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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 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.)

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19., Competing Interests: Declaration of interests MSW has received unrestricted funding from Sartorius. GL reports personal fees from Swedish Orphan Biovitrum. TSp and JCS disclose institutional funding (received by the University of Bern) from Orion Pharma, Abbott Nutrition International, B Braun Medical, CSEM, Edwards Lifesciences, Kenta Biotech, Maquet Critical Care, Omnicare Clinical Research, Nestlé, Pierre Fabre Pharma, Pfizer, Bard Medica, Abbott, Anandic Medical Systems, PanGas Healthcare, Bracco, Hamilton Medical, Fresenius Kabi, Getinge Group Maquet, Dräger, Teleflex Medical, GlaxoSmithKline, Merck Sharp and Dohme, Eli Lilly, Baxter, Astellas, AstraZeneca, CSL Behring, Novartis, Covidien, Nycomed, Phagenesis, and Hemotune. MGN reports grants from GlaxoSmithKline and ViiV Healthcare, and was a scientific founder of TTxD. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: There is currently no evidence suggesting that COVID-19 takes a different course in HIV-positive patients on antiretroviral treatment compared to the general population. However, little is known about the relation between specific HIV-related factors and the severity of the COVID-19 disease., Methods: We performed a retrospective analysis of cases collected through an on-line survey distributed by the Euroguidelines in Central and Eastern Europe Network Group. In statistical analyses characteristics of HIV-positive patients, asymptomatic/moderate and moderate/severe course were compared., Results: In total 34 HIV-positive patients diagnosed with COVID-19 were reported by 12 countries (Estonia, Czech Republic, Lithuania, Albania, Belarus, Romania, Serbia, Bosnia and Herzegovina, Poland, Russia, Hungary, Bulgaria). Asymptomatic courses of COVID-19 were reported in four (12%) cases, 11 (32%) patients presented with mild disease not requiring hospitalization, moderate disease with respiratory and/or systemic symptoms was observed in 14 (41%) cases, and severe disease with respiratory failure was found in five (15%) patients. The HIV-related characteristics of patients with an asymptomatic/mild course of COVID-19 were comparable to those with a moderate/severe course of COVID-19, except for the use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in cART regimen (0.0% vs. 31.6% respectively, p = 0.0239)., Conclusions: In our analyses HIV viral suppression and immunological status were not associated with the course of COVID-19 disease. On the contrary the cART regimen could contribute to severity of SARS-CoV-2 infection. Large and prospective studies are necessary to further investigate this relationship., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The coronavirus disease 2019 (COVID-19) pandemic outbreak forced cancer care providers to face different challenges in terms of prevention and treatment management due to specific precautions implemented for oncological patients. We aimed to describe the level of knowledge, attitude and practices (KAP) among cancer patients, with the purpose to provide an image of the impact of COVID-19 and evaluate the effectiveness of pandemic response measures., Patients and Methods: We developed a cross-sectional multicentric study that targeted adults with active cancer during the COVID-19 outbreak, aiming to describe KAP related to COVID-19 among Romanian oncological patients. A questionnaire investigating 64 items on KAP related to the novel coronavirus was designed and applied in seven Romanian hospitals. The group of participants consisted of 1585 oncological patients who completed the questionnaire during the outbreak (April-May 2020)., Results: Only 172 patients (10.8%) had very good knowledge about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection symptoms, treatment options and incubation period. Only 44.3% of patients identified diarrhoea as a sign of COVID-19. About one-third of patients (32.6%) declared that they are 'very worried' about getting infected with the novel coronavirus. More than two-thirds of participants (68%) considered that having cancer represents an additional risk for infection with SARS-CoV-2, but 27.8% would rather not vaccinate against SARS-CoV-2 should a vaccine be available. A small percentage (8.8%) believed that the risk of infection justifies delaying/stopping oncological treatment until after the pandemic. Around half of the participants (55.5%) declared being compliant with all the protective measures against coronavirus infection listed in the questionnaire., Conclusion: Romanian oncological patients have a less than expected knowledge about SARS-CoV-2, appropriate prevention behaviours, with limited trust in their efficacy, optimistic attitudes towards COVID-19 and low level of trust in information sources. Good COVID-19 knowledge was associated with appropriate practices towards COVID-19 and optimistic attitudes., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Sepsis predisposes for poor stroke outcome. This association suggests that sepsis disturbs post-ischemic tissue survival and brain remodeling. To elucidate this link, we herein exposed mice to 30 min intraluminal middle cerebral artery occlusion (MCAO) and induced a sepsis-like state at 72 h post-ischemia by intraperitoneal delivery of Escherichia coli lipopolysaccharide (LPS; three doses of 0.1 or 1 mg/kg, separated by 6 h), a major component of the bacterium's outer membrane. Neurological recovery, ischemic injury, brain remodeling and immune responses were evaluated over up to 56 days post-sepsis (dps) by behavioral tests, immunohistochemistry and flow cytometry. Delivery of 1 mg/kg but not 0.1 mg/kg LPS reduced rectal temperature over 48 h by up to 3.4 ± 3.1 °C, increased general and focal neurological deficits in the Clark score over 72 h and increased motor-coordination deficits in the tight rope test over up to 21 days. Notably, 1 mg/kg, but not 0.1 mg/kg LPS increased intercellular adhesion molecule-1 abundance on ischemic microvessels, increased microvascular thrombosis and increased patrolling monocyte and T cell infiltrates in ischemic brain tissue at 3 dps. Infarct volume was increased by 1 mg/kg, but not 0.1 mg/kg LPS at 3 dps (that is, 6 days post-MCAO), as was brain atrophy at 28 and 56 dps. Microglial activation in ischemic brain tissue, evaluated by morphology analysis of Iba-1 immunostainings, was transiently increased by 0.1 and 1 mg/kg LPS at 3 dps. Our data provide evidence that neurological recovery and brain remodeling are profoundly compromised in the ischemic brain post-sepsis as a consequence of cerebral thromboinflammation., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Changes in cellular metabolism have proven to be important factors in driving cell behavior. It has been shown that cellular metabolism of immune cells changes when exposed to or infected by several pathogens: while this is often an adaptation of the host cells to the infection, sometimes it represents a mechanism through which the pathogens evade immune activation. Borrelia burgdorferi sensu lato, the causative agent of Lyme borreliosis, is a pathogen that highly depends on the host to survive, as the bacterium lacks many central metabolic pathways to generate its own nutrients. It is therefore quite likely that the bacterium interacts with host cells to obtain these metabolites and thereby affects metabolism in the host. Previously, several studies have assessed metabolic pathways in B. burgdorferi s.l. and how it adapts to its different host species. However, few studies have looked into how the interaction with the bacterium might affect the host cell metabolism. In this review we present the major metabolic pathways activated during Lyme borreliosis, viewed from both bacterium and host metabolism, and we discuss how these pathways interact with each other, and how they influence pathogenesis of Lyme borreliosis., Competing Interests: Declaration of Competing Interest No potential conflict of interest was reported by the authors, (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: A broad literature base exists for measuring medication adherence to monotherapeutic regimens, but publications are less extensive for measuring adherence to multiple medications., Objectives: To identify and characterize the multiple medication adherence (MMA) methods used in the literature., Methods: A literature search was conducted using PubMed, PsycINFO, the International Pharmaceutical Abstracts, the Cumulative Index to Nursing and Allied Health Literature and the Cochrane Library databases on methods used to measure MMA published between January 1973 and May 2015. A two-step screening process was used; all abstracts were screened by pairs of researchers independently, followed by a full-text review identifying the method for calculating MMA. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed to conduct this systematic review. For studies that met the eligibility criteria, general study and adherence-specific characteristics and the number and type of MMA measurement methods were summarized., Results: The 147 studies that were included originated from 32 countries, in 13 disease states. Of these studies, 26 used proportion of days covered, 23 used medication possession ratio, and 72 used self-reported questionnaires (e.g., the Morisky Scale) to assess MMA. About 50% of the studies included more than one method for measuring MMA, and different variations of medication possession ratio and proportion of days covered were used for measuring MMA., Conclusions: There appears to be no standardized method to measure MMA. With an increasing prevalence of polypharmacy, more efforts should be directed toward constructing robust measures suitable to evaluate adherence to complex regimens. Future research to understand the validity and reliability of MMA measures and their effects on objective clinical outcomes is also needed., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

The paradigm that only adaptive immunity can develop immunological memory has recently been challenged by studies showing that cells from the innate immune system can undergo functional reprogramming, facilitating a faster and enhanced response to secondary infections. This improved secondary response is not always specific, as it can also protect from infections caused by non-related pathogens. This has been termed innate immune memory or trained immunity. Trained immunity not only involves rewiring the intracellular immune signaling of innate immune cells, but also induces profound changes in cellular metabolic pathways such as glycolysis, oxidative phosphorylation, fatty acid and amino acid metabolism, increasing the capacity of the innate immune cells to respond to a secondary stimulation. The understanding of these intracellular processes opens new therapeutic possibilities for the modulation of the innate immune responses during infections and inflammatory diseases., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Our current understanding of the pathophysiology and management of sepsis is associated with a lack of progress in clinical trials, which partly reflects insufficient appreciation of the heterogeneity of this syndrome. Consequently, more patient-specific approaches to treatment should be explored., Aims: To summarize the current evidence on precision medicine in sepsis, with an emphasis on translation from theory to clinical practice. A secondary objective is to develop a framework enclosing recommendations on management and priorities for further research., Sources: A global search strategy was performed in the MEDLINE database through the PubMed search engine (last search December 2017). No restrictions of study design, time, or language were imposed., Content: The focus of this Position Paper is on the interplay between therapies, pathogens, and the host. Regarding the pathogen, microbiologic diagnostic approaches (such as blood cultures (BCs) and rapid diagnostic tests (RDTs)) are discussed, as well as targeted antibiotic treatment. Other topics include the disruption of host immune system and the use of biomarkers in sepsis management, patient stratification, and future clinical trial design. Lastly, personalized antibiotic treatment and stewardship are addressed (Fig. 1)., Implications: A road map provides recommendations and future perspectives. RDTs and identifying drug-response phenotypes are clear challenges. The next step will be the implementation of precision medicine to sepsis management, based on theranostic methodology. This highly individualized approach will be essential for the design of novel clinical trials and improvement of care pathways., (Copyright © 2018 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Percutaneous transluminal coronary angioplasty and subsequent vascular scaffold implantation remains the prevalent invasive treatment of coronary heart disease. In-stent restenosis remained a problem with bare metal stents, until drug-eluting stents were introduced. The inhibition of the healing process by the antimitotic drug coating and the permanent metallic remnant can promote sub-acute and delayed stent thrombosis. Thus, the development of biodegradable stents emerged as a subject of research. Magnesium-based bioabsorbable devices can provide sufficient radial force in the acute phase of vessel-treatment and degrade thoroughly in aqueous environment, making them potential new candidates for vascular scaffold applications. Magnesium alloys tend to degrade very quickly due to their high electrochemical corrosion potential. Plasma Electrolytic Oxidation modification of magnesium alloys improves interface and degradadation properties and may therefore enhance the performance and suitability for vascular scaffold applications of these materials. Assuring the hemocompatibility and foremost assessing the thrombogenicity of new biomaterials prior to their use is essential in order to avoid adverse effects. The goal was to assess thrombocyte adhesion on coated Mg-RE and Mg-Zn-Ca alloys. Static experiments with human blood were carried out on the plasma-electrolytically treated or corresponding untreated Mg alloy in order to assess quantity and quality of thrombocyte adhesion via standardized SEM imaging. In a second step, a parallel plate flow chamber was designed in order to examine thrombocyte adhesion under dynamic flow conditions. During flow chamber experiments the test-materials were exposed to human thrombocyte concentrate and the number of adherent thrombocytes was assessed. The flow chamber was additionally perfused with human blood and thrombocyte adhesion was semiquantitatively and qualitatively assessed via SEM imaging and subsequent scoring. In conclusion, a new parallel plate flow chamber design simulating blood-circulation was successfully established, enabling the further assessment of platelet adhesion on bioabsorbable materials under dynamic flow conditions. Static and dynamic experiments showed, that plasma-electrolytically treated specimens showed low thrombocyte adhesion on both alloys, proposing their potential use in vascular scaffolds. The uncoated magnesium alloys showed rapid degradation along with gas formation due to the chemically active surface and therefore give concern regarding their safety and suitability for vascular applications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Polymeric nanoparticles were prepared from self-assembled amphiphilic N-vinylpyrrolidone polymers in aqueous media and evaluated as novel carriers of indomethacin, a non-steroidal, anti-inflammatory drug. It was determined that these nanoparticles could be created in spherical morphologies with sizes less than 100nm, narrow size distributions and high indomethacin contents(up to 35%) combined with high drug loading efficiencies(up to 95%). In cytotoxicity tests using the human embryonic stem cell derived fibroblasts (EBF-H9) and hepatocellular carcinoma cells (HepG2), the indomethacin-loaded polymeric nanoparticles showed higher cell viability compared to that of free indomethacin at the same concentration. The median LD 50 values, determined by the Litchfield-Wilcoxon method, were 55-70mg/kg body weight depending on the polymer molecular design in both mice and rats. Based on the acquired results, these novel amphiphilic poly-N-vinylpyrrolidone nanoparticles can be considered as potential carriers for new, highly efficient, injectable drug delivery systems for hydrophobic drugs such as indomethacin., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Stroke is a major cause of disability for which no neuroprotective measures are available. Age is the principal nonmodifiable risk factor for this disease. Previously, we reported that exposure to hydrogen sulfide for 48 hours after stroke lowers whole body temperature and confers neuroprotection in aged animals. Because the duration of hypothermia in most clinical trials is between 24 and 48 hours, we questioned whether 24 hours exposure to gaseous hypothermia confers the same neuroprotective efficacy as 48 hours exposure. We found that a shorter exposure to hypothermia transiently reduced both inflammation and infarct size. However, after 1 week, the infarct size became even larger than in controls and after 2 weeks there was no beneficial effect on regenerative processes such as neurogenesis. Behaviorally, hypothermia also had a limited beneficial effect. Finally, after hydrogen sulfide-induced hypothermia, the poststroke aged rats experienced a persistent sleep impairment during their active nocturnal period. Our data suggest that cellular events that are delayed by hypothermia in aged rats may, in the long term, rebound, and diminish the beneficial effects., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The objective of this study was to determine the effect of propranolol pretreatment on mepivacaine serum concentrations in dental patients., Study Design: In a double blind, randomized, 2-way crossover study, 10 patients ingested 30 mg propranolol or placebo, 2 hours before local anesthesia for dental scaling. Each subject received a single dose of 51 mg mepivacaine for posterior superior alveolar nerve block. Mepivacaine in venous serum was measured for up to 1 hour, after 5, 15, 30, 45, and 60 minutes from injection. Serum concentrations of mepivacaine were determined by gas chromatography. Blood pressure and heart rate were measured before and after propranolol or placebo and after each sampling., Results: Peak serum concentrations of mepivacaine, C(max) (1.214 +/- 0.746 microg/mL(-1)), were significantly increased by propranolol (2.249 +/- 1.559 microg/mL(-1), P < .05). Propranolol pretreatment reduced blood pressure and heart rate., Conclusion: Although propranolol pretreatment increased almost doublefold mepivacaine serum concentrations and reduced blood pressure and heart rate, mepivacaine can be used safely in dental patients taking propranolol for short-duration interventions.

The growth pattern of hepatocellular carcinoma (HCC) arising from cirrhosis is variable and depends on the degree of differentiation and vascularization. Because growth is not constant in the natural history of HCC, prediction of subsequent growth rate based on tumor volume doubling time and correlation with histological and ultrasonographical characteristics at the moment of initial diagnosis are usually unreliable. The aim of our study was to assess the growth patterns of HCC with the aid of stochastic modeling. Thus, we included in our study 27 patients with histologically proven HCC, which had multiple (more than three)follow-up ultrasound studies in a six months interval. The patients did not receive any treatment during the observation period. HCC was visualized by computer aided ultrasound imaging, obtaining both the primary size quantification and the edge-detection enhancement. By a bi-cubic B-spline interpolation of points on the edges (3-D Bezier approximation) we approximated the surfaces shapes, and using the hit or miss Monte Carlo method we accurately estimate the tumor volume. Starting from the previous tumor volumes time series recorded during the first six months of evolution we applied both a linear, exponential and logarithmic smoothing to forecast the future size of the HCC tumor in the next six months. Our conclusion was that a dynamic forecasting model of HCC volumes could be very accurate for the assessment of tumor volume doubling time usually obtained by two discrete volume measurements of the tumor.