Lower or higher oxygenation targets in the intensive care unit: an individual patient data meta-analysis.

PURPOSE: Optimal oxygenation targets for patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are not clearly defined due to substantial variability in design of previous trials. This study aimed to perform a pre-specified individual patient data meta-analysis of the Handling Oxygenation Targets in the ICU (HOT-ICU) and the Handling Oxygenation Targets in coronavirus disease 2019 (COVID-19) (HOT-COVID) trials to compare targeting a partial pressure of arterial oxygen (PaO2) of 8-12 kPa in adult ICU patients, assessing both benefits and harms. METHODS: We assessed 90-day all-cause mortality and days alive without life support in 90 days using a generalised mixed model. Heterogeneity of treatment effects (HTE) was evaluated in 14 subgroups, and results graded using the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN). RESULTS: At 90 days, mortality was 40.4% (724/1792) in the 8 kPa group and 40.9% (733/1793) in the 12 kPa group (risk ratio, 0.99; 95% confidence interval [CI] 0.92-1.07; P = 0.80). No difference was observed in number of days alive without life support. Subgroup analyses indicated more days alive without life support in COVID-19 patients targeting 8 kPa (P = 0.04) (moderate credibility), and lower mortality (P = 0.03) and more days alive without life support (P = 0.02) in cancer-patients targeting 12 kPa (low credibility). CONCLUSION: This study reported no overall differences comparing a PaO2 target of 8-12 kPa on mortality or days alive without life support in 90 days. Subgroup analyses suggested HTE in patients with COVID-19 (moderate credibility) and cancer (low credibility).

Cardiovascular events according to blood pressure thresholds recommended by ACC/AHA.

AIM: The latest guidelines from ACC/AHA define hypertension at systolic blood pressure (SBP) 130-139 mmHg or diastolic blood pressure (DBP) 80-89 mmHg in contrast to guidelines from ESC/ESH defining hypertension at SBP ≥ 140 mmHg or DBP ≥ 90 mmHg. The aim was to determine whether the ACC/AHA definition of hypertension identifies persons at elevated risk for future cardiovascular outcome. METHODS: In a Danish prospective cardiovascular study, 19,721 white men and women aged 20-98 years were examined up to five occasions between 1976 and 2015. The population was followed until December 2018. The ACC/AHA definition of the BP levels were applied: Normal: SBP <120 mmHg and DBP <80 mmHg, Elevated: SBP 120-129 mmHg and DBP <80 mmHg, Stage 1: SBP 130-139 mmHg or DBP 80-89 mmHg, Stage 2: SBP ≥140 mmHg or DBP ≥90 mmHg. Absolute 10-year risk was calculated taking repeated examinations, covariates, and competing risk into account. RESULTS: For all outcomes, the 10-year risk in stage 1 hypertension did not differ significantly from risk in subjects with normal BP: The 10-year risk of cardiovascular events in stage 1 hypertension was 14.1% [95% CI 13.2;15.0] and did not differ significantly from the risk in normal BP at 12.8% [95% CI 11.1;14.5] (p = 0.19). The risk was highest in stage 2 hypertension 19.4% [95% CI 18.9;20.0] and differed significantly from normal BP, elevated BP, and stage 1 hypertension (p < 0.001). The 10-year risk of cardiovascular death was 6.6% [95% CI 5.9;7.4] in stage 1 hypertension and did not differ significantly from the risk in normal BP at 5.7% [95% CI 4.1;7.3] (p = 0.33). CONCLUSIONS: Stage 1 hypertension as defined by the ACC/AHA guidelines has the same risk for future cardiovascular events as normal BP. In contrast, the definition of hypertension as suggested by ESC/ESH identifies patients with elevated risk of cardiovascular events.

Until 2017, there was worldwide agreement on defining hypertension at systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg.In 2017, the American Cardiology Societies (ACC and AHA) lowered the threshold for defining hypertension at SBP 130-139 mmHg or DBP 80-89 mmHg.Lowering the threshold might make healthy persons sick if the thresholds do not identify persons at high risk.Unnecessary medical treatment is associated with high economic cost for the health care systems.We wanted to explore whether applying the American BP definition in a Scandinavian population identified persons with elevated risk for cardiovascular disease.As part of the Copenhagen City Heart study, 19,721 men and women aged 20-98 years were followed from 1976.They went through up to five examinations between 1976 and 2018 including BP measurements.We applied the American BP thresholds and followed the persons until death or 2018.In Denmark all citizens have a unique identification number which is linked to all health care contacts and administrative registers.We used advanced statistical methods and linked the BP measurements with the data for cardiovascular disease and death date from the Danish registries for each person.The results showed that the American definition of hypertension has same risk for future cardiovascular disease as the definition of normal BP.This means that healthy persons will be diagnosed with hypertension if the US guidelines were applied in Denmark.

Effect of Implantable Cardioverter-defibrillators in Nonischemic Heart Failure According to Background Medical Therapy: Extended Follow-up of the DANISH Trial.

BACKGROUND: The Heart Failure Collaboratory (HFC) score integrates types and dosages of guideline-directed pharmacotherapies for heart failure (HF) with reduced ejection fraction (HFrEF). We examined the effects of cardioverter-defibrillator (ICD) implantation according to the modified HFC (mHFC) score in 1116 patients with nonischemic HFrEF from the Danish Study to Assess the Efficacy of ICDs in Patients with Nonischemic Systolic HF on Mortality (DANISH). METHODS AND RESULTS: Patients were assigned scores for renin-angiotensin-system inhibitors, beta-blockers and mineralocorticoid receptor antagonists (0, no use; 1, < 50% of maximum dosage; 2, ≥ 50% of maximum dosage). The maximum score was 6, corresponding to ≥ 50% of maximum dosage for all therapies. The median baseline mHFC score was 4, and the median follow-up was 9.5 years. Compared with an mHFC score of 3-4, an mHFC score of 1-2 was associated with a higher rate of all-cause death (mHFC = 1-2: adjusted HR 1.67 [95% CI, 1.23-2.28]; mHFC = 3-4, reference; mHFC = 5-6: adjusted HR 1.07 [95% CI, 0.87-1.31]). ICD implantation did not reduce all-cause death compared with control (reference) (HR 0.89 [95% CI, 0.74-1.08]), regardless of mHFC score (mHFC = 1-2: HR 0.98 [95% CI, 0.56-1.71]; mHFC = 3-4: HR 0.89 [95% CI,0.66-1.20]; mHFC = 5-6: HR 0.85 [95% CI, 0.64-1.12]; Pinteraction, 0.65). Similarly, ICD implantation did not reduce cardiovascular death (HR 0.87 [95% CI, 0.70-1.09]), regardless of mHFC score (Pinteraction, 0.59). The ICD group had a lower rate of sudden cardiovascular death (HR, 0.60 [95% CI,0.40-0.92]); this association was not modified by mHFC score (Pinteraction, 0.35). CONCLUSIONS: Lower mHFC scores were associated with higher rates of all-cause death. ICD implantation did not result in an overall survival benefit in patients with nonischemic HFrEF, regardless of mHFC score.

New York Heart Association functional class and implantable cardioverter-defibrillator in non-ischaemic heart failure with reduced ejection fraction: Extended follow-up of the DANISH trial.

AIMS: Current guidelines recommend implantable cardioverter-defibrillator (ICD) therapy in patients with heart failure, a left ventricular ejection fraction of ≤35%, and New York Heart Association (NYHA) class II-III. However, the evidence regarding the benefit of primary prevention ICD is less consistent in patients with NYHA class III. We investigated the long-term effects of primary prevention ICD implantation according to NYHA class in an extended follow-up study of the DANISH trial. METHODS AND RESULTS: The DANISH trial randomized 1116 patients with non-ischaemic heart failure with reduced ejection fraction (HFrEF) to ICD implantation or usual care. Outcomes were analysed according to NYHA class at baseline (NYHA class II and III/IV). The primary outcome was all-cause mortality. Of the 1116 patients randomized in the DANISH trial, 597 (53.5%) were in NYHA class II at baseline, 505 (45.3%) in NYHA class III, and 14 (1.3%) in NYHA class IV. During a median follow-up of 9.5 years, NYHA class III/IV, compared with NYHA class II, were associated with a greater long-term rate of all-cause mortality (hazard ratio [HR] 1.52, 95% confidence interval [CI] 1.20-1.93) and cardiovascular death (HR 1.95 [1.47-2.60]). ICD implantation, compared with usual care, did not reduce the long-term rate of all-cause mortality (all participants: HR 0.89 [95% CI 0.74-1.08]; NYHA class II: HR 0.85 [0.64-1.13]; NYHA class III/IV: HR 0.89 [0.69-1.14]; pinteraction = 0.78) or cardiovascular death (all participants: HR 0.87 [95% CI 0.70-1.09]; NYHA class II: HR 0.78 [0.54-1.12]; NYHA class III/IV: HR 0.89 [0.67-1.19]; pinteraction = 0.58), irrespective of NYHA class. Similarly, NYHA class did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (all participants: HR 0.60 [95% CI 0.40-0.92]; NYHA class II: HR 0.73 [0.40-1.36]; NYHA class III/IV: HR 0.52 [0.29-0.94]; pinteraction = 0.39). CONCLUSIONS: In patients with non-ischaemic HFrEF, ICD implantation, compared with usual care, did not reduce the overall mortality rate, but it did reduce sudden cardiovascular death, regardless of baseline NYHA class. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT00542945.

Association Between Vegetation Size and Outcome in the Partial Oral Antibiotic Endocarditis Treatment Trial.

Step-down oral antibiotic therapy is associated with a non-inferior long-term outcome compared with continued intravenous antibiotic therapy in the treatment of left-sided infective endocarditis. We aimed to analyze whether step-down oral therapy compared with continued intravenous antibiotic therapy is also associated with a non-inferior outcome in patients with large vegetations (vegetation length ≥ 10 mm) or among patients who underwent surgery before step-down oral therapy. We included patients without presence of aortic root abscess at diagnosis from the POET (Partial Oral Antibiotic Endocarditis Treatment) study. Multivariable Cox regression analyses were used to find associations between large vegetation, cardiac surgery, step-down oral therapy, and the primary end point (composite of all-cause mortality, unplanned cardiac surgery, embolic event, or relapse of positive blood cultures during follow-up). A total of 368 patients (age 68 ± 12, 77% men) were included. Patients with large vegetations (n = 124) were more likely to undergo surgery compared with patients with small vegetations (n = 244) (65% vs 20%, p <0.001). During a median 1,406 days of follow-up, 146 patients reached the primary end point. Large vegetations were not associated with the primary end point (hazard ratio 0.74, 95% confidence interval 0.47 to 1.18, p = 0.21). Step-down oral therapy was non-inferior to continued intravenous antibiotic in all subgroups when stratified by the presence of a large vegetation at baseline and early cardiac surgery. Step-down oral therapy is safe in the presence of a large vegetation at diagnosis and among patients who underwent early cardiac surgery.

Exercise and Pain Neuroscience Education for Patients With Chronic Pain After Total Knee Arthroplasty: A Randomized Clinical Trial.

Importance: Up to 20% of patients develop chronic pain after total knee arthroplasty (TKA), yet there is a scarcity of effective interventions for this population. Objective: To evaluate whether neuromuscular exercise and pain neuroscience education were superior to pain neuroscience education alone for patients with chronic pain after TKA. Design, Setting, and Participants: A superiority randomized clinical trial was conducted at 3 outpatient clinics at Aalborg University Hospital in Denmark. Participants with moderate-to-severe average daily pain intensity and no signs of prosthesis failure at least 1 year after primary TKA were included. Participant recruitment was initiated on April 12, 2019, and completed on October 31, 2022. The 12-month follow-up was completed on March 21, 2023. Interventions: The study included 24 sessions of supervised neuromuscular exercise (2 sessions per week for 12 weeks) and 2 total sessions of pain neuroscience education (6 weeks between each session) or the same pain neuroscience education sessions alone. The interventions were delivered in groups of 2 to 4 participants. Main Outcomes and Measures: The primary outcome was change from baseline to 12 months using the mean score of the Knee Injury and Osteoarthritis Outcome Score, covering the 4 subscales pain, symptoms, activity of daily living, and knee-related quality of life (KOOS4; scores range from 0 to 100, with higher scores indicating better outcomes). The outcome assessors and statistician were blinded. All randomized participants were included in the intention-to-treat analysis. Results: Among the 69 participants (median age, 67.2 years [IQR, 61.2-71.9 years]; 40 female [58%]) included in the study, 36 were randomly assigned to the neuromuscular exercise and pain neuroscience education group, and 33 to the pain neuroscience education-alone group. The intention-to-treat analysis showed no between-group difference in change from baseline to 12 months for the KOOS4 (7.46 [95% CI, 3.04-11.89] vs 8.65 [95% CI, 4.67-12.63] points; mean difference, -1.33 [95% CI, -7.59 to 4.92]; P = .68). Among the 46 participants who participated in the 12-month assessment in the 2 groups, 16 (34.8%) experienced a clinically important improvement (a difference of ≥10 points on the KOOS4) with no between-group difference. No serious adverse events were observed. Conclusions and Relevance: In this randomized clinical trial, the results demonstrated that neuromuscular exercises and pain neuroscience education were not superior to pain neuroscience education alone in participants with chronic pain after TKA. Approximately one-third of the participants, regardless of intervention, experienced clinically important improvements. Future studies should investigate which patient characteristics indicate a favorable response to exercises and/or pain neuroscience education. Trial Registration: ClinicalTrials.gov Identifier: NCT03886259.

An Unusual Presentation of an Enterococcus faecalis Endocarditis With Wrist and Forearm Infection: A Case Report.

In this case, an unusual presentation of Enterococcus faecalis (E.faecalis) endocarditis and clinical signs of wrist and forearm infection are reported. Before the patient was diagnosed with E.faecalis endocarditis, the patient managed to be treated with both prednisolone, various antibiotics, and colchicine on suspicion of gout, erysipelas, and deep tissue infection. Growth of E.faecalis in blood cultures raised the suspicion of endocarditis, and transesophageal echocardiography revealed vegetations on the aortic and the mitral valves with a perforation of the anterior mitral leaflet. Since the patient responded well to antibiotic treatment and there was no progression of the size of the vegetations or the perforation, it was decided by the endocarditis team to refrain from surgery. E. faecalis endocarditis can be difficult to diagnose because the patients are often elderly, and symptoms may be subtle and misleading. In the present case, the diagnostic process was based on the Danish IE guidelines, which state that E. faecalis is a typical IE bacterium. Accepting E. faecalis as a typical infective endocarditis bacterium may lead to an earlier diagnosis and treatment.

Tension band versus locking plate fixation for patella fractures - a protocol of a randomised controlled trial.

INTRODUCTION: Following surgical management of patella fractures, patients commonly report pain; difficulties with weight-bearing tasks such as walking, running and climbing stairs; and restrictions in quality of life. Recently, a locking plate system for surgical management of patella fractures has been introduced. To date, no studies have compared standard treatment with tension band wiring with locking plate fixation in a randomised study design. We aim to compare the one-year patient-reported Knee Injury and Osteoarthritis Outcome subscale scores (KOOS5-subscales) after standard care tension band fixation with locking plate fixation for patients with patella fractures. METHODS: This is a multicentre randomised and prospective clinical trial. A total of 122 patients will be included in the study, and the primary outcome will be the KOOS subscales at 12 months after surgery. CONCLUSIONS: Findings from the present study are expected to advance our understanding of outcome following surgical treatment of patella fractures. FUNDING: This study is funded, in part, by the Novo Nordisk Foundation, Denmark. CLINICALTRIALS: gov ID: NCT04891549.

Maxillary sinus floor augmentation with autogenous bone graft compared with composite grafts: A one-year single-blinded randomized controlled trial.

OBJECTIVE: The objective was to assess the one year implant treatment outcome and patient-related outcome measures (PROMs) following maxillary sinus floor augmentation (MSFA) with autogenous bone graft (ABG) from the zygomatic buttress (control) compared with 1:1 mixture of ABG and anorganic porcine bone mineral (APBM) (Test I) or biphasic bone graft material (BBGM) (Test II). MATERIALS AND METHODS: Sixty healthy patients (34 females, 26 males) were randomly allocated to either control or test groups. Outcome measures included survival of suprastructures and implants, implant stability quotient, health status of peri-implant tissue, peri-implant marginal bone loss, frequency of complications, and PROMs using Oral Health Impact Profile-14 combined with questionnaire assessing patient perception of peri-implant soft tissue, prosthetic solution, implant function, and implant treatment outcome using visual analogue scale. Mean differences were expressed with standard deviation and 95% confidence interval. Level of significance was .05. RESULTS: All suprastructures and implants were well-functioning after one year of functional implant loading. There was no significant difference between control and test groups in any of the applied outcome measures. The implant stability significantly increased from implant placement to abutment connection within all groups (p < .001). High patient satisfaction and significant improvement in oral health-related quality of life was also reported within all groups. CONCLUSION: This study demonstrates that MSFA with composite grafts containing minimal amounts of ABG reveals comparable implant treatment outcomes as compared with ABG alone, after one year of functional implant loading. Extensive ABG harvesting in conjunction with MSFA therefore seems not to be needed.

DANSPOT: A Multicenter Stepped-Wedge Cluster-Randomized Trial of the Reclassification of Acute Myocardial Infarction: Rationale and Study Design.

BACKGROUND: Cardiac troponins are the preferred biomarkers for the diagnosis of acute myocardial infarction. Although sex-specific 99th percentile thresholds of troponins are recommended in international guidelines, the clinical effect of their use is poorly investigated. The DANSPOT Study (The Danish Study of Sex- and Population-Specific 99th percentile upper reference limits of Troponin) aims to evaluate the clinical effect of a prospective implementation of population- and sex-specific diagnostic thresholds of troponins into clinical practice. METHODS: This study is a nationwide, multicenter, stepped-wedge cluster-randomized trial of the implementation of population- and sex-specific thresholds of troponins in 22 of 23 clinical centers in Denmark. We established sex-specific thresholds for 5 different troponin assays based on troponin levels in a healthy Danish reference population. Centers will sequentially cross over from current uniform manufacturer-derived thresholds to the new population- and sex-specific thresholds. The primary cohort is defined as patients with symptoms suggestive of acute coronary syndrome having at least 1 troponin measurement performed within 24 hours of arrival with a peak troponin value between the current uniform threshold and the new sex-specific female and male thresholds. The study will compare the occurrence of the primary outcome, defined as a composite of nonfatal myocardial infarction, unplanned revascularization, and all-cause mortality within 1 year, separately for men and women before and after the implementation of the new sex-specific thresholds. CONCLUSIONS: The DANSPOT Study is expected to show the clinical effects on diagnostics, treatment, and clinical outcomes in patients with myocardial infarction of implementing sex-specific diagnostic thresholds for troponin based on a national Danish reference population. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05336435.

Stimulating thyrotropin receptor antibodies in early pregnancy.

OBJECTIVES: Thyrotropin-receptor antibodies (TRAb) are used to diagnose Graves' hyperthyroidism in pregnant women. Bioassays provide a measure of thyrotropin-receptor stimulatory antibodies (TSI) specifically. The objective was to measure TSI in pregnant women for establishment of a pregnancy-specific cut-off and comparison with immunoassay measurements of TRAb. METHODS: The retrospective Danish study was performed within the North Denmark Region Pregnancy Cohort (2011-2015) that includes stored biobank samples from early pregnancy (median week 10) with immunoassay measurements of thyroid function parameters and TRAb. TSI were measured in the same samples using the Turbo TSI bioassay (Quidel/Ortho-Clinical Diagnostics) with a recommended cut-off of 0.0241 IU/L in non-pregnant adults. A pregnancy-specific TSI cut-off (95-percentile) was established using Regression on Order Statistics. RESULTS: The established TSI cut-off was 0.0418 IU/L (95 % CI: 0.0417-0.0419). Among women with early pregnancy hyperthyroidism (n=438), 43 women (9.8 %) were TSI positive using the established cut-off, and these women had lower TSH (median 0.008 mIU/L) compared to women with TSI levels below 0.0241 (median TSH 0.040 mIU/L) or in the range from 0.0241 to 0.0418 (median TSH 0.033 mIU/L). Among the 438 women with early pregnancy hyperthyroidism, 22 women were positive for TSI and TRAb, 388 were negative for both, and 28 women were positive for either TSI or TRAb. CONCLUSIONS: This is the first study on TSI measurements in a large cohort of early pregnant women. A pregnancy-specific cut-off for TSI was established and agreement in the classification with immunoassay measurements of TRAb was seen in 94 % of cases.

Changes in acromegaly comorbidities, treatment, and outcome over three decades: a nationwide cohort study.

Objective: To study the time-dependent changes in disease features of Danish patients with acromegaly, including treatment modalities, biochemical outcome, and comorbidities, with a particular focus on cancer and mortality. Methods: Pertinent acromegaly-related variables were collected from 739 patients diagnosed since 1990. Data are presented across three decades (1990-1999, 2000-2009, and 2010-2021) based on the year of diagnosis or treatment initiation. Results: Adenoma size and insulin-like growth factor I (IGF-I) levels at diagnosis did not differ significantly between study periods. The risk of being diagnosed with diabetes, heart disease, sleep apnea, joint disease, and osteoporosis increased from the 1990s to the later decades, while the mortality risk declined to nearly half. The risk of cancer did not significantly change. Treatment changed toward the use of more medical therapy, and fewer patients underwent repeat surgeries or pituitary irradiation. A statistically significant increase in the proportion of patients achieving IGF-I normalization within 3-5 years was observed over time (69%, 83%, and 88%). The proportion of patients with three or more deficient pituitary hormones decreased significantly over time. Conclusion: Modern medical treatment regimens of acromegaly as well as increased awareness and improved diagnostics for its comorbidities have led to better disease control, fewer patients with severe hypopituitarism, and declining mortality in the Danish cohort of acromegaly patients. The risk of cancer did not increase over the study period.

Metabolic Sequelae and All-Cause Mortality in Chronic Pancreatitis With and Without Prior Acute Pancreatitis: A Nationwide Population-Based Cohort Study.

INTRODUCTION: The purpose of this study was to investigate the risk of metabolic sequelae and all-cause mortality in a population-based cohort of chronic pancreatitis (CP) patients with and without prior acute pancreatitis (AP). METHODS: We used nationwide health registries to identify all Danish residents (18 years and older) with incident CP from 2000 to 2018. Information on AP/CP diagnoses, metabolic sequelae (post-pancreatitis diabetes mellitus [PPDM], exocrine pancreatic dysfunction, and osteoporosis), and all-cause mortality were obtained from Danish national health registries. CP cases were stratified based on the presence of AP before CP diagnosis. The risk of metabolic sequelae and all-cause mortality was expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), calculated using multivariate Cox proportional hazards models. RESULTS: A total of 9,655 patients with CP were included. Among patients with CP, 3,913 (40.5%) had a prior AP diagnosis. Compared with patients without a history of AP, patients with prior AP had a decreased risk of death (HR 0.79, 95% CI 0.74-0.84), which was largely confined to the initial period after CP diagnosis. Patients with prior AP had an increased risk of PPDM (HR 1.53, 95% CI 1.38-1.69), which persisted for up to a decade after CP diagnosis. No overall differences in risk were observed for exocrine pancreatic dysfunction (HR 0.97, 95% CI 0.87-1.07) and osteoporosis (HR 0.87, 95% CI 0.74-1.02). DISCUSSION: This nationwide study revealed that most of the patients with CP have no prior episode(s) of AP, indicating that an attack of AP sensitizing the pancreas is not essential for CP development. CP patients with and without prior AP have different risk profiles of PPDM and all-cause mortality.

Transcription Factor Regulation of Gene Expression Network by ZNF385D and HAND2 in Carotid Atherosclerosis.

Carotid intima-media thickness (CIMT) is a surrogate indicator for atherosclerosis and has been shown to predict cardiovascular risk in multiple large studies. Identification of molecular markers for carotid atheroma plaque formation can be critical for early intervention and prevention of atherosclerosis. This study performed transcription factor (TF) network analysis of global gene expression data focusing on two TF genes, ZNF385D and HAND2, whose polymorphisms have been recently reported to show association with CIMT. Genome-wide gene expression data were measured from pieces of carotid endarterectomy collected from 34 hypertensive patients (atheroma plaque of stages IV and above according to the Stary classification) each paired with one sample of distant macroscopically intact tissue (stages I and II). Transcriptional regulation networks or the regulons were reconstructed for ZNF385D (5644 target genes) and HAND2 (781 target genes) using network inference. Their association with the progression of carotid atheroma was examined using gene-set enrichment analysis with extremely high statistical significance for regulons of both ZNF385D and HAND2 (p < 6.95 × 10-7) suggesting the involvement of expression quantitative loci (eQTL). Functional annotation of the regulon genes found heavy involvement in the immune system's response to inflammation and infection in the development of atherosclerosis. Detailed examination of the regulation and correlation patterns suggests that activities of the two TF genes could have high clinical and interventional impacts on impairing carotid atheroma plaque formation and preventing carotid atherosclerosis.

Can nerve monitoring during radical prostatectomy improve functional outcomes? A randomised trial.

OBJECTIVE: To explore how the use of the ProPep® Nerve Monitoring System (ProPep Surgical, Austin, TX, USA) for intraoperative specific sparing of the pudendal nerve fibres influences postoperative functional outcomes after unilateral nerve-sparing (UNS) or non-nerve-sparing (NNS) robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: We randomised 100 men undergoing UNS or NNS RARP to ProPep nerve monitoring during RARP (intervention) or standard of care RARP (control). Functional outcomes were assessed at 3, 6, and 12 months using the International Consultation on Incontinence Questionnaire Short Form (ICIQ-SF), the International Prostate Symptom Score, the Danish Prostate Symptom Score, the International Index of Erectile Function, the Erection Hardness Scale, and 24-h pad tests. The primary outcome was the difference in ICIQ-SF score between the groups at 12 months. Secondary outcomes included differences in the remaining outcome measures and continence rates at all time points. Continence was defined as the use of no pads and the answer 'Never' to the question: 'How often do you experience urinary incontinence?' or a urine loss of <8 g on the 24-h pad test. RESULTS: A total of 82 patients were included in the per-protocol analysis at 12 months with 41 in each group. At 12 months the mean ICIQ-SF scores were 5.37 (95% confidence interval [CI] 3.71-7.03) and 5.66 (95% CI 4.05-7.27) for the intervention and control groups, respectively (P = 0.8). There were no statistically significant differences in any of the remaining outcomes. However, the continence rate was higher in the intervention group at 6 months (63% vs 44%, P = 0.09). CONCLUSIONS: Intraoperative nerve monitoring did not result in better functional outcomes following UNS or NNS RARP. Larger studies are needed to explore if ProPep can reduce the time to continence after RARP.

Estimated Glomerular Filtration Rate and Implantable Cardioverter-Defibrillator in Nonischemic Systolic Heart Failure: Extended Follow-Up of DANISH.

BACKGROUND: Patients with heart failure and chronic kidney disease (CKD) may have an increased risk of death from causes competing with arrhythmic death, which could have implications for the efficacy of implantable cardioverter-defibrillators (ICDs). We examined the long-term effects of primary prophylactic ICD implantation, compared with usual care, according to baseline CKD status in an extended follow-up study of DANISH (Danish Study to Assess the Efficacy of ICDs in Patients With Nonischemic Systolic Heart Failure on Mortality). METHODS AND RESULTS: In the DANISH trial, 1116 patients with nonischemic heart failure with reduced ejection fraction were randomized to receive an ICD (N=556) or usual care (N=550). Outcomes were analyzed according to CKD status (estimated glomerular filtration rate ≥/<60 mL/min per 1.73 m2) at baseline. In total, 1113 patients had an available estimated glomerular filtration rate measurement at baseline (median estimated glomerular filtration rate 73 mL/min per 1.73 m2), and 316 (28%) had CKD. During a median follow-up of 9.5 years, ICD implantation, compared with usual care, did not reduce the rate of all-cause mortality (no CKD, HR, 0.82 [95% CI, 0.64-1.04]; CKD, HR, 1.02 [95% CI, 0.75-1.38]; Pinteraction=0.31) or cardiovascular death (no CKD, HR, 0.77 [95% CI, 0.58-1.03]; CKD, HR, 1.05 [95% CI, 0.73-1.51]; Pinteraction=0.20), irrespective of baseline CKD status. Similarly, baseline CKD status did not modify the beneficial effects of ICD implantation on sudden cardiovascular death (no CKD, HR, 0.57 [95% CI, 0.32-1.00]; CKD, HR, 0.65 [95% CI, 0.34-1.24]; Pinteraction=0.70). CONCLUSIONS: ICD implantation, compared with usual care, did not reduce the overall mortality rate, but it did reduce the rate of sudden cardiovascular death, regardless of baseline kidney function in patients with nonischemic heart failure with reduced ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00542945.

Implication of Inflammatory Bowel Disease Diagnosed Before the Age of 18 for Achieving an Upper Secondary Education: A Nationwide Population-Based Cohort Study.

BACKGROUND: Educational achievement may be adversely affected by chronic conditions in childhood and adolescence. This study aimed to examine the effect of being diagnosed with IBD on achievement of an upper secondary education and the influence of disease severity and psychiatric comorbidity. METHODS: This cohort study was based on nationwide Danish administrative registries. We compared a cohort of patients with IBD with a matched population-based cohort. The IBD cohort included patients born between 1970 and 1994 who were diagnosed with IBD (age <18 years). The outcome was achieving an upper secondary education and was analyzed using Cox regression. The impact of disease severity (expressed by surgery or corticosteroid prescriptions) or psychiatric comorbidity within the IBD cohort was assessed using Poisson regression. RESULTS: We identified 3178 patients with IBD (Crohn's disease [CD] n = 1344, ulcerative colitis [UC] n = 1834) and matched them with 28 204 references. The hazard ratio of achieving an upper secondary education was 1.14 (95% confidence interval, 1.07-1.21) for CD and 1.16 (95% confidence interval, 1.10-1.23) for UC. In the IBD cohort, having surgery, a steroid prescription, or a comorbid psychiatric condition was associated with a lower chance of achieving an upper secondary education. CONCLUSION: Being diagnosed with IBD before 18 years of age increased the chance of achieving an upper secondary education. However, patients with more severe disease or psychiatric comorbidity were at higher risk of not achieving an upper secondary education than patients with milder disease.

Infective Endocarditis After Transcatheter Versus Surgical Aortic Valve Replacement.

BACKGROUND: Scarce data are available comparing infective endocarditis (IE) following surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). This study aimed to compare the clinical presentation, microbiological profile, management, and outcomes of IE after SAVR versus TAVR. METHODS: Data were collected from the "Infectious Endocarditis after TAVR International" (enrollment from 2005 to 2020) and the "International Collaboration on Endocarditis" (enrollment from 2000 to 2012) registries. Only patients with an IE affecting the aortic valve prosthesis were included. A 1:1 paired matching approach was used to compare patients with TAVR and SAVR. RESULTS: A total of 1688 patients were included. Of them, 602 (35.7%) had a surgical bioprosthesis (SB), 666 (39.5%) a mechanical prosthesis, 70 (4.2%) a homograft, and 350 (20.7%) a transcatheter heart valve. In the SAVR versus TAVR matched population, the rate of new moderate or severe aortic regurgitation was higher in the SB group (43.4% vs 13.5%; P < .001), and fewer vegetations were diagnosed in the SB group (62.5% vs 82%; P < .001). Patients with an SB had a higher rate of perivalvular extension (47.9% vs 27%; P < .001) and Staphylococcus aureus was less common in this group (13.4% vs 22%; P = .033). Despite a higher rate of surgery in patients with SB (44.4% vs 27.3%; P < .001), 1-year mortality was similar (SB: 46.5%; TAVR: 44.8%; log-rank P = .697). CONCLUSIONS: Clinical presentation, type of causative microorganism, and treatment differed between patients with an IE located on SB compared with TAVR. Despite these differences, both groups exhibited high and similar mortality at 1-year follow-up.

NatIonal Danish endocarditis stUdieS - Design and objectives of the NIDUS registry.

AIMS: The NatIonal Danish endocarditis stUdieS (NIDUS) registry aims to investigate the mechanisms contributing to the increasing incidence of infective endocarditis (IE) and to discover risk factors associated to the course, treatment and clinical outcomes of the disease. METHODS: The NIDUS registry was created to investigate a nationwide unselected group of patients hospitalized for IE. The National Danish healthcare registries have been queried for validated IE diagnosis codes (International Classification of Disease, 10th edition [ICD-10]: DI33, DI38, and DI398). Subsequently, a team of 28 healthcare professionals, including experts in endocarditis, will systematically review and evaluate all identified patient records using the modified Duke Criteria and the 2015 European Society of Cardiology modified diagnostic criteria. The registry will contain all cases with definite or possible IE found in primary data sources in Denmark between January 1, 2016, and December 31, 2021. We will gather individual patient data, such as clinical, microbiological, and echocardiographic characteristics, treatment regimens, and clinical outcomes. A digital data collection form will be used to the gathering of data. A sample of approximately 4,300 individual patients will be evaluated using primary data sources. CONCLUSIONS AND PERSPECTIVES: The NIDUS registry will be the first comprehensive nationwide IE registry, contributing critical knowledge about the course, treatment, and clinical outcomes of the disease. Additionally, it will significantly aid in identifying areas in which future research is needed.