Metacarpophalangeal hyperextension in trapeziometacarpal osteoarthritis: relationship to first metacarpal head shape, and clinical impact.

PURPOSE: The aim of this study was to determine whether the shape of the first metacarpal head influences metacarpophalangeal hyperextension, and to evaluate the influence of metacarpophalangeal hyperextension on hand pain and function in patients with trapeziometacarpal osteoarthritis. METHODS: 362 patients with painful basal thumb osteoarthritis were evaluated over a 2-year period. Pain rating on a visual analog scale, trapeziometacarpal and metacarpophalangeal motion, and grip and pinch strength were evaluated. The shape of the metacarpal head was assessed on strict lateral radiographs using the "A/r" ratio. RESULTS: Round metacarpal heads had significantly greater and more frequent metacarpophalangeal hyperextension than flat heads (28 ° versus 8 °, and 78% versus 29%). Metacarpophalangeal hyperextension adversely impacted trapeziometacarpal motion in antepulsion (27 ° versus. 32 °), abduction (25 ° versus. 30 °) and pinch strength (3.6 versus. 4.6 KgF). CONCLUSION: Our findings indicate that the shape of the metacarpal head influences metacarpophalangeal hyperextension in trapeziometacarpal osteoarthritis. Metacarpophalangeal hyperextension adversely impacted pinch strength and trapeziometacarpal motion. LEVEL OF EVIDENCE: Level IV, Retrospective case series.

SCO-pH: Microfluidic dynamic phenotyping platform for high-throughput screening of single cell acidification.

Studies on the dynamics of single cell phenotyping have been hampered by the lack of quantitative high-throughput metabolism assays. Extracellular acidification, a prominent phenotype, yields significant insights into cellular metabolism, including tumorigenicity. Here, we develop a versatile microfluidic system for single cell optical pH analysis (SCO-pH), which compartmentalizes single cells in 140-pL droplets and immobilizes approximately 40,000 droplets in a two-dimensional array for temporal extracellular pH analysis. SCO-pH distinguishes cells undergoing hyperglycolysis induced by oligomycin A from untreated cells by monitoring their extracellular acidification. To facilitate pH sensing in each droplet, we encapsulate a cell-impermeable pH probe whose fluorescence intensities are quantified. Using this approach, we can differentiate hyperglycolytic cells and concurrently observe single cell heterogeneity in extracellular acidification dynamics. This high-throughput system will be useful in applications that require dynamic phenotyping of single cells with significant heterogeneity.

Outcomes of patients aged ≥26 years with relapsed or refractory B-cell acute lymphoblastic leukemia in ZUMA-3 and historical trials.

Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 CAR T-cell therapy approved in the USA and European Union (EU) for adults with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL; aged ≥26 years in EU). Here, outcomes for patients with R/R B-ALL aged ≥26 years in ZUMA-3 treated with brexu-cel were compared with historical standard-of-care (SOC) therapy. After median follow-up of 26.8 months, the overall complete remission (CR) rate among patients treated with brexu-cel in Phase 2 (N = 43) was 72% and median overall survival (OS) was 25.4 months (95% CI, 15.9-NE). Median OS was improved in Phase 2 patients versus matched historical SOC-treated patients. Compared with aggregate historical trial data, Phase 1 and 2 patients had improved OS versus blinatumomab, inotuzumab, and chemotherapy in a matching-adjusted indirect comparison (MAIC) study. These data demonstrate clinical benefit of brexu-cel relative to SOC in patients ≥26 years with R/R B-ALL.

Development of Novel Models of Aggressive Variants of Castration-resistant Prostate Cancer.

BACKGROUND: Genomic studies have identified new subsets of aggressive prostate cancer (PCa) with poor prognosis (eg, neuroendocrine prostate cancer [NEPC], PCa with DNA damage response [DDR] alterations, or PCa resistant to androgen receptor pathway inhibitors [ARPIs]). Development of novel therapies relies on the availability of relevant preclinical models. OBJECTIVE: To develop new preclinical models (patient-derived xenograft [PDX], PDX-derived organoid [PDXO], and patient-derived organoid [PDO]) representative of the most aggressive variants of PCa and to develop a new drug evaluation strategy. DESIGN, SETTING, AND PARTICIPANTS: NEPC (n = 5), DDR (n = 7), and microsatellite instability (MSI)-high (n = 1) PDXs were established from 51 patients with metastatic PCa; PDXOs (n = 16) and PDOs (n = 6) were developed to perform drug screening. Histopathology and treatment response were characterized. Molecular profiling was performed by whole-exome sequencing (WES; n = 13), RNA sequencing (RNA-seq; n = 13), and single-cell RNA-seq (n = 14). WES and RNA-seq data from patient tumors were compared with the models. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships with outcome were analyzed using the multivariable chi-square test and the tumor growth inhibition test. RESULTS AND LIMITATIONS: Our PDXs captured both common and rare molecular phenotypes and their molecular drivers, including alterations of BRCA2, CDK12, MSI-high status, and NEPC. RNA-seq profiling demonstrated broad representation of PCa subtypes. Single-cell RNA-seq indicates that PDXs reproduce cellular and molecular intratumor heterogeneity. WES of matched patient tumors showed preservation of most genetic driver alterations. PDXOs and PDOs preserve drug sensitivity of the matched tissue and can be used to determine drug sensitivity. CONCLUSIONS: Our models reproduce the phenotypic and genomic features of both common and aggressive PCa variants and capture their molecular heterogeneity. Successfully developed aggressive-variant PCa preclinical models provide an important tool for predicting tumor response to anticancer therapy and studying resistance mechanisms. PATIENT SUMMARY: In this report, we looked at the outcomes of preclinical models from patients with metastatic prostate cancer enrolled in the MATCH-R trial (NCT02517892).

Modelling the impact of liver regeneration on hepatoblastoma patient-derived-xenograft tumor growth.

BACKGROUND: Twenty percent of children with hepatoblastoma (HB) have lung metastasis at diagnosis. Treatment protocols recommend surgical removal of chemotherapy-refractory lung nodules, however no chronological order is established. As hepatectomy is followed by release of growth factors, it has been proposed that partial hepatectomy (PH) could boost local or distant residual tumor growth. METHODS: To evaluate the impact of PH on distant tumor growth, PH was performed in mice subcutaneously implanted with a HB patient-derived xenograft (PDX). The influence of PH on tumor growth at primary site was assessed by performing PH concomitantly to HB PDXs orthotopic implantation. RESULTS: Subcutaneously implanted HB PDX failed to show any influence of hepatectomy on tumor growth. Instead, intrahepatic tumor growth of one of the 4 HB PDXs implanted orthotopically was clearly enhanced. Cells derived from the hepatectomy-sensitive HB PDX exposed to hepatic growth factor (HGF) showed increased proliferation rate compared to cells derived from a hepatectomy-insensitive model, suggesting that the HGF/MET pathway could be one of the effectors of the crosstalk between liver regeneration and HB growth. CONCLUSION: These results suggest that hepatectomy can contribute to HB growth in some patients, further studies will be necessary to identify biomarkers predictive of patient risk of PH-induced HB recurrence. IMPACT: Key message: Cytokines and growth factors secreted following partial hepatectomy can contribute to intrahepatic tumor growth in some hepatoblastoma models. What does it add to the existing literature: It is the first article about the impact of liver regeneration induced by partial hepatectomy on hepatoblastoma local or distant tumoral growth in nude mice. What is the impact: It is important to identify the secreted factors that enhance tumor growth and to define biomarkers predictive of patient risk of partial hepatectomy-induced hepatoblastoma recurrence.

Snake and arthropod venoms: Search for inflammatory activity in human cells involved in joint diseases.

Most anti-inflammatory drugs currently adopted to treat chronic inflammatory joint diseases can alleviate symptoms but they do not lead to remission. Therefore, new and more efficient drugs are needed to block the course of joint inflammatory diseases. Animal venoms, rich in bioactive compounds, can contribute as valuable tools in this field of research. In this study, we first demonstrate the direct action of venoms on cells that constitute the articular joints. We established a platform consisting of cell-based assays to evaluate the release of cytokines (IL-6, IL-8, TNFα, IL-1ß, and IL-10) by human chondrocytes, synoviocytes and THP1 macrophages, as well as the release of neuropeptides (substance-P and ß-endorphin) by differentiated sensory neuron-like cells, 24 h after stimulation of cells with 21 animal venoms from snake and arthropod species, sourced from different taxonomic families and geographic origins. Results demonstrated that at non-cytotoxic concentrations, the venoms activate at varying degrees the secretion of inflammatory mediators involved in the pathology of articular diseases, such as IL-6, IL-8, and TNF-α by chondrocytes, synoviocytes, and macrophages and of substance P by neuron-like cells. Venoms of the Viperidae snake family were more inflammatory than those of the Elapidae family, while venoms of Arthropods were less inflammatory than snake venoms. Notably, some venoms also induced the release of the anti-inflammatory IL-10 by macrophages. However, the scorpion Buthus occitanus venom induced the release of IL-10 without increasing the release of inflammatory cytokines by macrophages. Since the cell types used in the experiments are crucial elements in joint inflammatory processes, the results of this work may guide future research on the activation of receptors and inflammatory signaling pathways by selected venoms in these particular cells, aiming at discovering new targets for therapeutic intervention.

Snake and arthropod venoms: search for inflammatory activity in human cells involved in joint diseases

Most anti-inflammatory drugs currently adopted to treat chronic inflammatory joint diseases can alleviate symptoms but they do not lead to remission. Therefore, new and more efficient drugs are needed to block the course of joint inflammatory diseases. Animal venoms, rich in bioactive compounds, can contribute as valuable tools in this field of research. In this study, we first demonstrate the direct action of venoms on cells that constitute the articular joints. We established a platform consisting of cell-based assays to evaluate the release of cytokines (IL-6, IL-8, TNFα, IL-1β, and IL-10) by human chondrocytes, synoviocytes and THP1 macrophages, as well as the release of neuropeptides (substance-P and β-endorphin) by differentiated sensory neuron-like cells, 24 h after stimulation of cells with 21 animal venoms from snake and arthropod species, sourced from different taxonomic families and geographic origins. Results demonstrated that at non-cytotoxic concentrations, the venoms activate at varying degrees the secretion of inflammatory mediators involved in the pathology of articular diseases, such as IL-6, IL-8, and TNF-α by chondrocytes, synoviocytes, and macrophages and of substance P by neuron-like cells. Venoms of the Viperidae snake family were more inflammatory than those of the Elapidae family, while venoms of Arthropods were less inflammatory than snake venoms. Notably, some venoms also induced the release of the anti-inflammatory IL-10 by macrophages. However, the scorpion Buthus occitanus venom induced the release of IL-10 without increasing the release of inflammatory cytokines by macrophages. Since the cell types used in the experiments are crucial elements in joint inflammatory processes, the results of this work may guide future research on the activation of receptors and inflammatory signaling pathways by selected venoms in these particular cells, aiming at discovering new targets for therapeutic intervention.

Hypergraph reconstruction from uncertain pairwise observations.

The network reconstruction task aims to estimate a complex system's structure from various data sources such as time series, snapshots, or interaction counts. Recent work has examined this problem in networks whose relationships involve precisely two entities-the pairwise case. Here, using Bayesian inference, we investigate the general problem of reconstructing a network in which higher-order interactions are also present. We study a minimal example of this problem, focusing on the case of hypergraphs with interactions between pairs and triplets of vertices, measured imperfectly and indirectly. We derive a Metropolis-Hastings-within-Gibbs algorithm for this model to highlight the unique challenges that come with estimating higher-order models. We show that this approach tends to reconstruct empirical and synthetic networks more accurately than an equivalent graph model without higher-order interactions.

Comparative Effects of Intra-Articular versus Intravenous Mesenchymal Stromal Cells Therapy in a Rat Model of Osteoarthritis by Destabilization of Medial Meniscus.

Transplanted mesenchymal stromal cells (MSCs) exhibit a robust anti-inflammatory and homing capacity in response to high inflammatory signals, as observed in studies focused on rheumatic diseases that target articular cartilage (AC) health. However, AC degradation in osteoarthritis (OA) does not necessarily coincide with a highly inflammatory joint profile. Often, by the time patients seek medical attention, they already have damaged AC. In this study, we examined the therapeutic potential of a single bone marrow MSC transplant (2 × 106 cells/kgbw) through two different routes: intra-articular (MSCs-IAt) and intravenous (MSCs-IVt) in a preclinical model of low-grade inflammatory OA with an established AC degeneration. OA was induced through the destabilization of the medial meniscus (DMM) in female Wistar Kyoto rats. The animals received MSCs 9 weeks after surgery and were euthanized 4 and 12 weeks post-transplant. In vivo and ex vivo tracking of MSCs were analyzed via bioluminescence and imaging flow cytometry, respectively. Cytokine/chemokine modulation in serum and synovial fluid was measured using a multiplex panel. AC degeneration was quantified through histology, and hindlimb muscle balance was assessed with precision weighing. To our knowledge, we are the first group to show the in vivo (8 h) and ex vivo (12 h) homing of cells to the DMM-OA joint following MSCs-IVt. In the case of MSCs-IAt, the detection of cellular bioluminescence at the knee joint persisted for up to 1 week. Intriguingly, intra-articular saline injection (placebo-IAt) resulted in a worse prognosis of OA when compared to a non-invasive control (placebo-IVt) without joint injection. The systemic cytokines/chemokines profile exhibited a time-dependent variation between transplant routes, displaying a transient anti-inflammatory systemic response for both MSCs-IVt and MSCs-IAt. A single injection of MSCs, whether administered via the intra-articular or intravenous route, performed 9 weeks after DMM surgery, did not effectively inhibit AC degeneration when compared to a non-invasive control.

Adaptive traits of cysts of the snow alga Sanguina nivaloides unveiled by 3D subcellular imaging.

Sanguina nivaloides is the main alga forming red snowfields in high mountains and Polar Regions. It is non-cultivable. Analysis of environmental samples by X-ray tomography, focused-ion-beam scanning-electron-microscopy, physicochemical and physiological characterization reveal adaptive traits accounting for algal capacity to reside in snow. Cysts populate liquid water at the periphery of ice, are photosynthetically active, can survive for months, and are sensitive to freezing. They harbor a wrinkled plasma membrane expanding the interface with environment. Ionomic analysis supports a cell efflux of K+, and assimilation of phosphorus. Glycerolipidomic analysis confirms a phosphate limitation. The chloroplast contains thylakoids oriented in all directions, fixes carbon in a central pyrenoid and produces starch in peripheral protuberances. Analysis of cells kept in the dark shows that starch is a short-term carbon storage. The biogenesis of cytosolic droplets shows that they are loaded with triacylglycerol and carotenoids for long-term carbon storage and protection against oxidative stress.

[Transitional care from hospital to home: how to target the right population?] / Soins de transition entre l'hôpital et le domicile: pour quels patient-es ?

When patients are discharged from the hospital and return home, they are at risk of adverse events if the continuity of care is broken. So far, the evidence for transitional care models to reduce readmission rates has focused mainly on patients with a single condition. Based on this observation, we identified the population that may benefit the most from the development of a new transitional care model, as part of the INSTEAD project, by consensus between patients and professionals in hospitals and the community. To ensure continuity of care, it is necessary to consider the patients' perception, their understanding of the care plan and changes impacting the home care plan. Interprofessional collaboration is essential to achieve this.

Lorsqu'un-e patient-e retourne à domicile suite à une hospitalisation il-elle est souvent confronté-e à des événements indésirables si la continuité de ses soins n'est pas assurée. Jusqu'à ce jour, les modèles de soins de transition qui ont montré une diminution du taux de réadmission concernaient des patient-es ne souffrant que d'une seule pathologie. Partant de ce constat, nous avons identifié la population qui pourrait le plus bénéficier de soins de transition, dans le cadre du projet INSTEAD, par un consensus incluant d'une part des patient-es et, d'autre part, des professionnel-les hospitaliers et communautaires. Pour assurer la continuité des soins, il s'avère nécessaire de prendre en compte la perception de la personne, sa compréhension ainsi que les changements influençant son plan de soins à domicile. Pour ce faire, une collaboration interprofessionnelle est indispensable.

Accurately summarizing an outbreak using epidemiological models takes time.

Recent outbreaks of Mpox and Ebola, and worrying waves of COVID-19, influenza and respiratory syncytial virus, have all led to a sharp increase in the use of epidemiological models to estimate key epidemiological parameters. The feasibility of this estimation task is known as the practical identifiability (PI) problem. Here, we investigate the PI of eight commonly reported statistics of the classic susceptible-infectious-recovered model using a new measure that shows how much a researcher can expect to learn in a model-based Bayesian analysis of prevalence data. Our findings show that the basic reproductive number and final outbreak size are often poorly identified, with learning exceeding that of individual model parameters only in the early stages of an outbreak. The peak intensity, peak timing and initial growth rate are better identified, being in expectation over 20 times more probable having seen the data by the time the underlying outbreak peaks. We then test PI for a variety of true parameter combinations and find that PI is especially problematic in slow-growing or less-severe outbreaks. These results add to the growing body of literature questioning the reliability of inferences from epidemiological models when limited data are available.

Opposing Responses to Scarcity Emerge from Functionally Unique Sociality Drivers.

AbstractFrom biofilms to whale pods, organisms across taxa live in groups, thereby accruing numerous diverse benefits of sociality. All social organisms, however, pay the inherent cost of increased resource competition. One expects that when resources become scarce, this cost will increase, causing group sizes to decrease. Indeed, this occurs in some species, but there are also species for which group sizes remain stable or even increase under scarcity. What accounts for these opposing responses? We present a conceptual framework, literature review, and theoretical model demonstrating that differing responses to sudden resource shifts can be explained by which sociality benefit exerts the strongest selection pressure on a particular species. We categorize resource-related benefits of sociality into six functionally distinct classes and model their effect on the survival of individuals foraging in groups under different resource conditions. We find that whether, and to what degree, the optimal group size (or correlates thereof) increases, decreases, or remains constant when resource abundance declines depends strongly on the dominant sociality mechanism. Existing data, although limited, support our model predictions. Overall, we show that across a wide diversity of taxa, differences in how group size shifts in response to resource declines can be driven by differences in the primary benefits of sociality.

Improving Romantic Relationship Functioning Among Young Men With First-Episode Psychosis: Impact of a Novel Group Intervention.

Previous research has highlighted many of the challenges faced by individuals with psychosis in romantic relationships. The present study aimed to evaluate the impact of a novel group intervention for men with first-episode psychosis (FEP) on dating success, romantic and sexual functioning, self-esteem, self-stigma, mentalizing skills, and symptomatology, while using a repeated single-case experimental design and comparing results across two treatment modalities (i.e., in-person or online). Twenty-seven participants from five treatment sites completed a 12-week group intervention. Qualitative data was also collected to assess participants' subjective experiences with the program. In both modalities, significant improvements were observed for romantic functioning, mentalizing skills, and symptomatology, with effect sizes ranging from small to large. Several participants also attended more dates and entered committed relationships after the intervention. Most participants were satisfied with the program and many felt that they had learned new skills and gained confidence in dating. Future research should replicate these findings in larger and more inclusive samples.

The earliest unambiguous Neanderthal engravings on cave walls: La Roche-Cotard, Loire Valley, France.

Here we report on Neanderthal engravings on a cave wall at La Roche-Cotard (LRC) in central France, made more than 57±3 thousand years ago. Following human occupation, the cave was completely sealed by cold-period sediments, which prevented access until its discovery in the 19th century and first excavation in the early 20th century. The timing of the closure of the cave is based on 50 optically stimulated luminescence ages derived from sediment collected inside and from around the cave. The anthropogenic origin of the spatially-structured, non-figurative marks found within the cave is confirmed using taphonomic, traceological and experimental evidence. Cave closure occurred significantly before the regional arrival of H. sapiens, and all artefacts from within the cave are typical Mousterian lithics; in Western Europe these are uniquely attributed to H. neanderthalensis. We conclude that the LRC engravings are unambiguous examples of Neanderthal abstract design.

A spatially explicit trait-based approach uncovers changes in assembly processes under warming.

The re-assembly of plant communities during climate warming depends on several concurrent processes. Here, we present a novel framework that integrates spatially explicit sampling, plant trait information and a warming experiment to quantify shifts in these assembly processes. By accounting for spatial distance between individuals, our framework allows separation of potential signals of environmental filtering from those of different types of competition. When applied to an elevational transplant experiment in the French Alps, we found common signals of environmental filtering and competition in all communities. Signals of environmental filtering were generally stronger in alpine than in subalpine control communities, and warming reduced this filter. Competition signals depended on treatments and traits: Symmetrical competition was dominant in control and warmed alpine communities, while hierarchical competition was present in subalpine communities. Our study highlights how distance-dependent frameworks can contribute to a better understanding of transient re-assembly dynamics during environmental change.

[Squamous cell carcinoma of the male perineum: a case report]. / Carcinome épidermoïde du périnée masculin: à propos d´un cas.

Squamous cell carcinoma of the male perineum is exceptional. We report the case of a 42-year-old patient with no previous medical history, presenting with pelvic discomfort lasting for 4 months. The patient was treated for perineal abscess in a health centre in Bamako. The anatomo-pathological examination confirmed the diagnosis. Treatment depends on the stage of the lesion and its location but it is associated with a poor prognosis. Given the results achieved in patients with epidermoid cancers of the esophagus and anus, treatment was based on therapeutic protocols combining chemotherapy and radiotherapy. The purpose of this work was to report the first case in our hospital unit.

Slc11a1 gene polymorphism influences dextran sulfate sodium (DSS)-induced colitis in a murine model of acute inflammation.

Ulcerative Colitis (UC) is an inflammatory disease characterized by colonic mucosal lesions associated with an increased risk of carcinogenesis. UC pathogenesis involves environmental and genetic factors. Genetic studies have indicated the association of gene variants coding for the divalent metal ion transporter SLC11A1 protein (formerly NRAMP1) with UC susceptibility in several animal species. Two mouse lines were genetically selected for high (AIRmax) or low (AIRmin) acute inflammatory responses (AIR). AIRmax is susceptible, and AIRmin is resistant to DSS-induced colitis and colon carcinogenesis. Furthermore, AIRmin mice present polymorphism of the Slc11a1 gene. Here we investigated the possible modulating effect of the Slc11a1 R and S variants in DSS-induced colitis by using AIRmin mice homozygous for Slc11a1 R (AIRminRR) or S (AIRminSS) alleles. We evaluated UC by the disease activity index (DAI), considering weight loss, diarrhea, blood in the anus or feces, cytokines, histopathology, and cell populations in the distal colon epithelium. AIRminSS mice have become susceptible to DSS effects, with higher DAI, IL6, G-CSF, and MCP-1 production and morphological and colon histopathological alterations than AIRminRR mice. The results point to a role of the Slc11a1 S allele in DSS colitis induction in the genetic background of AIRmin mice.