therefore, this study investigated the cognitive memory structure of tactical knowledge of handball actions in teams of different expertise and age groups. In the first experiment, tactical mental representation structures (TMRS) of 30 adult handball players of two different level of expertise were investigated. In the second experiment, TMRS of 57 youth handball players from three age levels were investigated. In both experiments the TMRS was measured with the structure dimensional analysis of mental representation (SDA-M) method. The SDA-M commences with a splitting procedure of a given set of concepts and reveals with a cluster analysis the relational structures of the concepts on an individual and a group level. Experiment one revealed that the TMRS differed significantly between skilled either/or less experienced handball players. Skilled handball players showed a hierarchical organized representation that shared more features with the basic tactical structure of the handball game than less experienced players. The second experiment revealed age-related differences of the TMRS between the age groups of the U15, U17 and U19 teams. Further data analysis revealed significant differences of the TMRS between experienced and less experienced handball players and between local and regional competition level players. We conclude that our current findings suggest that tactical expertise is mediated by elaborate cognitive tactical knowledge in memory. Furthermore, our results indicate that tactical knowledge plays a substantial role during tactical skill learning as it differs as function of age, experience, and competition level. From this point of view, team representations of game situations can be seen as a crucial factor for efficient and common interaction in fast-paced team sports.

Systemic AA-amyloidosis is a protein-misfolding disease characterized by fibril deposition of serum amyloid-A protein (SAA) in several organs in humans and many animal species. Fibril deposits originate from abnormally high serum levels of SAA during chronic inflammation. A high prevalence of AA-amyloidosis has been reported in captive cheetahs and a horizontal transmission has been proposed. In domestic cats, AA-amyloidosis has been mainly described in predisposed breeds but only rarely reported in domestic short-hair cats. Aims of the study were to determine AA-amyloidosis prevalence in dead shelter cats. Liver, kidney, spleen and bile were collected at death in cats from 3 shelters. AA-amyloidosis was scored. Shedding of amyloid fibrils was investigated with western blot in bile and scored. Descriptive statistics were calculated. In the three shelters investigated, prevalence of AA-amyloidosis was 57.1% (16/28 cats), 73.0% (19/26) and 52.0% (13/25), respectively. In 72.9% of cats (35 in total) three organs were affected concurrently. Histopathology and immunofluorescence of post-mortem extracted deposits identified SAA as the major protein source. The duration of stay in the shelters was positively associated with a histological score of AA-amyloidosis (B = 0.026, CI95% = 0.007-0.046; p = 0.010). AA-amyloidosis was very frequent in shelter cats. Presence of SAA fragments in bile secretions raises the possibility of fecal-oral transmission of the disease. In conclusion, AA-amyloidosis was very frequent in shelter cats and those staying longer had more deposits. The cat may represent a natural model of AA-amyloidosis.

Background Antenatal corticosteroids (ACS) are widely prescribed to improve outcomes following preterm birth. Significant knowledge gaps surround their safety, long-term effects, optimal timing and dosage. Almost half of women given ACS give birth outside the “therapeutic window” and have not delivered over 7 days later. Overtreatment with ACS is a concern, as evidence accumulates of risks of unnecessary ACS exposure. Methods The Consortium for the Study of Pregnancy Treatments (Co-OPT) was established to address research questions surrounding safety of medications in pregnancy. We created an international birth cohort containing information on ACS exposure and pregnancy and neonatal outcomes by combining data from four national/provincial birth registers and one hospital database, and follow-up through linked population-level data from death registers and electronic health records. Results and discussion The Co-OPT ACS cohort contains 2.28 million pregnancies and babies, born in Finland, Iceland, Israel, Canada and Scotland, between 1990 and 2019. Births from 22 to 45 weeks’ gestation were included; 92.9% were at term (≥ 37 completed weeks). 3.6% of babies were exposed to ACS (67.0% and 77.9% of singleton and multiple births before 34 weeks, respectively). Rates of ACS exposure increased across the study period. Of all ACS-exposed babies, 26.8% were born at term. Longitudinal childhood data were available for 1.64 million live births. Follow-up includes diagnoses of a range of physical and mental disorders from the Finnish Hospital Register, diagnoses of mental, behavioural, and neurodevelopmental disorders from the Icelandic Patient Registers, and preschool reviews from the Scottish Child Health Surveillance Programme. The Co-OPT ACS cohort is the largest international birth cohort to date with data on ACS exposure and maternal, perinatal and childhood outcomes. Its large scale will enable assessment of important rare outcomes such as perinatal mortality, and comprehensive evaluation of the short- and long-term safety and efficacy of ACS.

BackgroundAntenatal corticosteroids (ACS) are widely prescribed to improve outcomes following preterm birth. Significant knowledge gaps surround their safety, long-term effects, optimal timing and dosage. Almost half of women given ACS give birth outside the "therapeutic window" and have not delivered over 7 days later. Overtreatment with ACS is a concern, as evidence accumulates of risks of unnecessary ACS exposure.MethodsThe Consortium for the Study of Pregnancy Treatments (Co-OPT) was established to address research questions surrounding safety of medications in pregnancy. We created an international birth cohort containing information on ACS exposure and pregnancy and neonatal outcomes by combining data from four national/provincial birth registers and one hospital database, and follow-up through linked population-level data from death registers and electronic health records.Results and discussionThe Co-OPT ACS cohort contains 2.28 million pregnancies and babies, born in Finland, Iceland, Israel, Canada and Scotland, between 1990 and 2019. Births from 22 to 45 weeks' gestation were included; 92.9% were at term (≥ 37 completed weeks). 3.6% of babies were exposed to ACS (67.0% and 77.9% of singleton and multiple births before 34 weeks, respectively). Rates of ACS exposure increased across the study period. Of all ACS-exposed babies, 26.8% were born at term. Longitudinal childhood data were available for 1.64 million live births. Follow-up includes diagnoses of a range of physical and mental disorders from the Finnish Hospital Register, diagnoses of mental, behavioural, and neurodevelopmental disorders from the Icelandic Patient Registers, and preschool reviews from the Scottish Child Health Surveillance Programme. The Co-OPT ACS cohort is the largest international birth cohort to date with data on ACS exposure and maternal, perinatal and childhood outcomes. Its large scale will enable assessment of important rare outcomes such as perinatal mortality, and comprehensive evaluation of the short- and long-term safety and efficacy of ACS.

Tinnitus affects a considerable part of the population and develops into a severe disorder in some sufferers. App-based interventions are able to provide low-threshold, cost-effective, and location-independent care for tinnitus patients. Therefore, we developed a smartphone app combining structured counseling with sound therapy and conducted a pilot study to evaluate treatment compliance and symptom improvement (trial registration: DRKS00030007). Outcome variables were Ecological Momentary Assessment (EMA) measured tinnitus distress and loudness and Tinnitus Handicap Inventory (THI) at baseline and final visit. A multiple-baseline design with a baseline phase (only EMA) followed by an intervention phase (EMA and intervention) was applied. 21 patients with chronic tinnitus (≥ 6 months) were included. Overall compliance differed between modules (EMA usage: 79% of days, structured counseling: 72%, sound therapy: 32%). The THI score improved from baseline to final visit indicating a large effect (Cohens d = 1.1). Tinnitus distress and loudness did not improve significantly from baseline phase to the end of intervention phase. However, 5 of 14 (36%) improved clinically meaningful in tinnitus distress (ΔDistress ≥ 10) and 13 of 18 (72%) in THI score (ΔTHI ≥ 7). The positive relationship between tinnitus distress and loudness weakened over the course of the study. A trend but no level effect for tinnitus distress could be demonstrated by a mixed effect model. The improvement in THI was strongly associated with the improvement scores in EMA of tinnitus distress (r = -0.75; 0.86). These results indicate that app-based structured counseling combined with sound therapy is feasible, has an impact on tinnitus symptoms and reduces distress for several patients. In addition, our data suggest that EMA could be used as a measurement tool to detect changes in tinnitus symptoms in clinical trials as has already been shown in other areas of mental health research.

Background More knowledge about the long-term impact of sperm donation is essential as the donor’s attitude towards donation may change over time. Personal and social developments may prompt a rethinking of previous actions and decisions, or even regret. Thus, the aim of this study was to explore the experiences and attitudes of men who were sperm donors more than 10 years ago. Methods From May to September 2021, semi-structured, qualitative interviews were conducted with 23 former donors (> 10 years since last donation) from Cryos International sperm bank. Two participants were non-anonymous donors and 21 were anonymous. The interviews were conducted by phone or via video (mean 24 minutes). All interviews were recorded, transcribed verbatim and rendered anonymous. Data were analyzed using thematic analysis. Results The analysis showed that most men had been donors for monetary and altruistic purposes, and now considered sperm donation as a closed chapter that was ’unproblematic and in the past’. Most men valued anonymity and emphasized the non-relatedness between donor and donor conceived offspring. Knowledge about recipients and donor offspring was seen as ’damaging’ as it could create unwanted feelings of relatedness and responsibility towards them. All men acknowledged donor conceived persons’ potential interests in knowing about their genetic heritage in order to understand appearance and personal traits, but also emphasized the donors’ rights to anonymity. Potential breach of anonymity was generally considered ’highly problematic’ as it was expected to disturb their families and force a relationship on them. Conclusion This study reports on former donors who might not have volunteered for research due to lack of interest or protection of privacy. The majority of men valued anonymity and clearly demarcated a line between sperm donation and fatherhood, which was enforced by not knowing about the donor offspring or recipients.

BackgroundMore knowledge about the long-term impact of sperm donation is essential as the donor's attitude towards donation may change over time. Personal and social developments may prompt a rethinking of previous actions and decisions, or even regret. Thus, the aim of this study was to explore the experiences and attitudes of men who were sperm donors more than 10 years ago.MethodsFrom May to September 2021, semi-structured, qualitative interviews were conducted with 23 former donors (> 10 years since last donation) from Cryos International sperm bank. Two participants were non-anonymous donors and 21 were anonymous. The interviews were conducted by phone or via video (mean 24 minutes). All interviews were recorded, transcribed verbatim and rendered anonymous. Data were analyzed using thematic analysis.ResultsThe analysis showed that most men had been donors for monetary and altruistic purposes, and now considered sperm donation as a closed chapter that was 'unproblematic and in the past'. Most men valued anonymity and emphasized the non-relatedness between donor and donor conceived offspring. Knowledge about recipients and donor offspring was seen as 'damaging' as it could create unwanted feelings of relatedness and responsibility towards them. All men acknowledged donor conceived persons' potential interests in knowing about their genetic heritage in order to understand appearance and personal traits, but also emphasized the donors' rights to anonymity. Potential breach of anonymity was generally considered 'highly problematic' as it was expected to disturb their families and force a relationship on them.ConclusionThis study reports on former donors who might not have volunteered for research due to lack of interest or protection of privacy. The majority of men valued anonymity and clearly demarcated a line between sperm donation and fatherhood, which was enforced by not knowing about the donor offspring or recipients.

Tinnitus affects a considerable part of the population and develops into a severe disorder in some sufferers. App-based interventions are able to provide low-threshold, cost-effective, and location-independent care for tinnitus patients. Therefore, we developed a smartphone app combining structured counseling with sound therapy and conducted a pilot study to evaluate treatment compliance and symptom improvement (trial registration: DRKS00030007). Outcome variables were Ecological Momentary Assessment (EMA) measured tinnitus distress and loudness and Tinnitus Handicap Inventory (THI) at baseline and final visit. A multiple-baseline design with a baseline phase (only EMA) followed by an intervention phase (EMA and intervention) was applied. 21 patients with chronic tinnitus (≥ 6 months) were included. Overall compliance differed between modules (EMA usage: 79% of days, structured counseling: 72%, sound therapy: 32%). The THI score improved from baseline to final visit indicating a large effect (Cohens d = 1.1). Tinnitus distress and loudness did not improve significantly from baseline phase to the end of intervention phase. However, 5 of 14 (36%) improved clinically meaningful in tinnitus distress (ΔDistress ≥ 10) and 13 of 18 (72%) in THI score (ΔTHI ≥ 7). The positive relationship between tinnitus distress and loudness weakened over the course of the study. A trend but no level effect for tinnitus distress could be demonstrated by a mixed effect model. The improvement in THI was strongly associated with the improvement scores in EMA of tinnitus distress (r = -0.75; 0.86). These results indicate that app-based structured counseling combined with sound therapy is feasible, has an impact on tinnitus symptoms and reduces distress for several patients. In addition, our data suggest that EMA could be used as a measurement tool to detect changes in tinnitus symptoms in clinical trials as has already been shown in other areas of mental health research. Author summary Tinnitus is the perception of a phantom sound which is generated in the brain. Many people are affected by tinnitus and some suffer severely. Management strategies can effectively reduce suffering of some patients. However, the access towards these treatments is limited due to long distances and lack of trained therapists. Therefore, there is increasing interest whether tinnitus management can be delivered via smartphone. In this study, we evaluated a smartphone application consisting of educational counseling and sound therapy with respect to treatment compliance and symptom improvement. We measured tinnitus symptoms at the beginning of baseline and at the end of intervention using clinical questionnaires, but also during the course of treatment using daily questions which were integrated in the mobile application. The app was used regularly by the patients (sound therapy: 32% of days, structured counseling: 72% of days; tinnitus assessment: 79% of days). Tinnitus handicap improved clinically meaningful for 13 of 18 patients, tinnitus distress for 5 of 14 and tinnitus loudness for 2 of 14. The correlation between tinnitus distress and loudness weakened during the study course. Thus, this study indicates that app-based tinnitus management has an impact on tinnitus symptoms and reduces suffering for several patients.

BackgroundMelanoma survivors are at increased risk of developing a second primary melanoma; however, some report sub-optimal sun behaviors and sunburns. We tested the effectiveness of a wearable device with ultraviolet radiation (UVR)-sensing technology to improve sun behaviors and reduce sunburns in cutaneous melanoma survivors.Materials and methodsWe conducted a randomized controlled trial using Shade 2, a commercially available wrist device that measures UVR. The intervention group received the device and mobile application notifications about their exposure and prompts to use sunscreen. The control group received the device and a separate research mobile application without information about their exposure or notifications. Participants wore the device for 12 weeks and self-reported sun behaviors before, during, and after the intervention. The primary outcome was a composite score of sun protection behaviors at week 12.Results386 participants were randomized (186 control, 182 intervention). Most were female and 5+ years past their first melanoma diagnosis. The average age was 56 years. Most (93%) completed the study, though 40% experienced device issues. No meaningful differences were observed in self-reported sun protection behaviors at week 12 (controls 3.0±0.5 vs. intervention 2.9±0.5, p = 0.06), any sunburn during the intervention period (controls 14.4% vs. intervention 12.7%, p = 0.75), or average daily objective UVR exposure (controls median 87 vs. intervention 83 J/m2, p = 0.43).ConclusionWearing a device that measured and alerted melanoma survivors to UVR exposure did not result in different sun behaviors, exposure, or sunburns relative to controls. The technology needs refinement before further attempts to assess the effectiveness of self-monitoring UVR exposure.Clinical trials registrationNCT03927742.

Influenza B viruses (IBV) are responsible for a considerable part of the burden caused by influenza virus infections. Since their emergence in the 1980s, the Yamagata and Victoria antigenic lineages of influenza B circulate in alternate patterns across the globe. Furthermore, their evolutionary divergence and the appearance of new IBV subclades complicates the prediction of future influenza vaccines compositions. It has been proposed that the addition of the neuraminidase (NA) antigen could potentially induce a broader protection and compensate for hemagglutinin (HA) mismatches in the current vaccines. Here we show that anti-NA and -HA sera against both Victoria and Yamagata lineages have limited inter-lineage cross-reactivity. When transferred to mice prior to infection with a panel of IBVs, anti-NA sera were as potent as anti-HA sera in conferring protection against homologous challenge and, in some cases, conferred superior protection against challenge with heterologous IBV strains.

IntroductionThe provision of maternity services in Australia has been significantly disrupted in response to the COVID-19 pandemic. Many changes were initiated quickly, often with rapid dissemination of information to women. The aim of this study was to better understand what information and messages were circulating regarding COVID-19 and pregnancy in Australia and potential information gaps.MethodsThis study adopted a qualitative approach using social media and interviews. A data analytics tool (TIGER-C19) was used to extract data from social media platforms Reddit and Twitter from June to July 2021 (in the middle of the third COVID-19 wave in Australia). A total of 21 individual semi-structured interviews were conducted with those who were, or had been, pregnant in Australia since March 2020. Social media data were analysis via inductive content analysis and interview data were thematically analysed.ResultsSocial media provided a critical platform for sharing and seeking information, as well as highlighting attitudes of the community towards COVID-19 vaccines in pregnancy. Women interviewed described wanting further information on the risks COVID-19 posed to themselves and their babies, and greater familiarity with the health service during pregnancy, in which they would labour and give birth. Health providers were a trusted source of information. Communication strategies that allowed participants to engage in real-time interactive discussions were preferred. A real or perceived lack of information led participants to turn to informal sources, increasing the potential for exposure to misinformation.ConclusionIt is vital that health services communicate effectively with pregnant women, early and often throughout public health crises, such as the COVID-19 pandemic. This was particularly important during periods of increased restrictions on accessing hospital services. Information and communication strategies need to be clear, consistent, timely and accessible to reduce reliance on informal and potentially inaccurate sources.

Analysis of convalescent plasma derived from individuals has shown that IgG3 has the most important role in binding to SARS-CoV-2 antigens; however, this has not yet been confirmed in large studies, and the link between binding and neutralization has not been confirmed. By analyzing plasma pools consisting of 247–567 individual convalescent donors, we demonstrated the binding of IgG3 and IgM to Spike-1 protein and the receptor-binding domain correlates strongly with viral neutralization in vitro. Furthermore, despite accounting for only approximately 12% of total immunoglobulin mass, collectively IgG3 and IgM account for approximately 80% of the total neutralization. This may have important implications for the development of potent therapies for COVID-19, as it indicates that hyperimmune globulins or convalescent plasma donations with high IgG3 concentrations may be a highly efficacious therapy.

Analysis of convalescent plasma derived from individuals has shown that IgG3 has the most important role in binding to SARS-CoV-2 antigens; however, this has not yet been confirmed in large studies, and the link between binding and neutralization has not been confirmed. By analyzing plasma pools consisting of 247-567 individual convalescent donors, we demonstrated the binding of IgG3 and IgM to Spike-1 protein and the receptor-binding domain correlates strongly with viral neutralization in vitro. Furthermore, despite accounting for only approximately 12% of total immunoglobulin mass, collectively IgG3 and IgM account for approximately 80% of the total neutralization. This may have important implications for the development of potent therapies for COVID-19, as it indicates that hyperimmune globulins or convalescent plasma donations with high IgG3 concentrations may be a highly efficacious therapy.

[This corrects the article DOI: 10.1371/journal.pmed.1004074.].

Background Preterm birth-related complications are the leading cause of death in newborns and children under 5. Health outcomes of preterm newborns can be improved with appropriate use of antenatal corticosteroids (ACSs) to promote fetal lung maturity, tocolytics to delay birth, magnesium sulphate for fetal neuroprotection, and antibiotics for preterm prelabour rupture of membranes. However, there are wide disparities in the rate and consistency in the use of these interventions across settings, which may underlie the differential health outcomes among preterm newborns. We aimed to assess factors (barriers and facilitators) affecting the appropriate use of ACS, tocolytics, magnesium sulphate, and antibiotics to improve preterm birth management. Methods and findings We conducted a mixed-methods systematic review including primary qualitative, quantitative, and mixed-methods studies. We searched MEDLINE, EMBASE, CINAHL, Global Health, and grey literature from inception to 16 May 2022. Eligible studies explored perspectives of women, partners, or community members who experienced preterm birth or were at risk of preterm birth and/or received any of the 4 interventions, health workers providing maternity and newborn care, and other stakeholders involved in maternal care (e.g., facility managers, policymakers). We used an iterative narrative synthesis approach to analysis, assessed methodological limitations using the Mixed Methods Appraisal Tool, and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. Behaviour change models (Theoretical Domains Framework; Capability, Opportunity, and Motivation (COM-B)) were used to map barriers and facilitators affecting appropriate use of these interventions. We included 46 studies from 32 countries, describing factors affecting use of ACS (32/46 studies), tocolytics (13/46 studies), magnesium sulphate (9/46 studies), and antibiotics (5/46 studies). We identified a range of barriers influencing appropriate use of the 4 interventions globally, which include the following: inaccurate gestational age assessment, inconsistent guidelines, varied knowledge, perceived risks and benefits, perceived uncertainties and constraints in administration, confusion around prescribing and administering authority, and inadequate stock, human resources, and labour and newborn care. Women reported hesitancy in accepting interventions, as they typically learned about them during emergencies. Most included studies were from high-income countries (37/46 studies), which may affect the transferability of these findings to low- or middle-income settings. Conclusions In this study, we identified critical factors affecting implementation of 4 interventions to improve preterm birth management globally. Policymakers and implementers can consider these barriers and facilitators when formulating policies and planning implementation or scale-up of these interventions. Study findings can inform clinical preterm birth guidelines and implementation to ensure that barriers are addressed, and enablers are reinforced to ensure these interventions are widely available and appropriately used globally. Rana Islamiah Zahroh and colleagues explore factors influencing appropriate use of interventions for management of women experiencing preterm birth globally. Author summary Why was this study done? Complications from preterm birth are the leading cause of death among newborns and children under age 5. There are 4 interventions (antenatal corticosteroids, magnesium sulphate, tocolytics, and antibiotics) that can improve health outcomes for preterm newborns, but these interventions are not used correctly or consistently across settings. In our research, we explored how and why these 4 interventions are used or not used, in order to help other healthcare providers and families better use them in the future. What did the researchers do and find? We conducted a systematic review, which means we collected and analysed all relevant research studies about what factors (such as barriers or facilitators) might influence whether or not these 4 interventions are used. We found 46 studies, mostly from high-income countries (37 studies), and from the perspectives of women and/or their families (5 studies), healthcare providers (38 studies), or both women and healthcare providers (3 studies). We identified several barriers to appropriate use of the 4 interventions, starting with challenges around accurately assessing gestational age, inconsistent clinical guidelines and protocols, healthcare providers’ variable knowledge of intervention benefits and harms, and system-level challenges around stock-outs of medicine, limited human resources, and substandard labour and newborn care. What do these findings mean? Most preterm birth–related deaths happen in low- or middle-income countries (LMICs), but most of the studies we found were from high-income countries, which means that we need to be cautious in applying these findings to LMICs. Policymakers and researchers can use these findings when developing policies and planning for scaling up of these interventions, in order to ensure equitable distribution and appropriate use of the interventions globally.

BackgroundPreterm birth-related complications are the leading cause of death in newborns and children under 5. Health outcomes of preterm newborns can be improved with appropriate use of antenatal corticosteroids (ACSs) to promote fetal lung maturity, tocolytics to delay birth, magnesium sulphate for fetal neuroprotection, and antibiotics for preterm prelabour rupture of membranes. However, there are wide disparities in the rate and consistency in the use of these interventions across settings, which may underlie the differential health outcomes among preterm newborns. We aimed to assess factors (barriers and facilitators) affecting the appropriate use of ACS, tocolytics, magnesium sulphate, and antibiotics to improve preterm birth management.Methods and findingsWe conducted a mixed-methods systematic review including primary qualitative, quantitative, and mixed-methods studies. We searched MEDLINE, EMBASE, CINAHL, Global Health, and grey literature from inception to 16 May 2022. Eligible studies explored perspectives of women, partners, or community members who experienced preterm birth or were at risk of preterm birth and/or received any of the 4 interventions, health workers providing maternity and newborn care, and other stakeholders involved in maternal care (e.g., facility managers, policymakers). We used an iterative narrative synthesis approach to analysis, assessed methodological limitations using the Mixed Methods Appraisal Tool, and assessed confidence in each qualitative review finding using the GRADE-CERQual approach. Behaviour change models (Theoretical Domains Framework; Capability, Opportunity, and Motivation (COM-B)) were used to map barriers and facilitators affecting appropriate use of these interventions. We included 46 studies from 32 countries, describing factors affecting use of ACS (32/46 studies), tocolytics (13/46 studies), magnesium sulphate (9/46 studies), and antibiotics (5/46 studies). We identified a range of barriers influencing appropriate use of the 4 interventions globally, which include the following: inaccurate gestational age assessment, inconsistent guidelines, varied knowledge, perceived risks and benefits, perceived uncertainties and constraints in administration, confusion around prescribing and administering authority, and inadequate stock, human resources, and labour and newborn care. Women reported hesitancy in accepting interventions, as they typically learned about them during emergencies. Most included studies were from high-income countries (37/46 studies), which may affect the transferability of these findings to low- or middle-income settings.ConclusionsIn this study, we identified critical factors affecting implementation of 4 interventions to improve preterm birth management globally. Policymakers and implementers can consider these barriers and facilitators when formulating policies and planning implementation or scale-up of these interventions. Study findings can inform clinical preterm birth guidelines and implementation to ensure that barriers are addressed, and enablers are reinforced to ensure these interventions are widely available and appropriately used globally.

BackgroundPreeclampsia and eclampsia are a leading cause of global maternal and newborn mortality. Currently, there are few effective medicines that can prevent or treat preeclampsia. Target Product Profiles (TPPs) are important tools for driving new product development by specifying upfront the characteristics that new products should take. Considering the lack of investment and innovation around new medicines for obstetric conditions, we aimed to develop two new TPPs for medicines to prevent and treat preeclampsia.Methods and findingsWe used a multi-methods approach comprised of a literature review, stakeholder interviews, online survey, and public consultation. Following an initial literature review, diverse stakeholders (clinical practice, research, academia, international organizations, funders, consumer representatives) were invited for in-depth interviews and an online international survey, as well as public consultation on draft TPPs. The level of stakeholder agreement with TPPs was assessed, and findings from interviews were synthesised to inform the final TPPs. We performed 23 stakeholder interviews and received 46 survey responses. A high level of agreement was observed in survey results, with 89% of TPP variables reaching consensus (75% agree or strongly agree). Points of discussion were raised around the target population for preeclampsia prevention and treatment, as well as the acceptability of cold-chain storage and routes of administration.ConclusionThere is consensus within the maternal health research community on the parameters that new medicines for preeclampsia prevention and treatment must achieve to meet real-world health needs. These TPPs provide necessary guidance to spur interest, innovation and investment in the development of new medicines to prevent and treat preeclampsia.

Companionship during labour and birth is a critical component of quality maternal and newborn care, resulting in improved care experiences and better birth outcomes. Little is known about the preferences and experiences of companionship in Papua New Guinea (PNG), and how it can be implemented in a culturally appropriate way. The aim of this study was to describe perspectives and experiences of women, their partners and health providers regarding labour and birth companionship, identify enablers and barriers and develop a framework for implementing this intervention in PNG health facilities. A mixed methods study was conducted with five facilities in East New Britain, PNG. Data included 5 facility audits, 30 labour observations and 29 in-depth interviews with women who had recently given birth, partners and maternity care providers. A conceptual framework was developed drawing on existing quality care implementation frameworks. Women and partners wanted companions to be present, whilst health providers had mixed views. Participants described benefits of companionship including encouragement and physical support for women, better communication and advocacy, improved labour outcomes and assistance with workforce issues. Adequate privacy and space constraints were highlighted as key barriers to address. Of the women observed, only 30% of women had a companion present during labour, and 10% had a companion at birth. A conceptual framework was used to highlight the interconnected inputs required at community, facility and provincial health system levels to improve the quality of care. Key elements to address included attitudes towards companionship, the need for education and training and restrictive hospital policies. Supporting women to have their companion of choice present during labour and birth is critical to improving women's experiences of care and improving the quality of maternal and newborn care. In order to provide companionship during labour and birth in PNG, a complex, intersecting, multi-faceted approach is required.

Companionship during labour and birth is a critical component of quality maternal and newborn care, resulting in improved care experiences and better birth outcomes. Little is known about the preferences and experiences of companionship in Papua New Guinea (PNG), and how it can be implemented in a culturally appropriate way. The aim of this study was to describe perspectives and experiences of women, their partners and health providers regarding labour and birth companionship, identify enablers and barriers and develop a framework for implementing this intervention in PNG health facilities. A mixed methods study was conducted with five facilities in East New Britain, PNG. Data included 5 facility audits, 30 labour observations and 29 in-depth interviews with women who had recently given birth, partners and maternity care providers. A conceptual framework was developed drawing on existing quality care implementation frameworks. Women and partners wanted companions to be present, whilst health providers had mixed views. Participants described benefits of companionship including encouragement and physical support for women, better communication and advocacy, improved labour outcomes and assistance with workforce issues. Adequate privacy and space constraints were highlighted as key barriers to address. Of the women observed, only 30% of women had a companion present during labour, and 10% had a companion at birth. A conceptual framework was used to highlight the interconnected inputs required at community, facility and provincial health system levels to improve the quality of care. Key elements to address included attitudes towards companionship, the need for education and training and restrictive hospital policies. Supporting women to have their companion of choice present during labour and birth is critical to improving women’s experiences of care and improving the quality of maternal and newborn care. In order to provide companionship during labour and birth in PNG, a complex, intersecting, multi-faceted approach is required.

Background Preeclampsia and eclampsia are a leading cause of global maternal and newborn mortality. Currently, there are few effective medicines that can prevent or treat preeclampsia. Target Product Profiles (TPPs) are important tools for driving new product development by specifying upfront the characteristics that new products should take. Considering the lack of investment and innovation around new medicines for obstetric conditions, we aimed to develop two new TPPs for medicines to prevent and treat preeclampsia. Methods and findings We used a multi-methods approach comprised of a literature review, stakeholder interviews, online survey, and public consultation. Following an initial literature review, diverse stakeholders (clinical practice, research, academia, international organizations, funders, consumer representatives) were invited for in-depth interviews and an online international survey, as well as public consultation on draft TPPs. The level of stakeholder agreement with TPPs was assessed, and findings from interviews were synthesised to inform the final TPPs. We performed 23 stakeholder interviews and received 46 survey responses. A high level of agreement was observed in survey results, with 89% of TPP variables reaching consensus (75% agree or strongly agree). Points of discussion were raised around the target population for preeclampsia prevention and treatment, as well as the acceptability of cold-chain storage and routes of administration. Conclusion There is consensus within the maternal health research community on the parameters that new medicines for preeclampsia prevention and treatment must achieve to meet real-world health needs. These TPPs provide necessary guidance to spur interest, innovation and investment in the development of new medicines to prevent and treat preeclampsia.

PurposeBrain perfusion imaging is of enormous importance for various neurological diseases. Fast gradient-echo sequences offering flow-related enhancement (FREE) could present a basis to generate perfusion-weighted maps. In this study, we obtained perfusion-weighted maps without contrast media by a previously described postprocessing algorithm from the field of functional lung MRI. At first, the perfusion signal was analyzed in fast low-angle shot (FLASH) and balanced steady-state free precession (bSSFP) sequences. Secondly, perfusion maps were compared to pseudo-continuous arterial spin labeling (pCASL) MRI in a healthy cohort. Thirdly, the feasibility of the new technique was demonstrated in a small selected group of patients with metastases and acute stroke.MethodsOne participant was examined with bSSFP and FLASH sequences at 1.5T and 3T, different flip angles and slice thicknesses. Twenty-five volunteers had bSSFP imaging and pCASL MRI. Three patients with cerebral metastases and one with acute ischemic stroke had bSSFP imaging and were compared to T1 post-contrast images and CT perfusion. Frequency analyses, SNR and perfusion contrast were compared at different flip angles and slice thicknesses. Regional correlations and Sorensen-Dice overlap were calculated in the healthy cohort. Dice overlap of the pathologies in the patient cohort were calculated.ResultsThe bSSFP sequence presented detectable perfusion signal within brain vessel and parenchyma together with superior SNR compared to FLASH. Perfusion contrast and its corticomedullary differentiation increased with flip angle. Mean regional correlation was 0.36 and highly significant between FREE maps and pCASL and grey and white matter Dice match were 72% and 60% in the healthy cohort. Pathologies presented good overlap between FREE perfusion-weighted and T1 post-contrast images.ConclusionThe feasibility of FREE brain perfusion imaging has been shown in a healthy cohort and selected patient cases with brain metastases and acute stroke. The study demonstrates a new approach for non-contrast brain perfusion imaging.

Background Birth order and having at least one sibling are known to be associated with an increased risk for development of overweight. However, there are no studies assessing pre- and postnatal factors for developing overweight within families. Therefore, the present study aimed to analyse the association of the mother’s weight gain during pregnancy, prepregnancy BMI, mother’s age at birth, breastfeeding, age gap between siblings, and physical activity together with sibling-related characteristics on the development of overweight in children and adolescents. Methods Data were obtained from the longitudinal LIFE Child cohort. The study sample included n = 1932 children, stratified into first-born (n = 578), second-born (n = 608), third-or-later-born single-born siblings (n = 162), only children (n = 526), and twin children (n = 58). Children with chronic or syndromic diseases, born prematurely or from mothers with gestational diabetes were excluded. Data were adjusted for multiple children per family using mixed models. Pregnancy weight gain, prepregnancy BMI and mother’s age were considered prenatal co-variates. Postnatal factors included the duration of breastfeeding and the children’s physical activity level. Results Particularly until the onset of puberty, the BMI-SDS differed between single-born siblings, only children and twins, and increased with birth order. Compared to children with siblings, only children exhibited a strong increase in BMI-SDS starting at age nine. A higher age gap between siblings was associated with a higher BMI-SDS in second- and third-or-later-born children. Single-born siblings had the highest rate and duration of breastfeeding. Physical activity was highest in twins and third-or-later-born children and lowest in only children. In a multivariate model, being an only child showed a highly significant association with BMI-SDS. Conclusion The present study demonstrated that siblings had a lower BMI-SDS than only children did. For single-born siblings, the association between birth order and increased BMI-SDS seemed to persist only up to 11 years of age.

Background Patients with Duchenne muscular dystrophy (DMD) adopt compensatory movement patterns as muscles weaken. The Duchenne Video Assessment (DVA) measures patient ease of movement through identification of compensatory movement patterns. The DVA directs caregivers to video record patients performing specific movement tasks at home using a secure mobile application, and DVA-certified physical therapists (PTs) score the videos using scorecards with prespecified compensatory movement criteria. The goal of this study was to develop and refine the DVA scorecards. Methods To develop the initial scorecards, 4 PTs collaboratively created compensatory movement lists for each task, and researchers structured the lists into scorecards. A 2-round modified Delphi process was used to gather expert opinion on the understandability, comprehensiveness, and clinical meaningfulness of the compensatory movements on the scorecards. Eight PTs who had evaluated ≥50 patients with DMD and participated in ≥10 DMD clinical trials were recruited for the panel. In Round 1, panelists evaluated compensatory movement criteria understandability via questionnaire and tested the scorecards. In Round 2, panelists participated in an in-person meeting to discuss areas of disagreement from Round 1 and reach consensus (≥75% agreement) on all revisions to the scorecards. Results During the Round 1 revisions to the scorecards, there were 67 changes (44%) to the wording of 153 original compensatory movement criteria and 3 criteria were removed. During the Round 2 revisions to the scorecards, there were 47 changes (31%) to the wording of 150 compensatory movement criteria, 20 criteria were added, and 30 criteria were removed. The panel reached 100% agreement on all changes made to scorecards during Round 2. Conclusion PTs with extensive experience evaluating patients with DMD confirmed that the compensatory movement criteria included in the DVA scorecards were understandable, comprehensive, and clinically meaningful.

BackgroundTo investigate the effects of B1-shimming and radiofrequency (RF) parallel transmission (pTX) on the visualization and quantification of the degree of stenosis in a coronary artery phantom using 7 Tesla (7 T) magnetic resonance imaging (MRI).MethodsStenosis phantoms with different grades of stenosis (0%, 20%, 40%, 60%, 80%, and 100%; 5 mm inner vessel diameter) were produced using 3D printing (clear resin). Phantoms were imaged with four different concentrations of diluted Gd-DOTA representing established arterial concentrations after intravenous injection in humans. Samples were centrally positioned in a thorax phantom of 30 cm diameter filled with a custom-made liquid featuring dielectric properties of muscle tissue. MRI was performed on a 7 T whole-body system. 2D-gradient-echo sequences were acquired with an 8-channel transmit 16-channel receive (8 Tx / 16 Rx) cardiac array prototype coil with and without pTX mode. Measurements were compared to those obtained with identical scan parameters using a commercially available 1 Tx / 16 Rx single transmit coil (sTX). To assess reproducibility, measurements (n = 15) were repeated at different horizontal angles with respect to the B0-field.ResultsB1-shimming and pTX markedly improved flip angle homogeneity across the thorax phantom yielding a distinctly increased signal-to-noise ratio (SNR) averaged over a whole slice relative to non-manipulated RF fields. Images without B1-shimming showed shading artifacts due to local B1+-field inhomogeneities, which hampered stenosis quantification in severe cases. In contrast, B1-shimming and pTX provided superior image homogeneity. Compared with a conventional sTX coil higher grade stenoses (60% and 80%) were graded significantly (pConclusionsB1-shimming and pTX at 7 T can distinctly improve image homogeneity and therefore provide considerably more accurate MR image analysis, which is beneficial for imaging of small vessel structures.

BackgroundBirth order and having at least one sibling are known to be associated with an increased risk for development of overweight. However, there are no studies assessing pre- and postnatal factors for developing overweight within families. Therefore, the present study aimed to analyse the association of the mother's weight gain during pregnancy, prepregnancy BMI, mother's age at birth, breastfeeding, age gap between siblings, and physical activity together with sibling-related characteristics on the development of overweight in children and adolescents.MethodsData were obtained from the longitudinal LIFE Child cohort. The study sample included n = 1932 children, stratified into first-born (n = 578), second-born (n = 608), third-or-later-born single-born siblings (n = 162), only children (n = 526), and twin children (n = 58). Children with chronic or syndromic diseases, born prematurely or from mothers with gestational diabetes were excluded. Data were adjusted for multiple children per family using mixed models. Pregnancy weight gain, prepregnancy BMI and mother's age were considered prenatal co-variates. Postnatal factors included the duration of breastfeeding and the children's physical activity level.ResultsParticularly until the onset of puberty, the BMI-SDS differed between single-born siblings, only children and twins, and increased with birth order. Compared to children with siblings, only children exhibited a strong increase in BMI-SDS starting at age nine. A higher age gap between siblings was associated with a higher BMI-SDS in second- and third-or-later-born children. Single-born siblings had the highest rate and duration of breastfeeding. Physical activity was highest in twins and third-or-later-born children and lowest in only children. In a multivariate model, being an only child showed a highly significant association with BMI-SDS.ConclusionThe present study demonstrated that siblings had a lower BMI-SDS than only children did. For single-born siblings, the association between birth order and increased BMI-SDS seemed to persist only up to 11 years of age.

Objectives The aim was to evaluate the longitudinal course of motor skills development in children with a view to improve the understanding of intra-individual variance. Previous publications have been based on cross-sectional data or analyzed longitudinal studies in a cross-sectional manner. Design Longitudinal. Year-to-year change. Methods The present study is based on motor function data collected in the LIFE Child study (Germany). The participants (6 to 17 years) completed parts of the motor tests according to the standard of the German Motor Performance Test 6–18 (DMT). For a total of 1653 participants, 4616 motor tests with an annual interval in the period 2011 to 2019 were included in the evaluation. Results We were able to produce gender and age-specific change centiles for the test items standing long jump, jumping sideways, push-ups, stand and reach and balancing walking backwards. Each set of centiles revealed a range of variability in motor development in children and adolescents, with distinct progressive patterns in the different test items and different genders. The supplied tables offer an indication of expected year-to-year change for each test item depending on age and gender. Depending on the test item and the mean age, a deterioration in test results after a one-year interval was observed, despite cross-sectional centiles showing an upward trend. Conclusion We present a user-friendly tool as a way to assess individual dynamic changes in motor development of children and adolescents. In combination with the well-known cross-sectional centiles as baseline, this can be helpful for the scientific evaluation of motor skills tests and can also be used in school settings.

IntroductionThe Australian National COVID-19 Clinical Evidence Taskforce is producing living, evidence-based, national guidelines for treatment of people with COVID-19 which are updated each week. To continually improve the process and outputs of the Taskforce, and inform future living guideline development, we undertook a concurrent process evaluation examining Taskforce activities and experience of team members and stakeholders during the first 5 months of the project.MethodsThe mixed-methods process evaluation consisted of activity and progress audits, an online survey of all Taskforce participants; and semi-structured interviews with key contributors. Data were collected through five, prospective 4-weekly timepoints (beginning first week of May 2020) and three, fortnightly retrospective timepoints (March 23, April 6 and 20). We collected and analysed quantitative and qualitative data.ResultsAn updated version of the guidelines was successfully published every week during the process evaluation. The Taskforce formed in March 2020, with a nominal start date of March 23. The first version of the guideline was published two weeks later and included 10 recommendations. By August 24, in the final round of the process evaluation, the team of 11 staff, working with seven guideline panels and over 200 health decision-makers, had developed 66 recommendations addressing 58 topics. The Taskforce website had received over 200,000 page views. Satisfaction with the work of the Taskforce remained very high (>90% extremely or somewhat satisfied) throughout. Several key strengths, challenges and methods questions for the work of the Taskforce were identified.ConclusionsIn just over 5 months of activity, the National COVID-19 Clinical Evidence Taskforce published 20 weekly updates to the evidence-based national treatment guidelines for COVID-19. This process evaluation identified several factors that enabled this achievement (e.g. an extant skill base in evidence review and convening), along with challenges that needed to be overcome (e.g. managing workloads, structure and governance) and methods questions (pace of updating, and thresholds for inclusion of evidence) which may be useful considerations for other living guidelines projects. An impact evaluation is also being conducted separately to examine awareness, acceptance and use of the guidelines.

Shear stress is extremely important for endothelial cell (EC) function. The popularity of 6-well plates on orbital shakers to impose shear stress on ECs has increased among biologists due to their low cost and simplicity. One characteristic of such a platform is the heterogeneous flow profile within a well. While cells in the periphery are exposed to a laminar and high-velocity pulsatile flow that mimics physiological conditions, the flow in the center is disturbed and imposes low shear stress on the cells, which is characteristic of atheroprone regions. For studies where such heterogeneity is not desired, we present a simple cell-patterning technique to selectively prevent cell growth in the center of the well and facilitate the exclusive collection and analysis of cells in the periphery. This guarantees that cell phenotypes will not be influenced by secreted factors from cells exposed to other shear profiles nor that interesting results are obscured by mixing cells from different regions. We also present a multi-staining platform that compartmentalizes each well into 5 smaller independent regions: four at the periphery and one in the center. This is ideal for studies that aim to grow cells on the whole well surface, for comparison with previous work and minimal interference in the cell culture, but require screening of markers by immunostaining afterwards. It allows to compare different regions of the well, reduces antibody-related costs, and allows the exploration of multiple markers essential for high-content screening of cell response. By increasing the versatility of the 6-well plate on an orbital shaker system, we hope that these two solutions motivate biologists to pursue studies on EC mechanobiology and beyond.

Influenza neuraminidase (NA) is implicated in various aspects of the virus replication cycle and therefore is an attractive target for vaccination and antiviral strategies. Here we investigated the potential for NA-specific antibodies to interfere with A(H1N1)pdm09 replication in primary human airway epithelial (HAE) cells. Mouse polyclonal anti-NA sera and a monoclonal antibody could block initial viral entry into HAE cells as well as egress from the cell surface. NA-specific polyclonal serum also reduced virus replication across multiple rounds of infection. Restriction of virus entry correlated with the ability of the serum or monoclonal antibody to mediate neuraminidase inhibition (NI). Finally, human sera with NI activity against the N1 of A(H1N1)pdm09 could decrease H6N1 virus infection of HAE cells, highlighting the potential contribution of anti-NA antibodies in the control of influenza virus infection in humans.

Numerous metallurgical and materials science applications depend on quantitative atomic-scale characterizations of environmentally-sensitive materials and their transient states. Studying the effect upon materials subjected to thermochemical treatments in specific gaseous atmospheres is of central importance for specifically studying a material’s resistance to certain oxidative or hydrogen environments. It is also important for investigating catalytic materials, direct reduction of an oxide, particular surface science reactions or nanoparticle fabrication routes. This manuscript realizes such experimental protocols upon a thermochemical reaction chamber called the "Reacthub" and allows for transferring treated materials under cryogenic & ultrahigh vacuum (UHV) workflow conditions for characterisation by either atom probe or scanning Xe+/electron microscopies. Two examples are discussed in the present study. One protocol was in the deuterium gas charging (25 kPa D2 at 200°C) of a high-manganese twinning-induced-plasticity (TWIP) steel and characterization of the ingress and trapping of hydrogen at various features (grain boundaries in particular) in efforts to relate this to the steel’s hydrogen embrittlement susceptibility. Deuterium was successfully detected after gas charging but most contrast originated from the complex ion FeOD+ signal and the feature may be an artefact. The second example considered the direct deuterium reduction (5 kPa D2 at 700°C) of a single crystal wüstite (FeO) sample, demonstrating that under a standard thermochemical treatment causes rapid reduction upon the nanoscale. In each case, further studies are required for complete confidence about these phenomena, but these experiments successfully demonstrate that how an ex-situ thermochemical treatment can be realised that captures environmentally-sensitive transient states that can be analysed by atomic-scale by atom probe microscope.

Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the likelihood of receiving a diagnosis when fetal structural anomalies are identified. However, some parents will receive uncertain results such as variants of uncertain significance and secondary findings. We aimed to develop a set of attributes and associated levels for a discrete-choice experiment (DCE) that will examine parents' preferences for tests that may reveal uncertain test results. A two phase mixed-methods approach was used to develop attributes for the DCE. In Phase 1, a "long list" of candidate attributes were identified via two approaches: 1) a systematic review of the literature around parental experiences of uncertainty following prenatal testing; 2) 16 semi-structured interviews with parents who had experienced uncertainty during pregnancy and 25 health professionals who return uncertain prenatal results. In Phase 2, a quantitative scoring exercise with parents prioritised the candidate attributes. Clinically appropriate levels for each attribute were then developed. A final set of five attributes and levels were identified: likelihood of getting a result, reporting of variants of uncertain significance, reporting of secondary findings, time taken to receive results, and who tells you about your result. These attributes will be used in an international DCE study to investigate preferences and differences across countries. This research will inform best practice for professionals supporting parents to manage uncertainty in the prenatal setting.

Influenza neuraminidase (NA) is implicated in various aspects of the virus replication cycle and therefore is an attractive target for vaccination and antiviral strategies. Here we investigated the potential for NA-specific antibodies to interfere with A(H1N1)pdm09 replication in primary human airway epithelial (HAE) cells. Mouse polyclonal anti-NA sera and a monoclonal antibody could block initial viral entry into HAE cells as well as egress from the cell surface. NA-specific polyclonal serum also reduced virus replication across multiple rounds of infection. Restriction of virus entry correlated with the ability of the serum or monoclonal antibody to mediate neuraminidase inhibition (NI). Finally, human sera with NI activity against the N1 of A(H1N1)pdm09 could decrease H6N1 virus infection of HAE cells, highlighting the potential contribution of anti-NA antibodies in the control of influenza virus infection in humans.

ObjectivesThe aim was to evaluate the longitudinal course of motor skills development in children with a view to improve the understanding of intra-individual variance. Previous publications have been based on cross-sectional data or analyzed longitudinal studies in a cross-sectional manner.DesignLongitudinal. Year-to-year change.MethodsThe present study is based on motor function data collected in the LIFE Child study (Germany). The participants (6 to 17 years) completed parts of the motor tests according to the standard of the German Motor Performance Test 6-18 (DMT). For a total of 1653 participants, 4616 motor tests with an annual interval in the period 2011 to 2019 were included in the evaluation.ResultsWe were able to produce gender and age-specific change centiles for the test items standing long jump, jumping sideways, push-ups, stand and reach and balancing walking backwards. Each set of centiles revealed a range of variability in motor development in children and adolescents, with distinct progressive patterns in the different test items and different genders. The supplied tables offer an indication of expected year-to-year change for each test item depending on age and gender. Depending on the test item and the mean age, a deterioration in test results after a one-year interval was observed, despite cross-sectional centiles showing an upward trend.ConclusionWe present a user-friendly tool as a way to assess individual dynamic changes in motor development of children and adolescents. In combination with the well-known cross-sectional centiles as baseline, this can be helpful for the scientific evaluation of motor skills tests and can also be used in school settings.

Shear stress is extremely important for endothelial cell (EC) function. The popularity of 6-well plates on orbital shakers to impose shear stress on ECs has increased among biologists due to their low cost and simplicity. One characteristic of such a platform is the heterogeneous flow profile within a well. While cells in the periphery are exposed to a laminar and high-velocity pulsatile flow that mimics physiological conditions, the flow in the center is disturbed and imposes low shear stress on the cells, which is characteristic of atheroprone regions. For studies where such heterogeneity is not desired, we present a simple cell-patterning technique to selectively prevent cell growth in the center of the well and facilitate the exclusive collection and analysis of cells in the periphery. This guarantees that cell phenotypes will not be influenced by secreted factors from cells exposed to other shear profiles nor that interesting results are obscured by mixing cells from different regions. We also present a multi-staining platform that compartmentalizes each well into 5 smaller independent regions: four at the periphery and one in the center. This is ideal for studies that aim to grow cells on the whole well surface, for comparison with previous work and minimal interference in the cell culture, but require screening of markers by immunostaining afterwards. It allows to compare different regions of the well, reduces antibody-related costs, and allows the exploration of multiple markers essential for high-content screening of cell response. By increasing the versatility of the 6-well plate on an orbital shaker system, we hope that these two solutions motivate biologists to pursue studies on EC mechanobiology and beyond.