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Emelie C Rotbain,1– 5 Klaus Rostgaard,3,5 Michael A Andersen,2,3 Caspar Da Cunha-Bang,2 Carsten U Niemann,2 Henrik Frederiksen,1,4,6 Henrik Hjalgrim2,3,5,7 1Department of Hematology, Odense University Hospital, Odense, Denmark; 2Department of Hematology, Rigshospitalet, Denmark; 3Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark; 4Department of Clinical Research, University of Southern Denmark, Odense, Denmark; 5Danish Cancer Society Research Center, Hematology Research Group, Copenhagen, Denmark; 6Academy of Geriatric Cancer Research (AGECARE), Odense University Hospital, Odense, Denmark; 7Department of Clinical Medicine, Copenhagen University, Copenhagen, DenmarkCorrespondence: Emelie C RotbainDepartment of Hematology, Odense University Hospital, Kløvervænget 6, Odense, DK-5000, DenmarkTel +45 5369 0201Email erot0006@regionh.dkPurpose: Age-related comorbidity is highly prevalent in chronic lymphocytic leukemia (CLL). The purpose of this study was to provide information on current patterns of healthcare utilization in CLL.Patients and Methods: We used data from Danish nation-wide registers to study healthcare utilization the year before and the year after CLL diagnosis and in relation to first-line treatment. Patients diagnosed with CLL between 1997 and 2018 were included and stratified on number of comorbidities, presence of specific comorbidities, and fitness status, respectively. Healthcare utilization was studied in terms of hospital admissions, in-hospital bed days, out-patient visits, emergency room visits, and prescription drugs. Odds ratios with 95% confidence intervals were calculated using multivariable logistic regression analyses adjusting for age, sex, and calendar year.Results: The study comprised 9170 patients with CLL with a median age of 71 years, of whom 35% had ≥ 1 comorbidity. Healthcare utilization increased markedly upon CLL diagnosis both in patients with and without comorbidities. During the year after CLL diagnosis, 39% were hospitalized, 16% visited an emergency room, 88% visited an out-patient clinic, and 93% received prescription drugs. Both individual comorbidities and the total number of comorbidities were associated with increased healthcare utilization of all types, except for contacts to hematological departments.Conclusion: Our results suggest that CLL diagnosis may unveil incipient diseases and aggravate comorbidities and thereby have considerably wider health implications than those directly related to CLL. These findings may be used by clinicians and decisions makers to guide planning of multidisciplinary care for cancer patients.Keywords: chronic lymphocytic leukemia, hematology, epidemiology, real-world data

Objective: To develop and clinically evaluate a customizable active upper extremity (UE) assistive system with integrated functional electrical stimulation (FES) that improves function and independence of individuals during activities of daily living (ADLs). Design: Single-arm, prospective, open-label cohort feasibility trial. Setting: An academic research institution. Participants: Subjects were 5 adults with a medical history of stroke resulting in distal UE impairment (N=5). The subjects volunteered from recruitment materials that detailed information about the study. Interventions: A novel, wearable, lightweight, low-profile, and patient-tailored UE assistive system. It comprises a splint component and FES unit that may each be controlled by electromyography (EMG) signals, inertial measurement units (IMUs), manual control source (joystick), and/or voice control. Main Outcome Measure(s): Several occupational therapy outcome measures were used, including the Canadian Occupational Performance Measure (COPM), Action Research Arm Test (ARAT), The Box and Blocks Test (BBT), the ABILHAND-Manual Ability Measure, and Patient Reported Outcomes Measurement Information System (PROMIS) UE Short Form. Results: All participants learned to use our UE assistive system to perform ADLs and were able to use it independently at home. Most participants experienced a clinically meaningful improvement in both performance and satisfaction for the majority of their COPM goals while using the system. All participants experienced improvement in hand grip and release as shown by their baseline and post assessment scores for hand function (BBT, ARAT) and patient-reported outcomes (ABILHAND, PROMIS). Conclusions: The clinical outcomes suggest that our UE assistive system improves functional performance in patients with UE impairment, allowing them to engage more actively in ADLs. Further innovation including elbow and shoulder components will allow users to have more degrees of freedom during tasks.

Recently, there have been multiple proposals for faster methods to calculate glare metrics, daylight glare probability (DGP) in particular. This is driven simultaneously by the lengthy times required to simulate DGP with a conventional image-based approach and accumulating evidence from subjective glare evaluation experiments showing that accounting for both the saturation and contrast in a view improves the accuracy of a glare prediction. While some of these methods have been presented with their own validations, comparisons of accuracy across methods are limited by the differences in tested scenarios and resulting distributions of daylight conditions. This study compares six point-based methods and two zonal estimations for quickly calculating hourly DGP values from three viewpoints with different relationships to the window across a range of scenarios. These include scenarios with direct and semi-specular transmission and others with specular and semi-specular reflection. We find that while some of these fast methods closely align with results from a reference simulation, others introduce large and consequential errors.

A recent study on the glare protection performance of electrochromic (EC) glazing showed that visible transmittance levels lower than 0.6% are necessary to achieve comfortable situations for sun positions, that were close to the central field of view. However, the question that arises is how often such situations occur throughout the year and how the glare protection performance of EC systems is for typical office situations for different climates and orientations. This study aims to quantify the annual performance for such configurations by applying improved simulation methods to conduct annual glare simulations and comparing them to the EN17037 classifications. The enhancement of the simulation method compared to existing methods was necessary to correctly consider the blurring effect in the lens of the eye – neglecting this would lead to an overestimation of glare. We found that for mid and north European climates the extreme situations do not occur such often, so that the ECglazing systems being able to switch to transmittance levels of 1% can mitigate glare throughout the year reasonably well for typical office situations and reaches typically the highest glare protection category according to EN17037 for a viewing direction, that is parallel to the facade. For more sunny climates such as Rome, slightly lower transmittance levels (around 0.5%) would be necessary to achieve a similar glare protection level. The study also revealed that tables E.7 and E.8 of EN17037 with pre-calculated 95-percentile Daylight Glare Probability (DGP) values should be re-calculated.

The ipRGCs in the human eye mediate several effects on people, such as alertness and circadian rhythms. The spectral, temporal and spatial characteristics of light influence the magnitude of these effects. To facilitate the anticipation of the ipRGC-influenced light (IIL) responses in building design, new simulation tools are needed. This paper presents an extension to the open-access simulation tool Lark, available as a plugin to Grasshopper for Rhino. The proposed extension includes a set of additional options, components, and templates that incorporate currently available knowledge on the IIL responses. The applicability of the extension is demonstrated in a simulation workflow.

Despite the fact that karst regions are recognised as significant groundwater resources, the nature of groundwater flow paths in the unsaturated zone of such fractured rock is at present poorly understood. Many traditional methods for constraining groundwater flow regimes in karst aquifers are focussed on the faster drainage components and are unable to inform on the smaller fracture or matrix-flow components of the system. Caves however, offer a natural inception point to observe both the long term storage and the preferential movement of water through the unsaturated zone of such fractured carbonate rock by monitoring of drip rates of stalactites, soda straws and seepage from fractures/micro fissures that emerge in the cave ceiling. Here we present the largest spatial survey of automated cave drip rate monitoring published to date with the aim of better understanding both karst drip water hydrogeology and the relationship between drip hydrology and surface climate. By the application of cross correlation functions and multi-dimensional scaling, clustered by k-means technique, we demonstrate the nature of the relationships between drip behaviour and initial surface infiltration and similarity amongst the drip rate time series themselves that may be interpreted in terms of flow regimes and cave chamber morphology and lithology.

Abstract Background Adoptive cell therapy may be based on isolation of tumor-specific T cells, e.g. autologous tumor infiltrating lymphocytes (TIL), in vitro activation and expansion and the reinfusion of these cells into patients upon chemotherapy induced lymphodepletion. Together with high-dose interleukin (IL)-2 this treatment has been given to patients with advanced malignant melanoma and impressive response rates but also significant IL-2 associated toxicity have been observed. Here we present data from a feasibility study at a Danish Translational Research Center using TIL adoptive transfer in combination with low-dose subcutaneous IL-2 injections. Methods This is a pilot trial (ClinicalTrials.gov identifier: NCT00937625) including patients with metastatic melanoma, PS ≤1, age Results Low-dose IL-2 considerably decreased the treatment related toxicity with no grade 3–4 IL-2 related adverse events. Objective clinical responses were seen in 2 of 6 treated patients with ongoing complete responses (30+ and 10+ months), 2 patients had stable disease (4 and 5 months) and 2 patients progressed shortly after treatment. Tumor-reactivity of the infused cells and peripheral lymphocytes before and after therapy were analyzed. Absolute number of tumor specific T cells in the infusion product tended to correlate with clinical response and also, an induction of peripheral tumor reactive T cells was observed for 1 patient in complete remission. Conclusion Complete and durable responses were induced after treatment with adoptive cell therapy in combination with low-dose IL-2 which significantly decreased toxicity of this therapy.

Abstract Since the amounts of arachidonic acid (AA) and EPA in food may have implications for human health, we investigated whether a small change in chicken feed influenced the blood lipid concentration in humans ingesting the chicken. Forty-six young healthy volunteers (age 20–29) were randomly allocated into two groups in a double-blind dietary intervention trial, involving ingestion of about 160 g chicken meat per day for 4 weeks. The ingested meat was either from chickens given a feed concentrate resembling the commercial chicken feed, containing 4% soybean oil (SO), or the meat was from chickens given a feed where the soybean oil had been replaced by 2% rapeseed oil plus 2% linseed oil (RLO). Serum total cholesterol, LDL and HDL cholesterol, triacylglycerols, serum phospholipid fatty acid concentration, blood pressure, body weight and C-reactive protein were determined at baseline and post-intervention. In subjects consuming chicken meat from the RLO group there was a significantly (p < 0.001) increased concentration of EPA in serum phospholipids, and a reduced ratio between AA and EPA. The participants that had a low% of EPA + DHA in serum phospholipids (less than 4.6%), all increased their% of EPA + DHA after the four week intervention period when consuming the RLO chicken. No significant response differences in cholesterol, triacylglycerol, C-reactive protein, body weight or blood pressure were observed between the groups. This trial demonstrates that a simple change in chicken feed can have beneficial effects on amount of EPA and the AA/EPA ratio in human serum phospholipids.

Abstract Background The protein tyrosine phosphatase nonreceptor type 2 (PTPN22) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA1c), glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA) and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab) in children during the first year after diagnosis of type 1 diabetes. Methods The C1858T variant was genotyped in an international cohort of children (n = 257 patients) with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide) and antibody status 1, 6 and 12 months after onset. In addition HbA1c and daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset. Results A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03) for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002), which did not influence the association between PTPN22 and proinsulin (est.: 1.28, p = 0.03). Conclusions The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.

Abstract Between 2002 and 2007, travel related cases of Shigella sonnei and S. flexneri in Alberta, Canada were acquired from Central America, the Indian subcontinent and North America. Of this group, resistance to ciprofloxacin and nalidixic acid was identified in isolates from patients who had travelled to the Indian subcontinent. This study provides a Canadian perspective to a growing body of literature linking ciprofloxacin and nalidixic acid resistance to travel to the Indian subcontinent. Shigella is a common cause of diarrheal illness in North America with a rate of 2.0 per 100,000 in Canada 1 and a rate of 3.2 per 100,000 in the United States 23. Imported cases of Shigella infections have been reported in developed countries following travel to a foreign or developing country 45 and may be impacted by factors including socio-economic factors 6, food distribution networks 5 and microbiologic factors 7. Across multiple geographic regions, high rates of antimicrobial resistance to multiple agents (e.g. sulfonamides, tetracycline, chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole) have limited the choices for empiric antimicrobial therapy required to manage Shigella infections and reduce fecal excretion of the bacteria 8910 with descriptions of shifting species dominance and changes in antimicrobial susceptibility 1011. Generally, Shigella flexneri and Shigella sonnei are the dominant species and are heavily impacted by changes in antimicrobial susceptibility 1213. This study identifies the global regions associated with travel-related cases of S. flexneri and S. sonnei in Alberta, Canada and compares antibiotic resistance patterns of these isolates for 2002 to 2007 inclusive. Specimens collected 2002-2007 (inclusive) from S. flexneri and S. sonnei infections in Alberta, Canada were included for study. Data collected at time of specimen submission included: date of specimen collection, outbreak association if present, travel history and antibiogram (data source-ProvLab Information Systems; Communicable Disease Report at Alberta Health and Wellness). Outbreaks were defined by public health officials as ≥ 2 epidemiologically related cases. Each outbreak was assigned a unique incident number. Repeat isolates received within six months of original case infections were excluded. Only one representative case for each outbreak was included, unless the isolates had different antibiotic susceptibility patterns. Based on travel history the origin of an isolate was grouped into corresponding regions and continents. Regions included in the study represented major travel destinations for individuals living in Canada. Domestic exposures were defined as "travel within North America."

Abstract Background Polar bears (Ursus maritimus) are major predators in the Arctic marine ecosystem, feeding mainly on seals, and living closely associated with sea ice. Little is known of their gut microbial ecology and the main purpose of this study was to investigate the microbial diversity in faeces of polar bears in Svalbard, Norway (74-81°N, 10-33°E). In addition the level of blaTEM alleles, encoding ampicillin resistance (ampr) were determined. In total, ten samples were collected from ten individual bears, rectum swabs from five individuals in 2004 and faeces samples from five individuals in 2006. Results A 16S rRNA gene clone library was constructed, and all sequences obtained from 161 clones showed affiliation with the phylum Firmicutes, with 160 sequences identified as Clostridiales and one sequence identified as unclassified Firmicutes. The majority of the sequences (70%) were affiliated with the genus Clostridium. Aerobic heterotrophic cell counts on chocolate agar ranged between 5.0 × 104 to 1.6 × 106 colony forming units (cfu)/ml for the rectum swabs and 4.0 × 103 to 1.0 × 105 cfu/g for the faeces samples. The proportion of ampr bacteria ranged from 0% to 44%. All of 144 randomly selected ampr isolates tested positive for enzymatic β-lactamase activity. Three % of the ampr isolates from the rectal samples yielded positive results when screened for the presence of blaTEM genes by PCR. BlaTEM alleles were also detected by PCR in two out of three total faecal DNA samples from polar bears. Conclusion The bacterial diversity in faeces from polar bears in their natural environment in Svalbard is low compared to other animal species, with all obtained clones affiliating to Firmicutes. Furthermore, only low levels of blaTEM alleles were detected in contrast to their increasing prevalence in some clinical and commensal bacterial populations.

Abstract Background Sepsis and complications to sepsis are major causes of mortality in critically ill patients. Rapid treatment of sepsis is of crucial importance for survival of patients. The infectious status of the critically ill patient is often difficult to assess because symptoms cannot be expressed and signs may present atypically. The established biological markers of inflammation (leucocytes, C-reactive protein) may often be influenced by other parameters than infection, and may be unacceptably slowly released after progression of an infection. At the same time, lack of a relevant antimicrobial therapy in an early course of infection may be fatal for the patient. Specific and rapid markers of bacterial infection have been sought for use in these patients. Methods Multi-centre randomized controlled interventional trial. Powered for superiority and non-inferiority on all measured end points. Complies with, "Good Clinical Practice" (ICH-GCP Guideline (CPMP/ICH/135/95, Directive 2001/20/EC)). Inclusion: 1) Age ≥ 18 years of age, 2) Admitted to the participating intensive care units, 3) Signed written informed consent. Exclusion: 1) Known hyper-bilirubinaemia. or hypertriglyceridaemia, 2) Likely that safety is compromised by blood sampling, 3) Pregnant or breast feeding. Computerized Randomisation: Two arms (1:1), n = 500 per arm: Arm 1: standard of care. Arm 2: standard of care and Procalcitonin guided diagnostics and treatment of infection. Primary Trial Objective: To address whether daily Procalcitonin measurements and immediate diagnostic and therapeutic response on day-to-day changes in procalcitonin can reduce the mortality of critically ill patients. Discussion For the first time ever, a mortality-endpoint, large scale randomized controlled trial with a biomarker-guided strategy compared to the best standard of care, is conducted in an Intensive care setting. Results will, with a high statistical power answer the question: Can the survival of critically ill patients be improved by actively using biomarker procalcitonin in the treatment of infections? 700 critically ill patients are currently included of 1000 planned (June 2008). Two interim analyses have been passed without any safety or futility issues, and the third interim analysis is soon to take place. Trial registration number at clinicaltrials.gov: Id. nr.: NCT00271752).

Abstract Background Our aim was to investigate the existence of a reciprocal relationship between patients' assessment of quality of life and their appraisal of health. If present, this relationship will interfere with the interpretation of heart surgery's effect on overall quality of life. Methods Path analysis was used to investigate reciprocal causal relationships between general health perceptions and overall quality of life before and after heart surgery. Longitudinal data from a study of coronary artery bypass surgery were used to model lagged, cross-lagged, and simultaneous paths over four time-points of assessment from before surgery to one year afterwards. The conceptual framework for the analysis was the Wilson and Cleary causal pathway model. General health perceptions were measured with the Short Form 36. Overall quality of life was measured with i) a single question regarding life satisfaction and ii) the multi-item Quality of Life Survey. Results Acceptable model fit was obtained for reciprocal causation between general health perceptions and overall quality of life. Regression coefficients changed over different phases of rehabilitation. Serial correlation accounted for much of the variance within variables over time. Conclusion The present analysis demonstrates that unidirectional models of causality are inadequate to explain the effect of heart surgery on overall quality of life. Overall quality of life can causally influence as well as be an outcome of health status after coronary artery bypass surgery.

Abstract Recently, it was described that an HLA-A24 restricted peptide derived from the survivin splice variant survivin-2B can be recognized by CD8(+) cytotoxic T-cells. The identification of an HLA-A24 epitope is critical for survivin-based immunotherapy as HLA-24 is the most frequent HLA allele in Asia. Consequently, this survivin-2B epitope is already a target in a clinical study in patients with advanced or recurrent colorectal cancer expressing survivin. However, the splice variant survivin-2B has been described to be pro-apoptotic, and is only expressed at low levels in most malignant tissues. Furthermore, survivin-2B expression are significantly decreased in later tumor stages and inversely correlated with tumor differentiation and invasion. Consequently, survivin is a more general vaccination candidate than the splice variant survivin-2B. Here, we on the basis of spontaneous immune responses in HLA-A24+ cancer patients describes that a HLA-A24-restricted survivin epitopes does indeed exist. Consequently, this epitope is an attractive target for the ongoing survivin-based peptide immunotherapy against cancer.

Abstract Background Differences in HLA allele frequencies between the diseased and healthy populations may signify efficient immune responses, a notion that has been successfully tested for infectious diseases or for association with genetic elements involved in a distinct type of immunity. This retrospective study is intended to detect differences in MHC class I carrier frequencies of advanced melanoma patients compared to healthy bone marrow donors. Methods The HLA-A and -B carrier frequencies of 748 stage IV melanoma patients retrieved from serotyping at 6 different centers in Germany were compared using a chi-square test to 13,386 fully HLA typed bone marrow donors registered in the German national bone marrow donor registry. Results The comparison of HLA carrier frequencies in advanced cancer patients with healthy bone marrow donors revealed a significant decrease in HLA-B8 carrier frequencies, which was also apparent in patients with advanced disease compared to patients with loco-regional disease. Conclusion The data suggest that protective immune responses restricted to distinct MHC class I molecules may be operational in a subset of melanoma patients, which is the prerequisite for a large scale screen for the corresponding epitopes. Alternatively, the known association of the ancestral haplotype HLA-A1, -B8 and -DR3 with genetic elements such as distinct TNF-α alleles might have a protective effect on disease progression. In any case, identification of the cause of protection within this patient subset might lead to a significant improvement in the efficacy of current immunotherapeutic approaches.

Abstract Cells of the immune system spontaneously recognize autologous tumor cells and T cells are believed to be the main effector cells for the immune surveillance of cancer. Recent advances in our understanding of basic and tumor immunology together with methodological developments implies that tumor specific T cells can now be studied functionally, phenotypically as well as molecularly. T cells recognize peptide antigens in the context of MHC molecules through the clonally distributed T-cell receptor (TCR), thus, the clonal distribution of the TCR offers the means to detect and track specific T cells based upon detection of the unique TCR. In this review, we present and discuss available data on TCR utilization of tumor specific T cells in murine models as well as spontaneous and treatment induced anti-tumor T-cell responses in humans.

Background: Individuals with diabetes and co-existing psychiatric disorders have more diabetes complications and lower life expectancy than those with diabetes but no co-existing psychiatric disorders. Psychiatric health professionals may have a role in improving these outcomes but often lack diabetes knowledge and skills. This study aims to examine the effectiveness of a diabetes training course for psychiatric health professionals on their diabetes knowledge and skills and clinical outcomes, diabetes support and diabetes distress among individuals with diabetes and psychiatric disorders treated in psychiatric outpatient clinics., Methods: A pragmatic non-randomized controlled cluster trial was conducted in eight psychiatric outpatient clinics in Denmark. All psychiatric health professionals from four clinics participated in the diabetes training course (the intervention) and completed a questionnaire on experience of the training course and a 20-item pre- and post-test to measure diabetes knowledge and skills. Difference in pre- and post-tests were analyzed using t-tests. From August 2018 - June 2019, individuals with diabetes were recruited from the intervention clinics (n = 49) and from four control clinics continuing usual clinical practice (n = 57). Differences in clinical outcomes, diabetes support and diabetes distress between the intervention and control groups at six and 12 months after the training course, were analyzed using logistic and linear regression models adjusted for baseline levels., Results: Psychiatric health professionals (n = 64) had more correct answers after completing the course, with a mean increase of 6.3 [95% CI 5.6 to 7.0] correct answers. A total of 49 and 57 individuals were recruited for the intervention and control group, respectively. At follow-up, individuals treated in the intervention group had lower levels (clinical improvement) of systolic blood pressure, but had lower receipt of annual assessment of blood pressure, and body mass index (BMI) (worsening of process measures). While there were observed differences in odds and means for several other outcomes, none of these received statistical significance (see Table 2 and Fig. 2)., Conclusions: Training psychiatric health professionals in diabetes care improved their diabetes knowledge and skills and improved clinical levels of systolic blood pressure in individuals treated in the intervention group. However, this training intervention was associated with a lower likelihood of receiving annual assessment of blood pressure and BMI., Trial Registration: ISRCTN registry registration number ISRCTN15523920, registration date: 02/10/2019., Competing Interests: Declarations Ethics approval and consent to participate This study was conducted according to the guidelines in the Declaration of Helsinki. The study was approved by the Danish Data Protection Agency P-2019–338. The Danish Committee on Health Research Ethics assessed that ethical approval was not required for this study according to the Danish Act on Research Ethics Review of Health Research Projects (H-18009189). Interested and eligible individuals with diabetes and psychiatric disorder were given written and verbal information about the study before giving oral and written informed consent to participate. Consent for publication Not applicable. Competing interests LEJ, LLN, AJ, MAN, KL, and DLH have no conflicts of interest to declare. LK, GSA and KKBC owns shares in Novo Nordisk A/S. LJD, KKBC and GSA are currently employed by Novo Nordisk A/S. During contribution to the manuscript, LJD, KKBC, and GSA were employed by Steno Diabetes Center Copenhagen. MEJ holds shares in Novo Nordisk, and has received research grants from AMGEN, Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, and Sanofi Aventis., (© 2024. The Author(s).)

For fixed-duration therapies against chronic lymphocytic leukemia (CLL), undetectable measurable residual disease (MRD) predicts overall and progression-free survival more accurately than complete remission. For indefinite therapies, MRD status can direct discontinuation of treatment. We systematically reviewed the relationship between antineoplastic drug exposures and undetectable MRD in CLL. Seventeen trials from MEDLINE and EMBASE met the inclusion criteria; four of which evaluated drug exposures in relation to MRD status. Undetectable MRD was associated with higher trough concentrations of ofatumumab and alemtuzumab, as well as increased maximum concentration and area under the plasma concentration curve (AUC) of ibrutinib. One study found an association between high rituximab AUC and undetectable MRD until adjusting for tumor burden. The limited studies, lack of exposure measurements of concomitant drugs, and high heterogeneity in designs limit the results' generalizability. Further research is needed to explore the exposure-MRD relationship and the possibility for therapeutic drug monitoring in CLL.

People with chronic conditions such as diabetes use social media to interact with peers. While these online interactions allow them to exchange advice and gain insight into how others cope with their condition, concerns about 'misinformation' being shared are persistently raised, especially among medical professionals. Rather than assessing whether information shared on social media is 'correct' from a clinical perspective, we explore how people with diabetes negotiate what counts as legitimate knowledge as they interact in Facebook groups. Empirically, we draw on a six-month observation of interactions in two Danish Facebook groups for people with type 1 and 2 diabetes, including a data sample of 300 posts and 7797 comments. Observations were carried out in 2021. Guided by the concept of boundary-work (Gieryn, 1983), we analyse how members of the Facebook groups demarcate legitimate knowledge from what they deem illegitimate, enacted as they scrutinise peer advice and knowledge claims. We refer to this ongoing process as 'online boundary-work' and draw out three distinct negotiations, specifying how group members (a) recognise sharing of personal experiences as useful but do not necessarily accept them as valid forms of self-management advice, (b) support each other in evaluating medical issues but delegate certain treatment decisions and responsibility to professionals and (c) do not necessarily agree on the most accurate answer but mobilise scientific or professionally managed sources to legitimise or question claims. Our work contributes to the science and technology studies (STS) literature on how social media facilitates a collective space for people with chronic conditions to 'diagnose' issues in daily self-management and reflect on solutions, especially through sharing personal experiences. By demonstrating how these activities involve an ongoing, collective task of negotiating what counts as legitimate knowledge, we elucidate the effort people with diabetes put into upholding peer support groups as digital spaces for solidarity and knowledge useful to daily self-management. However, as we highlight, online boundary-work does not necessarily result in consensus, prevent certain types of advice from being shared or guarantee that answers are considered useful to members or 'correct' from a clinical perspective., Competing Interests: Declaration of competing interest The first and second authors are employed at Copenhagen University Hospital – Steno Diabetes Center Copenhagen, a public hospital and research institution under the Capital Region of Denmark, which is partly funded by a grant from the Novo Nordisk Foundation. The funders had no role in any part of this study., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The Danish National Hospital Medicine Register (SMR) was established in 2018 to centralize and standardize medication use data across Danish hospitals. This task was previously managed by individual hospital registration systems across the five regions. This initiative addresses the need for a unified, detailed understanding of hospital medication use to monitor healthcare delivery, improve patient outcomes, and support research., Methods: The SMR has comprehensive coverage of medication use in hospitals in Denmark, offering a national overview that was previously missing. It features high-quality data, with efforts to ensure completeness and accuracy. The data collected encompasses key categories such as types of medications, doses, administration times and practices, and specific treatment indications. The SMR facilitates collaboration among Danish regional health authorities and national health agencies, enhancing decision-making and planning across the regions., Results: The establishment of the SMR has provided a centralized and standardized database for medication use across Danish hospitals. This unification replaces the previously fragmented systems, allowing for better monitoring of healthcare delivery and supporting improvements in patient outcomes and research., Conclusion: The upcoming version of the SMR will include data on dispensed outpatient medications, covering most medication use across all hospitals. This expansion will further enhance the register's utility for health authorities, clinicians, and researchers by providing a more comprehensive understanding of medication use in Denmark., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Background: Treatment with opioids is a mainstay in perioperative pain management. While the leading treatment paradigm has been procedure-specific pain management, efforts regarding personalized pain treatment are increasing. The OPI•AID project aims to develop personalized algorithms for perioperative pain management, taking demographic, surgical, and anaesthesiologic factors into account. We will undertake five parallel reviews to illuminate current evidence on different aspects of individual responses to perioperative opioid treatment., Methods: Inclusion of adult populations in English-written studies. Review-specific searches are developed for the following databases: CENTRAL, MEDLINE, Embase, clinicaltrials.gov, and clinicaltrial.eu. Two authors will independently screen citations, extract data, and assess the risks of bias in each review (QUIPS, PROBAST and RoB2, as relevant)., Conclusion: These reviews will evaluate various aspects of perioperative opioid treatment, including individualized treatment strategies, selection of specific opioids, and individual patient responses. These will guide future development of a personalized perioperative opioid treatment algorithm (OPI•AID) that will be validated and tested clinically against standard of care., (© 2024 The Author(s). Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.)

Background: Dyslipidemia is a known risk factor for cardiovascular disease. While statins are the primary treatment, some individuals require additional lipid-lowering therapies, such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Alirocumab and evolocumab have shown efficacy in reducing low-density lipoprotein cholesterol (LDL-C) levels and reduce the risk of major cardiovascular events (MACE) but have not been directly compared in clinical trials. This study aims to assess the effects of PCSK9 inhibitors on LDL-C levels and evaluate the impact of a mandated switch from alirocumab to evolocumab., Methods: Taking advantage of the mandated switch in PCSK9 treatment in Denmark, we conducted a register-based cohort study of 907 individuals with dyslipidemia treated with PCSK9 inhibitors in the Capital Region of Denmark from 2016 to 2022. We analyzed LDL-C levels, treatment retention, and MACE, adjusting for variables such as age, sex, dose, and concurrent lipid-lowering medications., Results: We show that PCSK9 inhibitors treatment resulted in a 49% reduction in LDL-C levels. Following a mandated switch from alirocumab to evolocumab, no significant difference was observed in LDL-C levels or adverse clinical outcomes, including MACE. Treatment discontinuation was most likely within the first 100 days, and no significant difference in discontinuation rates was found between the two drugs., Conclusions: Our study demonstrates that both alirocumab and evolocumab are effective in significantly reducing LDL-C levels in individuals with dyslipidemia. The mandated switch from alirocumab to evolocumab did not result in significant changes in LDL-C or clinical outcomes, suggesting that these treatments can be used interchangeably. These findings support the clinical equivalence of the two PCSK9 inhibitors and may guide therapeutic decisions in lipid management., (© 2024. The Author(s).)

Background: Immunodeficiency is a shared feature of B cell malignancies. The risk of infections and their prognostic significance after diagnosis are well characterized, but, conversely, less is known about prediagnostic infections in these domains., Methods: In matched case-control analyzes, using Danish nationwide registers, we assessed the rate of prediagnostic infections in chronic lymphocytic leukemia (CLL), diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM), follicular lymphoma (FL), marginal zone lymphoma (MZL), and lymphoplasmacytic lymphoma (LPL). Survival analyzes of data from clinical registers were then used to determine the effect of infections in the year preceding diagnosis on overall survival. To yield results for as many patients as possible, antimicrobial prescriptions were used as surrogates for infections., Results: The nationwide and clinical registers comprised 30,389 patients, accumulating 213,649 antimicrobial prescriptions, and 18,560 patients accumulating 107,268 prescriptions, respectively. The relative risk of infections was increased up to 15 years prior to diagnosis of malignancy and markedly increased in the year just prior to diagnosis. More than two antimicrobials within one year prior to diagnosis were associated with significantly shorter overall survival, independently of known prognostic factors., Conclusion: Patients with B cell-derived malignancies exhibit marked immunodeficiency several years prior to diagnosis such that different disease subtypes demonstrate both overlapping and distinct trends in infection risk preceding diagnosis. Moreover, multiple infections within the year preceding diagnosis are independently associated with shorter overall survival for all the examined malignancies., (© 2024. The Author(s).)

N-acetylcysteine (NAC) is regarded as an effective treatment of paracetamol overdoses. However, in cases of "massive" paracetamol overdoses, recent studies indicate that patients may not be sufficiently treated with the standard dose of NAC (300 mg/kg over 20-21 h). The subject is further complicated because "massive overdoses" and "high-risk" are defined differently; some studies use the ingested amount (e.g., >40 g), and some studies use blood concentrations of paracetamol and transaminases. This narrative review investigates whether high-dose NAC significantly decreases the risk of hepatotoxicity in patients with massive paracetamol overdoses. Three observational studies were analysed; one study with 373 patients found no significant difference (odds ratio [OR]: 1.27, 95% confidence interval [CI]: 0.49-3.29). One study with 79 patients found a significant difference (OR: 0.27, 95% CI: 0.08-0.94). The third study with 89 patients found a significant difference in hepatoxicity between the groups (p = 0.043). There are no solid evidence to support that treatment with high-dose NAC significantly reduces the rate of hepatotoxicity in patients presenting with massive paracetamol overdoses. Differences in inclusion criteria in the included studies make the studies incomparable. This paper shows that standardized inclusion is needed to determine whether a high-dose NAC regimen should be included in clinical practice., (© 2024 The Author(s). Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Objective: Adjuvant chemotherapy is often indicated in patients diagnosed with early breast cancer (EBC). Among others, weight gain is one of the observed side effects of both chemotherapy and other cancer treatments; however, the mechanism is not well-described. In this study, we aimed to assess thyroid function before and shortly after the course of chemotherapy for EBC., Methods: This is a prospective cohort study of women diagnosed with EBC. The main outcome was the thyroid function and body weight before and after completing chemotherapy. Secondary outcomes were the presence of thyroid autoantibodies and treatment radiation dosage. We included 72 patients treated with adjuvant chemotherapy, whereas 59 patients also received supraclavicular locoregional radiotherapy. Triple-negative breast cancer (BC) patients receiving chemoimmunotherapy were excluded., Results: After the chemotherapy, we observed an increase in thyroid-stimulating hormone (p = 0.03) and a decrease in free-thyroxine (p = 0.0006), with no significant weight change. The prevalence of autoimmune thyroiditis was low. On average 3 months post-chemo, we found no statistically significant difference in the thyroid function of women treated versus not treated with supraclavicular locoregional radiotherapy., Conclusions: Although statistically significant changes in thyroid hormones were observed, this study suggests no obvious clinically significant changes in thyroid function in women with early BC after the course of chemotherapy. The decrease in thyroid function was not related to autoimmunity, non-thyroidal illness, radiotherapy, or high-dose corticosteroids. Further studies with a longer follow-up of thyroid function after adjuvant chemotherapy and supraclavicular locoregional radiotherapy are needed., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Plasma membrane damage and rupture occurs frequently in cells, and holes must be sealed rapidly to ensure homeostasis and cell survival. The membrane repair machinery is known to involve recruitment of curvature-inducing annexin proteins, but the connection between membrane remodeling and hole closure is poorly described. The induction of curvature by repair proteins leads to the possible formation of a membrane neck around the hole as a key intermediate structure before sealing. We formulate a theoretical model of equilibrium neck shapes to examine the potential connection to a repair mechanism. Using variational calculus, the shape equations for the membrane near a hole are formulated and solved numerically. The system is described under a condition of fixed area, and a shooting approach is applied to fulfill the boundary conditions at the free membrane edge. A state diagram of neck shapes is produced describing the variation in neck morphology with respect to the membrane area. Two distinct types of necks are predicted, one with conformations curved beyond π existing at positive excess area, whereas flat neck conformations (curved below π) have negative excess area. The results indicate that in cells, the supply of additional membrane area and a change in edge tension is linked to the formation of narrow and curved necks. Such necks may be susceptible to passive or actively induced membrane fission as a possible mechanism for hole sealing during membrane repair in cells., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Purpose: Metronidazole, a widely used antimicrobial medication, has been linked to neurologic adverse drug reactions. This study investigates the association between metronidazole use and first-time neurologic events., Methods: We conducted a case-time-control study using data from the Danish National Patient Register and the National Prescription Register in years 2013 to 2021. Patients with a first-time diagnosis of encephalopathy, cerebellar dysfunction, or peripheral neuropathy were included. Conditional logistic regression analyses were performed to estimate the risk of neurologic events associated with metronidazole use., Findings: Out of 476,066 first-time metronidazole prescriptions, the 100-day cumulative incidence of peripheral neuropathy was 0.016%, and 0.002% for cerebellar dysfunction or encephalopathy. In the case-time control study, we identified 17,667 persons with a first-time neurologic event and were included for the analysis. The estimated odds ratio for the combined neurologic events was 0.98 (95% CI, 0.59-1.64, P = 0.95) with no statistically significant association across different subgroups and time windows., Implications: Our findings suggest that metronidazole-induced neurologic events may be rarer than previously described, and we did not find any consistent or statistically significant association between metronidazole exposure. Nonetheless, clinicians should remain vigilant to potential neurologic risks in patients receiving metronidazole, to ensure its safe and effective use., Competing Interests: Declaration of competing interest The authors declare no competing interests at the time of manuscript preparation and submission. Subsequent to manuscript finalization, author MAA has initiated employment with Novo Nordisk., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Train-the-trainer (TTT) programs are widely applied to disseminate knowledge within healthcare systems, but evidence of the effectiveness of this educational model remains unclear. We systematically reviewed studies evaluating the impact of train-the-trainer models on the learning outcomes of nurses., Methods: The reporting of our systematic review followed PRISMA 2020 checklist. Records identified from MEDLINE, Embase, CINAHL, and ERIC were independently screened by two researchers and deemed eligible if studies evaluated learning outcomes of a train-the-trainer intervention for trainers or trainees targeting nurses. Study quality was assessed with Joanna Briggs Institute's critical appraisal tools and data of study characteristics extracted (objective, design, population, outcomes, results). Heterogeneity of outcomes ruled out meta-analysis; a narrative synthesis and vote counting based on direction of effects (p < 0.05) synthesized the results. All records were uploaded and organized in EPPI-Reviewer., Results: Of the 3800 identified records 11 studies were included. The included studies were published between 1998 and 2021 and mostly performed in the US or Northern Europe. Nine studies had quasi-experimental designs and two were randomized controlled trials. All evaluated effects on nurses of which two also included nurses' assistants. The direction of effects of the 13 outcomes (knowledge, n = 10; skills, n = 2; practice, n = 1) measured in the 11 included studies were all beneficial. The statistical analysis of the vote counting showed that train-the-trainer programs could significantly (p < 0.05) improve trainees' knowledge, but the number of outcomes measuring impact on skills or practice was insufficient for synthesis., Conclusions: Train-the-trainer models can successfully disseminate knowledge to nurses within healthcare systems. Considering the nurse shortages faced by most Western healthcare systems, train-the-trainer models can be a timesaving and sustainable way of delivering education. However, new comparative studies that evaluate practice outcomes are needed to conclude whether TTT programs are more effective, affordable and timesaving alternatives to other training programs., Trial Registration: The protocol was registered in Research Registry ( https://www.researchregistry.com , unique identifying number 941, 29 June 2020)., (© 2024. The Author(s).)

Optogenetics is highly useful to stimulate or inhibit defined neuronal populations and is often used together with electrophysiological recordings. Due to poor penetration of light in tissue, there is a need for biocompatible wave guides. Glass wave guides are relatively stiff and known to cause glia reaction that likely influence the activity in the remaining neurons. We developed highly flexible micro wave guides for optogenetics that can be used in combination with long-lasting electrophysiological recordings. We designed and evaluated polydimethylsiloxane (PDMS) mono-fibers, which use the tissue as cladding, with a diameter of 71 ± 10 µm and 126 ± 5 µm. We showed that micro PDMS fibers transmitted 9-33 mW/mm 2 light energy enough to activate channelrhodopsin. This was confirmed in acute extracellular recordings in vivo in which optogenetic stimulation through the PDMS fibers generated action potentials in rat hippocampus with a short onset latency. PDMS fibers had significantly less microglia and astrocytic activation in the zone nearest to the implant as compared to glass. There was no obvious difference in number of adjacent neurons between size matched wave guides. Micro PDMS wave guide demonstrates in vivo functionality and improved biocompatibility as compared to glass. This enables the delivery of light with less tissue damage., (© 2023. Springer Nature Limited.)

Age-related comorbid conditions are exceedingly common in patients with chronic lymphocytic leukemia (CLL). As the prevalence of type 2 diabetes (T2D) is predicted to double during the next two decades, a better understanding of the interplay between CLL and T2D is of increasing importance. In this study, analyses were performed in parallel in two separate cohorts, based on Danish national registers and the Mayo Clinic CLL Resource. The primary outcomes were overall survival (OS) from time of CLL diagnosis, OS from time of treatment, and time to first treatment (TTFT), studied using Cox proportional hazard regression analysis and Fine-Gray regression analysis. In the Danish CLL cohort, the prevalence of T2D was 11%, in the Mayo CLL cohort, it was 12%. Patients with CLL and T2D had shorter OS both from time of diagnosis and from first-line treatment for were less likely to receive treatment for CLL compared with patients with CLL and without T2D. The increased mortality was largely driven by an increased risk of death due to infections, especially in the Danish cohort. The findings of this study emphasize a substantial subgroup of CLL patients with co-occurring T2D with an inferior prognosis and a possible unmet treatment need requiring additional interventions and further research., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Aims: People with type 2 diabetes experience a range of negative work-related outcomes at a time when people are expected to remain active within the labour market for longer. This study sought to identify the work-related challenges faced by people with type 2 diabetes and ways to address them., Methods: Recruitment was undertaken in two contexts and focussed on people living with type 2 diabetes of working age (18-67). A further inclusion criterion for participants was that they were registered as having at least one diabetes-related complication. Qualitative data was gathered via semi-structured interviews and interactive workshops and analysed using systematic text condensation., Results: Three themes were identified. The first theme highlighted that participants did not generally believe that their diabetes caused them any problems in the context of work, though this was not fully supported in their own accounts. The second theme pointed to the positive value attached to work, simultaneously indicating that work could negatively impact diabetes management and general health. The final theme highlighted the ways that both participants and their healthcare providers considered diabetes in isolation from other aspects of life, potentially delaying remedial actions., Conclusions: Epidemiological data indicate that there are serious issues linked to living with type 2 diabetes and work-related outcomes. The extent to which these issues are recognized and understood may be obfuscated or contained by the value which people attach to work-life. More needs to be done to tease out work-related challenges for people with type 2 diabetes to better initiate timely remedial actions., (© 2023 Diabetes UK.)

For chronic lymphocytic leukaemia (CLL), targeted drugs have become the standard of care, in particular for second-line treatment. In this study, overall survival (OS), treatment-free survival (TFS) and adverse events (AE) were registered retrospectively in a Danish population-based cohort upon second-line treatment for CLL. Data were collected from medical records and the Danish National CLL register. For 286 patients receiving second-line treatment, three-year TFS was higher upon targeted treatment (ibrutinib/venetoclax/idelalisib) [63%, 95% confidence interval (CI) 50%-76%] compared with fludarabine, cyclophosphamide and rituximab or bendamustine and rituximab (FCR/BR) (37%, CI: 26%-48%) and chlorambucil+/-CD20-antibody (CD20Clb/Clb) (22%, CI: 10%-33%). Upon targeted treatment, three-year OS estimates were higher for targeted treatment (79%, CI: 68%-91%) compared with FCR/BR (70%, CI: 60%-81%) or CD20Clb/Clb (60%, CI: 47%-74%). The most common AEs were infections and haematological AEs; 92% of patients treated with targeted drugs had AEs, 53% of which were severe. Upon FCR/BR and CD20Clb/Clb, AEs were present for 75% and 53% respectively, of which 63% and 31% were severe. These real-world data demonstrate higher TFS and a tendency towards higher OS following targeted second-line treatment for CLL compared to chemoimmunotherapy, also for patients who may be frailer and more comorbid., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: People living with chronic conditions such as diabetes turn to peers on social media to obtain and share information. Although social media use has grown dramatically in the past decade, little is known about its implications for the relationships between people with chronic conditions and health care professionals (HCPs)., Objective: We aimed to systematically review the content and quality of studies examining what the retrieval and sharing of information by people with chronic conditions on social media implies for their relationships with HCPs., Methods: We conducted a search of studies in MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid), and CINAHL (EBSCO). Eligible studies were primary studies; examined social media use; included adults with any type of diabetes, cardiovascular diseases that are closely linked with diabetes, obesity, hypertension, or dyslipidemia; and reported on the implications for people with chronic conditions-HCP relationships when people with chronic conditions access and share information on social media. We used the Mixed Methods Appraisal Tool version 2018 to assess the quality of the studies, and the included studies were narratively synthesized., Results: Of the 3111 screened studies, 17 (0.55%) were included. Most studies (13/17, 76%) were of low quality. The narrative synthesis identified implications for people with chronic conditions-HCP relationships when people with chronic conditions access and share information on social media, divided into 3 main categories with 7 subcategories. These categories of implications address how the peer interactions of people with chronic conditions on social media can influence their communication with HCPs, how people with chronic conditions discuss advice and medical information from HCPs on social media, and how relationships with HCPs are discussed by people with chronic conditions on social media. The implications are illustrated collectively in a conceptual model., Conclusions: More evidence is needed to draw conclusions, but the findings indicate that the peer interactions of people with chronic conditions on social media are implicated in the ways in which people with chronic conditions equip themselves for clinical consultations, evaluate the information and advice provided by HCPs, and manage their relationships with HCPs. Future populations with chronic conditions will be raised in a digital world, and social media will likely remain a strategy for obtaining support and information. However, the generally low quality of the studies included in this review points to the relatively immature state of research exploring social media and its implications for people with chronic conditions-HCP relationships. Better study designs and methods for conducting research on social media are needed to generate robust evidence., (©Emilie Mølholm Kjærulff, Tue Helms Andersen, Natasja Kingod, Mette Andersen Nexø. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 17.04.2023.)

Background: Cancer treatments suppress immune function and are associated with increased risk of infections, but the overall burden of serious infectious diseases in treated patients has not been clearly elucidated., Methods: All patients treated for solid malignant tumours with radiotherapy (RT) and/or standard first-line chemotherapy (C) at the Department of Oncology at Rigshospitalet between 01/1/2010 and 31/12/2016 were included. Patients were followed from treatment initiation until the first of new cancer treatment, 1 year after treatment initiation, end of follow-up or death. Incidence rates (IR) of positive blood culture (PBC) per 1000 person-years follow-up (PYFU) were calculated., Findings: 12,433 individuals were included, 3582 (29%), 6349 (51%), and 2502 (20%) treated with RT, C, or both RT & C, respectively, contributing 8182 PYFU. 429 (3%) individuals experienced 502 unique episodes of PBC, incidence rate (95% CI) 52.43 (47.7, 57.6) per 1000 PYFU. The 30-day mortality rate after PBC was 24% independent of treatment modality. Adjusted incidence rate ratios in the first 3 months (95% CI) after PBC significantly varied by treatment: 2.89 (1.83, 4.55) and 2.52 (1.53, 4.14) for C and RT & C compared to RT. Escherichia coli (n = 127, 25%) was the top microorganism identified., Interpretation: PBCs are not common, but when they occur, mortality is high., (© 2022. The Author(s).)

Objectives: To identify the prevalence of diabetes among adults (>18 years) living in residential care facilities in Denmark and to identify the structural, practical, and individual barriers and drivers related to their participation in screening programmes., Design: SETTING: The register-based study included all residents living in residential care facilities in Denmark. The survey and qualitative analysis were carried out exclusively in the Capital Region of Denmark., Participants: For the register-based study, we identified 11 620 residents of care facilities in Denmark (>18 years) and identified the number of residents with diagnosis codes of type 1 or type 2 diabetes or dispensed prescriptions of blood glucose-lowering medication. Staff from 102 psychiatric facilities housing adults with severe psychiatric disabilities were invited to participate in the survey. Of these, 56 facilities participated with one responder each, of which n=16 also participated in follow-up qualitative interviews., Results: Register-based study: of the residents at the facilities, 954 (8%) were diagnosed with diabetes. Descriptive statistics of responses and results from content analysis of interviews were summarised in five themes that illuminated how a screening programme could be tailored to the care facilities: (1) characteristics of residents and care facilities, (2) the care needs of residents, (3) the way care was organised, (4) the specific barriers and drivers for participating in programmes, (5) number of hours and settings for screening programmes., Conclusion: To increase the participation of people living in psychiatric care facilities in screening programmes, future programmes should be tailored to the identified needs and barriers experienced by the residential care staff., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Individuals with a prior Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection have a moderate to high degree of protection against reinfection, though seemingly less so when the Omicron variant of SARS-CoV-2 started to circulate. The aim of this study was to evaluate the vaccine effectiveness (VE) against SARS-CoV-2 reinfection, Coronavirus Disease 2019 (COVID-19)-related hospitalization, and COVID-19-related death, in individuals with prior SARS-CoV-2 infection, and to assess the effect of time since vaccination during periods with different dominant SARS-CoV-2 variants., Methods and Findings: This study used a nationwide cohort design including all individuals with a confirmed SARS-CoV-2 infection, who were alive, and residing in Denmark between 1 January 2020 and 31 January 2022. Using Danish nationwide registries, we obtained information on SARS-CoV-2 infections, COVID-19 vaccination, age, sex, comorbidity, staying at hospital, and country of origin. The study population included were individuals with prior SARS-CoV-2 infection. Estimates of VE against SARS-CoV-2 reinfection with 95% confidence intervals (CIs) were calculated using a Poisson regression model and adjusted for age, sex, country of origin, comorbidity, staying at hospital, calendar time, and test incidence using a Cox regression model. The VE estimates were calculated separately for three periods with different dominant SARS-CoV-2 variants (Alpha (B.1.1.7), Delta (B.1.617.2), or Omicron (B.1.1.529)) and by time since vaccination using unvaccinated as the reference. In total, 148,527 person-years and 44,192 SARS-CoV-2 infections were included for the analysis regarding reinfections. The study population comprised of 209,814 individuals infected before or during the Alpha period, 292,978 before or during the Delta period, and 245,530 before or during the Omicron period. Of these, 40,281 individuals had completed their primary vaccination series during the Alpha period (19.2%), 190,026 during the Delta period (64.9%), and 158,563 during the Omicron period (64.6%). VE against reinfection following any COVID-19 vaccine type administered in Denmark, peaked at 71% (95% CI: -Inf to 100%) at 104 days or more after vaccination during the Alpha period, 94% (95% CI: 92% to 96%) 14 to 43 days after vaccination during the Delta period, and 60% (95% CI: 58% to 62%) 14 to 43 days after vaccination during the Omicron period. Waning immunity following vaccination was observed and was most pronounced during the Omicron period. Due to too few events, it was not possible to estimate VE for hospitalization and death. Study limitations include potentially undetected reinfections, differences in health-seeking behavior, or risk behavior between the compared groups., Conclusions: This study shows that in previously infected individuals, completing a primary vaccination series was associated with a significant protection against SARS-CoV-2 reinfection compared with no vaccination. Even though vaccination seems to protect to a lesser degree against reinfection with the Omicron variant, these findings are of public health relevance as they show that previously infected individuals still benefit from COVID-19 vaccination in all three variant periods., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Nielsen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Polymerase chain reaction (PCR) and antigen tests have been used extensively for screening during the severe acute respiratory syndrome coronavirus 2 pandemics. However, the real-world sensitivity and specificity of the two testing procedures in the field have not yet been estimated without assuming that the PCR constitutes a gold standard test. We use latent class models to estimate the in situ performance of both tests using data from the Danish national registries. We find that the specificity of both tests is very high (>99.7%), while the sensitivities are 95.7% (95% confidence interval [CI]: 92.8%-98.4%) and 53.8% (95% CI: 49.8%-57.9%) for the PCR and antigen tests, respectively. These findings have implications for the use of confirmatory PCR tests following a positive antigen test result: we estimate that serial testing is counterproductive at higher prevalence levels., (© 2022 The Authors. Journal of Medical Virology Published by Wiley Periodicals LLC.)

Background: The immune pathogenesis underlying the diverse clinical course of COVID-19 is poorly understood. Currently, there is an unmet need in daily clinical practice for early biomarkers and improved risk stratification tools to help identify and monitor COVID-19 patients at risk of severe disease., Methods: We performed longitudinal assessment of stimulated immune responses in 30 patients hospitalized with COVID-19. We used the TruCulture whole-blood ligand-stimulation assay applying standardized stimuli to activate distinct immune pathways, allowing quantification of cytokine responses. We further characterized immune cell subsets by flow cytometry and used this deep immunophenotyping data to map the course of clinical disease within and between patients., Results: Here we demonstrate impairments in innate immune response pathways at time of COVID-19 hospitalization that are associated with the development of severe disease. We show that these impairments are transient in those discharged from hospital, as illustrated by functional and cellular immune reconstitution. Specifically, we identify lower levels of LPS-stimulated IL-1β, and R848-stimulated IL-12 and IL-17A, at hospital admission to be significantly associated with increasing COVID-19 disease severity during hospitalization. Furthermore, we propose a stimulated immune response signature for predicting risk of developing severe or critical COVID-19 disease at time of hospitalization, to validate in larger cohorts., Conclusions: We identify early impairments in innate immune responses that are associated with subsequent COVID-19 disease severity. Our findings provide basis for early identification of patients at risk of severe disease which may have significant implications for the early management of patients hospitalized with COVID-19., Competing Interests: Competing interestsThe authors declare no competing interests., (© The Author(s) 2022.)

Objectives: Diabetes technology provides people with diabetes with new opportunities, but the transformations allowed by new technology do not necessarily provide improvements in clinical metrics applied in diabetes care. This study seeks to understand how everyday life impacts on the way people use diabetes technology and how this influences diabetes care., Methods: Individual semi-structured qualitative interviews with 21 adults with type 1 diabetes treated with insulin pumps were recruited from two Danish diabetes outpatient clinics. Data were analyzed abductively and interpreted according to predetermined and emergent perspectives., Results: Transformations in care practices derived from new technological therapies were generally well-supported by healthcare providers, but adaptation to everyday life was often challenging. More advanced technology enabled people to better control diabetes, but the control they sought was defined by individual life experiences/factors. Work involved in controlling blood glucose could cause a sense of feeling controlled by diabetes in everyday life., Discussion: Everyday life with diabetes is often characterized by uncertainty and individual coping strategies are imbued with values that extend beyond purely clinical concerns and reflect the sociality of everyday life. The social values influencing individual decision-making regarding diabetes technology could be effectively expanded and enhanced with integrated peer-supported learning.

Background: The dynamics of pre-diagnostic lymphocytosis in patients with ensuing chronic lymphocytic leukemia (CLL) need to be explored as a better understanding of disease progression may improve treatment options and even lead to disease avoidance approaches. Our aim was to investigate the development of lymphocytosis prior to diagnosis in a population-based cohort of patients with CLL and to assess the prognostic information in these pre-diagnostic measurements., Methods: All patients diagnosed with CLL in the Greater Copenhagen area between 2008 and 2016 were included in the study. Pre-diagnostic blood test results were obtained from the Copenhagen Primary Care Laboratory Database encompassing all blood tests requested by Copenhagen general practitioners. Using pre-diagnostic measurements, we developed a model to assess the prognosis following diagnosis. Our model accounts for known prognostic factors and corresponds to lymphocyte dynamics after diagnosis., Results: We explore trajectories of lymphocytosis, associated with known recurrent mutations. We show that the pre-diagnostic trajectories are an independent predictor of time to treatment. The implementation of pre-diagnostic lymphocytosis slope groups improved the model predictions (compared to CLL-IPI alone) for treatment throughout the period. The model can manage the heterogeneous data that are to be expected from the real-world setting and adds further prognostic information., Conclusions: Our findings further knowledge of the development of CLL and may eventually make prophylactic measures possible., Competing Interests: Competing interestsC.U.N. received grants/consultancy fees from AbbVie, Janssen, Gilead, AstraZeneca, CSL Behring, Takeda, Octapharma, Roche, and Novartis outside of this study. M.A.A., M.K.G., C.B., V.S., and C.L.A. report no conflict of interest., (© The Author(s) 2022.)

Introduction: Early-stage chronic lymphocytic leukemia (CLL) challenges specialized management and follow-up., Methods: We developed and validated a prognostic index to identify newly diagnosed patients without need of treatment (CLL-WONT) by a training/validation approach using data on 4708 patients. Composite scores derived from weighted hazards by multivariable analysis defined CLL-WONT risk groups., Results: Age (>65 years: 1 point), Binet stage (B: 2 points), lactate dehydrogenase (LDH) (>205 U/L: 1 point), absolute lymphocyte count (15-30 × 10 9 /L: 1 point; >30 × 10 9 /L; 2 points), β2-microglobulin (>4 mg/L: 1 point), IGHV mutation status (unmutated: 1 point), and 11q or 17p deletion (1 point) were independently associated with shorter time to first treatment (TTFT). Low-risk patients demonstrated 5-year TTFT of 2% by internal validation, but 7-19% by external validation. Including all patients with complete scores, the 5-year TTFT was 10% for the 756 (39%) CLL-WONT low-risk patients, and the 704 (37%) patients who were both CLL-WONT and CLL-IPI low risk demonstrated even lower 5-year TTFT (8%)., Conclusion: We have adopted the CLL-WONT at an institution covering 1 800 000 individuals to allow patients with both low-risk CLL-WONT and CLL-IPI to be managed by primary healthcare providers, thereby prioritizing specialized hematology services for patients in dire need., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Studies have demonstrated an increasing mean age of the population with multiple sclerosis (MS). The association between increased age and socioeconomic outcomes has been investigated sparsely., Objective: The purpose of this study is to describe the demographic and socioeconomic status of the current Danish population of patients with MS according to age and to assess the age-related risks of no income or losing all income from earnings or receiving disability pension., Methods: The nationwide population-based Danish Multiple Sclerosis Registry provided data linked with the Danish Income Statistics Register and the Danish Rational Economic Agents Model (DREAM) database. The prevalence of socioeconomic milestones of the current MS population was compared with healthy controls and the risks of reaching socioeconomic milestones were assessed using cause-specific Cox models and cumulative incidence functions compared to healthy controls., Results: The current Danish population of patients with MS of working age (18-65 years of age) consists of 11,287 patients, of which 29.3% was older than 55 years. In 2018, 38.0% of all patients and 18.9% of controls had no income from earnings, whereas 30.5% of all patients and 7.7% of controls received disability pension. The risk of losing all income from earnings was higher for patients with MS with a hazard ratio (HR) peaking at of 4.0 (95% CI, 3.8-4.2) for the ages of 45-54 years. The risk of receiving disability pension was much higher for patients with MS peaking at a HR of 22.6 (95% CI, 20.9-24.4) for the ages of 25-34 years. Likewise, the absolute risks of both outcomes were higher for the patients with MS at all ages., Conclusion: Danish patients with MS are at a higher risk of losing all income from earnings and at a much higher risk of receiving disability pension compared with healthy controls., Competing Interests: MM has served on Scientific Advisory Board for Biogen, Sanofi, Roche, Novartis, Merck, and AbbVie, has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi, and Genzyme, and has received research support and support for congress participation from Biogen, Genzyme, Teva, Roche, Merck, and Novartis. The remaining 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 © 2022 Wandall-Holm, Andersen, Buron and Magyari.)

Objective: To describe patient characteristics and assess the risk of disability worsening in patients of different age groups with focus on late-onset multiple sclerosis (LOMS) defined as disease onset after the age of 50 years., Methods: The nationwide population-based Danish Multiple Sclerosis Registry served as data source. We described baseline characteristics and analyzed rates of reaching Expanded Disability Status Scale (EDSS) milestones., Results: We identified 28,232 patients with MS with a known year of clinical onset, of which 2661 had LOMS. The LOMS group had a higher proportion of males and patients with primary progressive disease course, and they were less likely to receive disease-modifying therapy. The initial rate of reaching EDSS milestone 6 after diagnosis was higher in LOMS [hazard ratio (HR) 1.53; 95% confidence interval (CI) 1.14-2.06]; however, when assessing the risk of reaching EDSS 6 according to age, the HR was significantly lower for the LOMS group (HR 0.307; 95% CI 0.221-0.426)., Conclusion: The clinical characteristics and treatment approaches for patients with LOMS differ from their younger counterparts. Following diagnosis, patients with LOMS initially have an increased rate of reaching EDSS score 6; however, the risk of reaching EDSS score 6 at any given age is higher in patients with non-LOMS., (© 2021. Springer-Verlag GmbH, DE part of Springer Nature.)