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Objective: To investigate the use of non-barrier contraceptives among women with HIV (WWH) compared to women from the general population (WGP) in Denmark., Design: Nationwide population-based matched cohort study., Methods: We included WWH aged 16-50, treated at an HIV specialized clinic, and included in The Danish HIV Cohort Study between 1995-2021 and an age-matched comparison cohort of WGP. We examined use of hormonal contraception (HC), intrauterine devices (IUD), and sterilization from 10 years before to 20 years after study inclusion. Additionally, we calculated age-standardized proportions and incidences over calendar time., Results: We included 1,720 WWH and 17,720 WGP. Median age was 33 years and almost half of WWH had African origin (41%). Non-barrier contraceptive use was lower among WWH (8.5%) compared to WGP (32.1%) at study inclusion. Before and after inclusion, WWH had nearly half the non-barrier contraceptive use of WGP, with notably lower HC and IUD use. Initially, fewer WWH were sterilized, but five years after inclusion, sterilization became the preferred method among WWH. HC use increased among WWH after 2010 but decreased among WGP after 2005. IUD use increased among both groups during 1995-2021 but remained lower among WWH. Incidence of sterilizations remained stable in both groups., Conclusion: Use of non-barrier contraceptives was lower among WWH compared to WGP. For WWH, sterilization became the preferred non-barrier method few years after study inclusion. HC and IUD use increased among WWH after 2010 but remained lower than for WGP. Improved contraceptive counseling is recommended to support reproductive health among WWH., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Influenza vaccination in patients with acute myocardial infarction (AMI) reduces major adverse cardiac events and is strongly recommended in clinical practice guidelines. Effective strategies to improve vaccination are needed in these high-risk patients., Objective: To evaluate whether electronically delivered behavioral nudges improve influenza vaccine uptake in patients with AMI across 3 nationwide implementation randomized clinical trials (RCTs)., Design, Setting, and Participants: Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake (NUDGE-FLU), Nationwide Utilization of Danish Government Electronic Letter System for Confirming the Effectiveness of Behavioral Nudges in Increasing Influenza Vaccine Uptake Among Older Adults (NUDGE-FLU-2), and Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake Among Adults With Chronic Disease (NUDGE-FLU-CHRONIC) were RCTs conducted during the 2022 to 2023 and 2023 to 2024 influenza seasons in Denmark. Participants were randomized to either usual care or various behaviorally informed, electronically delivered, letter-based nudges. In a prespecified participant-level pooled meta-analysis, interaction of AMI status on the effects of letter-based nudges vs usual care was examined. Pooled treatment effects were estimated using binomial regression models with identity link, adjustment for trial, and 2-way clustered SEs at the household and participant levels. Effect modification by recency of AMI as a continuous variable was assessed using restricted cubic spline modeling in NUDGE-FLU-CHRONIC., Interventions: Behaviorally informed, electronically delivered, letter-based nudges or usual care., Main Outcome and Measures: The primary end point was influenza vaccination receipt., Results: Of 2 146 124 individual randomizations (mean [SD] age, 71.1 [11.6] years; 1 114 725 female [51.9%]) across all 3 trials, 59 458 (2.8%) had a history of AMI. Improvement in vaccine uptake was similar in patients with vs without a history of AMI who received any nudge letter compared with usual care (+1.81 vs +1.32 percentage points; P for interaction by AMI status = .09). A letter highlighting the cardiovascular benefits of vaccination (ie, cardiovascular-gain frame) resulted in larger improvements in vaccine uptake among patients with (vs without) a history of AMI (+3.91 vs +2.03 percentage points; P for interaction by AMI status = .002). Among patients with AMI, the benefits of the cardiovascular-gain frame letter were more pronounced in those not vaccinated in the prior season (+13.7 vs +1.48 percentage points; P for interaction <.001). Among younger participants with chronic disease, the cardiovascular-gain frame letter was particularly effective in patients with more recent AMI (P for interaction by continuous recency of AMI <.001)., Conclusions and Relevance: Across 3 nationwide RCTs of Danish citizens, messaging emphasizing the cardiovascular benefits of vaccination improved influenza vaccination uptake, with greater benefits observed in patients with a history of AMI. This low-cost, scalable implementation strategy should be considered to encourage influenza vaccination in high-risk patients., Trial Registration: ClinicalTrials.gov Identifiers: NCT05542004, NCT06030726, NCT06030739.

Soil salinization is a gradual degradation process that begins as a minor problem and grows to become a significant economic loss if no control action is taken. It progressively alters the soil environment which eventually negatively affects plants and organism that were not originally adapted for saline conditions. Soil salinization arises from diverse sources such as side-effects of long-term use of agro-chemicals, saline parent rocks, periodic inundation of soil with saline water, etc. In Africa, soil salinization has not been adequately documented particularly in the croplands. The objective of this study was to identify trends of cropland salinization in Africa and how its relationship with long-term land use practices affected the soil environment. The study analysed soil salinization between 1965 and 2020 using measured electrical conductivity (EC), spatial modelling with environmental covariates, and national statistics on cropland expansion and application of mineral fertilizers, herbicides, and pesticides. The results showed increasing trends of EC in Africa due to climatic and land use drivers. Increasing trends of EC, which evidenced salinization, was found in 31 million hectares of topsoils and 18 million hectares of subsoils. About 2 million hectares of croplands were depicted with salinization and >25 million hectares at the risk of salinization in the arid and semi-arid areas. The study also found statistical relationships between semi-arid cropland salinization and trends of agro-chemical use and cropland sizes. There were significant (p < 0.001) positive correlations between semi-arid cropland salinization and trends of cropland expansion and applied nitrogenous fertilizers. It found that increasing trend of applied mineral nitrogenous fertilizers could double the odds of salinization in semi-arid croplands while cropland expansion could increase the odds of semi-arid cropland salinization by >10 %. These findings present ground-breaking baseline information for future works on sustainable land-use practices that can control cropland soil salinization in Africa., 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 Elsevier B.V. All rights reserved.)

Background: Despite evidence demonstrating that influenza vaccination is associated with reduced risk of cardiovascular events and all-cause mortality in individuals with diabetes mellitus (DM), vaccine uptake remains suboptimal., Objectives: The purpose of this study was to assess the effectiveness of electronically delivered nudges on influenza vaccine uptake according to the presence of DM status versus other chronic diseases., Methods: NUDGE-FLU-CHRONIC was a nationwide, randomized, pragmatic implementation trial among younger and middle-aged (18-64 years) Danish citizens with chronic disease during the 2023/2024 influenza season. Participants were randomized in a 2.45:1:1:1:1:1:1 ratio to usual care (no electronic letter) or 1 of 6 different electronic nudge letters. The endpoint was receipt of a seasonal influenza vaccine on or before January 1, 2024., Results: Of 299,881 participants, 57,666 (19.2%) had DM (median age: 51.6 years, 43.0% female). During the season, 43.0% of those with DM vs 34.6% of those without DM received the vaccine ( P  < 0.001). Any electronic letter vs usual care was highly effective in increasing vaccine uptake in participants with DM (45.6% vs 36.5%, difference: +9.1 percentage points [99.29% CI: 7.9-10.3], relative risk ratio: 1.42 [99.29% CI: 1.39-1.44]). However, DM status modified the effect of the interventions such that participants without DM at baseline experienced a greater relative gain than those with DM (37.3% vs 25.9%, difference: +12.3 percentage points [99.29% CI: 11.7-12.8], risk ratio: 1.47 [99.29% CI: 1.45-1.50]; P interaction <0.001)., Conclusions: Electronic nudge letters effectively boosted vaccine uptake in individuals with DM and in individuals free of DM but with other chronic diseases, but the effect was lower among those with DM. Electronic nudges represent a low-cost and effective strategy to boost influenza vaccination rates in the DM population. (Nationwide Utilization of Danish Government Electronic Letter System for Increasing InFLUenza Vaccine Uptake Among Adults With Chronic Disease; NCT06030739)., Competing Interests: No funding was obtained for the NUDGE-FLU-CHRONIC trial. Dr Højbjerg Lassen was funded by a research grant from the Danish Heart Foundation (Grant no.: 21-R149-A10082-22194). Dr Biering-Sørensen has received research grants from 10.13039/100014588Sanofi Pasteur, 10.13039/100004330GSK, 10.13039/501100004191Novo Nordisk, 10.13039/100004325AstraZeneca, 10.13039/100008497Boston Scientific, and 10.13039/100006775GE Healthcare; consulting fees from Novo Nordisk, IQVIA, Parexel, Amgen, CSL Seqirus, GSK, and Sanofi Pasteur; and lecture fees from Bayer, Novartis, Sanofi Pasteur, GE healthcare, and GSK. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; has speaker engagements with AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; and participates on clinical trial committees for studies sponsored by 10.13039/100004325AstraZeneca, 10.13039/100004326Bayer AG, Galmed, Occlutech, 10.13039/100004336Novartis, and 10.13039/100019443Impulse Dynamics. Dr Bhatt has received fees from Sanofi. Dr Claggett has received consulting fees from Amgen, Cardurion, Corvia, Myokardia, and Novartis. Dr Køber has received speaker fees from Novo Nordisk, Novartis, AstraZeneca, Boehringer Ingelheim, and Bayer. Dr Solomon has received research grants from Actelion, 10.13039/100006400Alnylam, 10.13039/100002429Amgen, 10.13039/100004325AstraZeneca, Bellerophon, 10.13039/100004326Bayer, 10.13039/100002491BMS, 10.13039/100008599Celladon, 10.13039/100014941Cytokinetics, Eidos, 10.13039/100005564Gilead, 10.13039/100004330GSK, Ionis, 10.13039/100004312Lilly, Mesoblast, 10.13039/100016619MyoKardia, 10.13039/100000002NIH/10.13039/100000050NHLBI, Neurotronik, 10.13039/100004336Novartis, 10.13039/501100004191Novo Nordisk, 10.13039/100019040Respicardia, 10.13039/100004339Sanofi, Theracos, US2.AI and consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Digital letter interventions have proven effective in increasing influenza vaccination rates. In this trial, we sought to further refine these strategies and investigated whether the effectiveness of the strategies could be sustained across consecutive influenza seasons. We enrolled all eligible Danish citizens 65 years of age or older in a nationwide registry-based randomized implementation trial during the 2023-2024 influenza season. Households of participants were randomly assigned in a 2.45:1:1:1:1:1:1 ratio to usual care or six different behaviorally informed electronic letter-based nudges delivered before the influenza vaccination period. The primary endpoint was receipt of influenza vaccination. Statistical analyses accounted for household-level clustering. A total of 881,373 participants (mean age 74.1 ± 6.5 years, 52.1% female) were randomized across 649,487 households. The primary endpoint was met; influenza vaccination rates were higher in the pooled intervention letter group compared to usual care (76.32% versus 76.02%; difference, 0.31 percentage points; 99.29% confidence interval, 0.00-0.61; P = 0.007). Although no individual letter significantly increased influenza vaccination rates, the directionality of effect was consistent across all letters. Effectiveness was particularly pronounced in participants who had not received influenza vaccination during the preceding season (P interaction  = 0.010). Effectiveness was consistent regardless of whether participants had received a similar electronic letter-based nudge in the preceding season (P interaction  = 0.26). In summary, electronic letter-based nudges successfully increased influenza vaccination among older adults, and our results suggest that these highly scalable strategies can be implemented effectively and safely across consecutive vaccination seasons.ClinicalTrials.gov registration: NCT06030726 ., Competing Interests: Competing interests M.V. has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi and Tricog Health; has speaker engagements with AstraZeneca, Boehringer Ingelheim, Novartis and Roche Diagnostics; and participates on clinical trial committees for studies sponsored by AstraZeneca, Bayer, Galmed, Occlutech, Novartis and Impulse Dynamics. A.S.B. has received research grant support to his institution from the National Institutes of Health/National Heart, Lung, and Blood Institute, the National Institutes of Health/National Institute on Aging, the American College of Cardiology Foundation and the Centers for Disease Control and Prevention and has received consulting fees from Sanofi Pasteur and Novo Nordisk. B.L.C. has received consulting fees from Amgen, Cardurion, Corvia, Myokardia and Novartis. C.S.L. has received speaker fees and served on advisory boards for GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Takeda and Valneva. L.K. has received speaker fees from Novo Nordisk, Novartis, AstraZeneca, Boehringer Ingelheim and Bayer. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Eli Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi, Theracos and US2.AI and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Eli Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros and Puretech Health. T.B.-S. has served as chief investigator of the Sanofi-financed NUDGE-FLU trial, the Sanofi-financed DANFLU-1 trial and the Sanofi-financed DANFLU-2 trial; served as steering committee member of the Amgen-financed GALACTIC-HF trial, the Boston Scientific–financed LUX-Dx TRENDS trial and the Boehringer Ingelheim–financed EASi-KIDNEY trial; served on advisory boards for Sanofi, GlaxoSmithKline, Amgen and CSL Squirus; received speaker honoraria from Bayer, GlaxoSmithKline, Novartis, GE Healthcare and Sanofi; consulted for Novo Nordisk, IQVIA and Parexel; and received research grants from GE Healthcare, Sanofi, Boston Scientific, AstraZeneca and Novo Nordisk. All other authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Ambient air pollution, detrimental built and social environments, social isolation (SI), low socioeconomic status (SES), and rural (versus urban) residence have been associated with cognitive decline and risk of Alzheimer's disease and related dementias (ADRD). Research is needed to investigate the influence of ambient air pollution and built and social environments on SI and cognitive decline among rural, disadvantaged, ethnic minority communities. To address this gap, this cohort study will recruit an ethnoracially diverse, rural Florida sample in geographic proximity to seasonal agricultural burning. We will (1) examine contributions of smoke-related fine particulate matter (PM 2.5 ) exposures to SI and cognitive function; (2) determine effects of built and social environments on SI and cognitive function; and (3) contextualize SI and cognitive function among residents from different ethnoracial groups during burn and non-burn seasons., Methods: We will recruit 1,087 community-dwelling, dementia-free, ≥45-year-olds from five communities in Florida's Lake Okeechobee region. Over 36 months, participants will complete baseline visits to collect demographics, health history, and health measurements (e.g., blood pressure, body mass index) and 6-month follow-ups assessing cognitive function and social isolation at each visit. A subsample of 120 participants representative of each community will wear smartwatches to collect sensor data (e.g., heart rate) and daily routine and predefined activities (e.g., GPS-captured travel, frequent destinations) over two months. Ecological momentary assessments (EMA) (e.g., whether smoke has bothered participant in last 30 minutes) will occur over two months during agricultural burning and non-burning months. PurpleAir monitors (36 total) will be installed in each community to continuously monitor outdoor PM 2.5 levels., Ethics and Expected Impact: This study received Florida Atlantic University's Institutional Review Board approval and will require participant informed consent. We expect to identify individual- and community-level factors that increase the risk for SI and cognitive decline in a vulnerable rural population.

Importance: Despite strong worldwide guideline recommendations, influenza vaccination rates remain suboptimal among young and middle-aged patients with chronic diseases. Effective scalable strategies to increase vaccination are needed., Objective: To investigate whether electronically delivered letter-based nudges informed by behavioral science could increase influenza vaccination uptake among patients aged 18 to 64 years with chronic diseases., Design, Setting, and Participants: Nationwide pragmatic registry-based randomized clinical implementation trial conducted between September 24, 2023, and May 31, 2024, enrolling all Danish citizens aged 18 to 64 years who met criteria for free-of-charge influenza vaccination in light of preexisting chronic disease. All trial data were sourced from nationwide administrative health registries., Intervention: Randomized in 2.45:1:1:1:1:1:1 ratio to no letter (usual care) or 6 different behaviorally informed electronic letters., Main Outcomes and Measures: The primary end point was receipt of influenza vaccination on or before January 1, 2024, assessed in 7 prespecified coprimary comparisons (all intervention groups pooled vs usual care and each individual intervention group vs usual care). Absolute risk difference in proportions and a crude relative risk were calculated for each comparison., Results: A total of 299 881 participants (53.2% [159 454] female, median age, 52.0 [IQR, 39.8-59.0] years) were randomized. Compared with usual care, influenza vaccination rates were higher among those receiving any intervention letter (any intervention letter, 39.6% vs usual care, 27.9%; difference, 11.7 percentage points; 99.29% CI, 11.2-12.2 percentage points; P < .001). Each individual letter type significantly increased influenza vaccination with the largest effect sizes observed with a repeated letter sent 10 days after the initial letter (repeated letter, 41.8% vs usual care, 27.9%; difference, 13.9 percentage points; 99.29% CI, 13.1-14.7 percentage points; P < .001) and a letter emphasizing potential cardiovascular benefits of vaccination (cardiovascular gain, 39.8% vs usual care, 27.9%; difference, 11.9 percentage points; 99.29% CI, 11.1-12.7 percentage points; P < .001). Vaccination rates were improved across major subgroups., Conclusions and Relevance: In a nationwide randomized clinical implementation trial, electronically delivered letter-based nudges markedly increased influenza vaccination compared with usual care among young and middle-aged patients with chronic diseases. The results of this study suggest that simple, scalable, and cost-efficient electronic letter strategies may have substantial public health implications., Trial Registration: ClinicalTrials.gov Identifier: NCT06030739.

SARS-CoV-2 variants of concern (VOC), such as Delta and Omicron have harbored mutations, which increased viral infectivity or ability to evade neutralizing antibodies. Immunocompromised patients might be a source of some of these emerging variants. In this study, we sequenced 17 consecutive samples from an immunocompromised patient with a long-term SARS-CoV-2 infection with the pre-VOC era lineage B.1.177.35. We here describe the emergence of 73 nonsynonymous minority variants in this patient and show that 10 of these mutations became dominant in the viral population during the treatment period. Four of these were seen throughout the infection period and had a very low global prevalence, although three of them were also observed later in the Alpha, Delta, and Omicron lineages. We also found that two adjacent nsp12 variants (M785I and S786P) belonged to different quasi-species and competed during the early stages of infection and remdesivir administration. This emphasizes the importance of ongoing genome surveillance of SARS-CoV-2 among immunocpromised patients., (© 2024 The Author(s). APMIS published by John Wiley & Sons Ltd on behalf of Scandinavian Societies for Pathology, Medical Microbiology and Immunology.)

Background: Within a year of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, vaccines inducing a robust humoral and cellular immune response were implemented worldwide. However, emergence of novel variants and waning vaccine-induced immunity led to implementation of additional vaccine boosters., Methods: This prospective study evaluated the temporal profile of cellular and serological responses in a cohort of 639 SARS-CoV-2-vaccinated participants, of whom a large proportion experienced a SARS-CoV-2 infection. All participants were infection naïve at the time of their first vaccine dose. Proportions of SARS-CoV-2 spike-specific T cells were determined after each vaccine dose using the activation-induced marker assay, while levels of circulating SARS-CoV-2 antibodies were determined by the Meso Scale serology assay., Results: We found a significant increase in SARS-CoV-2 spike-specific CD4+ and CD8+ T-cell responses following the third dose of a SARS-CoV-2 messenger RNA vaccine as well as enhanced CD8+ T-cell responses after the fourth dose. Furthermore, increased age was associated with a poorer response. Finally, we observed that SARS-CoV-2 infection boosts both the cellular and humoral immune response, relative to vaccine-induced immunity alone., Conclusions: Our findings highlight the boosting effect on T-cell immunity of repeated vaccine administration. The combination of multiple vaccine doses and SARS-CoV-2 infections maintains population T-cell immunity, although with reduced levels in the elderly., Competing Interests: Potential conflicts of interest . T. B. reports the following grants from the past 36 months: unrestricted grant to his institution from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen’s Charitable Fund; unrestricted grant to his institution, principal investigator [PI]/clinical trial, advisory board from Pfizer, MSD, GSK, and Gilead Sciences; and grant for PI/clinical trial from Boehringer Ingelheim, Roche, Novartis, Kancera AB, Janssen, and AstraZeneca. T. B. is board member in Pentabase; serves on advisory boards for Janssen and AstraZeneca; and reports receiving payment or honoraria for lectures at GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, AbbVie, and AstraZeneca. L. W. M. reports receiving travel support from AbbVie in September 2023. N. B. S. reports receiving funding from Danish Ministry of Health for the manuscript and consulting fees on study regarding respiratory syncytial virus from Pfizer and serving as PI in clinical studies sponsored by Pfizer, Bavarian Nordic, Moderna, and AstraZeneca. O. S. S. reports receiving funding from Danish Ministry of Health for the manuscript and consulting fees from UNION therapeutics and participation on a data and safety monitoring board or advisory board with Immunocore, ViiV Healthcare, and Gilead. M.T. reports funding from Danish Ministry of Health for the manuscript. All other authors report no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: This study aimed to compare antibody trajectories among individuals with SARS-CoV-2 hybrid and vaccine-induced immunity., Methods: Danish adults receiving three doses of BTN162b2 or mRNA-1237 were included prior to first vaccination (Day 0). SARS-CoV-2 anti-spike IgG levels were assessed before each vaccine dose, at Day 90, Day 180, 28 days after 3rd vaccination (Day 251), Day 365, and prior to 4th vaccination (Day 535). SARS-CoV-2 PCR results were extracted from the national microbiology database. Mixed-effect multivariable linear regression investigated the impact of hybrid-immunity (stratified into 4 groups: no hybrid immunity, PCR+ prior to 3rd dose, PCR+ after 3rd dose and before Day 365, PCR+ after Day 365) on anti-spike IgG trajectories., Results: A total of 4,936 individuals were included, 47% developed hybrid-immunity. Anti-spike IgG increases were observed in all groups at Day 251, with the highest levels in those PCR+ prior to 3rd dose (Geometric Mean; 535,647AU/mL vs. 374,665AU/mL with no hybrid-immunity, P<0.0001). Further increases were observed in participants who developed hybrid immunity after their 3rd dose. Anti-spike IgG levels declined from Day 251-535 in individuals without hybrid-immunity and in those who developed hybrid-immunity prior to their 3rd dose, with lower rate of decline in those with hybrid-immunity., Conclusion: Hybrid-immunity results in higher and more durable antibody trajectories in vaccinated individuals., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: To investigate whether there is a dose-dependent association between empiric dexamethasone and outcome in viral meningitis., Methods: Observational cohort study of adults hospitalized for viral meningitis, both with and without a microbiologically confirmed diagnosis, in Denmark between 2015 and 2020. Dose-dependent associations between dexamethasone (one dose = 10 mg) and an unfavourable outcome (Glasgow Outcome Scale score 1-4) at 30 days after discharge were assessed using weighted logistic regression. Entropy balancing was used to compute weights., Results: Of 1025 included patients, 658 (64%) did not receive dexamethasone, 115 (11%) received 1-2 doses, 131 (13%) received 3-4 doses, and 121 (12%) received ≥5 doses. Among patients treated with dexamethasone, the median number of doses was higher for those without an identified pathogen than for those with a microbiologically confirmed viral aetiology (5 [interquartile range (IQR) 3-8] vs. 3 [IQR 2-5]; p < 0.001). Using no doses of dexamethasone as a reference, the weighted OR for an unfavourable outcome were 0.55 (95% CI, 0.29-1.07) for 1-2 doses, 1.13 (95% CI, 0.67-1.89) for 3-4 doses, and 1.43 (95% CI, 0.77-2.64) for ≥5 doses. In the subgroup of enteroviral meningitis, the weighted OR was 3.08 (95% CI, 1.36-6.94) for ≥5 doses, but decreased to 2.35 (95% CI, 0.65-8.40) when the reference group was restricted to patients treated with antibiotics for suspected bacterial meningitis., Discussion: This study showed no dose-dependent association between dexamethasone and an unfavourable outcome in patients with viral meningitis. In enteroviral meningitis, ≥5 doses were associated with an increased risk of an unfavourable outcome. However, sensitivity analysis indicated that the association was affected by unmeasured or residual confounding by severity., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The integration of deep learning in image segmentation technology markedly improves the automation capabilities of medical diagnostic systems, reducing the dependence on the clinical expertise of medical professionals. However, the accuracy of image segmentation is still impacted by various interference factors encountered during image acquisition., Methods: To address this challenge, this paper proposes a loss function designed to mine specific pixel information which dynamically changes during training process. Based on the triplet concept, this dynamic change is leveraged to drive the predicted boundaries of images closer to the real boundaries., Results: Extensive experiments on the PH2 and ISIC2017 dermoscopy datasets validate that our proposed loss function overcomes the limitations of traditional triplet loss methods in image segmentation applications. This loss function not only enhances Jaccard indices of neural networks by 2.42 % and 2.21 % for PH2 and ISIC2017, respectively, but also neural networks utilizing this loss function generally surpass those that do not in terms of segmentation performance., Conclusion: This work proposed a loss function that mined the information of specific pixels deeply without incurring additional training costs, significantly improving the automation of neural networks in image segmentation tasks. This loss function adapts to dermoscopic images of varying qualities and demonstrates higher effectiveness and robustness compared to other boundary loss functions, making it suitable for image segmentation tasks across various neural networks., (© 2024. The Author(s).)

Background: A score to differentiate autoimmune (AE) and viral encephalitis (VE) early upon admission has recently been developed but needed external validation. The objective of this study was to evaluate the performance of the score in a larger and more diagnostically diverse patient cohort., Methods: We conducted a retrospective nationwide and population-based cohort study including all adults with encephalitis of definite viral (2015-2022) or autoimmune aetiology (2009-2022) in Denmark. Variables included in the score-model were extracted from patient records and individual risk scores were assessed. The performance of the score was assessed by receiver-operating characteristics (ROC) curve analyses and calculation of the area under the curve (AUC)., Results: A total of 496 patients with encephalitis [AE n = 90, VE n = 287 and presumed infectious encephalitis (PIE) n = 119] were included in the study. The score was highly accurate in predicting cases of AE reaching an AUC of 0.94 (95% CI 0.92-0.97). Having a score ≥ 3 predicted AE with a PPV of 87% and an NPV of 91%. The risk score was found to perform well across aetiological subgroups and applied to the PIE cohort resulted in an AUC of 0.88 (95% CI 0.84-0.93)., Conclusion: The excellent performance of the score as reported in the development study was confirmed in this significantly larger and more diverse cohort of patients with encephalitis in Denmark. These results should prompt further prospective testing with wider inclusion criteria., (© 2024. The Author(s).)

Patients with chronic lymphocytic leukemia (CLL) are at high risk of developing severe COVID-19. The present study was undertaken to elucidate COVID-19 related morbidity and mortality in CLL patients treated with venetoclax. We present a single-center study of 108 patients with small lymphocytic lymphoma or CLL treated with venetoclax. Primary outcome was 30-day COVID-19 mortality. Secondary outcomes included COVID-19 severity and hospitalization rate. Forty-eight (44%) patients had PCR-verified SARS-COV-2 between March 2020 and January 2023. Thirty-six patients (75%) presented with asymptomatic/mild COVID-19 and 12 (25%) with severe/critical disease. The hospitalization rate was 46% with a 30-day mortality rate of only 4% and severe comorbidities as the primary cause of death. COVID-19 severity and mortality were similar before and during the Omicron era. High CIRS-scores (P < 0.02) and thrombocytopenia (P < 0.01) were more frequent in patients with severe/critical disease. In real-world data, most venetoclax treated patients presented with mild COVID-19. Hospitalization and mortality rates were low compared to data of general CLL populations. Our data indicate that venetoclax was a safe treatment option for CLL patients during the pandemic., (© 2024. The Author(s).)

Purpose: To describe clinical features and outcomes of viral lumbosacral radiculitis (Elsberg syndrome)., Methods: Nationwide population-based cohort study of all adults hospitalised for viral lumbosacral radiculitis at departments of infectious diseases in Denmark from 2015 to 2020., Results: Twenty-eight patients with viral lumbosacral radiculitis were included (mean annual incidence: 1.2/1,000,000 adults). The median age was 35 years (IQR 27-43), and 22/28 (79%) were female. All patients had urinary retention, with 17/28 (61%) needing a catheter. On admission, at least one sign or symptom of meningitis (headache, neck stiffness, photophobia/hyperacusis) was present in 18/22 (82%). Concurrent genital herpetic lesions were present in 11/24 (46%). The median cerebrospinal fluid leukocyte count was 153 cells/µL (IQR 31-514). Magnetic resonance imaging showed radiculitis/myelitis in 5/19 (26%). The microbiological diagnosis was herpes simplex virus type 2 in 19/28 (68%), varicella-zoster virus in 2/28 (7%), and unidentified in 7/28 (25%). Aciclovir/valaciclovir was administered in 27/28 (96%). At 30 days after discharge, 3/27 (11%) had persistent urinary retention with need of catheter. At 180 days after discharge, moderate disabilities (Glasgow Outcome Scale score of 4) were observed in 5/25 (20%)., Conclusions: Urinary retention resolved within weeks in most patients with viral lumbosacral radiculitis, but moderate disabilities according to the Glasgow Outcome Scale were common at the end of follow-up., (© 2023. The Author(s).)

Background: Yearly influenza vaccination is strongly recommended for older adults and patients with chronic diseases including cardiovascular disease (CVD); however, vaccination rates remain suboptimal, particularly among younger patients. Electronic letters incorporating behavioral nudges are highly scalable public health interventions which can potentially increase vaccination, but further research is needed to determine the most effective strategies and to assess effectiveness across different populations. The purpose of NUDGE-FLU-CHRONIC and NUDGE-FLU-2 are to evaluate the effectiveness of electronic nudges delivered via the Danish governmental electronic letter system in increasing influenza vaccination among patients with chronic diseases and older adults, respectively., Methods: Both trials are designed as pragmatic randomized implementation trials enrolling all Danish citizens in their respective target groups and conducted during the 2023/2024 influenza season. NUDGE-FLU-CHRONIC enrolls patients aged 18-64 years with chronic diseases. NUDGE-FLU-2 builds upon the NUDGE-FLU trial conducted in 2022/2023 and aims to expand the evidence by testing both previously successful and new nudges among adults ≥65 years during a subsequent influenza season. Persons with exemptions from the electronic letter system are excluded from both trials. In both trials, participants are randomized in a 2.45:1:1:1:1:1:1 ratio to either receive no electronic letter (usual care) or to receive one of 6 different behaviorally informed electronic letters. NUDGE-FLU-CHRONIC has randomized 299,881 participants with intervention letters delivered on September 24, 2023, while NUDGE-FLU-2 has randomized 881,373 participants and delivered intervention letters on September 13, 2023. Follow-up is currently ongoing. In both trials, the primary endpoint is receipt of influenza vaccination on or before January 1, 2024, and the secondary endpoint is time to vaccination. Clinical outcomes including respiratory and cardiovascular hospitalizations, all-cause hospitalization, and mortality are included as prespecified exploratory endpoints. Prespecified individual-level pooled analyses will be conducted across NUDGE-FLU, NUDGE-FLU-CHRONIC, and NUDGE-FLU-2., Discussion: NUDGE-FLU-CHRONIC is the first nationwide randomized trial of electronic nudges to increase influenza vaccination conducted among 18-64-year-old high-risk patients with chronic diseases. NUDGE-FLU-2 will provide further evidence on the effectiveness of electronic nudges among older adults ≥65 years. Collectively, the NUDGE-FLU trials will provide an extensive evidence base for future public health communications., Trial Registration: NUDGE-FLU-CHRONIC: Clinicaltrials.gov: NCT06030739, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030739. NUDGE-FLU-2: Clinicaltrials.gov: NCT06030726, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030726., Competing Interests: Declaration of competing interest MV has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; has speaker engagements with AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics; and participates on clinical trial committees for studies sponsored by AstraZeneca, Bayer AG, Galmed, Occlutech, Novartis, and Impulse Dynamics. ASB has received research grant support to his institution from National Institutes of Health/National Heart, Lung, and Blood Institute, National Institutes of Health/National Institute on Aging, American College of Cardiology Foundation, and the Centers for Disease Control and Prevention and consulting fees from Sanofi Pasteur and Novo Nordisk. BLC has received consulting fees from Amgen, Cardurion, Corvia, Myokardia, and Novartis. CSL has received speaker fees and served on advisory boards for GSK, MSD, Pfizer, Takeda, and Valneva. LK has received speaker fees from Novo Nordisk, Novartis, AstraZeneca, Boehringer Ingelheim, and Bayer. SDS has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi, Theracos, US2.AI and consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health. TB-S has served as chief investigator of the Sanofi financed NUDGE-FLU trial, the Sanofi financed DANFLU-1 trial, and the Sanofi financed DANFLU-2 trial, served as steering committee member of the Amgen financed GALACTIC-HF trial, the Boston Scientific financed LUX-Dx TRENDS trial, and the Boehringer Ingelheim financed EASi-KIDNEY trial, served on advisory boards for Sanofi, GSK, Amgen, and CSL Squirus, received speaker honoraria from Bayer, GSK, Novartis, GE Healthcare, and Sanofi, consulted for Novo Nordisk, IQVIA, and Parexel, and received research grants from GE Healthcare, Sanofi, Boston Scientific, AstraZeneca, and Novo Nordisk. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The first chemical synthesis of the phloroglucinol meroterpenoid cleistocaltone A (1) is presented. This compound, previously isolated from Cleistocalyx operculatus was reported to show promising antiviral properties. Based on a modified biosynthesis proposal, a synthetic strategy was devised featuring an intramolecular Diels-Alder reaction and an epoxidation/elimination sequence to generate the allyl alcohol handle in the side chain. The strategy was successfully executed and synthetic cleistcaltone A was evaluated against a contemporary RSV-A strain., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Background and Purpose: Pulmonary arteriovenous malformations (PAVMs) may cause recurrent brain abscess. The primary aim was to determine the prevalence of PAVM amongst survivors of brain abscess. The proportion with cardiac right-to-left shunts was also assessed post hoc., Methods: This was a cross-sectional population-based study of adult (≥18 years) survivors of cryptogenic bacterial brain abscess in Denmark from 2007 through 2016. Patients were invited for bubble-echocardiography to detect vascular right-to-left shunting and, if abnormal, subsequent computed tomography thorax for diagnosis of PAVM. Data are presented as n/N (%) or median with interquartile range (IQR)., Results: Study participation was accepted by 47/157 (30%) eligible patients amongst whom two did not appear for scheduled bubble-echocardiography. The median age of participants was 54 years (IQR 45-62) and 19/57 (33%) were females compared with 59 years (IQR 48-68, p = 0.05) and 41/85 females (48%, p = 0.22) in non-participants. Bubble-echocardiography was suggestive of shunt in 10/45 (22%) participants and PAVM was subsequently confirmed by computed tomography in one patient with grade 1 shunting. The corresponding prevalence of PAVM was 2% (95% confidence interval 0.06-11.8) amongst all examined participants. Another 9/45 (20%) were diagnosed with patent in persistent foramen ovale (n = 8) or atrial septum defect (n = 1), which is comparable with the overall prevalence of 25% amongst adults in the Danish background population., Conclusions: Undiagnosed PAVM amongst adult survivors of cryptogenic bacterial brain abscess is rare but may be considered in select patients. The prevalence of cardiac right-to-left shunts amongst brain abscess patients corresponds to the prevalence in the general population., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Oral cavity bacteria are the most frequent etiology of brain abscess. Yet, data on the clinical presentation and outcome are scarce., Methods: We performed a nationwide, population-based study comprising all adults (aged ≥18 years) with brain abscess due to oral cavity bacteria in Denmark from 2007 through 2020. Prognostic factors for unfavorable outcome (Glasgow outcome scale, 1-4) were examined using modified Poisson regression to compute adjusted relative risks (RRs) with 95% confidence intervals (CIs)., Results: Among 287 identified patients, the median age was 58 years (interquartile range, 47-66), and 96 of 287 (33%) were female. Preexisting functional impairment was absent or mild in 253 of 280 (90%), and risk factors for brain abscess included immunocompromise in 95 of 287 (33%), dental infection in 68 of 287 (24%), and ear-nose-throat infection in 33 of 287 (12%). Overall, a neurological deficit was present in 246 of 276 (86%) and in combination with headache and fever in 64 of 287 (22%). Identified microorganisms were primarily the Streptococcus anginosus group, Fusobacterium, Actinomyces, and Aggregatibacter spp., and 117 of 287 (41%) were polymicrobial. Unfavorable outcome occurred in 92 of 246 (37%) at 6 months after discharge and was associated with antibiotics before neurosurgery (RR, 3.28; 95% CI, 1.53-7.04), rupture (RR, 1.89; 95% CI, 1.34-2.65), and immunocompromise (RR, 1.80; 95% CI, 1.29-2.51), but not with specific targeted antibiotic regimens. Identified dental infection was associated with favorable prognosis (RR, 0.58; 95% CI, .36-.93)., Conclusions: Brain abscess due to oral cavity bacteria often occurred in previously healthy individuals without predisposing dental infections. Important risk factors for unfavorable outcome were rupture and immunocompromise. However, outcome was not associated with specific antibiotic regimens supporting carbapenem-sparing strategies., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Achieving health equity requires creating evidence that reflects the nuance and diversity of experiences among populations disproportionately impacted by age- and race-related disparities. Community-engaged research (CEnR) is one way to pursue equity in research on health and aging to ensure the relevance and translational potential of findings. The current review synthesizes best practices regarding CEnR that promote health equity among older adults, including an overview of CEnR, benefits, and fundamental principles, and three research exemplars from the authors' CEnR. Finally, we discuss these best practices and considerations for advancing CEnR to reduce health disparities experienced by historically underserved older adults and their families. [ Research in Gerontological Nursing, 17 (1), 9-16.].

Since December 2019, digital health applications (DiGA) have been included in standard care in Germany and are therefore reimbursed by the statutory health insurance funds to support patients in the treatment of diseases or impairments. There are 48 registered DiGA listed in the directory of the Federal Institute of Drugs and Medical Devices (BfArM), mainly in the areas of mental health; hormones and metabolism; and muscles, bones, and joints. In this article, the "Digital Health" specialist group of the German Informatics Society describes the current developments around DiGA as well as the current sentiment on topics such as user-centricity, patient and practitioner acceptance, and innovation potential. In summary, over the past three years, DiGA have experienced a positive development, characterized by a gradually increasing availability of various DiGA and coverage areas as well as prescription numbers. Nevertheless, significant regulatory adjustments are still required in some areas to establish DiGA as a well-established instrument in long-term routine healthcare. Key challenges include user-centeredness and the sustainable use of the applications., (© 2023. The Author(s).)

Background and Purpose: Data on clinical features and outcomes of benign recurrent lymphocytic meningitis (BRLM) are limited., Methods: This was a nationwide population-based cohort study of all adults hospitalized for BRLM associated with herpes simplex virus type 2 (HSV-2) at the departments of infectious diseases in Denmark from 2015 to 2020. Patients with single-episode HSV-2 meningitis were included for comparison., Results: Forty-seven patients with BRLM (mean annual incidence 1.2/1,000,000 adults) and 118 with single-episode HSV-2 meningitis were included. The progression risk from HSV-2 meningitis to BRLM was 22% (95% confidence interval [CI] 15%-30%). The proportion of patients with the triad of headache, neck stiffness and photophobia/hyperacusis was similar between BRLM and single-episode HSV-2 meningitis (16/43 [37%] vs. 46/103 [45%]; p = 0.41), whilst the median cerebrospinal fluid leukocyte count was lower in BRLM (221 cells vs. 398 cells; p = 0.02). Unfavourable functional outcomes (Glasgow Outcome Scale score of 1-4) were less frequent in BRLM at all post-discharge follow-up visits. During the study period, 10 (21%) patients with BRLM were hospitalized for an additional recurrence (annual rate 6%, 95% CI 3%-12%). The hazard ratio for an additional recurrence was 3.93 (95% CI 1.02-15.3) for patients with three or more previous episodes of meningitis., Conclusions: Clinical features of BRLM were similar to those of single-episode HSV-2 meningitis, whilst post-discharge outcomes were more favourable. Patients with three or more previous episodes of meningitis had higher risk of an additional recurrence., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: It is important to understand current trends in cancer risk among people living with HIV (PLWH) to improve outcomes and to commission and delivery appropriate services., Methods: Nationwide, population-based, matched cohort study on all adult PLWH treated at Danish HIV health care centres since 1 January 1995 and a comparison cohort, randomly selected from the background population and matched on sex and date of birth., Results: We included 6327 PLWH and 63,270 individuals in the comparison cohort - 74% were men and median age was 37 (interquartile range: 30-46). For both smoking related cancers, virological cancers and other cancers, incidence was substantially higher in the first year of observation for PLWH than for the remaining observation period. The risk of smoking related cancer remained stably increased throughout the observation period, whereas the relative risk of virological cancers decreased, especially in the first year of follow up. Finally, the risk of other cancers for PLWH decreased to a level below that of the background population during the study period., Conclusion: The fact that the risk of other cancers was probably not higher among PLWH than in the comparison cohort is encouraging, as the excess risk of virological and smoking related cancers is potentially preventable by timely treatment of HIV and smoking cessation.

The diterpenoid paclitaxel (Taxol) is a chemotherapy medication widely used as a first-line treatment against several types of solid cancers. The supply of paclitaxel from natural sources is limited. However, missing knowledge about the genes involved in several specific metabolic steps of paclitaxel biosynthesis has rendered it difficult to engineer the full pathway. In this study, we used a combination of transcriptomics, cell biology, metabolomics, and pathway reconstitution to identify the complete gene set required for the heterologous production of paclitaxel. We identified the missing steps from the current model of paclitaxel biosynthesis and confirmed the activity of most of the missing enzymes via heterologous expression in Nicotiana benthamiana. Notably, we identified a new C4β-C20 epoxidase that could overcome the first bottleneck of metabolic engineering. We used both previously characterized and newly identified oxomutases/epoxidases, taxane 1β-hydroxylase, taxane 9α-hydroxylase, taxane 9α-dioxygenase, and phenylalanine-CoA ligase, to successfully biosynthesize the key intermediate baccatin III and to convert baccatin III into paclitaxel in N. benthamiana. In combination, these approaches establish a metabolic route to taxoid biosynthesis and provide insights into the unique chemistry that plants use to generate complex bioactive metabolites., (Copyright © 2023 The Author. Published by Elsevier Inc. All rights reserved.)

Ramsay Hunt syndrome (RHS) is a manifestation of reactivated varicella-zoster virus (VZV) from the geniculate ganglion. Data on clinical features and outcomes of patients with RHS and concurrent VZV meningitis (henceforth RHS meningitis) are limited. Thus, we conducted a nationwide population-based cohort study of all adults hospitalized for RHS meningitis at the departments of infectious diseases in Denmark from 2015 to 2020. Patients with VZV meningitis without cranial nerve palsies were included for comparison. In total, 37 patients with RHS meningitis (mean annual incidence: 1.6/1 000 000 adults) and 162 with VZV meningitis without cranial nerve palsies were included. In RHS meningitis, the median age was 52 years (interquartile range: 35-64), and in addition to peripheral facial nerve palsy (100%), dizziness (46%), and hearing loss (35%) were common symptoms. The triad of headache, neck stiffness, and photophobia/hyperacusis was less common in RHS meningitis than in VZV meningitis without cranial nerve palsies (0/27 [0%] vs. 24/143 [17%]; p = 0.02). At 30 days after discharge, 18/36 (50%) patients with RHS meningitis had persistent peripheral facial nerve palsy, with no statistically significant difference between those treated with and without adjuvant glucocorticoids (6/16 [38%] vs. 12/20 [60%]; p = 0.18). Additional sequelae of RHS meningitis included dizziness (29%), neuralgia (14%), tinnitus/hyperacusis (11%), hearing loss (9%), headache (9%), fatigue (6%), and concentration difficulties (3%). In conclusion, clinical features and outcomes of RHS meningitis were primarily related to cranial neuropathies., (© 2023 Wiley Periodicals LLC.)

Background: Continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outpaces monovalent vaccine cross-protection to new viral variants. Consequently, bivalent coronavirus disease 2019 (COVID-19) vaccines including Omicron antigens were developed. The contrasting immunogenicity of the bivalent vaccines and the impact of prior antigenic exposure on new immune imprinting remains to be clarified., Methods: In the large prospective ENFORCE cohort, we quantified spike-specific antibodies to 5 Omicron variants (BA.1 to BA.5) before and after BA.1 or BA.4/5 bivalent booster vaccination to compare Omicron variant-specific antibody inductions. We evaluated the impact of previous infection and characterized the dominant antibody responses., Results: Prior to the bivalent fourth vaccine, all participants (N = 1697) had high levels of Omicron-specific antibodies. Antibody levels were significantly higher in individuals with a previous polymerase chain reaction positive (PCR+) infection, particularly for BA.2-specific antibodies (geometric mean ratio [GMR] 6.79, 95% confidence interval [CI] 6.05-7.62). Antibody levels were further significantly boosted in all individuals by receiving either of the bivalent vaccines, but greater fold inductions to all Omicron variants were observed in individuals with no prior infection. The BA.1 bivalent vaccine generated a dominant response toward BA.1 (adjusted GMR 1.31, 95% CI 1.09-1.57) and BA.3 (1.32, 1.09-1.59) antigens in individuals with no prior infection, whereas the BA.4/5 bivalent vaccine generated a dominant response toward BA.2 (0.87, 0.76-0.98), BA.4 (0.85, 0.75-0.97), and BA.5 (0.87, 0.76-0.99) antigens in individuals with a prior infection., Conclusions: Vaccination and previous infection leave a clear serological imprint that is focused on the variant-specific antigen. Importantly, both bivalent vaccines induce high levels of Omicron variant-specific antibodies, suggesting broad cross-protection of Omicron variants., Competing Interests: Potential conflicts of interest. N. B. S. declares to have served as an investigator in clinical trials sponsored by Pfizer, Gilead, and Bavarian Nordic, and AstraZeneca. H. N. declares to have been on advisory boards for GSK and MSD and reports grants or contracts from Novo Nordisk Foundation (payment to institution, RCT of brain abscess treatment strategy). T. B. declares receipt of unrestricted grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Foundation, Erik and Susanna Olesen's Charitable Fund, GSK, Pfizer, Gilead Sciences, and MSD; and being advisory board member for GSK, Pfizer, Gilead Sciences, MSD, Janssen, and Astra Zeneca; and being principal investigator on clinical trials conducted by Pfizer, Boehringer Ingelheim, Gilead Sciences, MSD, Roche, Novartis, Kancera AB, Bavarian Nordic, and Janssen; and being board member on Pentabase; and receiving consulting fees from GSK and Pfizer; and receiving honorarium for lectures from GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, Abbvie, Astra Zeneca, and Bavarian Nordic; and receiving donation of trial medication (baricitinib) from Eli Lilly. M. T. declares to be on a Data Safety Monitoring Board for ImmunoCore. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Human immunodeficiency virus (HIV) infection is associated with depression. However, previous studies have not addressed familial factors., Methods: Nationwide, population-based, matched cohort study of people with HIV (PWH) in Denmark between 1995 and 2021 who were matched on sex and date of birth with a comparison cohort randomly selected from the Danish population. Family-related factors were examined by inclusion of siblings of those in the cohorts. We calculated hazard ratios (HRs) for depression, receipt of antidepressants, electroconvulsive therapy (ECT), and suicide, as well as the yearly proportions of study cohorts with psychiatric hospital contact due to depression and receipt of antidepressants from 10 years before to 10 years after study inclusion., Results: We included 5943 PWH and 59 430 comparison cohort members. Median age was 38 years, and 25% were women. We observed an increased risk of depression, receipt of antidepressants, ECT, and suicide among PWH in the 2 first years of observation (HR, 3.3; 95% confidence interval [CI]: 2.5-4.4), HR, 3.0 (95% CI: 2.7-3.4), HR, 2.8 (95% CI: .9-8.6), and HR, 10.7 (95% CI: 5.2-22.2), thereafter the risk subsided but remained increased. The proportions of PWH with psychiatric hospital contact due to depression and receipt of antidepressants were increased prior to and especially after HIV diagnosis. Risk of all outcomes was substantially lower among siblings of PWH than among PWH (HR for receipt of antidepressants, 1.1; 95% CI: 1.0-1.2)., Conclusions: PWH have an increased risk of depression. Family-related factors are unlikely to explain this risk., Competing Interests: Potential conflicts of interest. A. M. L. reports unrestricted research grants from Gilead and speaker honoraria/advisory board activity from Gilead, GSK, and Pfizer, with no relation to the current study; consulting fees from AbbVie and MSD (paid to institution); participation on a data and safety monitoring board for Novo Nordisk (paid to author); grants or contracts outside this work to institution from the Lundbeck Foundation and Novo Nordisk; payment or honoraria for lectures unrelated to this work from MSD, Pfizer, and GSK; and support for attending meetings from MSD, Chiesi, and Advanz. I. S. J. reports grants or contracts to institution from Odense University Hospital and consulting fees (to author) from Pfizer. M. M. T. reports a grant or contract from the Research Fund of Copenhagen University Hospital—Rigshospitalet (PhD scholarship) and travel grants for participation in a conference from GSK Pharma A/S. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Human cerebral organoids (HCOs) are model systems that enable researchers to investigate the human brain in ways that had previously been impossible. The emergence of HCOs was accompanied by both expert and layperson discussions concerning the possibility of these novel entities developing sentience or consciousness. Such concerns are reflected in deliberations about how to handle and regulate their use. This perspective article resulted from an international and interdisciplinary research retreat "Ethical, Legal and Social Aspects of Human Cerebral Organoids and their Governance in Germany, the United Kingdom and the United States", which took place in Tübingen, Germany, in August 2022. The retreat focused on whether HCO research requires new ethical and regulatory approaches. It addressed epistemic issues around the detection and theorisation of consciousness, ethical concerns around moral status and research conduct, difficulties for legislation and guidelines managing these entities, and public engagement., Competing Interests: JS is a member of Merck KGaA’s Ethics Advisory Panel and Stem Cell Research Oversight Committee; a member of IQVIA’s Ethics Advisory Panel; a member of Aspen Neurosciences Clinical Advisory Panel; and previously a member of a Merck Data Monitoring Committee and a consultant to Biogen. The other 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 © 2023 Pichl, Ranisch, Altinok, Antonakaki, Barnhart, Bassil, Boyd, Chinaia, Diner, Gaillard, Greely, Jowitt, Kreitmair, Lawrence, Lee, McKeown, Sachdev, Schicktanz, Sugarman, Trettenbach, Wiese, Wolff and Árnason.)

Clinical features applicable to the entire spectrum of viral meningitis are limited, and prognostic factors for adverse outcomes are undetermined. This nationwide population-based prospective cohort study included all adults with presumed and microbiologically confirmed viral meningitis in Denmark from 2015 until 2020. Prognostic factors for an unfavourable outcome (Glasgow Outcome Scale score of 1-4) 30 days after discharge were examined by modified Poisson regression. In total, 1066 episodes of viral meningitis were included, yielding a mean annual incidence of 4.7 episodes per 100 000 persons. Pathogens were enteroviruses in 419/1066 (39%), herpes simplex virus type 2 in 171/1066 (16%), varicella-zoster virus in 162/1066 (15%), miscellaneous viruses in 31/1066 (3%) and remained unidentified in 283/1066 (27%). The median age was 33 years (IQR 27-44), and 576/1066 (54%) were females. In herpes simplex virus type 2 meningitis, 131/171 (77%) were females. Immunosuppression [32/162 (20%)] and shingles [90/149 (60%)] were frequent in varicella-zoster virus meningitis. The triad of headache, neck stiffness and hyperacusis or photophobia was present in 264/960 (28%). The median time until lumbar puncture was 3.0 h (IQR 1.3-7.1), and the median CSF leucocyte count was 160 cells/µl (IQR 60-358). The outcome was unfavourable in 216/1055 (20%) 30 days after discharge. Using unidentified pathogen as the reference, the adjusted relative risk of an unfavourable outcome was 1.34 (95% CI 0.95-1.88) for enteroviruses, 1.55 (95% CI 1.00-2.41) for herpes simplex virus type 2, 1.51 (95% CI 0.98-2.33) for varicella-zoster virus and 1.37 (95% CI 0.61-3.05) for miscellaneous viruses. The adjusted relative risk of an unfavourable outcome was 1.34 (95% CI 1.03-1.75) for females. Timing of acyclovir or valacyclovir was not associated with the outcome in meningitis caused by herpes simplex virus type 2 or varicella-zoster virus. In summary, the outcome of viral meningitis was similar among patients with different aetiologies, including those with presumed viral meningitis but without an identified pathogen. Females had an increased risk of an unfavourable outcome. Early antiviral treatment was not associated with an improved outcome in meningitis caused by herpes simplex virus type 2 or varicella-zoster virus., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Reproductive health in women with human immunodeficiency virus (HIV) (WWH) has improved in recent decades. We aimed to investigate incidences of childbirth, pregnancy, spontaneous abortion, and induced abortion among WWH in a nationwide, population-based, matched cohort study., Methods: We included all WWH aged 20-40 years treated at an HIV healthcare center in Denmark from 1995 to 2021 and a matched comparison cohort of women from the general population (WGP). We calculated incidence rates per 1000 person-years and used Poisson regression to calculate adjusted incidence rate ratios (aIRRs) of childbirth, pregnancy, spontaneous abortion, and induced abortion stratified according to calendar periods (1995-2001, 2002-2008, and 2009-2021)., Results: We included 1288 WWH and 12 880 WGP; 46% of WWH were of African origin, compared with 1% of WGP. Compared with WGP, WWH had a decreased incidence of childbirth (aIRR, 0.6 [95% confidence interval, .6-.7]), no difference in the incidence of pregnancy (0.9 [.8-1.0]) or spontaneous abortion (0.9 [.8-1.0]), but an increased incidence of induced abortion (1.9 [1.6-2.1]) from 1995 to 2021. The aIRRs for childbirth, pregnancy, and spontaneous abortion increased from 1995-2000 to 2009-2021, while the aIRR for induced abortion remained increased across all time periods for WWH., Conclusions: From 1995 to 2008, the incidences of childbirth, pregnancy, and spontaneous abortion were decreased among WWH compared with WGP. From 2009 to 2021, the incidence of childbirth, pregnancy, and spontaneous abortion no longer differed among WWH compared with WGP. The incidence of induced abortions remains increased compared with WGP., Competing Interests: Potential conflicts of interest. N. W. reports unrestricted research grants from AbbVie and Gilead, consulting fees from AbbVie and MSD, and participation on a data and safety monitoring board for Novo Nordisk. A. M. L. reports unrestricted research grants from Gilead and speaker honoraria/advisory board activity from Gilead, GSK, and Pfizer, with no relation to the current study; consulting fees from AbbVie and MSD (both as clinical investigator; paid to institution); and participation on a data and safety monitoring board for Novo Nordisk (paid to author). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: To evaluate the experience with use of sotrovimab following severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in high-risk groups., Methods: In a nationwide, population-based cohort study, we identified all individuals treated with sotrovimab (N = 2933) and stratified them by 4 high-risk groups: (A) malignant haematological disease, (B) solid organ transplantation, (C) anti-CD20 therapy ≤1 year and (D) other risks. Cox regression analysis was used to calculate hazard ratios for hospitalization, death and associated prognostic factors., Results: Of 2933 sotrovimab-treated individuals, 83% belonged to high-risk groups (37.6% haematological malignancy, 27.4% solid organ transplantation and 17.5% treatment with anti-CD20 ≤1 year). Only 17.8% had other risks (11.8% were pregnant, 10.7% primary immunodeficiency, 21.2% other malignancy, 4.3% received anti-CD20 >1 year and 52.0% other/unknown causes). Within 90 days of infusion, 30.2% were hospitalized and 5.3% died. The main prognostic factors were the predefined high-risk groups, mainly malignant haematological disease and age ≥65 years. Number of COVID-19 vaccines (≥3) was associated with a decreased risk of hospitalization. The Delta but not the Omicron BA.2 variant was associated with a higher risk of death compared to the BA.1 variant., Conclusion: More than 90% of the patients treated with sotrovimab belonged to the very high-risk groups as described in the Danish guidelines. Sotrovimab-treated individuals remained at a high risk of hospitalization and death which was strongly associated with the underlying immunocompromised state and age. Having received >3 COVID-19 vaccines was association with decreased risk of death and hospitalization., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Side effects to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are a key concern contributing to vaccine hesitancy, but more individuals may be encouraged if SARS-CoV-2 vaccines were known to lead to a stronger immune response., Methods: Included were adult participants from the Danish National Cohort Study of Effectiveness and Safety of SARS-CoV-2 Vaccines (ENFORCE) who completed a questionnaire to assess systemic reactions following SARS-CoV-2 vaccination (BTN162b2, mRNA-1273, ChAdOx1) and had SARS-CoV-2 spike immunoglobulin G (IgG) levels measured at baseline and post-vaccine. A symptom score was developed to measure severity of systemic adverse reactions (+1 for each moderate, +2 for each severe). Post-vaccination SARS-CoV-2 spike IgG levels were compared between participants with different scores using multivariable linear regression., Results: A total of 6528 participants were included (56.3% females; median age [interquartile range], 64 [54-75] years). After the first vaccination, no association was found between symptom score and post-vaccine dose spike IgG level ( P = .575). Following the second vaccination, significantly higher spike IgG levels were observed according to higher symptom scores ( P < .001); adjusted geometric mean ratios were 1.16 (95% CI, 1.04-1.30), 1.24 (95% CI, 1.09-1.41), 1.25 (95% CI, 1.06-1.46), and 1.21 (95% CI, 1.08-1.35), for scores of 2, 3, 4, and ≥5, respectively, compared with a score of 0. After adjustment for pre-vaccine dose spike IgG, this association was attenuated., Conclusions: An association was found between more severe adverse reactions and stronger antibody response after the second vaccination but not the first, likely attributed to higher levels of preexisting immunity gained from response to first vaccination. Regardless of side effects, most people experienced an effective immune response following vaccination., Competing Interests: Potential conflicts of interest. N.B.S. declares having served as primary investigator on clinical studies sponsored by Pfizer and Bavarian Nordic. T.B. declares receipt of unrestricted research or travel grants from GSK, Pfizer, Gilead Sciences, and MSD; being principal investigator on trials conducted by Boehringer Ingelheim, Roche, Novartis, Kancera, Pfizer, MSD, and Gilead; being a board member for Pentabase; and being an advisory board member for MSD, Gilead, Pfizer, GSK, Janssen, and AstraZeneca; receipt of consulting fees from GSK and Pfizer; receipt of a donation of study drug from Eli Lilly; and receipt of honoraria for lectures from GSK, Pfizer, Gilead Sciences, Boehringer Ingelheim, AbbVie, and AstraZeneca. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The combined effectiveness of remdesivir and dexamethasone in subgroups of hospitalised patients with COVID-19 is poorly investigated., Methods: In this nationwide retrospective cohort study, we included 3826 patients with COVID-19 hospitalised between February 2020 and April 2021. The primary outcomes were use of invasive mechanical ventilation and 30-day mortality, comparing a cohort treated with remdesivir and dexamethasone with a previous cohort treated without remdesivir and dexamethasone. We used inverse probability of treatment weighting logistic regression to assess associations with progression to invasive mechanical ventilation and 30-day mortality between the two cohorts. The analyses were conducted overall and by subgroups based on patient characteristics., Results: Odds ratio for progression to invasive mechanical ventilation and 30-day mortality in individuals treated with remdesivir and dexamethasone compared to treatment with standard of care alone was 0.46 (95% confidence interval, 0.37-0.57) and 0.47 (95% confidence interval, 0.39-0.56), respectively. The reduced risk of mortality was observed in elderly patients, overweight patients and in patients requiring supplemental oxygen at admission, regardless of sex, comorbidities and symptom duration., Conclusions: Patients treated with remdesivir and dexamethasone had significantly improved outcomes compared to patients treated with standard of care alone. These effects were observed in most patient subgroups.