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Background: CheckMate 8HW prespecified dual primary endpoints, assessed in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient status: progression-free survival with nivolumab plus ipilimumab compared with chemotherapy as first-line therapy and progression-free survival with nivolumab plus ipilimumab compared with nivolumab alone, regardless of previous systemic treatment for metastatic disease. In our previous report, nivolumab plus ipilimumab showed superior progression-free survival versus chemotherapy in first-line microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer in the CheckMate 8HW trial. Here, we report results from the prespecified interim analysis for the other primary endpoint of progression-free survival for nivolumab plus ipilimumab versus nivolumab across all treatment lines., Methods: CheckMate 8HW is a randomised, open-label, international, phase 3 trial at 128 hospitals and cancer centres across 23 countries. Immunotherapy-naive adults with unresectable or metastatic colorectal cancer across different lines of therapy and microsatellite instability-high or mismatch repair-deficient status per local testing were randomly assigned (2:2:1) to nivolumab plus ipilimumab (nivolumab 240 mg, ipilimumab 1 mg/kg, every 3 weeks for four doses; then nivolumab 480 mg every 4 weeks; all intravenously), nivolumab (240 mg every 2 weeks for six doses, then 480 mg every 4 weeks; all intravenously), or chemotherapy with or without targeted therapies. The dual independent primary endpoints were progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus chemotherapy (first line) and progression-free survival by blinded independent central review with nivolumab plus ipilimumab versus nivolumab (all lines) in patients with centrally confirmed microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. This study is registered with ClinicalTrials.gov (NCT04008030)., Findings: Between Aug 16, 2019, and April 10, 2023, 707 patients were randomly assigned to nivolumab plus ipilimumab (n=354) or nivolumab alone (n=353). 296 (84%) of 354 patients in the nivolumab plus ipilimumab group and 286 (81%) of 353 patients in the nivolumab group were centrally confirmed to have microsatellite instability-high or mismatch repair-deficient status. At the data cutoff on Aug 28, 2024, median follow-up (from randomisation to data cutoff) was 47·0 months (IQR 38·4 to 53·2). Nivolumab plus ipilimumab treatment showed significant and clinically meaningful improvement in progression-free survival versus nivolumab (hazard ratio 0·62, 95% CI 0·48-0·81; p=0·0003). Median progression-free survival was not reached with nivolumab plus ipilimumab (95% CI 53·8 to not estimable) and was 39·3 months with nivolumab (22·1 to not estimable). Treatment-related adverse events of any grade occurred in 285 (81%) of 352 patients receiving nivolumab plus ipilimumab and in 249 (71%) of 351 patients receiving nivolumab; grade 3 or 4 treatment-related adverse events occurred in 78 (22%) and 50 (14%) patients, respectively. There were three treatment-related deaths: one event of myocarditis and pneumonitis each in the nivolumab plus ipilimumab group and one pneumonitis event in the nivolumab group., Interpretation: Nivolumab plus ipilimumab showed superior progression-free survival versus nivolumab across all treatment lines, with a manageable safety profile, in patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer. These results, together with the first-line results of superior progression-free survival with nivolumab plus ipilimumab versus chemotherapy, suggest nivolumab plus ipilimumab as a potential new standard of care for patients with microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer., Funding: Bristol Myers Squibb and Ono Pharmaceutical., Competing Interests: Declaration of interests TA reports consulting or advisory roles for Amgen, Aptitude Health, Astellas Pharma, Bristol Myers Squibb, GamaMabs Pharma, Gritstone Bio, Gilead Sciences, GlaxoSmithKline, MSD Oncology, Nordic Bioscience, Seagen, Servier, Pfizer, Pierre Fabre, Takeda-Lundbeck, Tesaro, and Transgene; receiving honoraria from Amgen, Bristol Myers Squibb, MSD Oncology, Merck Serono, GlaxoSmithKline, Pierre Fabre, Roche-Genentech, Sanofi, Seagen, Servier, and Ventana Medical Systems; a data monitoring committee role for Inspirna; being President of the ARCAD foundation (Aide à la recherché en cancérologie digestive), a member of the ACCENT Collaborative Group and Gercor; and travel or accommodation expenses from Bristol Myers Squibb, MSD Oncology, Takeda, and Servier. EE reports consulting or advisory roles for Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cureteq, Jannsen, Merck Serono, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, Repare Therapeutics, RIN Institute, Roche-Genentech, Sanofi, Seagen, Servier, and Takeda; receiving honoraria from Amgen, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cureteq, Janssen, Lilly, Medscape, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Pierre Fabre, Repare Therapeutics, RIN Institute, Roche-Genentech, Sanofi, Seagen, Servier, and Takeda; research funding to their institution from AbbVie, Amgen, Array BioPharma, AstraZeneca, Bayer, BeiGene, Bioncotech, BioNTech, Boehringer Ingelheim, Boehringer Ingelheim (Spain), Bristol Myers Squibb, Celgene, Daiichi Sankyo, Debiopharm Group, Gercor, HalioDx, Hutchison MediPharma, Iovance Biotherapeutics, Janssen-Cilag, Janssen R&D, MedImmune, Menarini, Merck, Merck Sharp & Dohme, Merus NV, Mirati, Novartis, Nouscom, PharmaMar, Pfizer, PledPharma, RedX Pharma, Pierre Fabre, Roche-Genentech, Sanofi, Scandion Oncology, Seagen, Servier, Sotio, Taiho, and WntResearch; and travel or accommodation expenses from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cureteq, Jannsen, Lilly, Medscape, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, Pierre Fabre, Repare Therapeutics, RIN Institute, Roche-Genentech, Sanofi, Servier, Seagen, and Takeda. H-JL reports consulting or advisory roles for Bayer, Bristol Myers Squibb, Fulgent Genetics, GlaxoSmithKline, Merck Serono, Roche-Genentech, and 3T BioSciences; receiving honoraria from Bayer, Boehringer Ingelheim, Fulgent Genetics, G1 Therapeutics, Isofol Medical, Jazz Pharmaceuticals, Merck Serono, Oncocyte, and Roche-Genentech; and travel or accommodation expenses from Bayer, Bristol Myers Squibb, and Merck Serono. LHJ reports receiving research grants to their institution from 2cureX, Bristol Myers Squibb, Roche-Genentech, Incyte, Merck Sharp & Dohme, and Pfizer. YT reports consulting or advisory roles for Bristol Myers Squibb, Merck Serono, Pierre Fabre, and Servier; and travel or accommodation expenses from Merck Serono, MSD Oncology, Pierre Fabre, and Servier. EVC reports consulting or advisory roles for AbbVie, Agenus, Amgen, ALX Oncology, Arcus Biosciences, Astellas Pharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Debiopharm Group, ElmediX, Eisai, GlaxoSmithKline, Hookipa Biotech, Incyte, Ipsen, Lilly, Merck KGaA, Merck Sharp & Dohme, Mirati, Nordic Group, Novartis, Pfizer-BioNTech, Pierre Fabre, Roche-Genentech, Seagen, Servier, Simcere, Taiho, Takeda, and Terumo. RG-C reports receiving honoraria from Advanced Accelerator Applications-Novartis, Astellas Pharma, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Esteve, Gilead Sciences, Hutchmed, Ipsen, Lilly, Merck, Merck Sharp & Dohme, Midatech Pharma, Mirati, Pfizer, Pharmamar, Roche-Genentech, Sanofi, Servier, and Takeda; receiving funding to their institution from Bristol Myers Squibb, Merck Sharp & Dohme, and Pfizer; and travel or accommodation expenses from Advanced Accelerator Applications-Novartis, Esteve, Ipsen, Merck Serono, and Merck Sharp & Dohme. DT reports consulting or advisory roles for AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pierre Fabre, Sanofi, Servier, and Takeda; receiving honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme, Pierre Fabre, Roche-Genentech, Sanofi, Servier-Pfizer, and Takeda; research funding to their institution from BTG, Merck Sharp & Dohme, Pierre Fabre, Roche-Genentech, and Takeda; and travel or accommodation expenses from Amgen, Bristol Myers Squibb, MSD Oncology, Pierre Fabre, Roche-Genentech, and Servier. GAM reports consulting or advisory roles for Amgen, Bristol Myers Squibb, Merck KGaA, Merck Sharp & Dohme, Pfizer, and Roche-Genentech; receiving speakers fees from Amgen, Bayer, Bristol Myers Squibb, Grupo Biotoscana, Merck KGaA, Merck Sharp & Dohme, Pfizer, Roche-Genentech, and Servier; research funding from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, and Roche-Genentech; patents, royalties, and intellectual properties with Bristol Myers Squibb and Merck Sharp & Dohme; and travel or accommodation expenses from Amgen, Grupo Biotoscana, Merck KGaA, Pfizer, and Servier. MS reports travel or accommodation expenses from Bristol Myers Squibb and Pfizer; and research funding from AbbVie, Amgen, Astellas Pharma, AstraZeneca, BeiGene, Bioven, Bristol Myers Squibb, Clovis Oncology, Daiichi Sankyo Europe, Eisai, Five Prime Therapeutics, Gilead Sciences, GlaxoSmithKline, Lilly, Merck Sharp & Dohme, Mylan, Novartis, Pfizer-EMD Serono, PharmaMar, Regeneron, Roche, Tesaro, Samsung Healthcare, and Sanofi-Regeneron. CdlF reports consulting or advisory roles for Amgen, Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Ipsen, Lilly, MSD Oncology, Pierre Fabre, Roche-Genentech, Servier, and Takeda; research funding to their institution from Merck Sharp & Dohme, Pierre Fabre, and Servier; and travel or accommodation expenses from Amgen, MSD Oncology, Pierre Fabre, Roche-Genentech, and Servier. TY reports consulting or advisory roles for Sumitomo Corporation; receiving honoraria from Chugai Pharma, Merck KGaA, Merck Sharp & Dohme, and Takeda; and research funding to their institution from Amgen, Bristol Myers Squibb Japan, Chugai Pharma, Daiichi Sankyo, Eisai, Falco Biosystems, Medical & Biological Laboratories Co, Merck Sharp & Dohme, Merus, Molecular Health, Ono Pharmaceutical, Pfizer, Roche-Genentech, Sanofi, Sysmex, Taiho, and Takeda. GT reports consulting or advisory roles for AstraZeneca, Bristol Myers Squibb, Merck KGaA, and Servier. MC reports consulting or advisory roles for Bristol Myers Squibb and Numab; and research funding to their institution from Bristol Myers Squibb, Merck Sharp and Dohme, and Roche-Genentech. EG reports consultancy roles for AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, and Merck Sharp and Dohme; and travel or accommodation expenses from Daiichi Sankyo. MIB reports consulting or advisory roles for Astellas, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Merck Sharp & Dohme, and Pfizer; receiving honoraria from Astellas, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Ipsen, Merck Sharp & Dohme, Pfizer, and Servier; and travel or accommodation expenses from Astellas and Daiichi Sankyo. RJ reports consulting or advisory roles for AstraZeneca, Merck Sharp & Dohme, and Roche-Genentech; receiving honoraria from Bristol Myers Squibb, Gilead Sciences, Ipsen, Merck Sharp & Dohme, Pfizer, Pfizer-EMD Serono, and Roche-Genentech; receiving speakers fees from Gilead Sciences; and travel or accommodation expenses from Novartis. FA reports consulting or advisory roles for Amgen, Bristol Myers Squibb, Merck KGaA, Pfizer, and Taiho; receiving honoraria from Amgen, Bristol Myers Squibb, Merck KGaA, Pfizer, and Taiho; and research funding to their institution from Bristol Myers Squibb, GlaxoSmithKline, Merck KGaA, and Novartis. EC, TCh, ML, LJ, and SIB report employment with Bristol Myers Squibb and ownership of stock in Bristol Myers Squibb. SL reports consulting or advisory roles for Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Incyte, Lilly, Merck Serono, Merck Sharp & Dohme, Servier, Rottapharm Biotech, and Takeda; receiving speakers fees from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Incyte, Lilly, Merck Serono, MSD Oncology, Pierre Fabre, Roche-Genentech, and Servier; and research funding from Amgen and Merck Serono (to self), and from AstraZeneca, Bayer, Bristol Myers Squibb, Lilly, and Roche-Genentech (to their institution). All other authors declare no competing interests., (Copyright © 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: The role of primary healthcare (PHC) during a pandemic varies across European countries. The coronavirus disease 2019 (COVID-19) pandemic has altered the working practices of family medicine doctors and impacted the resilience of healthcare systems., Objectives: This study aimed to examine European healthcare system responses to the pandemic, focusing on rural and urban differences., Material and Methods: This cross-sectional, mixed-methods study used a semi-structured online questionnaire with 68 questions, including 21 free-text comments. Data were collected from May 2020 to January 2021. Key informants from 16 European Rural and Isolated Practitioners Association (EURIPA) member countries distributed questionnaires to 406 PHC doctors. Data were analyzed using descriptive statistics and nonparametric tests (χ2, Kruskal-Wallis, Mann-Whitney U) with a significance threshold of 0.05., Results: A statistically significant difference was found between rural (36.4%, 55/151), semirural (19.4%, 24/124) and urban populations (29.8%, 39/131) regarding medicine shortages (χ2 = 9.91, degrees of freedom (df) = 4, p = 0.042). The semirural setting showed a statistically significant difference from the other settings (p = 0.004 in post hoc χ2 test). Significant differences were found between countries in resilience features including, effectiveness of triage, adapting to the rapidly changing requirements, government help, existence of a community resilience group, improved interprofessional collaboration, medicine shortage, and general practitioners (GPs) involvement in palliative care., Conclusions: Medicine shortage was more prevalent in rural and urban areas compared to semirural areas. Differences were observed between countries in their responses to the pandemic, particularly in adapting to the rapidly changing requirements, effectiveness of triage, government help, and the existence of a community resilience group. These differences were confirmed with qualitative analysis. The results emphasize the need for tailored approaches considering diverse contexts in shaping effective healthcare system resilience.

Objectives: To develop a deep learning (DL)-model using convolutional neural networks (CNN) to automatically identify the fetal head position at transperineal ultrasound in the second stage of labor., Material and Methods: Prospective, multicenter study including singleton, term, cephalic pregnancies in the second stage of labor. We assessed the fetal head position using transabdominal ultrasound and subsequently, obtained an image of the fetal head on the axial plane using transperineal ultrasound and labeled it according to the transabdominal ultrasound findings. The ultrasound images were randomly allocated into the three datasets containing a similar proportion of images of each subtype of fetal head position (occiput anterior, posterior, right and left transverse): the training dataset included 70 %, the validation dataset 15 %, and the testing dataset 15 % of the acquired images. The pre-trained ResNet18 model was employed as a foundational framework for feature extraction and classification. CNN 1 was trained to differentiate between occiput anterior (OA) and non-OA positions, CNN 2 classified fetal head malpositions into occiput posterior (OP) or occiput transverse (OT) position, and CNN 3 classified the remaining images as right or left OT. The DL-model was constructed using three convolutional neural networks (CNN) working simultaneously for the classification of fetal head positions. The performance of the algorithm was evaluated in terms of accuracy, sensitivity, specificity, F1-score and Cohen's kappa., Results: Between February 2018 and May 2023, 2154 transperineal images were included from eligible participants across 16 collaborating centers. The overall performance of the model for the classification of the fetal head position in the axial plane at transperineal ultrasound was excellent, with an of 94.5 % (95 % CI 92.0--97.0), a sensitivity of 95.6 % (95 % CI 96.8-100.0), a specificity of 91.2 % (95 % CI 87.3-95.1), a F1-score of 0.92 and a Cohen's kappa of 0.90. The best performance was achieved by the CNN 1 - OA position vs fetal head malpositions - with an accuracy of 98.3 % (95 % CI 96.9-99.7), followed by CNN 2 - OP vs OT positions - with an accuracy of 93.9 % (95 % CI 89.6-98.2), and finally, CNN 3 - right vs left OT position - with an accuracy of 91.3 % (95 % CI 83.5-99.1)., Conclusions: We have developed a DL-model capable of assessing fetal head position using transperineal ultrasound during the second stage of labor with an excellent overall accuracy. Future studies should validate our DL model using larger datasets and real-time patients before introducing it into routine clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Small extracellular vesicles (sEVs) obtained from mesenchymal stromal cells (MSCs) have shown considerable promise as restorative stroke treatment. In a head-to-head comparison in mice exposed to transient proximal middle cerebral artery occlusion (MCAO), sEVs obtained from MSCs cultured under hypoxic conditions particularly potently enhanced long-term brain tissue survival, microvascular integrity, and angiogenesis. These observations suggest that hypoxic preconditioning might represent the strategy of choice for harvesting MSC-sEVs for clinical stroke trials. To test the efficacy of hypoxic MSCs in a second stroke model in an additional species, we now exposed 6-8-month-old Sprague-Dawley rats to permanent distal MCAO and intravenously administered vehicle, platelet sEVs, or sEVs obtained from hypoxic MSCs (1% O 2 ; 2 × 10 6 or 2 × 10 7 cell equivalents/kg) at 24 h, 3, 7, and 14 days post-MCAO. Over 28 days, motor-coordination recovery was evaluated by rotating pole and cylinder tests. Ischemic injury, brain inflammatory responses, and peri-infarct angiogenesis were assessed by infarct volumetry and immunohistochemistry. sEVs obtained from hypoxic MSCs did not influence infarct volume in this permanent MCAO model, but promoted motor-coordination recovery over 28 days at both sEV doses. Ischemic injury was associated with brain ED1 + macrophage infiltrates and Iba1 + microglia accumulation in the peri-infarct cortex of vehicle-treated rats. Hypoxic MSC-sEVs reduced brain macrophage infiltrates and microglia accumulation in the peri-infarct cortex. In vehicle-treated rats, CD31 + /BrdU + proliferating endothelial cells were found in the peri-infarct cortex. Hypoxic MSC-sEVs increased the number of CD31 + /BrdU + proliferating endothelial cells. Our results provide evidence that hypoxic MSC-derived sEVs potently enhance neurological recovery, reduce neuroinflammation. and increase angiogenesis in rat permanent distal MCAO., (© 2024. The Author(s).)

Fabry disease (FD) is an X-linked rare disorder caused by mutations in the GLA gene. Women with FD have been less enrolled in studies and less treated compared with men. The aim of the present study is to describe the complete phenotype of the women cohort with FD diagnosed and evaluated in Romania and compare it to the male population. This study included all consecutive patients diagnosed with FD referred to the Expert Center for Rare Genetic Cardiovascular Diseases between 2014-2023 which included 73 consecutive Romanian FD patients: 41 women (56.2%) and 32 men (43.8%) from 33 unrelated families. Women with FD were diagnosed later and had a later symptom onset. Comparing with men, women were less often symptomatic, but with similar symptom severity. They had similar ophthalmologic and ENT involvement, but less angiokeratomas. Both women and men had similar heart failure symptoms, which were usually mild to moderate, with no difference between the age of developing of the heart failure symptoms. There were also similar rates of acroparesthesia and stroke between sexes, but women presented less renal involvement, with less requirement for renal transplant. This study demonstrates that women with Fabry disease are not just carriers of the disease, they can present symptoms as severe as men, and they have less or later access to pathogenic therapy. Further studies with more female participations are needed to better understand the burden of Fabry disease in women., (© 2024 Adriana Mursă et al., published by Sciendo.)

Background: Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB)., Patients and Methods: Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne ® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab., Results: In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals., Conclusions: Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab., Trial Registration Number: NCT03668119., Competing Interests: Competing interests: AG has received consulting fees from AstraZeneca, Novartis, MSD, and Gilead; has a patent interest with Mylan; has participated in a data safety monitoring board or advisory board for Novartis, AstraZeneca, MSD, and Gilead. AL has received grants from AstraZeneca and Sanofi; consulting fees from Seattle Genetics; honoraria/reimbursement and advisory board fees from AstraZeneca; advisory board fees or continuing medical education from Ability Pharma, Biocad, Clovis Oncology, GSK, Medscape, Merck Serono, MSD, TouchCongress, and Zentalis; support for attending meetings and/or travel from AstraZeneca, Clovis Oncology, GSK, and Roche; and participation on a data safety monitoring board or advisory board for ARIEL4 and TROPHIMMUNE. DSPT has received personal fees for advisory board membership from AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, Genmab, GSK, MSD, and Roche; personal fees as an invited speaker from AstraZeneca, Eisai, GSK, Merck Serono, MSD, Roche, and Takeda; ownership of stocks/shares of Asian Microbiome Library (AMiLi); institutional research grants from AstraZeneca, Bayer, Karyopharm Therapeutics, and Roche; institutional funding as coordinating PI from AstraZeneca, MSD, Eisai, Roche and Bergen Bio; institutional funding as local PI from Roche, GSK, Sutro Pharma, Bayer, Byondis B.V. and Zeria Pharmaceutical; a previous non-renumerated role as Chair of the Asia Pacific Gynecologic Oncology Trials Group (APGOT); a previous non-renumerated role as the Society President of the Gynecologic Cancer Group Singapore; non-renumerated membership of the Board of Directors of the GCIG; research funding from the Pangestu Family Foundation Gynaecological Cancer Research Fund; and product samples from AstraZeneca, Eisai, and MSD (non-financial interest). IL has received consulting fees from Boehringer Ingelheim; honoraria from Agenus, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Celon, Cullinan Oncology, Jacobio, Janssen, Loxo, Macrogenics, Menarini, MSD, Pfizer, Rhizen, Roche, Sanofi, and Takeda; institutional research funding from Agenus and Roche; and has been reimbursed for travel, accommodations, or expenses from Bristol Myers Squibb. J-PD has participated in advisory boards for Bristol Myers Squibb, Pierre Fabre, and Roche; has been an invited speaker for Merck Serono; has received research grants from Amgen, AstraZeneca, Bristol Myers Squibb, Genentech, MSD, and Transgene. JV has participated in a data safety monitoring board for IO Biotech; has stock options in Genentech-Roche. MB has received consulting fees from AstraZeneca, Bristol Myers Squibb, MSD Oncology, Novartis, and Roche/Genentech; has received fees for participating in speakers’ bureaus for Astra Zeneca, Bristol Myers Squibb, MSD Oncology, and Roche/Genentech. MM has received payment for a speaker for Alfasigma, Amgen, Astex, Bristol Myers Squibb, Eli Lilly, GSK, Incyte, IOnctura, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and SciClone; has received support for attending meetings and/or travel from Alfasigma, Amgen, Astex, Bristol Myers Squibb, Eli Lilly, GSK, Incyte, IOnctura, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and SciClone; has participated on a data safety monitoring board or advisory board for Alfasigma, Amgen, Astex, Bristol Myers Squibb, Eli Lilly, GSK, Incyte, IOnctura, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, Sanofi, and SciClone; has stock options in EpiGen and Theravance. MS has received research grants from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Clovis, Daiichi Sankyo, EISAI, Eli Lilly, Five Prime, Gilead, GSK, Mylan, Novartis, Pfizer, Pharma Mar, Samsung, and Takeda. NS provided consultation or attended advisory boards for Boehringer Ingelheim, Ellipses Pharma, GlaxoSmithKline, Incyte, and Luszana, with all payments to the Netherlands Cancer Institute; has received institutional research grants from AbbVie, Actuate Therapeutics, Amgen, Array, Ascendis Pharma, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, BridgeBio, Bristol Myers Squibb, Cantargia, CellCentric, Cogent Biosciences, Cresecendo Biologics, Cytovation, Deciphera, Dragonfly, Eli Lilly, Exelixis, Genentech, GSK, IDRx, Immunocore, Incyte, InteRNA, Janssen, Kinnate Biopharma, Kling Biotherapeutics, Lixte, Luszana, Merck, MSD, Merus, Molecular Partners, Navire Pharma, Novartis, Numab Therapeutics, Pfizer, Relay Pharmaceuticals, Revolution Medicin, Roche, Sanofi, Seattle Genetics, Taiho, and Takeda. PAA has received research grants from Bristol Myers Squibb, Pfizer, Roche/Genentech, and Sanofi; has received consulting fees from Bayer, Bio-Al Health, Bristol Myers Squibb, Italfarmaco, Lunaphore, Medicenna, Merck Serono, MSD, Nektar, Novartis, Pfizer, Philogen, Pierre-Fabre, Replimune, Roche-Genentech, Sandoz, Sanofi, Sun Pharma, and ValoTx; has received support for attending meetings and/or travel from Bio-AI-Health, MSD, Pfizer, and Replimune; has participated on a data safety monitoring board or advisory board for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Erasca, iTeos, MSD, Nouscom, Novartis, Oncosec, Regeneron, Roche-Genentech, and Seagen. T-EC has received research grants from Amgen, AstraZeneca, Merck Serono, MSD, Pfizer, Roche, and Takeda; consulting fees from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda; payment as a speaker for Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda; support for attending meetings and/or travel from Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda; has participated on a data safety monitoring board or advisory board for Amgen, AstraZeneca, Bristol Myers Squibb, Merck Serono, MSD, Pfizer, Servier, and Takeda. MP, PD and QD are employed by Bristol Myers Squibb. GK, JB, MP, MT, NH and SVV are employed by and hold stock options in Bristol Myers Squibb., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: After ST-segment elevation myocardial infarction (STEMI), follow-up imaging is currently recommended only in patients with left ventricular ejection fraction (LVEF) <40%. Left ventricular global longitudinal strain (LVGLS) was shown to improve risk stratification over LVEF in these patients but has not been thoroughly studied during follow-up. The aim of this study was to explore the changes in LVGLS after STEMI and their potential prognostic value., Materials and Methods: Data were analyzed from an ongoing STEMI registry. Echocardiography was performed during the index hospitalization and 1 year after STEMI; LVGLS was expressed as an absolute value and the relative LVGLS change (ΔGLS) was calculated. The study end point was all-cause mortality., Results: A total of 1,409 STEMI patients (age 60 ± 11 years; 75% men) who survived at least 1 year after STEMI and underwent echocardiography at follow-up were included. At 1-year follow-up, LVEF improved from 50% ± 8% to 53% ± 8% (P < .001) and LVGLS from 14% ± 4% to 16% ± 3% (P < .001). Median ΔGLS was 14% (interquartile range, 0.5%-32%) relative improvement. Starting 1 year after STEMI, a total of 87 patients died after a median follow-up of 69 (interquartile range, 38-103) months. The optimal ΔGLS threshold associated with the end point (derived by spline curve analysis) was a relative decrease >7%. Cumulative 10-year survival was 91% in patients with ΔGLS improvement or a nonsignificant decrease, versus 85% in patients with ΔGLS decrease of >7% (P = .001). On multivariate Cox regression analysis, ΔGLS decrease >7% remained independently associated with the end point (hazard ratio, 2.5 [95% CI, 1.5-4.1]; P < .001) after adjustment for clinical and echocardiographic parameters., Conclusions: A significant decrease in LVGLS 1 year after STEMI was independently associated with long-term all-cause mortality and might help further risk stratification and management of these patients during follow-up., Competing Interests: Conflicts of Interest This study is supported by a Novartis AG research grant. J.J.B. has received speaker fees from Abbott Vascular, Edwards Lifesciences, and Omron. N.A.M. has received speaker fees from Philips Ultrasound, Abbott Vascular, Omron, and GE Healthcare. K.T. has received speaker fees from Astra Zeneca, Bayer, Berlin Menarini, Boehringer-Ingelheim, Biotronik, Novo-Nordisk, and Servier. The Department of Cardiology of the Leiden University Medical Centre has received unrestricted research grants from Abbott Vascular, Alnylam, Bayer, Biotronik, Bioventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Medis, Pfizer, Pie Medical, and Medtronic. All other authors have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Objectives: to assess the impact of pulmonary hypertension (PH) on short and long-term respiratory and neurodevelopmental outcomes in extremely preterm infants, diagnosed with moderate to severe bronchopulmonary dysplasia (MSBPD)., Study Design: cohort study, with retrospective analysis of the medical records of infants born at ≤32 weeks gestation admitted to a single neonatal tertiary centre from 2010 to 2020. Primary outcome was consistent with hospital re-admissions by 2 years post menstrual age. Neurodevelopment was assessed using Bayley's Scales of Infant and Toddler Development 3rd edition (Bayley-III) as a secondary outcome., Results: 201 infants with no PH and 23 infants with PH were analysed. The PH group showed higher risk for respiratory and paediatric intensive care unit re-admission (65%) during the first 2 years of life (OR: 3.15; 95% CI: 1.28 to 7.78; p<0.5). In contrast to current published literature, our study showed that pulmonary hypertension complicating moderate to severe bronchopulmonary dysplasia had no negative impact on neurodevelopmental outcomes (OR: 1.87; 95% CI: 0.72 to 4.88; p value=0.19). However, in our population, ethnicity, chorioamnionitis and need for persistent ductus arteriosus treatment were all independently associated with poor neurodevelopmental outcomes (p values <0.5)., Conclusion: infants with MSBPD associated pulmonary hypertension (MSBPD-PH) are more likely to need intensive care and respiratory hospital re-admissions. Ethnicity, chorioamnionitis and need for ductus arteriosus treatment are independently associated with poor neurodevelopmental outcomes regardless of the pulmonary hypertension status., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2022, Medical University Publishing House Craiova.)

Background: Orthodontic therapy is a complex process involving a series of specialists in the dental field: the oral-maxillo-facial surgeon, the periodontologist, sometimes even the prosthetist, implantologist, or general practitioners. The injuries of the oral mucosa induced by orthodontic therapy include gingival overgrowths, traumatic lesions of the oral mucosa, different degrees of periodontal damage manifested by gingival retraction, alveolar bone resorption., Methods: From a total of 327 subjects who came to the Dental Clinic in Craiova 74 subjects were selected, who presented with gingival overgrowth associated with fixed orthodontic therapy. Subjects' age ranged from 14 to 56 years and experienced bleeding and gingival discomfort as well as alterations in physiognomic function. None of the patients included in the study have systemic diseases and are not under medical treatment. The clinical and statistical study took place between May 2022 and December 2023. Each patient was given a personal record containing personal data as well as oral and systemic health status. The examination of the periodontal status aimed at the evaluation of the following indices: assessment of oral hygiene using the OHI-S index and the O'Leary plaque index, assessment of superficial periodontal status using the Löe/Silness gingival inflammation index, periodontometry was performed in order to determine the depth of periodontal pockets, the level of gingival insertion, and the McGaw gingival overgrowth index. OHI-S index comprises two elements: the Debris Index and the Calculus Index. The purpose of our study is to present the incidence of cases of gingival overgrowth induced by fixed orthodontic therapy and to highlight how certain irritating factors can exacerbate the symptoms of gingival overgrowth of orthodontic etiology., Results: The majority of patients were female, aged between 30 and 55 years. Most clinically examined patients have presented with Grade II gingival hyperplasia. Factors that have exacerbated the symptoms of orthodontically induced gingival overgrowth include: incorrectly adapted prosthetic restorations, unpolished massive coronal fillings, root remnants, bacterial plaque, and tartar. Clinical examination of the oral cavity revealed the presence of gingival inflammation (localized or generalized), simple or complicated, treated and untreated odontal lesions, and coronal fillings made of light-curing composite material of significant size, being unfinished and unpolished, sometimes with sharp edges directly injuring the adjacent gingival mucosa, marginally incorrectly adapted prosthetic works. In the case of child and adolescent patients, significant amounts of bacterial plaque and tartar buildup were observed. In most of the cases examined, it was observed that the gingival overgrowth had a firm consistency, pinkish-reddish colour and gingival bleeding was evident during probing., Conclusion: Gingival overgrowth caused by orthodontics induces a number of important periodontal changes. It is worth noting that gingival overgrowth induced by fixed orthodontic therapy, in most of the cases examined, co-exists with favouring factors that amplify its severity. In our study, the favouring factors were bacterial plaque and calculus accumulation, sharp-edged odontal lesions, marginally ill-fitting prosthetic restorations or massive unfinished crown fillings. Therefore, removing the contributing factors can help improve the symptoms but also to reverse the inflammatory phenomena.

Background and Aims: Hepatocellular carcinoma (HCC) is a significant public health issue, with an increasing incidence and prevalence and a high incidence-to-mortality ratio. The prognosis of HCC depends on two competing factors, tumor burden and underlying liver disease severity, encompassed in the Barcelona Clinic Liver Cancer (BCLC) classification. To assess HCC staging and the way staging affects eligibility for treatment at the time of the first diagnosis in Romania in the setting of opportunistic diagnosis, in the absence of a national HCC screening policy., Methods: Data regarding HCC staging, underlying liver disease, and eligibility for treatment at the time of diagnosis was analyzed using a prospectively maintained multicentric database, which included patients from the five largest tertiary care hepatology units in the country between June 2016 and February 2020., Results: A consecutive series of 477 patients was included. The distribution within BCLC classes was as follows: very early (0) 7.1%, early (A) 34.3%, intermediate (B) 19.4%, advanced (C) 14.2%, terminal (D) 24.7%. At the time of the diagnosis, 198 (41.5%) were eligible for a curative intent treatment, while 359 (75.2%) were eligible for a disease-modifying therapy. 228 patients (47.8%) had decompensated liver disease at the time of diagnosis, the most common decompensating event being ascites (78.1%)., Conclusions: A large proportion of HCC cases are diagnosed at the time of a decompensating event, severely restricting the therapeutic potential. Proactive diagnostic strategies should be implemented to improve the rate of actionable diagnosis.

Background: Acute fatty liver disease in pregnancy (AFLP) is a low-incidence condition that usually affects women in the third trimester of pregnancy or the early postpartum period. This article reviews recent advances in the diagnosis and treatment of AFLP with pancreatitis in pregnancy induced by in vitro fertilization (IVF)., Case Report: A rare case of AFLP and pancreatitis occurred in a pregnant woman with an IVF-induced twin pregnancy delivered by cesarean section. Diagnosis of this condition is difficult, and delay in accurate diagnosis and timely and appropriate treatment can lead to serious complications such as acute pancreatitis or extensive damage to multiple organs and systems, which can have significant consequences. The main therapeutic approach was the rapid administration of drugs accompanied by therapeutic measures to support liver function and pancreatic complications., Conclusions: We would like to reemphasize the importance of multidisciplinary management and rapid intervention in AFLP with acute pancreatitis after IVF.

Introduction: Depressive-like behavior has been shown to be associated with liver damage. This study aimed to evaluate the impact of three different models of depression on the behavior of mice with liver injury., Methods: During the 4 weeks of methionine/choline deficiency diet (MCD), adult C57BL/6 mice were randomly divided into four groups: MCD (no stress protocol, n  = 6), chronic unpredictable mild stress (CUMS, n  = 9), acute and repeated forced swim stress [aFSS ( n  = 9) and rFSS ( n  = 9)]., Results: All depression protocols induced increased anhedonia and anxiety-like behavior compared to baseline and had no impact on the severity of liver damage, according to ultrasonography. However, different protocols evoked different overall behavior patterns. After the depressive-like behavior induction protocols, animals subjected to aFSS did not exhibit anxiety-like behavior differences compared to MCD animals, while mice subjected to CUMS showed additional weight loss compared to FSS animals. All tested protocols for inducing depressive-like behavior decreased the short-term memory of mice with liver damage, as assessed by the novel object recognition test (NORT)., Discussion: Our results show that the use of all protocols seems to generate different levels of anxiety-like behavior, but only the depressive-like behavior induction procedures associate additional anhedonia and memory impairment in mice with liver injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mușat, Mitran, Udriștoiu, Albu and Cătălin.)

SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients' primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis., (© 2024. The Author(s).)

Although the impact of host genetics on gut microbial diversity and the abundance of specific taxa is well established 1-6 , little is known about how host genetics regulates the genetic diversity of gut microorganisms. Here we conducted a meta-analysis of associations between human genetic variation and gut microbial structural variation in 9,015 individuals from four Dutch cohorts. Strikingly, the presence rate of a structural variation segment in Faecalibacterium prausnitzii that harbours an N-acetylgalactosamine (GalNAc) utilization gene cluster is higher in individuals who secrete the type A oligosaccharide antigen terminating in GalNAc, a feature that is jointly determined by human ABO and FUT2 genotypes, and we could replicate this association in a Tanzanian cohort. In vitro experiments demonstrated that GalNAc can be used as the sole carbohydrate source for F. prausnitzii strains that carry the GalNAc-metabolizing pathway. Further in silico and in vitro studies demonstrated that other ABO-associated species can also utilize GalNAc, particularly Collinsella aerofaciens. The GalNAc utilization genes are also associated with the host's cardiometabolic health, particularly in individuals with mucosal A-antigen. Together, the findings of our study demonstrate that genetic associations across the human genome and bacterial metagenome can provide functional insights into the reciprocal host-microbiome relationship., (© 2024. The Author(s).)

PERLA is a global, double-blind, parallel phase II trial (NCT04581824) comparing efficacy and safety of anti-PD-1 antibodies dostarlimab and pembrolizumab, plus chemotherapy (DCT and PCT, respectively) as first-line treatment in patients with metastatic non-squamous NSCLC without known targetable genomic aberrations. Patients stratified by PD-L1 tumor proportion score and smoking status were randomized 1:1, receiving ≤35 cycles 500 mg dostarlimab or 200 mg pembrolizumab, ≤35 cycles 500 mg/m 2 pemetrexed and ≤4 cycles cisplatin (75 mg/m 2 ) or carboplatin (AUC 5 mg/ml/min) Q3W. Primary endpoint was overall response rate (ORR) (blinded independent central review). Secondary endpoints include progression-free survival (PFS) based on investigator assessment, overall survival (OS) and safety. Exploratory endpoints include ORR by PD-L1 subgroup and duration of response. PERLA met its pre-specified endpoint. ORR (n/N; 95% CI) is 45% (55/121; 36.4-54.8) for DCT and 39% (48/122; 30.6-48.6) for PCT (data cut-off: 07 July 23), numerically favoring dostarlimab in PD-L1-positive subgroups. Median PFS (months [95% CI]) is 8.8 (6.7-10.4) for DCT and 6.7 (4.9-7.1) for PCT (HR 0.70 [95% CI: 0.50-0.98]; data cut-off: 04 August 22). Median OS (months [95% CI]) is 19.4 (14.5-NR) for DCT and 15.9 (11.6-19.3) for PCT (HR 0.75 [95% CI: 0.53-1.05]) (data cut-off: 07 July 23). Safety profiles are similar between groups. In this study, DCT shows similar efficacy to PCT and demonstrates clinical efficacy as first-line treatment for patients with metastatic non-squamous NSCLC., (© 2023. The Author(s).)

Background: No new agent has improved overall survival in patients with unresectable or metastatic urothelial carcinoma when added to first-line cisplatin-based chemotherapy., Methods: In this phase 3, multinational, open-label trial, we randomly assigned patients with previously untreated unresectable or metastatic urothelial carcinoma either to receive intravenous nivolumab (at a dose of 360 mg) plus gemcitabine-cisplatin (nivolumab combination) every 3 weeks for up to six cycles, followed by nivolumab (at a dose of 480 mg) every 4 weeks for a maximum of 2 years, or to receive gemcitabine-cisplatin alone every 3 weeks for up to six cycles. The primary outcomes were overall and progression-free survival. The objective response and safety were exploratory outcomes., Results: A total of 608 patients underwent randomization (304 to each group). At a median follow-up of 33.6 months, overall survival was longer with nivolumab-combination therapy than with gemcitabine-cisplatin alone (hazard ratio for death, 0.78; 95% confidence interval [CI], 0.63 to 0.96; P = 0.02); the median survival was 21.7 months (95% CI, 18.6 to 26.4) as compared with 18.9 months (95% CI, 14.7 to 22.4), respectively. Progression-free survival was also longer with nivolumab-combination therapy than with gemcitabine-cisplatin alone (hazard ratio for progression or death, 0.72; 95% CI, 0.59 to 0.88; P = 0.001). The median progression-free survival was 7.9 months and 7.6 months, respectively. At 12 months, progression-free survival was 34.2% and 21.8%, respectively. The overall objective response was 57.6% (complete response, 21.7%) with nivolumab-combination therapy and 43.1% (complete response, 11.8%) with gemcitabine-cisplatin alone. The median duration of complete response was 37.1 months with nivolumab-combination therapy and 13.2 months with gemcitabine-cisplatin alone. Grade 3 or higher adverse events occurred in 61.8% and 51.7% of the patients, respectively., Conclusions: Combination therapy with nivolumab plus gemcitabine-cisplatin resulted in significantly better outcomes in patients with previously untreated advanced urothelial carcinoma than gemcitabine-cisplatin alone. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 901 ClinicalTrials.gov number, NCT03036098.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose: Despite marked advances in the treatment of unresectable or metastatic melanoma, the need for novel therapies remains. Bempegaldesleukin (BEMPEG), a pegylated interleukin-2 (IL-2) cytokine prodrug, demonstrated efficacy in the phase II PIVOT-02 trial. PIVOT IO 001 (ClinicalTrials.gov identifier: NCT03635983) is a phase III, randomized, open-label study that builds on the PIVOT-02 results in first-line melanoma., Methods: Patients with previously untreated, unresectable, or metastatic melanoma were randomly assigned 1:1 to receive BEMPEG plus nivolumab (NIVO) or NIVO monotherapy. Primary end points were objective response rate (ORR) and progression-free survival (PFS) by blinded independent central review and overall survival (OS). Secondary and exploratory end points included additional efficacy measures, safety, and pharmacokinetics (PKs) and pharmacodynamics analyses., Results: In 783 patients (n = 391, BEMPEG plus NIVO; n = 392, NIVO monotherapy), the median follow-up was 11.6 months in the intent-to-treat population. The ORR with BEMPEG plus NIVO was 27.7% versus 36.0% with NIVO (two-sided P = .0311). The median PFS with BEMPEG plus NIVO was 4.17 months (95% CI, 3.52 to 5.55) versus 4.99 months (95% CI, 4.14 to 7.82) with NIVO (hazard ratio [HR], 1.09; 97% CI, 0.88 to 1.35; P = .3988). The median OS was 29.67 months (95% CI, 22.14 to not reached [NR]) with BEMPEG plus NIVO versus 28.88 months (95% CI, 21.32 to NR) with NIVO (HR, 0.94; 99.929% CI, 0.59 to 1.48; P = .6361). Grade 3-4 treatment-related adverse events (AEs) and serious AE rates were higher with the combination (21.7% and 10.1%, respectively) versus NIVO (11.5% and 5.5%, respectively). BEMPEG PK exposure and absolute lymphocyte count changes after BEMPEG plus NIVO were comparable between PIVOT IO 001 and PIVOT-02., Conclusion: The PIVOT IO 001 study did not meet its primary end points of ORR, PFS, and OS. Increased toxicity was observed with BEMPEG plus NIVO versus NIVO.

Triple-chamber cardiac devices are utilized for cardiac resynchronization therapy (CRT) and is the standard-of-care therapy for heart failure (HF) patients in the current guidelines. In the setting of biventricular (BIV) pacing it involves a mandatory implantation of right ventricular (RV) lead that allows simultaneous BIV pacing with 0 ms VV (ventricular to ventricular) interval. Nevertheless, it seems that response to CRT is not related to RV lead position. RV pacing is known for deleterious effects on RV/Left Ventricle (LV) function and should not be used in persons with normal atrioventricular conduction (AV) and sinus rhythm. As it compensates for the additional asynchrony induced by unnecessary stimulation of RV pacing, only pacing the left ventricle (LV) may result in improved cardiac resynchronization therapy (CRT) outcomes and a decrease in the number of individuals who do not respond to the procedure. Furthermore, leadless LV fusion CRT pacing without RV lead could be a potential CRT therapy alternative to BIV pacing in nonischemic heart failure patients with preserved AV conduction. The aim of our study is to made an update in cardiac resynchronization therapy with LV only fusion pacing., Competing Interests: The authors have no conflict of interest to declare., (Copyright © 2022, Medical University Publishing House Craiova.)

Background: The coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can present with a broad range of clinical manifestations, ranging from asymptomatic to severe multiple organ failure. The severity of the disease can vary depending on factors such as age, sex, ethnicity, and pre-existing medical conditions. Despite multiple efforts to identify reliable prognostic factors and biomarkers, the predictive capacity of these markers for clinical outcomes remains poor. Circulating proteins, which reflect the active mechanisms in an individual, can be easily measured in clinical practice and therefore may be useful as biomarkers for COVID-19 disease severity. In this study, we sought to identify protein biomarkers and endotypes for COVID-19 severity and evaluate their reproducibility in an independent cohort., Methods: We investigated a cohort of 153 Greek patients with confirmed SARS-CoV-2 infection in which plasma protein levels were measured using the Olink Explore 1536 panel, which consists of 1472 proteins. We compared the protein profiles from severe and moderate COVID-19 patients to identify proteins associated with disease severity. To evaluate the reproducibility of our findings, we compared the protein profiles of 174 patients with comparable COVID-19 severities in a US COVID-19 cohort to identify proteins consistently correlated with COVID-19 severity in both groups., Results: We identified 218 differentially regulated proteins associated with severity, 20 proteins were also replicated in an external cohort which we used for validation. Moreover, we performed unsupervised clustering of patients based on 97 proteins with the highest log2 fold changes in order to identify COVID-19 endotypes. Clustering of patients based on differentially regulated proteins revealed the presence of three clinical endotypes. While endotypes 2 and 3 were enriched for severe COVID-19 patients, endotypes 3 represented the most severe form of the disease., Conclusions: These results suggest that identified circulating proteins may be useful for identifying COVID-19 patients with worse outcomes, and this potential utility may extend to other populations., Trial Registration: NCT04357366., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)