Long-Term Survival Of Subcutaneous Biosimilar TNFα Inhibitors Compared To Originators: Results From A Multicenter Prospective Registry.

OBJECTIVE: To analyze the long-term survival of subcutaneous biosimilar TNFα-inhibitors (TNFi) compared to the originator molecules in patients with rheumatic diseases, and the factors associated with drug discontinuation. METHODS: Retrospective analysis of BIOBADASER, the Spanish multicenter prospective registry of rheumatic patients on biological and targeted disease-modifying anti-rheumatic drugs. Patients who started etanercept or adalimumab from January 2016 to October 2023 were included. The survival probabilities of biosimilars and originators were compared using Kaplan-Meier estimating curves. To identify factors associated with differences in the retention rates, hazard ratios (HR) were estimated using Cox regression models for all and specific (inefficacy or adverse events) causes of discontinuation. RESULTS: A total of 4162 patients received 4723 treatment courses (2991 courses of adalimumab and 1732 courses of etanercept), of which 722 (15.29%) were originator molecules and 4001 (84.71%) biosimilars. The originators were more frequently discontinued than biosimilars (53.32% and 33.37%, respectively). The main reason for discontinuation was inefficacy (60.35% of the treatments). The risk of overall discontinuation was lower for biosimilars (adjusted HR 0.84, 95% CI: 0.75-0.95). Female sex, obesity and second or later treatment lines increased the risk of discontinuation, while disease duration and the use of concomitant methotrexate were associated to a greater survival. When assessing cause-specific reasons of discontinuation, excluding nonmedical switching, the results from the crude and adjusted analyses showed no significant differences in the retention rate between biosimilars and originators. CONCLUSION: No significant differences were found between treatmens in the longterm survival due to inefficacy or adverse events.

Examining tactical sprint actions and distribution among playing positions attending to match status in soccer: Implications for specific training.

The study aimed to analyze the tactical sprint actions performed by Spanish professional soccer players, considering their playing positions and the match status at the time of each action. Thirty-two Spanish male professional soccer players from a LaLiga Spanish Second Division (LaLiga SmarthBank) team participated in this study. Actions above 85% of the players' maximum velocity during 42 official matches were collected by an optical tracking system ChyronHego® and were synchronized using Mediacoach software (LaLiga, Madrid, Spain). Then, actios were analyzed trough an observation instrument designed to assess the type of tactical action performed by players. Central defenders (CD) and wide defenders (WD) were mainly involved in recovery runs. Central midfielders (CM) also frequently performed recovery runs and pressing actions. Wide midfielders (WM) were often engaged in runs in behind/penetrate actions, while forwards (F) had a diverse range of sprint actions, including pressing, runs in behind/penetrate, and breaking into the box. It was observed that F performed fewer chase actions than expected. On the other hand, CD, WD, and CM engaged in a greater number of recovery run actions than expected. CD also performed more close down/interception actions than expected, while CM, WM, and F performed fewer close down/interception actions than expected. When their team was losing, WM performed more recovery run actions than expected. CM made more runs with the ball when their team was winning CD showed a higher frequency of breaks into the box when their team was winning. These findings provide valuable information regarding the tactical aspects of sprinting in soccer, facilitating the design of specific training tasks that not only address the physical demands associated with each playing position but also considering the tactical context in which sprints occur.

Development of a population pharmacokinetic model for the novel long-acting injectable antipsychotic risperidone ISM®.

AIMS: The aims of this study were to develop a population pharmacokinetic (PK) model for risperidone ISM® and to investigate the relationships between active moiety exposure, as described by apparent clearance (CL40), and several covariates using all data from five clinical studies. METHODS: A population PK model was developed using active moiety concentrations from a study in healthy volunteers and two studies in patients with schizophrenia. Data from a comparative bioavailability study in medically stable patients and a Phase III study in patients with acute exacerbation of schizophrenia were then incorporated, using empirical Bayesian feedback and model refinement in NONMEM. Finally, covariate analysis was performed on CL40. RESULTS: The final model adequately described the pharmacokinetics of 6288 active moiety concentrations in 17 healthy volunteers and 430 patients with schizophrenia. This one-compartment disposition model had a complex absorption process, combining a small amount immediately entering the central active moiety compartment, two first-order absorption processes and a combined zero-order and first order process, with first-order elimination from the central compartment. Significant covariates on CL40 were BMI and sex. Goodness-of-fit (GOF) plots and visual predictive checks (VPC) confirmed acceptable description of the data. CONCLUSIONS: The population PK model adequately described active moiety concentrations from five clinical studies after risperidone ISM® administration. Relationships between active moiety exposure and covariates were defined in order to facilitate simulations for future studies. The model showed that risperidone ISM® rapidly achieves therapeutic plasma levels within the first hours after the first injection that are maintained sustainedly throughout the whole dosing interval following once-monthly gluteal injections of 100 mg and 75 mg.

Optimizing the kidney donor pool: transplanting donor kidneys after partial nephrectomy of masses or cysts.

Background: A limiting factor in expanding the kidney donor pool is donor kidneys with renal tumors or cysts. Partial nephrectomy (PN) to remove these lesions prior to transplantation may help optimize organ usage without recurrence of malignancy or increased risk of complications. Methods: We retrospectively analyzed all recipients of a living or deceased donor graft between February 2009 and October 2022 in which a PN was performed prior to transplant due to the presence of one or more concerning growths. Donor and recipient demographics, perioperative data, donor allograft pathology, and recipient outcomes were obtained. Results: Thirty-six recipients received a graft in which a PN was performed to remove suspicious masses or cysts prior to transplant. Majority of pathologies turned out to be a simple renal cyst (65%), followed by renal cell carcinoma (15%), benign multilocular cystic renal neoplasm (7.5%), angiomyolipoma (5%), benign renal tissue (5%), and papillary adenoma (2.5%). No renal malignancy recurrences were observed during the study period (median follow-up: 67.2 months). Fourteen complications occurred among 11 patients (30.6% overall) during the first 6mo post-transplant. Mean eGFR (± standard error) at 36 months post-transplant was 51.9 ± 4.2 ml/min/1.73 m2 (N = 23). Three death-censored graft losses and four deaths with a functioning graft and were observed. Conclusion: PN of renal grafts with suspicious looking masses or cysts is a safe option to optimize organ usage and decrease the kidney non-use rate, with no observed recurrence of malignancy or increased risk of complications.

Influence of the External Workload on Calf Muscle Strain Injuries in Professional Football Players: A Pilot Study.

BACKGROUND: The influence of external workload variables on the development of calf muscle strainsin football players has not been previously explored. HYPOTHESIS: Overloaded players would have an increased risk of calf muscle strain injury. STUDY DESIGN: Prospective observational study. LEVEL OF EVIDENCE: Level 4. METHODS: A total of 41 professional football players from 1 team were monitored for 2 consecutive seasons. Total distance covered (TD), and distances covered at high-intensity running, high sprint running, low (LACC) and high (HACC) acceleration, low (LDEC) and high (HDEC) deceleration, and at high metabolic load distance (HMLD) were monitored with GPS units. Accumulated players' external workload in the week before injury was compared with the weekly mean value of the 6 weeks before injury occurred for each player. RESULTS: Ten players (24.3%) suffered 16 calf muscle strain injuries (3.1 injuries per 1000 hours of match play; 0.5 injuries per 1000 hours of training exposure). Players with a calf muscle injury were older (p = 0.03), with higher body weight (p = 0.01) and height (p = 0.03). Injured players displayed substantially higher total training volume (p < 0.01), TD (p < 0.01), LACC (p < 0.01), LDEC (p < 0.01), HACC (p < 0.01), HDEC (p < 0.01), and HMLD (p = 0.03) in the week before injury, in comparison with the mean values of these variables in the 6 weeks before injury. CONCLUSION: A week with a higher-than-habitual external workload might increase the risk of calf muscle strain injury in professional football players. Calf muscle injuries were preceded by a week with unusually high workloads associated with accelerating and decelerating distances and higher training volumes. CLINICAL RELEVANCE: Monitoring external workload indicators may be helpful in determine players with a higher risk of calf muscle strain injury due to excessive workload during training/competition.

Quality assessment of oral antimalarial and antiretroviral medicines used by public health systems in Sahel countries.

Malaria and Human Immunodeficiency Virus infections are among the top 10 causes of death in low income countries. Furthermore, many medicines used in these treatment areas are substandard, which contributes to the high death rate. Using a monitoring system to identify substandard and falsified medicines, the study aims to evaluate the quality of antimalarial and antiretroviral medicines in Sahel countries, assessing site conditions, compliance of medicines with pharmacopoeia tests, formulation equivalence with a reference medicine, and the influence of climate on quality attributes. Ultra Performance Liquid Chromatography methods for eight active pharmaceutical ingredients were validated following the International Conference for Harmonization guideline for its detection and quantification. Quality control consists of visual inspections to detect any misinformation or imperfections and pharmacopeial testing to determine the quality of pharmaceutical products. Medicines which complied with uniformity dosage units and dissolution tests were stored under accelerated conditions for 6 months. Artemether/Lumefantrine and Lopinavir/Ritonavir formulations failed uniformity dosage units and disintegration tests respectively, detecting a total of 28.6% substandard medicines. After 6 months stored under accelerated conditions (40 °C // 75% relative humidity) simulating climatic conditions in Sahel countries, some medicines failed pharmacopeia tests. It demonstrated the influence of these two factors in their quality attributes. This study emphasizes the need of certified quality control laboratories as well as the need for regulatory systems to maintain standards in pharmaceutical manufacturing and distribution in these countries, especially when medicines are transported to rural areas where these climatic conditions are harsher.

Characterising 24-h skeletal muscle gene expression alongside metabolic & endocrine responses under diurnal conditions.

CONTEXT: Skeletal muscle plays a central role in the storage, synthesis, and breakdown of nutrients, yet little research has explored temporal responses of this human tissue, especially with concurrent measures of systemic biomarkers of metabolism. OBJECTIVE: To characterise temporal profiles in skeletal muscle expression of genes involved in carbohydrate metabolism, lipid metabolism, circadian clocks, and autophagy and descriptively relate them to systemic metabolites and hormones during a controlled laboratory protocol. METHODS: Ten healthy adults (9M/1F, mean ± SD: age: 30 ± 10 y; BMI: 24.1 ± 2.7 kg·m-2) rested in the laboratory for 37 hours with all data collected during the final 24 hours of this period (i.e., 0800-0800 h). Participants ingested hourly isocaloric liquid meal replacements alongside appetite assessments during waking before a sleep opportunity from 2200-0700 h. Blood samples were collected hourly for endocrine and metabolite analyses, with muscle biopsies occurring every 4 h from 1200 h to 0800 h the following day to quantify gene expression. RESULTS: Plasma insulin displayed diurnal rhythmicity peaking at 1804 h. Expression of skeletal muscle genes involved in carbohydrate metabolism (Name - Acrophase; GLUT4 - 1440 h; PPARGC1A -1613 h; HK2 - 1824 h) and lipid metabolism (FABP3 - 1237 h; PDK4 - 0530 h; CPT1B - 1258 h) displayed 24 h rhythmicity that reflected the temporal rhythm of insulin. Equally, circulating glucose (0019 h), NEFA (0456 h), glycerol (0432 h), triglyceride (2314 h), urea (0046 h), CTX (0507 h) and cortisol concentrations (2250 h) also all displayed diurnal rhythmicity. CONCLUSION: Diurnal rhythms were present in human skeletal muscle gene expression as well systemic metabolites and hormones under controlled diurnal conditions. The temporal patterns of genes relating to carbohydrate and lipid metabolism alongside circulating insulin are consistent with diurnal rhythms being driven in part by the diurnal influence of cyclic feeding and fasting.

Proposal and Validation of a Measurement Scale of the Acceptance of Ultra-Processed Food Products.

Today, there is an increasing consumption of ultra-processed food products (UPFs), while more healthy options are available; however, there is no scale available that can adequately measure this phenomenon. In this context, the present study aims to develop and validate a measurement scale of the consumers' acceptance of ultra-processed food products. Research data (n = 478) were analyzed using Exploratory Factor Analysis (EFA), followed by a Confirmatory Factor Analysis (CFA). The results confirm the validity of the proposed measurement scale comprising nine factors: the quality of ultra-processed food products, ability to save time, low affordable price, effortless preparation, convenience, hedonic nature, marketing strategies, satisfaction and purchase intention. The present study makes a noticeable contribution to food marketing, and food companies could consider these factors to design and commercialize ultra-processed foods.

Myths and Methodologies: Standardisation in human physiology research-should we control the controllables?

The premise of research in human physiology is to explore a multifaceted system whilst identifying one or a few outcomes of interest. Therefore, the control of potentially confounding variables requires careful thought regarding the extent of control and complexity of standardisation. One common factor to control prior to testing is diet, as food and fluid provision may deviate from participants' habitual diets, yet a self-report and replication method can be flawed by under-reporting. Researchers may also need to consider standardisation of physical activity, whether it be through familiarisation trials, wash-out periods, or guidance on levels of physical activity to be achieved before trials. In terms of pharmacological agents, the ethical implications of standardisation require researchers to carefully consider how medications, caffeine consumption and oral contraceptive prescriptions may affect the study. For research in females, it should be considered whether standardisation between- or within-participants in regards to menstrual cycle phase is most relevant. The timing of measurements relative to various other daily events is relevant to all physiological research and so it can be important to standardise when measurements are made. This review summarises the areas of standardisation which we hope will be considered useful to anyone involved in human physiology research, including when and how one can apply standardisation to various contexts.

Elevated Shear Stress Modulates Heterogenous Cellular Subpopulations to Induce Vascular Remodeling.

Rationale: Elevated shear stress (ESS) induces vascular remodeling in veins exposed to arterial blood flow, which can lead to arteriovenous (AV) fistula failure. The molecular mechanisms driving remodeling have not been comprehensively examined with a single-cell resolution before. Objective: Using an in vivo animal mode, single-cell RNA sequencing, and histopathology, we precisely manipulate blood flow to comprehensively characterize all cell subpopulations important during vascular remodeling. Methods: AV loops were created in saphenous vessels of rats using a contralateral saphenous vein interposition graft to promote ESS. Saphenous veins with no elevated shear stress (NSS) were anastomosed as controls. Findings: ESS promoted transcriptional homogeneity, and NSS promoted considerable heterogeneity. Specifically, ESS endothelial cells (ECs) showed a more homogeneous transcriptional response promoting angiogenesis and upregulating endothelial-to-mesenchymal transition inhibiting genes (Klf2). NSS ECs upregulated antiproliferation genes such as Cav1, Cst3, and Btg1. In macrophages, ESS promoted a large homogeneous subpopulation, creating a mechanically activated, proinflammatory and thus proangiogenic myeloid phenotype, whereas NSS myeloid cells expressed the anti-inflammatory and antiangiogenetic marker Mrc1. Conclusion: ESS activates unified gene expression profiles to induce adaption of the vessel wall to hemodynamic alterations. Targeted depletion of the identified cellular subpopulations may lead to novel therapies to prevent excessive venous remodeling, intimal hyperplasia, and AV fistula failure.

A whole-slide foundation model for digital pathology from real-world data.

Digital pathology poses unique computational challenges, as a standard gigapixel slide may comprise tens of thousands of image tiles1-3. Prior models have often resorted to subsampling a small portion of tiles for each slide, thus missing the important slide-level context4. Here we present Prov-GigaPath, a whole-slide pathology foundation model pretrained on 1.3 billion 256 × 256 pathology image tiles in 171,189 whole slides from Providence, a large US health network comprising 28 cancer centres. The slides originated from more than 30,000 patients covering 31 major tissue types. To pretrain Prov-GigaPath, we propose GigaPath, a novel vision transformer architecture for pretraining gigapixel pathology slides. To scale GigaPath for slide-level learning with tens of thousands of image tiles, GigaPath adapts the newly developed LongNet5 method to digital pathology. To evaluate Prov-GigaPath, we construct a digital pathology benchmark comprising 9 cancer subtyping tasks and 17 pathomics tasks, using both Providence and TCGA data6. With large-scale pretraining and ultra-large-context modelling, Prov-GigaPath attains state-of-the-art performance on 25 out of 26 tasks, with significant improvement over the second-best method on 18 tasks. We further demonstrate the potential of Prov-GigaPath on vision-language pretraining for pathology7,8 by incorporating the pathology reports. In sum, Prov-GigaPath is an open-weight foundation model that achieves state-of-the-art performance on various digital pathology tasks, demonstrating the importance of real-world data and whole-slide modelling.

Myths and Methodologies: Standardisation in Human Physiology Research-Should We Control the Controllables?

The premise of research in human physiology is to explore a multifaceted system whilst identifying one or a few outcomes of interest. Therefore, the control of potentially confounding variables requires careful thought regarding the extent of control and complexity of standardisation. One common factor to control prior to testing is diet, as food and fluid provision may deviate from participants' habitual diets, yet a self-report and replication method can be flawed by under-reporting. Researchers may also need to consider standardisation of physical activity, whether it be through familiarisation trials, wash-out periods, or guidance on levels of physical activity to be achieved before trials. In terms of pharmacological agents, the ethical implications of standardisation require researchers to carefully consider how medications, caffeine consumption and oral contraceptive prescriptions may affect the study. For research in females, it should be considered whether standardisation between- or within-participants in regards to menstrual cycle phase is most relevant. The timing of measurements relative to various other daily events is relevant to all physiological research and so it can be important to standardise when measurements are made. This review summarises the areas of standardisation which we hope will be considered useful to anyone involved in human physiology research, including when and how one can apply standardisation to various contexts.

Inequality on the frontline: A multi-country study on gender differences in mental health among healthcare workers during the COVID-19 pandemic.

Healthcare workers (HCWs) were at increased risk for mental health problems during the COVID-19 pandemic, with prior data suggesting women may be particularly vulnerable. Our global mental health study aimed to examine factors associated with gender differences in psychological distress and depressive symptoms among HCWs during COVID-19. Across 22 countries in South America, Europe, Asia and Africa, 32,410 HCWs participated in the COVID-19 HEalth caRe wOrkErS (HEROES) study between March 2020 and February 2021. They completed the General Health Questionnaire-12, the Patient Health Questionnaire-9 and questions about pandemic-relevant exposures. Consistently across countries, women reported elevated mental health problems compared to men. Women also reported increased COVID-19-relevant stressors, including insufficient personal protective equipment and less support from colleagues, while men reported increased contact with COVID-19 patients. At the country level, HCWs in countries with higher gender inequality reported less mental health problems. Higher COVID-19 mortality rates were associated with increased psychological distress merely among women. Our findings suggest that among HCWs, women may have been disproportionately exposed to COVID-19-relevant stressors at the individual and country level. This highlights the importance of considering gender in emergency response efforts to safeguard women's well-being and ensure healthcare system preparedness during future public health crises.

Surgical modifications to the conventional kidney transplant technique - the miami transplant institute approach: a retrospective cohort study.

BACKGROUND: At our center, surgical modifications to the conventional kidney transplant technique were developed with two goals in mind: to minimize the risk of developing post-transplant urologic/vascular/other surgical complications, and to simultaneously eliminate the need for initial ureteral stent placement and surgical drainage. METHODS: Here, we describe these modifications along with(what we believe are) their advantages over the conventional technique: creating an abdominal flap for easier abdominal closure(reflecting the parietal peritoneum from the abdominal wall), mobilizing the bladder before transplant(creating more space for bladder dissection, allowing it to move upward during abdominal wall closure), minimizing the dissection of iliac vessels to only anterior lymphatic tissue(attempting to minimize the incidence of fluid collections), using plastic arterial vascular bulldog clamps(causing less trauma to the iliac artery), performing vascular anastomosis of the renal artery first(making it easier for the surgeon to perform this anastomoses), creating longer ureteral spatulation, and inclusion of bladder mucosa along with some detrusor muscle layer in performing the ureteral anastomosis(attempting to minimize the incidence of urologic complications). Of note, no initial ureteral stent placement or surgical drainage was used. We report our experience during the first 12mo post-transplant of a single transplant surgeon who used each of these modifications among 707 consecutive recipients of kidney-alone transplants at our center since 2014. RESULTS: During the first 12mo post-transplant, 2.3%(16/707) of patients developed a urologic complication; only 1.0%(7/707) required surgical repair of their original ureteroneocystostomy. Additionally, 2.7%(19/707) developed a vascular complication; 8.8%(62/707) developed some other type of surgical complication(wound complication, lymphocele development, or development of a peri-renal hematoma or peri-renal collection). These overall results were clearly advantageous when compared with other studies. CONCLUSION: We believe that this modified kidney transplant technique clearly helped in reducing post-transplant risks of developing urologic/vascular/other surgical complications. Importantly, these results were achieved without initial ureteral stent placement or surgical drainage.

The role of Patient and public involvement (PPI) in pre-clinical spinal cord research: An interview study.

BACKGROUND: Patient and public involvement in research (PPI) has many benefits including increasing relevance and impact. While using PPI in clinical research is now an established practice, the involvement of patients and the public in pre-clinical research, which takes place in a laboratory setting, has been less frequently described and presents specific challenges. This study aimed to explore the perspectives of seriously injured rugby players' who live with a spinal cord injury on PPI in pre-clinical research. METHODS: Semi-structured interviews were conducted via telephone with 11 seriously injured rugby players living with spinal cord injury on the island of Ireland. A purposive sampling approach was used to identify participants. Selected individuals were invited to take part via gatekeeper in a charitable organisation that supports seriously injured rugby players. Interviews were transcribed verbatim and analysed thematically. FINDINGS: Six themes were identified during analysis: 'appreciating potential benefits of PPI despite limited knowledge', 'the informed perspectives of people living with spinal cord injury can improve pre-clinical research relevance', 'making pre-clinical research more accessible reduces the potential for misunderstandings to occur', 'barriers to involvement include disinterest, accessibility issues, and fear of losing hope if results are negative', 'personal contact and dialogue helps people feel valued in pre-clinical research, and 'PPI can facilitate effective dissemination of pre-clinical research as desired by people living with spinal cord injury.' CONCLUSION: People affected by spinal cord injury in this study desire further involvement in pre-clinical spinal cord injury research through dialogue and contact with researchers. Sharing experiences of spinal cord injury can form the basis of PPI for pre-clinical spinal cord injury research.

Force Production and Electromyographic Activity during Different Flywheel Deadlift Exercises.

This study aimed to characterize and compare force production and muscle activity during four flywheel deadlift exercises (bilateral [Bi] vs. unilateral [Uni]) with different loading conditions (vertical [Ver] vs. horizontal [Hor]). Twenty-three team-sport athletes underwent assessments for exercise kinetics (hand-grip force), along with surface electromyography (sEMG) of the proximal (BFProx) and medial biceps femoris (BFMed), semitendinosus (ST), and gluteus medius (GM). Mean and peak force were highest (p < 0.001) in Bi + Ver compared with Bi + Hor, Uni + Ver, and Uni + Hor. Although no significant differences were observed between Bi + Hor and Uni + Ver, both variants showed higher (p < 0.001) average force and peak eccentric force when compared with Uni + Hor. The presence of eccentric overload was only observed in the vertically loaded variants. Bi + Ver and Uni + Ver showed higher (p < 0.05) sEMG levels in BFProx and BFMed compared with the Uni + Hor variant. In addition, Uni + Ver registered the largest GM and ST sEMG values. In conclusion, the vertical variants of the flywheel deadlift exercise led to higher muscle force production and sEMG compared with their horizontal counterparts. Both Bi + Ver and Uni + Ver may be effective in promoting an increase in hamstring muscles activity and muscle force at long muscle length, while the Uni + Ver variant may be more effective in promoting GM and ST involvement.