Application of computational fluid dynamics to investigate pathophysiological mechanisms in exercise-induced laryngeal obstruction.

The underlying pathophysiological mechanisms of exercise-induced laryngeal obstruction (EILO) remain to be fully established. It is hypothesised that high inspiratory flow rates can exert a force on laryngeal airway wall that contributeto its inward collapse causing obstruction. Computational fluid dynamics (CFD) presents an opportunity to explore the distribution of forces in a patient specific upper airway geometry. The current study combined exercise physiological data and CFD simulation to explore differences in airflow and force distribution between an EILO patient and a healthy-matched control. Subjects underwent incremental exercise testing with continuous recording of respiratory airflow and laryngoscopic video, followed by an MRI scan. The respiratory and MRI data were used to generate a subject specific CFD model of upper respiratory airflow. In the EILO patient, the posterior supraglottis experiences an inwardly directed net force, whose magnitude increases nonlinearly with larger flow rates, with slight changes in the direction toward the centre of the airway. The control demonstrated an outwardly directed force at all regions of the wall, with a magnitude that increases linearly with larger flow rates. A comparison is made between the CFD results and endoscopic visualisation of supraglottic collapse, and very good agreement is found. We present the first hybrid physiological / computational approach to investigate the pathophysiological mechanisms of EILO. The method shows great potential and the preliminary findings should be confirmed in larger sample sizes.

Mirtazapine in pregnancy and lactation: A systematic review of adverse outcomes.

INTRODUCTION: Peripartum depression is common and treatment with mirtazapine may be indicated. However, evidence on its safety in pregnancy and lactation is fragmented. The objective of this systematic review was to evaluate the literature on the safety of mirtazapine in pregnancy and lactation. METHODS: PubMed, Embase, Medline, PsycInfo, and clinicaltrials.gov were searched for 'antidepressants' or 'mirtazapine' in combination with 'pregnancy', 'lactation' or 'offspring'. No restrictions on type of study were applied and selection was performed by two independent reviewers using Covidence. Two reviewers extracted data and performed risk of bias assessment and evidence synthesis was performed for each outcome individually. The protocol was registered at PROSPERO (registration number CRD42021275127). RESULTS: The initial search yielded 15,380 articles after removal of duplicates. After screening based on title and abstract, 431 articles remained for full text review. Of these, 41 studies were included (15 cohort studies, one case-control study, 11 case series, and 14 case reports). In most studies, the outcomes in mirtazapine-exposed pregnancies were comparable to controls. However, results on congenital malformations and spontaneous abortion were conflicting. Neonatal adaptation syndrome was reported after mirtazapine exposure in late pregnancy. Data on mirtazapine exposure during lactation were scarce. CONCLUSIONS: We identified no substantial evidence indicating that mirtazapine exposure is associated with adverse outcomes in pregnancy or in offspring, other than neonatal adaptation syndrome. However, overall quality of evidence was low, and results on congenital malformations and spontaneous abortions were conflicting. Data on mirtazapine exposure through breastfeeding were limited and did not allow for conclusions.

The combined impact of migraine and gestational diabetes on long-term risk of premature myocardial infarction and stroke: A population-based cohort study.

OBJECTIVE: To examine the combined impact of migraine and gestational diabetes mellitus (GDM) on the risks of premature (persons aged ≤60 years) major adverse cardiovascular and cerebrovascular events (MACCE) based on a composite endpoint of fatal and non-fatal myocardial infarction (MI) and stroke. BACKGROUND: Migraine and GDM are risk factors for cardiovascular disease. It is unknown how the combination of migraine and GDM may affect cardiovascular disease risk. METHODS: In a Danish population-based cohort longitudinal study, we established four cohorts among women with at least one pregnancy during 1996-2018: women with migraine, women with GDM, women with both migraine and GDM, and women free of migraine and free of GDM. Risks of premature MACCE and component endpoints were assessed for each cohort. RESULTS: We included 1,307,456 women free of migraine and free of GDM, 56,811 women with migraine, 24,700 women with GDM, and 1484 women with migraine and GDM. The 20-year absolute risk of MACCE was 1.3% (MI: 0.4%, ischemic stroke: 0.6%, hemorrhagic stroke: 0.3%) among women free of migraine and free of GDM, 2.3% (MI: 0.8%, ischemic stroke: 1.2%, hemorrhagic stroke: 0.5%) among women with migraine, 2.2% (MI: 1.0%, ischemic stroke: 1.0%, hemorrhagic stroke: 0.4%) among women with GDM, and 3.7% (MI: 1.7%, ischemic stroke: 1.7%, hemorrhagic stroke: 0.3%) among women with both migraine and GDM. The 20-year adjusted hazard ratio of premature MACCE was 1.65 (95% confidence interval [CI] 1.49-1.82) for women with migraine; 1.64 (95% CI 1.37-1.96) for women with GDM; and 2.35 (95% CI 1.03-5.36) for women with both GDM and migraine when compared with women free of migraine and free of GDM. CONCLUSIONS: Migraine and GDM were each independently associated with an increased risk of MACCE. Risk of premature MACCE was greatest among women with both migraine and GDM, although this risk estimate was imprecise.

Structures of the mitochondrial single-stranded DNA binding protein with DNA and DNA polymerase γ.

The mitochondrial single-stranded DNA (ssDNA) binding protein, mtSSB or SSBP1, binds to ssDNA to prevent secondary structures of DNA that could impede downstream replication or repair processes. Clinical mutations in the SSBP1 gene have been linked to a range of mitochondrial disorders affecting nearly all organs and systems. Yet, the molecular determinants governing the interaction between mtSSB and ssDNA have remained elusive. Similarly, the structural interaction between mtSSB and other replisome components, such as the mitochondrial DNA polymerase, Polγ, has been minimally explored. Here, we determined a 1.9-Å X-ray crystallography structure of the human mtSSB bound to ssDNA. This structure uncovered two distinct DNA binding sites, a low-affinity site and a high-affinity site, confirmed through site-directed mutagenesis. The high-affinity binding site encompasses a clinically relevant residue, R38, and a highly conserved DNA base stacking residue, W84. Employing cryo-electron microscopy, we confirmed the tetrameric assembly in solution and capture its interaction with Polγ. Finally, we derived a model depicting modes of ssDNA wrapping around mtSSB and a region within Polγ that mtSSB binds.

Pregnancy and Infant Outcomes After Prenatal Exposure to Golimumab in Denmark, Finland, and Sweden 2006-2019.

PURPOSE: To present the main findings of a post-authorization safety study assessing pregnancy and infant outcomes after prenatal golimumab exposure in a real-world setting. METHODS: This observational population-based cohort study included data from pregnancies ending in 2006-2018 (Finland) or 2019 (Denmark, Sweden). Infants born to women with rheumatic diseases or ulcerative colitis diagnoses were identified. Based on prescription fills from 90 days prior to pregnancy until delivery, infants were assigned to one of the four drug-exposure cohorts: golimumab, other anti-TNF biologics, other biologics, and nonbiologic systemic therapy, and the general population. Prevalence of adverse pregnancy outcomes, mortality, diagnoses of major congenital anomalies (MCA), and inpatient infections in the infants' first year of life were assessed. Odds ratios and 95% CIs were calculated for MCA and infection. RESULTS: Among 134 infants in the golimumab cohort, none were stillborn or died in the first year of life. MCA were diagnosed in 4.5% of the infants in the golimumab cohort, versus 6.8%, 10.9%, 5.5%, and 4.6% in the other anti-TNF biologics, other biologics, nonbiologic systemic therapy and general population cohorts, respectively. Inpatient infections were diagnosed in 11% of golimumab-exposed infants, compared with 9%-11% of infants in the other cohorts. Unadjusted and selected adjusted comparisons showed no association between prenatal golimumab exposure and MCA or infection compared with the other exposure cohorts or general population. CONCLUSIONS: The number of infants with prenatal golimumab exposure was low, but results are reassuringly consistent with the evidence available for other anti-TNF biologics. Continued monitoring is needed.

Comparative Cardiovascular Effectiveness of Empagliflozin Versus Dapagliflozin in Adults With Treated Type 2 Diabetes: A Target Trial Emulation.

BACKGROUND: Empagliflozin and dapagliflozin have proven cardiovascular benefits in people with type 2 diabetes at high cardiovascular risk, but their comparative effectiveness is unknown. METHODS: This study used nationwide, population-based Danish health registries to emulate a hypothetical target trial comparing empagliflozin versus dapagliflozin initiation, in addition to standard care, among people with treated type 2 diabetes from 2014 through 2020. The outcome was a composite of myocardial infarction, ischemic stroke, heart failure (HF), or cardiovascular death (major adverse cardiovascular event). Participants were followed until an outcome, emigration, or death occurred; 6 years after initiation; or December 31, 2021, whichever occurred first. Logistic regression was used to compute inverse probability of treatment and censoring weights, controlling for 57 potential confounders. In intention-to-treat analyses, 6-year adjusted risks, risk differences, and risk ratios considering noncardiovascular death competing risks were estimated. Analyses were stratified by coexisting atherosclerotic cardiovascular disease and HF. A per-protocol design was performed as a secondary analysis. RESULTS: There were 36 670 eligible empagliflozin and 20 606 eligible dapagliflozin initiators. In the intention-to-treat analysis, the adjusted 6-year absolute risk of major adverse cardiovascular event was not different between empagliflozin and dapagliflozin initiators (10.0% versus 10.0%; risk difference, 0.0% [95% CI, -0.9% to 1.0%]; risk ratio, 1.00 [95% CI, 0.91 to 1.11]). The findings were consistent in people with atherosclerotic cardiovascular disease (risk difference, -2.3% [95% CI, -8.2% to 3.5%]; risk ratio, 0.92 [95% CI, 0.74 to 1.14]) and without atherosclerotic cardiovascular disease (risk difference, 0.3% [95% CI, -0.6% to 1.2%]; risk ratio, 1.04 [95% CI, 0.93 to 1.16]) and in people with HF (risk difference, 1.1% [95% CI, -6.5% to 8.6%]; risk ratio, 1.04 [95% CI, 0.79 to 1.37]) and without HF (risk difference, -0.1% [95% CI, -1.0% to 0.8%]; risk ratio, 0.99 [95% CI, 0.90 to 1.09]). The 6-year risks of major adverse cardiovascular event were also not different in the per-protocol analysis (9.1% versus 8.8%; risk difference, 0.2% [95% CI, -2.1% to 2.5%]; risk ratio, 1.03 [95% CI, 0.80 to 1.32]). CONCLUSIONS: Empagliflozin and dapagliflozin initiators had no differences in 6-year cardiovascular outcomes in adults with treated type 2 diabetes with or without coexisting atherosclerotic cardiovascular disease or HF.

Histomolecular Validation of [18F]-FACBC in Gliomas Using Image-Localized Biopsies.

BACKGROUND: Gliomas have a heterogeneous nature, and identifying the most aggressive parts of the tumor and defining tumor borders are important for histomolecular diagnosis, surgical resection, and radiation therapy planning. This study evaluated [18F]-FACBC PET for glioma tissue classification. METHODS: Pre-surgical [18F]-FACBC PET/MR images were used during surgery and image-localized biopsy sampling in patients with high- and low-grade glioma. TBR was compared to histomolecular results to determine optimal threshold values, sensitivity, specificity, and AUC values for the classification of tumor tissue. Additionally, PET volumes were determined in patients with glioblastoma based on the optimal threshold. [18F]-FACBC PET volumes and diagnostic accuracy were compared to ce-T1 MRI. In total, 48 biopsies from 17 patients were analyzed. RESULTS: [18F]-FACBC had low uptake in non-glioblastoma tumors, but overall higher sensitivity and specificity for the classification of tumor tissue (0.63 and 0.57) than ce-T1 MRI (0.24 and 0.43). Additionally, [18F]-FACBC TBR was an excellent classifier for IDH1-wildtype tumor tissue (AUC: 0.83, 95% CI: 0.71-0.96). In glioblastoma patients, PET tumor volumes were on average eight times larger than ce-T1 MRI volumes and included 87.5% of tumor-positive biopsies compared to 31.5% for ce-T1 MRI. CONCLUSION: The addition of [18F]-FACBC PET to conventional MRI could improve tumor classification and volume delineation.

Confounding and Negative Control Methods in Observational Study of SARS-CoV-2 Vaccine Effectiveness: A Nationwide, Population-Based Danish Health Registry Study.

Background: Observational studies of SARS-CoV-2 vaccine effectiveness are prone to confounding, which can be illustrated using negative control methods. Methods: Nationwide population-based cohort study including two cohorts of Danish residents 60-90 years of age matched 1:1 on age and sex: A vaccinated and a non-vaccinated cohort, including 61052 SARS-CoV-2 vaccinated individuals between 1 March and 1 July 2021 and 61052 individuals not vaccinated preceding 1 July 2021. From these two cohorts, we constructed negative control cohorts of individuals diagnosed with SARS-CoV-2 infection or acute myocardial infarction, stroke, cancer, low energy fracture, or head-trauma. Outcomes were SARS-CoV-2 infection, negative control outcomes (eg, mammography, prostate biopsy, operation for cataract, malignant melanoma, examination of eye and ear), and death. We used Cox regression to calculate adjusted incidence and mortality rate ratios (aIRR and aMRR). Results: Risks of SARS-CoV2 infection and all negative control outcomes were elevated in the vaccinated population, ranging from an aIRR of 1.15 (95% CI: 1.09-1.21) for eye examinations to 3.05 (95% CI: 2.24-4.14) for malignant melanoma. Conversely, the risk of death in the SARS-CoV-2 infected cohort and in all negative control cohorts was lower in vaccinated individuals, ranging from an aMRR of 0.23 (95% CI: 0.19-0.26) after SARS-CoV-2 infection to 0.50 (95% CI: 0.37-0.67) after stroke. Conclusion: Our findings indicate that observational studies of SARS-CoV-2 vaccine effectiveness may be subject to substantial confounding. Therefore, randomized trials are essential to establish vaccine efficacy after the emergence of new SARS-CoV-2 variants and the rollout of multiple booster vaccines.

Why was this study done: : After the emergence of new SARS-CoV-2 variants and the rollout of multiple booster SARS-CoV-2 vaccines, the impact of vaccination on risk of SARS-CoV-2 infection and death after the infection has mainly been explored in observational studies. We used negative control methods to investigate whether confounding affects the results of observational SARS-CoV-2 vaccine effectiveness studies. Findings: : We used Danish registry data obtained during the SARS-CoV-2 vaccine roll-out to conduct a nationwide, matched population-based cohort study of Danish residents 60­90 years in which we compared vaccinated individuals with non-vaccinated individuals. Compared with unvaccinated individuals, vaccinated individuals had increased risks of SARS-CoV2 infection but also had increased risks of all negative control outcomes (mammography, prostate biopsy, operation for cataract, malignant melanoma, examination of eye and ear). The risk of death after SARS-CoV2 infection was lower in the vaccinated cohort, as was the risk of death after acute myocardial infarction, stroke, cancer, low energy fracture, and head-trauma. Meaning: : The negative control methods indicate that observational studies of SARS-CoV-2 vaccine effectiveness may be prone to substantial confounding which may impact the observed associations. This bias may both lead to underestimation of vaccine effectiveness (increased risk of SARS-CoV2 infection among vaccinated individuals) and overestimation of the vaccine effectiveness (decreased risk of death after of SARS-CoV2 infection among vaccinated individuals). Our results highlight the need for randomized vaccine efficacy studies after the emergence of new SARS-CoV-2 variants and the rollout of multiple booster vaccines.

Sexual health and testosterone concentration in male lymphoma survivors: A systematic review.

Advancements in lymphoma treatment have increased the number of long-term survivors who may experience late effects such as impaired sexual function and testosterone deficiency. The aim of this review was to determine the prevalence of testosterone deficiency and sexual dysfunction among male lymphoma survivors; and associations between the two. A systematic search identified 20 articles for inclusion. The prevalence of low total testosterone was 0%-50 %, with mean values within reference levels, and for luteinizing hormone above reference levels in 0%-80 %. Four studies included SHBG and free testosterone, with mixed results. Compromised sexual health was found in 23%-61 %. Overall, total testosterone and sexual health were associated. The risk of bias (ROBINS-E and RoB 2) was high/very high, leading to low/very low overall confidence in the bulk of evidence (GRADE). Longitudinal studies evaluating biologically active testosterone and sexual health are needed, to develop evidence based standard procedures for follow-up of sexual health.

Mediating pathways between neighborhood disadvantage and cardiovascular risk: Quasi-experimental evidence from a Danish refugee dispersal policy.

Research has documented that neighborhood disadvantage is associated with increased cardiovascular disease risk, but it is unclear which mechanistic pathways mediate this association across the life course. Leveraging a natural experiment in which refugees to Denmark were quasi-randomly assigned to neighborhoods across the country during 1986-1998 and using 30 years of follow-up data from population and health registers, we assessed whether and how individual-level poverty, unstable employment, and poor mental health mediate the relation between neighborhood disadvantage and the risk of hypertension, hyperlipidemia, and type 2 diabetes among Danish refugees (N= 40,811). Linear probability models using the discrete time-survival framework showed that neighborhood disadvantage was associated with increased risk of hypertension (0.05 percentage points [pp] per year [95%CI -0.00, 0.10]); hyperlipidemia (0.03 pp per year [95%CI -0.01, 0.07]), and diabetes (0.01 pp per year (95%CI -0.02, 0.03)). The Baron-Kenny product-of-coefficients method for counterfactual mediation analysis indicated that cumulative income mediated 6%-28% of the disadvantage effect on these outcomes. We find limited evidence of mediation by unstable employment and poor mental health. This study informs our theoretical understanding of the pathways linking neighborhood disadvantage with cardiovascular disease risk and identifies income security as a promising point of intervention in future research.

Association between patient activation level and functional outcomes in older adults with hip fractures.

BACKGROUND: Hip fractures can significantly impact older adults' mobility and function. Effective rehabilitation is crucial to help them regain independence and quality of life. However, little is known about the association between patient activation and hip fracture rehabilitation. This study aims to assess the association between the PAM-13 scores and the level of physical function, mobility, and activities of daily living in older adults following a hip fracture rehabilitation program. METHOD: An exploratory outcome study from a cluster-randomized stepped-wedge clinical controlled trial. Two hundred thirty-nine patients were classified into four Patient Activation Measure-Levels (PAM-13) according to their PAM-13 scores, reflecting their confidence and preparedness to manage their health. Level 1 represents the lowest level of confidence. The patient's mobility, function, and daily activities were evaluated at discharge and after 12 and 24 weeks. RESULTS: The cohort had a median age of 78; 67% were female, and 50% lived alone. There were no significant differences in demographics between the PAM-Levels. PAM-Level 1 patients had longer hospital stays and lower mobility scores than PAM-Level 4 patients. However, all patients improved over time, and higher initial PAM levels resulted in better outcomes. PAM-Level 1 patients improved in Time Up and Go score from a median score of 54 seconds to 14 seconds at 24 weeks, while PAM-Level 4 patients improved from 26 to 9 seconds. CONCLUSION: Our study found an association between PAM levels and functional outcomes in hip fracture rehabilitation. Patients with higher activation levels had better mobility and functional outcomes.

Outcome of Pregnancy Oral Glucose Tolerance Test and Preterm Birth.

BACKGROUND: Gestational diabetes is associated with adverse outcomes such as preterm birth (<37 weeks). However, there is no international consensus on screening criteria or diagnostic levels for gestational diabetes, and it is unknown whether body mass index (BMI) or obesity modifies the relation between glucose level and preterm birth. METHODS: We studied a pregnancy cohort restricted to two Danish regions from the linked Danish Medical Birth Register to study associations between glucose measurements from the 2-hour postload 75-g oral glucose tolerance test (one-step approach) and preterm birth from 2004 to 2018. In Denmark, gestational diabetes screening is a targeted strategy for mothers with identified risk factors. We used Poisson regression to estimate rate ratios (RR) of preterm birth with z-standardized glucose measurements. We assessed effect measure modification by stratifying analyses and testing for heterogeneity. RESULTS: Among 11,337 pregnancies (6.2% delivered preterm), we observed an adjusted preterm birth RR of 1.2 (95% confidence interval [CI] = 1.1, 1.3) for a one-standard deviation glucose increase of 1.4 mmol/l from the mean of 6.7 mmol/l. There was evidence for effect measure modification by obesity, for example, adjusted RR for nonobese (BMI, <30): 1.2 (95% CI = 1.1, 1.3) versus obese (BMI, ≥30): 1.3 (95% CI = 1.2-1.5), P = 0.05 for heterogeneity. CONCLUSION: Among mothers screened for gestational diabetes, increased glucose levels, even those below the diagnostic level for gestational diabetes in Denmark, were associated with increased preterm birth risk. Obesity (BMI, ≥30) may be an effect measure modifier, not just a confounder, of the relation between blood glucose and preterm birth risk.

Timing and dosage of intrapartum prophylactic penicillin for preventing early-onset group B streptococcal disease: assessing maternal and umbilical cord blood concentration.

OBJECTIVE: Timing of administration of antibiotics and concentrations in maternal blood and the umbilical cord blood are important prerequisites for optimal intrapartum antibiotic prophylaxis (IAP) of neonatal early-onset group B streptococcus (GBS) disease. This cohort study aimed to explore penicillin concentrations in mothers and infants at birth in relation to time elapsed from administration to delivery and to the minimal inhibitory concentration (MIC) for GBS. MAIN OUTCOME MEASURES: Penicillin G concentrations in maternal and umbilical cord blood in relation to time and dose from administration to time of delivery. RESULTS: In 44 mother-infant dyads, median maternal penicillin G concentration was 0.2 mg/L (IQR 0-0.8 mg/L; range 0-1.6 mg/L). Median infant penicillin G concentration was 1.2 mg/L (IQR 0.5-5.0 mg/L; range 0-12.7 mg/L). In all infants (N=38) born less than 4 hours after the latest IAP administration, penicillin G concentrations far exceeded MIC (0.125 mg/L), even after short time intervals between IAP administration and birth. The highest plasma concentrations were reached in umbilical cord blood within 1 hour from IAP administration to birth.For 44 mother-infant dyads, maternal concentrations were very low compared with their infants'; particularly, very high concentrations were seen in the 20 infants with only one dose of IAP. CONCLUSION: High concentrations of penicillin G were found in umbilical cord blood of infants born less than 4 hours after IAP administration, well above the MIC for GBS.

Treatment of nausea in hospitalized patients with acute illness.

Evidence suggests that available antiemetics are equal to intravenous fluid treatment against acute nausea of other causes than motion sickness, pregnancy, anaesthesia, chemo- or radiation therapy. Each antiemetic is associated with adverse effects, which include movement disorders, sedation, and QT prolongation. Intravenous fluid and treatment directed against underlying pathology is recommended as a first-line treatment against nausea in these patients. If an antiemetic is clinically warranted, ondansetron has the most favourable ratio between side effects and price, as argued in this review.

Informal care after hip fracture: prospective cohort.

BACKGROUND: Hip fracture is very common and it has life-shattering consequences for older persons. After discharge the older persons need help with even basic everyday activities from formal and informal caregivers. In Scandinavia formal care are well-developed however the presence of informal caregivers likely reflect on the amount of formal care and wears on the informal caregivers. This study explore how often and how much informal care (IC) older persons receive after hip fracture. METHOD: We contacted 244 community-dwelling older persons every two weeks the first twelve weeks after discharge after hip fracture and asked them if they received care from family and/or friends and how much. We used non-parametric statistics and level of significance was 95%. RESULTS: The proportion of older persons receiving IC was 90% and the median amount of IC was 32 hours (IQR 14-66). The number of older persons who received IC was highest the first four weeks after discharge and so was the amount of hours of IC. The older persons that were high-dependence on IC received a median of 66 (IQR 46-107) hours compared to the low-dependent of 11 hours (IQR 2-20). CONCLUSION: IC is very frequent, especially the first two to four weeks after discharge. The median IC was 32 hours from discharge to the 12-week follow-up. However, this figure tended to rise for persons with, among other, reduced functionality and those residing with a partner. IMPLICATIONS: With respect to local differences, the findings in this study are likely applicable to other Scandinavian countries. We strongly suggest that the variation in older person need for informal caregiver be given consideration in the prioritisation of resources. TRIAL REGISTRATION: This prospective cohort study of informal care, was part of a cluster-randomised stepped-wedge clinical controlled trial. Written consent was obtained required by regional ethics committee S-20200070. Data was collected in accordance with the Danish Data Protection Agency (20-21854).

Longitudinal HbA1c patterns before the first treatment of diabetes in routine clinical practice: A latent class trajectory analysis.

AIMS: To examine the longitudinal heterogeneity of HbA1c preceding the initiation of diabetes treatment in clinical practice. METHODS: In this population-based study, we used HbA1c from routine laboratory and healthcare databases. Latent class trajectory analysis was used to classify individuals according to their longitudinal HbA1c patterns before first glucose-lowering drug prescription irrespective of type of diabetes. RESULTS: Among 21,556 individuals initiating diabetes treatment during 2017-2018, 20,733 (96 %) had HbA1c measured (median 4 measurements [IQR 2-7]) in the 5 years preceding treatment initiation. Four classes with distinct HbA1c trajectories were identified, with varying steepness of increase in HbA1c. The largest class (74 % of the individuals) had mean HbA1c above the 48 mmol/mol threshold 9 months before treatment initiation. Mean HbA1c was 52 mmol/mol (95 % CI 52-52) at treatment initiation. In the remaining three classes, mean HbA1c exceeded 48 mmol/mol almost 1.5 years before treatment initiation and reached 79 mmol/mol (95 % CI 78-80), 105 mmol/mol (95 % CI 104-106), and 137 mmol/mol (95 % CI 135-140) before treatment initiation. CONCLUSION: We identified four distinct longitudinal HbA1c patterns before initiation of diabetes treatment in clinical practice. All had mean HbA1c levels exceeding the diagnostic threshold many months before treatment initiation, indicating therapeutic inertia.

COVID-19 severity in patients with chronic lymphocytic leukemia treated with venetoclax: a single-center observational cohort study.

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.

Influence of Low-Density Lipoprotein Cholesterol Levels on NSAID-Associated Cardiovascular Risks After Myocardial Infarction: A Population-Based Cohort Study.

Aim: To examine whether low-density lipoprotein cholesterol (LDL-C) levels influence the cardiovascular risk associated with non-aspirin non-steroidal anti-inflammatory drug (NSAID) use after myocardial infarction (MI). Methods: Using Danish health registries, we conducted a population-based cohort study of all adult patients with first-time MI during 2010-2020 with an LDL-C value before discharge. Based on the latest LDL-C value, we categorized patients into a low and a high LDL-C group (<3.0 vs ≥3.0 mmol/L). We used time varying Cox regression to compute hazard ratios (HRs) with 95% confidence intervals of the association between NSAID use and a major adverse cardiovascular event (MACE: recurrent MI, ischemic stroke, and all-cause death). Results: We followed 50,573 patients for a median of 3.1 years. While exposed, 521 patients experienced a MACE: 312 in the low LDL-C group and 209 in the high LDL-C group. The HRs for MACE comparing NSAID use with non-use were 1.21 (1.11-1.32) overall, 1.19 (1.06-1.33) in the low LDL-C group, and 1.23 (1.07-1.41) in the high LDL-group. The HRs for recurrent MI and ischemic stroke were comparable between the LDL-C subgroups. The HRs for all-cause death were 1.22 (1.07-1.39) in the low LDL-C group and 1.54 (1.30-1.83) in the high LDL-C group. Changing the cut-off value for LDL-C to 1.8 and 1.4 mmol/L showed consistent results. Conclusion: In patients with MI, LDL-C levels did not influence the increased risk of MACE associated with NSAID use, but might influence the association between NSAID use and all-cause death.