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This study aimed to determine how guanidinoacetic acid (GAA) or its combined administration with betaine (B) or creatine (C) influences the cardiac function, morphometric parameters, and redox status of rats subjected to high-intensity interval training (HIIT). This research was conducted on male Wistar albino rats exposed to HIIT for 4 weeks. The animals were randomly divided into five groups: HIIT, HIIT + GAA, HIIT + GAA + C, HIIT + GAA + B, and HIIT + GAA + C + B. After completing the training protocol, GAA (300 mg/kg), C (280 mg/kg), and B (300 mg/kg) were applied daily per os for 4 weeks. GAA supplementation in combination with HIIT significantly decreased the level of both systemic and cardiac prooxidants ([O.sup.-.sub.2], [H.sub.2][O.sub.2], N[O.sup.-.sub.2], and thiobarbituric acid reactive substances) compared with nontreated HIIT (p < 0.05). Also, GAA treatment led to an increase in glutathione and superoxide dismutase levels. None of the treatment regimens altered cardiac function. A larger degree of cardiomyocyte hypertrophy was observed in the HIIT + GAA group, which was reflected through an increase of the crosssectional area of 27% (p < 0.05) and that of the left ventricle wall thickness of 27% (p < 0.05). Since we showed that GAA in combination with HIIT may ameliorate oxidative stress and does not alter cardiac function, the present study is a basis for future research exploring the mechanisms of cardioprotection induced by this supplement in an HIIT scenario. Key words: guanidinoacetic acid, creatine, betaine, high-intensity interval training, cardioprotection Cette etude visait a etablir comment l'acide guanidinoacetique (GAA) ou son administration en association avec de la betaine (B) ou de la creatine (C) a une influence sur le fonctionnement du coeur, les parametres morphometriques et l'etat redox chez le rat auquel on administre un entrainement physique par intervalle a haute intensite (ou HIIT pour << high-intensity interval training >>). Nous avons mene cette etude chez des rats Wistar albinos males exposes au HIIT pendant 4 semaines. Nous avons reparti aleatoirement tous les animaux dans cinq groupes : HIIT, HIIT + GAA, HIIT + GAA + C, HIIT + GAA + B, HIIT + GAA + C + B. Une fois le protocole d'entrainement physique avec GAA (300 mg/kg) termine, nous avons administre C (280 mg/kg) et B (300 mg/kg) quotidiennement par voie orale pendant 4 semaines. La supplementation en GAA en association avec le HIIT entrainait une diminution nettement plus marquee des taux des prooxydants generaux comme cardiaques ([O.sub.2]-, H2[O.sub.2], N[O.sub.2]-, TBARS) que le HIIT seul (p < 0,05). De plus, l'administration de GAA a mene a une augmentation des taux de GSH et de SOD. Aucune des conditions experimentales n'a entraine de modification du fonctionnement du coeur. Nous avons observe une hypertrophie des cardiomyocytes plus marquee dans le groupe HIIT + GAA, avec une augmentation de l'aire de la section transversale de 27 % (p < 0,05) et de l'epaisseur de la paroi du ventricule gauche de 27 % (p < 0,05). Puisque nous avons montre que l'association du GAA avec le HIIT pourrait permettre d'attenuer le stress oxydatif et qu'elle n'a pas d'effet sur le fonctionnement du coeur, la presente etude constitue le fondement de futures recherches portant sur les modes d'action de la cardioprotection qu'engendre ce supplement au scenario du HIIT. [Traduit par la Redaction] Mots-cles : acide guanidinoacetique, creatine, betaine, entrainement physique par intervalle a haute intensite, cardioprotection, 1. Introduction For decades, physical exercise has been recognized both as a healthy habit and as a useful strategy for reduction of cardiovascular risk factors, thus preserving cardiovascular health. Regular [...]

BACKGROUND. Relatlimab plus nivolumab (anti-lymphocyte-activation gene 3 plus anti-programmed death 1 [anti- [LAG3.sup.+]anti-PD-1]) has been approved by the FDA as a first-line therapy for stage III/IV melanoma, but its detailed effect on the immune system is unknown. METHODS. We evaluated blood samples from 40 immunotherapy-naive or prior immunotherapy-refractory patients with metastatic melanoma treated with anti-LAG-3+anti-PD-1 in a phase I trial using single-cell RNA and T cell receptor sequencing (scRNA+TCR[alpha][beta]-Seq) combined with other multiomics profiling. RESULTS. The highest LAG3 expression was noted in NK cells, Tregs, and [CD8.sup.+] T cells, and these cell populations underwent the most significant changes during the treatment. Adaptive NK cells were enriched in responders and underwent profound transcriptomic changes during the therapy, resulting in an active phenotype. [LAG3.sup.+] Tregs expanded, but based on the transcriptome profile, became metabolically silent during the treatment. Last, higher baseline TCR clonality was observed in responding patients, and their expanding [CD8.sup.+] T cell clones gained a more cytotoxic and NK-like phenotype. CONCLUSION. Anti-LAG-3+anti-PD-1 therapy has profound effects on NK cells and Tregs in addition to [CD8.sup.+] T cells. TRIAL REGISTRATION. ClinicalTrials.gov (NCT01968109) FUNDING. Cancer Foundation Finland, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, State funding for university-level health research in Finland, a Helsinki Institute of Life Sciences Fellow grant, Academy of Finland (grant numbers 314442, 311081, 335432, and 335436), and an investigator-initiated research grant from BMS., Introduction Even though immune checkpoint inhibitor therapies have revolutionized the treatment of metastatic melanoma, a majority of patients fail to achieve sustainable responses. As currently available immune checkpoint inhibitor therapies [...]

Byline: Divyani. Garg, Suvasini. Sharma Subacute sclerosing panencephalitis (SSPE) is a neurodegenerative disorder because of the persistence of mutated measles virus in the central nervous system. Till date, no curative [...]

Author(s): Nick van Dijk [sup.1] , Alberto Gil-Jimenez [sup.2] [sup.3] , Karina Silina [sup.4] , Kees Hendricksen [sup.5] , Laura A. Smit [sup.6] , Jeantine M. de Feijter [sup.1] , [...], Preoperative immunotherapy with anti-PD1 plus anti-CTLA4 antibodies has shown remarkable pathological responses in melanoma.sup.1 and colorectal cancer.sup.2. In NABUCCO (ClinicalTrials.gov: NCT03387761), a single-arm feasibility trial, 24 patients with stage III urothelial cancer (UC) received two doses of ipilimumab and two doses of nivolumab, followed by resection. The primary endpoint was feasibility to resect within 12 weeks from treatment start. All patients were evaluable for the study endpoints and underwent resection, 23 (96%) within 12 weeks. Grade 3-4 immune-related adverse events occurred in 55% of patients and in 41% of patients when excluding clinically insignificant laboratory abnormalities. Eleven patients (46%) had a pathological complete response (pCR), meeting the secondary efficacy endpoint. Fourteen patients (58%) had no remaining invasive disease (pCR or pTisN0/pTaN0). In contrast to studies with anti-PD1/PD-L1 monotherapy, complete response to ipilimumab plus nivolumab was independent of baseline CD8.sup.+ presence or T-effector signatures. Induction of tertiary lymphoid structures upon treatment was observed in responding patients. Our data indicate that combined CTLA-4 plus PD-1 blockade might provide an effective preoperative treatment strategy in locoregionally advanced UC, irrespective of pre-existing CD8.sup.+ T cell activity. Neoadjuvant immunotherapy combination in the NABUCCO trial elicits high pathological complete response rates in patients with locoregionally advanced (stage III) urothelial cancer and provides molecular biomarkers of treatment efficacy.

Background Early antiviral treatment is effective for Coronavirus Disease 2019 (COVID-19) but currently available agents are expensive. Favipiravir is routinely used in many countries, but efficacy is unproven. Antiviral combinations have not been systematically studied. We aimed to evaluate the effect of favipiravir, lopinavir-ritonavir or the combination of both agents on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) viral load trajectory when administered early. Methods and findings We conducted a Phase 2, proof of principle, randomised, placebo-controlled, 2 x 2 factorial, double-blind trial of ambulatory outpatients with early COVID-19 (within 7 days of symptom onset) at 2 sites in the United Kingdom. Participants were randomised using a centralised online process to receive: favipiravir (1,800 mg twice daily on Day 1 followed by 400 mg 4 times daily on Days 2 to 7) plus lopinavir-ritonavir (400 mg/100 mg twice daily on Day 1, followed by 200 mg/50 mg 4 times daily on Days 2 to 7), favipiravir plus lopinavir-ritonavir placebo, lopinavir-ritonavir plus favipiravir placebo, or both placebos. The primary outcome was SARS-CoV-2 viral load at Day 5, accounting for baseline viral load. Between 6 October 2020 and 4 November 2021, we recruited 240 participants. For the favipiravir+lopinavir-ritonavir, favipiravir+placebo, lopinavir-ritonavir+placebo, and placebo-only arms, we recruited 61, 59, 60, and 60 participants and analysed 55, 56, 55, and 58 participants, respectively, who provided viral load measures at Day 1 and Day 5. In the primary analysis, the mean viral load in the favipiravir+placebo arm had changed by -0.57 log.sub.10 (95% CI -1.21 to 0.07, p = 0.08) and in the lopinavir-ritonavir+placebo arm by -0.18 log.sub.10 (95% CI -0.82 to 0.46, p = 0.58) compared to the placebo arm at Day 5. There was no significant interaction between favipiravir and lopinavir-ritonavir (interaction coefficient term: 0.59 log.sub.10, 95% CI -0.32 to 1.50, p = 0.20). More participants had undetectable virus at Day 5 in the favipiravir+placebo arm compared to placebo only (46.3% versus 26.9%, odds ratio (OR): 2.47, 95% CI 1.08 to 5.65; p = 0.03). Adverse events were observed more frequently with lopinavir-ritonavir, mainly gastrointestinal disturbance. Favipiravir drug levels were lower in the combination arm than the favipiravir monotherapy arm, possibly due to poor absorption. The major limitation was that the study population was relatively young and healthy compared to those most affected by the COVID-19 pandemic. Conclusions At the current doses, no treatment significantly reduced viral load in the primary analysis. Favipiravir requires further evaluation with consideration of dose escalation. Lopinavir-ritonavir administration was associated with lower plasma favipiravir concentrations. Trial registration Clinicaltrials.gov NCT04499677 EudraCT: 2020-002106-68, Author(s): David M. Lowe 1,2,*, Li-An K. Brown 1, Kashfia Chowdhury 3, Stephanie Davey 4, Philip Yee 4, Felicia Ikeji 3, Amalia Ndoutoumou 3, Divya Shah 5, Alexander Lennon 5, [...]

UNAIDS and a broad range of partners have collaborated to establish a new set of HIV prevention targets to be achieved by 2025 as an intermediate step towards the sustainable development target for 2030. The number of new HIV infections in the world continues to decline, in part due to the extraordinary expansion of effective HIV treatment. However, the decline is geographically heterogeneous, with some regions reporting a rise in incidence. The incidence target that was agreed for 2020 has been missed. A range of exciting new HIV prevention technologies have become available or are in the pipeline but will only have an impact if they are accessible and affordable and delivered within systems that take full account of the social and political context in which most infections occur. Most new infections occur in populations that are marginalised or discriminated against due to structural, legal, and cultural barriers. The new targets imply a new approach to HIV prevention that emphasises appropriate, person-centred, prioritised, effective, combination HIV prevention within a framework that reduces existing barriers to services and acknowledges heterogeneity, autonomy, and choice. These targets have consequences for people working in HIV programmes both for delivery and for monitoring and evaluation, for health planners setting local and national priorities, and for funders both domestic and global. Most importantly, they have consequences for people who are at risk of HIV exposure and infection. Achieving these targets will have a huge impact on the future of the HIV epidemic and put us back on track towards ending AIDS as a public health threat by 2030., Author(s): Peter Godfrey-Faussett 1,2,*, Luisa Frescura 1, Quarraisha Abdool Karim 3, Michaela Clayton 4, Peter D. Ghys 1,(on behalf of the 2025 prevention targets working group) Introduction Course correction needed [...]

: Introduction: Tenofovir disoproxil fumarate with emtricitabine (TDF/FTC) is used for HIV pre‐exposure prophylaxis (PrEP). TDF may affect bone mineral density (BMD), particularly in youth who are at a stage of peak bone mass accrual. The objective of this study was to evaluate the effect of vitamin D and calcium supplementation on BMD among Thai youth receiving daily oral PrEP. Methods: This open‐label randomized trial was conducted in male youth aged between 15 and 24 years. Participants were randomized to Arm A who received once‐daily TDF/FTC plus vitamin D3 and calcium supplementation with meals twice daily (400 units of vitamin D3 and 1200 mg of elemental calcium/day) or Arm B who received once‐daily TDF/FTC only. PrEP users were defined as taking at least two tablets/week (tenofovir‐diphosphate level of >350 fmol/punch). Adherence to vitamin D/calcium supplementation was defined as self‐reported adherence of >50%. Lumbar spine (L2‐L4) BMD (LSBMD) was evaluated by dual‐energy X‐ray absorptiometry scan zero and six months after PrEP initiation. Results: From March 2019 to March 2020, 100 youth were enrolled. Baseline characteristics between the two arms were similar. Median (IQR) age was 18 (17 to 20) years. At entry, median (IQR) LSBMD z‐score was −0.8 (−1.5 to −0.3), 17% had low LSBMD (Z‐score < −2). The median amount of calcium intake from nutritional three‐day recall was 167 (IQR 94 to 272) mg/day, 39% of participants had vitamin D deficiency, defined as 25(OH)D levels 3% increase in LSBMD at month 6 compared to baseline (67.6% vs. 42.9% respectively; p = 0.03). There were significantly higher increases in LSBMD among youth with vitamin D deficiency who were supplemented; arm A + 0.05 (0 to 0.05) compared to arm B + 0.03 (−0.1 to 0.03), p = 0.04. Conclusions: Increases in LSBMD over six months among youth using PrEP who received vitamin D/calcium supplementation was greater than those not supplemented. Long‐term follow‐up should be considered to explore long‐term outcomes., INTRODUCTION Men who have sex with men (MSM) make up the largest population receiving new HIV diagnoses in the United States (87%) [1], a trend also seen in Thailand where [...]