Developments in the Design, Conduct, and Reporting of Child Health Trials.

To identify priority areas to improve the design, conduct, and reporting of pediatric clinical trials, the international expert network, Standards for Research (StaR) in Child Health, was assembled and published the first 6 Standards in Pediatrics in 2012. After a recent review summarizing the 247 publications by StaR Child Health authors that highlight research practices that add value and reduce research "waste," the current review assesses the progress in key child health trial methods areas: consent and recruitment, containing risk of bias, roles of data monitoring committees, appropriate sample size calculations, outcome selection and measurement, and age groups for pediatric trials. Although meaningful change has occurred within the child health research ecosystem, measurable progress is still disappointingly slow. In this context, we identify and review emerging trends that will advance the agenda of increased clinical usefulness of pediatric trials, including patient and public engagement, Bayesian statistical approaches, adaptive designs, and platform trials. We explore how implementation science approaches could be applied to effect measurable improvements in the design, conducted, and reporting of child health research.

Prospective randomized trial comparing relapse rates in dogs with steroid-responsive meningitis-arteritis treated with a 6-week or 6-month prednisolone protocol.

BACKGROUND: Traditionally, 6-month courses of prednisolone are used to treat steroid-responsive meningitis-arteritis (SRMA), but this medication is associated with adverse effects that can lead to poor quality of life. HYPOTHESIS/OBJECTIVES: Resolution of clinical signs and rate of relapse of SRMA would not be significantly different between a 6-month prednisolone protocol and a 6-week protocol. ANIMALS: Forty-four hospital cases from multiple referral centers in the United Kingdom (2015-2019). Twenty of 44 were treated with the 6-month protocol and 24/44 with the 6-week protocol. METHODS: Prospective, randomized trial with 12-month follow-up. The same prednisolone protocol reinitiated in the event of relapse. Analysis of relapses with binary logistic and Poisson regression modeling. RESULTS: All cases responded to their treatment protocol. Relapses occurred in 6/20 (30%) of the 6-month protocol and 9/24 (38%) of the 6-week protocol. There was no statistical difference in the incidence risk of at least 1 relapse between the 2 groups (odds ratio = 1.40; 95% confidence interval [CI], 0.40-4.96, P = 0.60). Among the 15 dogs that relapsed, 10/15 (67%) relapsed once, 3/15 (20%) relapsed twice, and 2/15 (13%) relapsed 3 times. No statistical difference was detected in the incidence rate ratio (IRR) of total relapse events between the 2 groups (IRR = 1.46; 95% CI, 0.61-3.48; P = 0.40). CONCLUSIONS AND CLINICAL IMPORTANCE: "Short" 6-week prednisolone protocols could be used to treat SRMA, thereby presumably reducing the duration and severity of prednisolone's adverse effects.

Understanding the Kinematic Profile of 2 Underwater Pullout Breaststroke Techniques.

PURPOSE: To compare the kinematic profile of 2 underwater pullout breaststroke techniques. METHODS: Sixteen swimmers (9 men, 20.67 [2.71] y old; 7 women, 18.86 [0.83] y old) performed 3 × 25-m breaststroke using 2 pullout breaststroke techniques: Fly-Kick first and Combined. A speedometer was used to assess the peak and the mean velocity during the glide, propulsion, and recovery phases of both techniques, as well as for the total underwater sequence. The underwater distance was retrieved from video footage and was considered for each pullout technique. The range of motion of the knee during the fly-kick was also retrieved, and the time to complete the 25 m was considered the performance outcome, accompanied by the mean velocity, stroke rate, stroke length, and stroke index. RESULTS: Velocity-time series showed different profiles between pullout techniques (P ≤ .05) mostly in the glide and propulsion phases for males and females, respectively. The mean velocity of 25 m was shown to be greater in females when using the Fly-Kick first technique (P = .05, d = 0.36). Greater values in total underwater distance and knee range of motion were also observed for this technique in both cohorts. Conclusions: Female swimmers presented a higher performance when using the Fly-Kick first technique. Different kinematic profiles arise when swimmers use different underwater pullout techniques where the Fly-Kick first may allow them to reach higher kinematical standard.

Simulation-based economic evaluation of the Wolbachia method in Brazil: a cost-effective strategy for dengue control.

Background: Dengue virus (DENV) is an arbovirus transmitted by Aedes aegypti mosquitoes, which can cause severe conditions such as hemorrhagic fever and dengue shock syndrome. These conditions are associated with adverse social, clinical, and economic consequences in Brazil. Herein, the Wolbachia mosquito replacement method is a promising dengue control strategy. Methods: We estimated the economic impact of implementing the Wolbachia mosquito replacement method in seven Brazilian cities. A mathematical microsimulation model tracked nearly 23 million inhabitants over a 20-year period, considering the transitions between five different health states (susceptible, inapparent, outpatient, hospitalised and death). Direct costs included local dengue control programs, Wolbachia implementation and dengue care. Indirect costs related to death and productivity loss, as well as disability-adjusted life-years (DALY) averted were also considered. Findings: Without Wolbachia, the model projected 1,762,688 reported dengue cases over 20 years. Implementing the Wolbachia method would avert at least 1,295,566 dengue cases, resulting in lower costs and greater effectiveness in all simulated cities. On average, for every 1000 inhabitants followed for 20 years, the Wolbachia method yielded a cost difference of USD 538,233.68 (BRL 2,691,168.40) and averted 5.56 DALYs. Net monetary benefits (NMB) were positive in all seven cities, ranging from USD 110.72 (BRL 553.59) to USD 1399.19 (BRL 6995.95) per inhabitant. Alternative scenarios have also shown a favourable return on investment with a positive benefit-cost ratio (BCR). Interpretation: Wolbachia is likely a cost-effective strategy in the Brazilian context, consistent with international studies. Sensitivity analysis and alternative scenarios confirmed the robustness of the results. Funding: This study was funded by the Wellcome Trust under a grant (224459/Z/21/Z).

Introducing Isotòpia: A stable isotope database for Classical Antiquity.

We present Isotòpia, an open-access database compiling over 36,000 stable isotope measurements (δ13C, δ15N, δ18O, δ34S, 87Sr/86Sr, 206Pb/204Pb, 207Pb/204Pb, 208Pb/204Pb, 207Pb/206Pb, and 208Pb/206Pb) on human, animal, and plant bioarchaeological remains dating to Classical Antiquity (approximately 800 BCE - 500 CE). These were recovered from different European regions, particularly from the Mediterranean. Isotòpia provides a comprehensive characterisation of the isotopic data, encompassing various historical, archaeological, biological, and environmental variables. Isotòpia is a resource for meta-analytical research of past human activities and paleoenvironments. The database highlights data gaps in isotopic classical archaeology, such as the limited number of isotopic measurements available for plants and animals, limited number of studies on spatial mobility, and spatial heterogeneity of isotopic research. As such, we emphasise the necessity to address and fill these gaps in order to unlock the reuse potential of this database.

Does Swimming Exercise Impair Bone Health? A Systematic Review and Meta-Analysis Comparing the Evidence in Humans and Rodent Models.

BACKGROUND: The effect of swimming on bone health remains unclear, namely due to discrepant findings between studies in humans and animal models. OBJECTIVE: The aim of this systematic review and meta-analysis is to identify the available evidence on the effects of swimming on bone mass, geometry and microarchitecture at the lumbar spine, femur and tibia in both humans and rodent animal models. METHODS: The study followed PRISMA guidelines and was registered at PROSPERO (CRD4202236347 and CRD42022363714 for human and animal studies). Two different systematic literature searches were conducted in PubMed, Scopus and Web of Science, retrieving 36 and 16 reports for humans and animal models, respectively. RESULTS: In humans, areal bone mineral density (aBMD) was similar between swimmers and non-athletic controls at the lumbar spine, hip and femoral neck. Swimmers' tibia diaphysis showed a higher cross-sectional area but lower cortical thickness. Inconsistent findings at the femoral neck cortical thickness were found. Due to the small number of studies, trabecular microarchitecture in human swimmers was not assessed. In rodent models, aBMD was found to be lower at the tibia, but similar at the femur. Inconsistent findings in femur diaphysis cross-sectional area were observed. No differences in femur and tibia trabecular microarchitecture were found. CONCLUSION: Swimming seems to affect bone health differently according to anatomical region. Studies in both humans and rodent models suggest that tibia cortical bone is negatively affected by swimming. There was no evidence of a negative effect of swimming on other bone regions, both in humans and animal models.

Harmonizing Quality Improvement Metrics Across Global Trial Networks to Advance Paediatric Clinical Trials Delivery.

BACKGROUND: Despite global efforts to improve paediatric clinical trials, significant delays continue in paediatric drug approvals. Collaboration between research networks is needed to address these delays. This paper is a first step to promote interoperability between paediatric networks from different jurisdictions by comparing drivers for, and content of, metrics about clinical trial conduct. METHODS: Three paediatric networks, Institute for Advanced Clinical Trials for Children, the Maternal Infant Child and Youth Research Network and conect4children, have each developed metrics to address delays and create efficiencies. We identified the methodology by which each network identified metrics, described the metrics of each network, and mapped consistency to come to consensus about core metrics that networks could share. RESULTS: Metric selection was driven by site quality improvement in one network (11 metrics), by network performance in one network (13 metrics), and by both in one network (five metrics). The domains of metrics were research capacity/capability, site identification/feasibility, trial start-up, and recruitment/enrolment. The network driven by site quality improvement did not have indicators for capacity/capability or identification/feasibility. Fifteen metrics for trial start up and conduct were identified. Metrics related to site approvals were found in all three networks. The themes for metrics can inform the development of 'shared' metrics. CONCLUSION: We found disparity in drivers, methodology and metrics. Tackling this disparity will result in a unified approach to addressing delays in paediatric drug approvals. Collaborative work to define inter-operable metrics globally is outlined.

Tracking in situ checkpoint inhibitor-bound target T cells in patients with checkpoint-induced colitis.

The success of checkpoint inhibitors (CPIs) for cancer has been tempered by immune-related adverse effects including colitis. CPI-induced colitis is hallmarked by expansion of resident mucosal IFNγ cytotoxic CD8+ T cells, but how these arise is unclear. Here, we track CPI-bound T cells in intestinal tissue using multimodal single-cell and subcellular spatial transcriptomics (ST). Target occupancy was increased in inflamed tissue, with drug-bound T cells located in distinct microdomains distinguished by specific intercellular signaling and transcriptional gradients. CPI-bound cells were largely CD4+ T cells, including enrichment in CPI-bound peripheral helper, follicular helper, and regulatory T cells. IFNγ CD8+ T cells emerged from both tissue-resident memory (TRM) and peripheral populations, displayed more restricted target occupancy profiles, and co-localized with damaged epithelial microdomains lacking effective regulatory cues. Our multimodal analysis identifies causal pathways and constitutes a resource to inform novel preventive strategies.

Archaeological and molecular evidence for ancient chickens in Central Asia.

The origins and dispersal of the chicken across the ancient world remains one of the most enigmatic questions regarding Eurasian domesticated animals. The lack of agreement concerning timing and centers of origin is due to issues with morphological identifications, a lack of direct dating, and poor preservation of thin, brittle bird bones. Here we show that chickens were widely raised across southern Central Asia from the fourth century BC through medieval periods, likely dispersing along the ancient Silk Road. We present archaeological and molecular evidence for the raising of chickens for egg production, based on material from 12 different archaeological sites spanning a millennium and a half. These eggshells were recovered in high abundance at all of these sites, suggesting that chickens may have been an important part of the overall diet and that chickens may have lost seasonal egg-laying.

South American Archaeological Isotopic Database, a regional-scale multi-isotope data compendium for research.

The South American Archaeological Isotopic Database (SAAID) is a comprehensive open-access resource that aggregates all available bioarchaeological stable and radiogenic isotope measurements, encompassing data from human individuals, animals, and plants across South America. Resulting from a collaborative effort of scholars who work with stable isotopes in this region, SAAID contains 53,781 isotopic measurements across 24,507 entries from individuals/specimens spanning over 12,000 years. SAAID includes valuable contextual information on archaeological samples and respective sites, such as chronology, geographical region, biome, and spatial coordinates, biological details like estimated sex and age for human individuals, and taxonomic description for fauna and flora. SAAID is hosted at the PACHAMAMA community within the Pandora data platform and the CORA repository to facilitate easy access. Because of its rich data structure, SAAID is particularly well-suited for conducting spatiotemporal meta-analyses. It serves as a valuable tool for addressing a variety of research topics, including the spread, adoption, and consumption intensification of food items, paleo-environmental reconstruction, as well as the exploration of mobility patterns across extensive geographic regions.

The Caribbean and Mesoamerica Biogeochemical Isotope Overview (CAMBIO).

The Caribbean & Mesoamerica Biogeochemical Isotope Overview (CAMBIO) is an archaeological data community designed to integrate published biogeochemical data from the Caribbean, Mesoamerica, and southern Central America to address questions about dynamic interactions among humans, animals, and the environment in the region over the past 10,000 years. Here we present the CAMBIO human dataset, which consists of more than 16,000 isotopic measurements from human skeletal tissue samples (δ13C, δ15N, δ34S, δ18O, 87Sr/86Sr, 206/204Pb, 207/204Pb, 208/204Pb, 207/206Pb) from 290 archaeological sites dating between 7000 BC to modern times. The open-access dataset also includes detailed chronological, contextual, and laboratory/sample preparation information for each measurement. The collated data are deposited on the open-access CAMBIO data community via the Pandora Initiative data platform ( https://pandoradata.earth/organization/cambio ).

Training zones in competitive swimming: a biophysical approach.

Since swimming performance depends on both physical conditioning and technical proficiency, training zones should be built based on physiology and biomechanics inputs to dispose of structured and effective training programs. This paper presents a zone-based swimming training, supported by the oxygen uptake (V˙O2) kinetics at low, moderate, heavy, severe and extreme intensities concurrently with lactate and heart rate values. Since technique is vital for efficiently moving through the water, upper limbs frequency and length should also be targeted during the workouts. The index of coordination was also added to our proposal since upper limbs synchronization is a key technical factor. To better establish and characterize a wide range of swimming intensities, the training methods and corresponding contents that better fit each training zone will be suggested. It will be shown that when under/at the anaerobic threshold (at low-to-moderate intensities), swimmers are at homeostasis and can maintain stable internal and external load indicators. However, above that boundary (at heavy and severe intensities), the physiological stable state is no longer observed and the anaerobic metabolism starts contributing significantly, with a technical degradation being more evident when performing near/at the V˙O2max intensity. Then, when performing above aerobic power, on typical anaerobic intensities, V˙O2 kinetics presents a very evident fast rise, ending abruptly due to exhaustion caused by muscle acidosis. This overall knowledge allows advancing toward more objective training programs and highlights the importance of systematic training control and swimmers' evaluation and advice.

First evidence for human occupation of a lava tube in Arabia: The archaeology of Umm Jirsan Cave and its surroundings, northern Saudi Arabia.

Recent advances in interdisciplinary archaeological research in Arabia have focused on the evolution and historical development of regional human populations as well as the diverse patterns of cultural change, migration, and adaptations to environmental fluctuations. Obtaining a comprehensive understanding of cultural developments such as the emergence and lifeways of Neolithic groups has been hindered by the limited preservation of stratified archaeological assemblages and organic remains, a common challenge in arid environments. Underground settings like caves and lava tubes, which are prevalent in Arabia but which have seen limited scientific exploration, offer promising opportunities for addressing these issues. Here, we report on an archaeological excavation and a related survey at and around Umm Jirsan lava tube in the Harrat Khaybar, north-western Saudi Arabia. Our results reveal repeated phases of human occupation of the site ranging from at least the Neolithic through to the Chalcolithic/Bronze Age. Pastoralist use of the lava tube and surrounding landscape is attested in rock art and faunal records, suggesting that Umm Jirsan was situated along a pastoral route linking key oases. Isotopic data indicates that herbivores primarily grazed on wild grasses and shrubs rather than being provided with fodder, while humans had a diet consistently high in protein but with increasing consumption of C3 plants through-time, perhaps related to the emergence of oasis agriculture. While underground and naturally sheltered localities are globally prominent in archaeology and Quaternary science, our work represents the first such combined records for Saudi Arabia and highlight the potential for interdisciplinary studies in caves and lava tubes.

Effect of experimentally induced muscle pain on neuromuscular control of force production.

PURPOSE: Neural and peripheral effects of induced muscle pain on explosive force production were investigated. METHODS: Nine participants performed two maximal, six explosive, and six electrical stimulations induced (twitches and octets) isometric knee extensions before and after (15 min of rest) receiving an intramuscular injection of hypertonic saline (pain inducer) or isotonic (placebo) infusions in two laboratory visits separated by 7 days. RESULTS: It was observed a reduction of peak torque production in maximal voluntary contraction in both conditions (9.3 and 3.3% for pain and placebo, respectively) and in the rate of torque development in placebo (7%). There was an increase in the rate of torque development for twitch and octets (10.5 and 15.8%, respectively) in the pain condition and peak torque for twitch (12%) in both conditions (as did the total rate of torque development for octets). CONCLUSION: Force production decreases and increases during voluntary and involuntary contractions, respectively, suggesting that acute pain impairs force production via central mechanisms.

Proximity proteomics reveals UCH-L1 as an essential regulator of NLRP3-mediated IL-1ß production in human macrophages and microglia.

Activation of the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome complex is an essential innate immune signaling mechanism. To reveal how human NLRP3 inflammasome assembly and activation are controlled, in particular by components of the ubiquitin system, proximity labeling, affinity purification, and RNAi screening approaches were performed. Our study provides an intricate time-resolved molecular map of different phases of NLRP3 inflammasome activation. Also, we show that ubiquitin C-terminal hydrolase 1 (UCH-L1) interacts with the NACHT domain of NLRP3. Downregulation of UCH-L1 decreases pro-interleukin-1ß (IL-1ß) levels. UCH-L1 chemical inhibition with small molecules interfered with NLRP3 puncta formation and ASC oligomerization, leading to altered IL-1ß cleavage and secretion, particularly in microglia cells, which exhibited elevated UCH-L1 expression as compared to monocytes/macrophages. Altogether, we profiled NLRP3 inflammasome activation dynamics and highlight UCH-L1 as an important modulator of NLRP3-mediated IL-1ß production, suggesting that a pharmacological inhibitor of UCH-L1 may decrease inflammation-associated pathologies.

Increasing obsidian diversity during the Chalcolithic Period at Yeghegis-1 Rockshelter (Armenia) reveals shifts in land use and social networks.

The newly excavated rockshelter of Yeghegis-1 in Armenia reflects an occupation of five centuries, as attested by radiocarbon dates from ∼ 4100 to 4000 cal BCE in the lowest layer to ∼ 3600-3500 cal BCE at the top. It is a partially collapsed cave in which pastoralists, we hypothesize, wintered with their herds. The stone tool assemblage is predominantly obsidian (92.1%), despite the shelter being > 60 km on foot from the nearest sources. We use obsidian sourcing to investigate two purported trends in the Southern Caucasus during the Chalcolithic Period: (1) occupation of more varied high-altitude environments and (2) more expansive social networks. Our data show both trends were dynamic phenomena. There was a greater balance in use of the nearest pasturelands over time, perhaps linked to risk management and/or resource sustainability. During later occupations, artifacts from distant sources reveal more extensive connections. This increase in connectivity likely played a central role in the shifts in societal complexity that gave rise to widely shared material culture throughout the Armenian Highlands around the start of the Early Bronze Age. In such a model, greater social connectivity becomes a key mechanism for, rather than a product of, the spread of cultural and/or technological innovations.

Economic evaluations of medical devices in paediatrics: a systematic review and a quality appraisal of the literature.

BACKGROUND: Although economic evaluations (EEs) have been increasingly applied to medical devices, little discussion has been conducted on how the different health realities of specific populations may impact the application of methods and the ensuing results. This is particularly relevant for pediatric populations, as most EEs on devices are conducted in adults, with specific aspects related to the uniqueness of child health often being overlooked. This study provides a review of the published EEs on devices used in paediatrics, assessing the quality of reporting, and summarising methodological challenges. METHODS: A systematic literature search was performed to identify peer-reviewed publications on the economic value of devices used in paediatrics in the form of full EEs (comparing both costs and consequences of two or more devices). After the removal of duplicates, article titles and abstracts were screened. The remaining full-text articles were retrieved and assessed for inclusion. In-vitro diagnostic devices were not considered in this review. Study descriptive and methodological characteristics were extracted using a structured template. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 checklist was used to assess the quality of reporting. A narrative synthesis of the results was conducted followed by a critical discussion on the main challenges found in the literature. RESULTS: 39 full EEs were eligible for review. Most studies were conducted in high-income countries (67%) and focused on high-risk therapeutic devices (72%). Studies comprised 25 cost-utility analyses, 13 cost-effectiveness analyses and 1 cost-benefit analysis. Most of the studies considered a lifetime horizon (41%) and a health system perspective (36%). Compliance with the CHEERS 2022 items varied among the studies. CONCLUSIONS: Despite the scant body of evidence on EEs focusing on devices in paediatrics results highlight the need to improve the quality of reporting and advance methods that can explicitly incorporate the multiple impacts related to the use of devices with distinct characteristics, as well as consider specific child health realities. The design of innovative participatory approaches and instruments for measuring outcomes meaningful to children and their families should be sought in future research.

Antibody-Drug Conjugates in the Treatment of Genitourinary Cancers: An Updated Review of Data.

The treatment landscape of genitourinary cancers has significantly evolved over the past few years. Renal cell carcinoma, bladder cancer, and prostate cancer are the most common genitourinary malignancies. Recent advancements have produced new targeted therapies, particularly antibody-drug conjugates (ADCs), due to a better understanding of the underlying oncogenic factors and molecular mechanisms involved. ADCs function as a 'drug delivery into the tumor' system. They are composed of an antigen-directed antibody linked to a cytotoxic drug that releases cytotoxic components after binding to the tumor cell's surface antigen. ADCs have been proven to be extremely promising in the treatment of several cancer types. For GU cancers, this novel treatment has only benefited patients with metastatic urothelial cancer (mUC). The rest of the GU cancer paradigm does not have any FDA-approved ADC treatment options available yet. In this study, we have thoroughly completed a narrative review of the current literature and summarized preclinical studies and clinical trials that evaluated the utility, activity, and toxicity of ADCs in GU cancers, the prospects of ADC development, and the ongoing clinical trials. Prospective clinical trials, retrospective studies, case reports, and scoping reviews were included.

Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity.

Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.