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.

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.

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 ).

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.

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.

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.

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.

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.

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.

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.

Surgical Outcomes of Laminectomy, Durotomy and a Non-Synthetic Dura Substitute Application in Ten Dogs with a Spinal Subarachnoid Diverticulum.

This retrospective study aimed to report the surgical treatment and outcomes of laminectomies followed by durotomy and the application of a non-synthetic collagen matrix dura substitute (DurepairTM) in ten dogs with a spinal subarachnoid diverticulum (SAD). The medical records of these ten client-owned dogs with SAD diagnosed by magnetic resonance imaging (MRI) were reviewed. All patients had chronic and progressive deficits. At presentation, common neurological signs were proprioceptive ataxia, ambulatory spastic paraparesis or tetraparesis, and faecal incontinence. Dorsal thoracolumbar laminectomy was performed in eight dogs; one dog underwent cervical dorsolateral laminectomy, and one patient had thoracic hemilaminectomy. Laminectomies were followed by durotomy, allowing the dissection of the pia-arachnoid adhesions. A rectangular patch of a non-synthetic dura substitute was applied as an onlay graft over the durotomy site before routine closure. Proprioceptive ataxia, paraparesis, and tetraparesis improved in all patients. Faecal incontinence in one patient resolved postoperatively. Laminectomy, durotomy, and the application of a non-synthetic dura substitute was a safe procedure facilitating postoperative improvement over a long-term follow-up period (from 9 to 40 months).

Analysis of guideline recommendations for treatment of asthma exacerbations in children: a Pediatric Emergency Research Networks (PERN) study.

RATIONALE: There is significant practice variation in acute paediatric asthma, particularly severe exacerbations. It is unknown whether this is due to differences in clinical guidelines. OBJECTIVES: To describe and compare the content and quality of clinical guidelines for the management of acute exacerbations of asthma in children between geographic regions. METHODS: Observational study of guidelines for the management of acute paediatric asthma from institutions across a global collaboration of six regional paediatric emergency research networks. MEASUREMENTS AND MAIN RESULTS: 158 guidelines were identified. Half provided recommendations for at least two age groups, and most guidelines provided treatment recommendations according to asthma severity.There were consistent recommendations for the use of inhaled short-acting beta-agonists and systemic corticosteroids. Inhaled anticholinergic therapy was recommended in most guidelines for severe and critical asthma, but there were inconsistent recommendations for its use in mild and moderate exacerbations. Other inhaled therapies such as helium-oxygen mixture (Heliox) and nebulised magnesium were inconsistently recommended for severe and critical illness.Parenteral bronchodilator therapy and epinephrine were mostly reserved for severe and critical asthma, with intravenous magnesium most recommended. There were regional differences in the use of other parenteral bronchodilators, particularly aminophylline.Guideline quality assessment identified high ratings for clarity of presentation, scope and purpose, but low ratings for stakeholder involvement, rigour of development, applicability and editorial independence. CONCLUSIONS: Current guidelines for the management of acute paediatric asthma exacerbations have substantial deficits in important quality domains and provide limited and inconsistent guidance for severe exacerbations.

Addressing controversial areas in the management of advanced prostate cancer in Canada Areas of consensus and controversy from the third Canadian consensus forum.

INTRODUCTION: The management of prostate cancer (PCa) is rapidly evolving. Treatment and diagnostic options grow annually, however, high-level evidence for the use of new therapeutics and diagnostics is lacking. In November 2022, the Genitourinary Research Consortium held its 3rd Canadian Consensus Forum (CCF3) to provide guidance on key controversial areas for management of PCa. METHODS: A steering committee of eight multidisciplinary physicians identified topics for discussion and adapted questions from the Advanced Prostate Cancer Consensus Conference 2022 for CCF3. Questions focused on management of metastatic castration-sensitive prostate cancer (mCSPC); use of novel imaging, germline testing, and genomic profiling; and areas of non-consensus from CCF2. Fifty-eight questions were voted on during a live forum, with threshold for "consensus agreement" set at 75%. RESULTS: The voting panel consisted of 26 physicians: 13 urologists/uro-oncologists, nine medical oncologists, and four radiation oncologists. Consensus was reached for 32 of 58 questions (one ad-hoc). Consensus was seen in the use of local treatment, to not use metastasis-directed therapy for low-volume mCSPC, and to use triplet therapy for synchronous high-volume mCSPC (low prostate-specific antigen). Consensus was also reached on sufficiency of conventional imaging to manage disease, use of germline testing and genomic profiling for metastatic disease, and poly (ADP-ribose) polymerase (PARP) inhibitors for BRCA-positive prostate cancer. CONCLUSIONS: CCF3 identified consensus agreement and provides guidance on >30 practice scenarios related to management of PCa and nine areas of controversy, which represent opportunities for research and education to improve patient care. Consensus initiatives provide valuable guidance on areas of controversy as clinicians await high-level evidence.

Effects of Probiotic Use on Gastrointestinal Symptoms in the Late Postoperative Period of Bariatric Surgery: A Cross-Over, Randomized, Triple-Blind, Placebo-Controlled Study.

INTRODUCTION: Despite the benefits associated with weight reduction, the anatomical and functional changes of bariatric surgery may favor the development of undesirable side effects such as the appearance of gastrointestinal symptoms (GIS). The aim of this study was to evaluate the effects of using probiotics in individuals with GIS 1 year after being submitted to Roux-en-Y Gastric Bypass (RYGB). MATERIALS AND METHODS: This is an experimental, prospective, randomized, cross-over, triple-blind, placebo-controlled study, carried out with patients 1 year after being submitted to RYGB and who reported at least one moderate GIS. Subjects were randomized into two groups and completed the two research periods: in one they received placebo capsules, in the other 50 billion CFU of probiotics (Lactobacillus acidophilus, Bifidobacterium lactis, Lactobacillus rhamnosus, Bifidobacterium longum, Lactobacillus plantarum, Bifidobacterium bifidum and Lactobacillus gasseri), both for 8 weeks, with 8 weeks of wash-out period in between, and were evaluated for the presence of Small Intestine Bacterial Overgrowth (SIBO) and GIS, through the Hydrogen breath test and Gastric Symptom Rating Scale (GSRS) questionnaire. RESULTS: Of a total of 56 participants, 47 individuals completed the study. No significant effects were observed in neither the gastrointestinal symptoms or in the prevalence of SIBO with the use of probiotics. CONCLUSION: Supplementation of the probiotics chosen for this study does not seem to alleviate GIS or influence the improvement of SIBO in symptomatic patients after 1 year of RYGB.

Historical dataset of osteological and archaeological records for equines on Crete.

We gathered evidence on the occurrence of equines in the island of Crete from the Neolithic until 1895. We relied on published archaeological and osteological records plus on historical written documents. Our dataset includes a description of the type of evidence, where this was located, and the associated absolute and relative chronologies. The collected data can be used to investigate the past spread of equids in Crete (Equus asinus and Equus caballus), their socioeconomic status, and the development of the local Cretan breed. The dataset is made available via the Abraxas data community within the Pandora data platform. This community is devoted to the historical study of horses. The dataset presented here is a component of a project tracing the history of the Cretan horse until present day.

Assessment of Cardiorespiratory and Metabolic Contributions in an Extreme Intensity CrossFit® Benchmark Workout.

Our purpose was to characterize the oxygen uptake kinetics (VO2), energy systems contributions and total energy expenditure during a CrossFit® benchmark workout performed in the extreme intensity domain. Fourteen highly trained male CrossFitters, aged 28.3 ± 5.4 years, with height 177.8 ± 9.4 cm, body mass 87.9 ± 10.5 kg and 5.6 ± 1.8 years of training experience, performed the Isabel workout at maximal exertion. Cardiorespiratory variables were measured at baseline, during exercise and the recovery period, with blood lactate and glucose concentrations, including the ratings of perceived exertion, measured pre- and post-workout. The Isabel workout was 117 ± 10 s in duration and the VO2 peak was 47.2 ± 4.7 mL·kg-1·min-1, the primary component amplitude was 42.0 ± 6.0 mL·kg-1·min-1, the time delay was 4.3 ± 2.2 s and the time constant was 14.2 ± 6.0 s. The accumulated VO2 (0.6 ± 0.1 vs. 4.8 ± 1.0 L·min-1) value post-workout increased substantially when compared to baseline. Oxidative phosphorylation (40%), glycolytic (45%) and phosphagen (15%) pathways contributed to the 245 ± 25 kJ total energy expenditure. Despite the short ~2 min duration of the Isabel workout, the oxygen-dependent and oxygen-independent metabolism energy contributions to the total metabolic energy release were similar. The CrossFit® Isabel requires maximal effort and the pattern of physiological demands identifies this as a highly intensive and effective workout for developing fitness and conditioning for sports.

Effect of Randall foils on the rowing propulsive cycle.

Rowing performance depends on the design and building materials used for competition. Recently, attempting to improve rowing performance, the Randall foil has been attached to the top edge of a rowing Big blade, making it spoon shaped. The current study aimed to analyse the differences between Big blades with and without Randall foils in force-related variables. Nineteen rowers performed two bouts of 90 s at maximal effort tethered rowing and differences were found in cycle average peak force (4.33 ± 1.46 vs. 5.26 ± 1.57 N/kg), propulsive cycle average time (1.79 ± 0.38 vs. 1.52 ± 0.24 N/kg.s) and rate of force development (8.79 ± 4.75 vs. 12.07 ± 4.60 N/kg/s) for Big blades with and without foils (respectively). Differences were also observed between the middle (4.79 ± 1.21 vs. 4.08 ± 1.48 N/kg) and final phases (4.86 ± 1.45 vs. 4.04 ± 1.47 N/kg) of the rowing effort for the cycle average peak force of Big blades with and without Randall foils. Data suggest a positive effect of these foils on the force-time curve profile. Future studies should focus on testing its influence on free on-water rowing.