Glucagon-like-peptide-1 receptor agonists versus dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes in diabetes in relation to achieved glycemic control. A Danish nationwide study.

AIM: To compare the cardiovascular preventive effect associated with glucagon-like-peptide-1 receptor agonists (GLP-1 RA) versus dipeptidyl peptidase-4 inhibitors (DPP-4i) according to the achieved target level of glycated hemoglobin (HbA1c). METHODS: We used retrospective Danish registries to include type 2 diabetes patients already in metformin treatment initiating GLP-1 RA or DPP-4i between 2007 and 2021. Patients were included 6 months after GLP-1 RA or DPP-4i initiation. The last available HbA1c measurement before inclusion was collected. The achieved HbA1c level was categorized according to a target level below or above 53 mmol/mol (7%). The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, and all-cause death. We used a multivariable Cox proportional hazard model to estimate the effect of HbA1c levels on the outcome among GLP-1 RA users compared to DPP-4i users. RESULTS: The study included 13 634 GLP-1 RA users (median age 56.9, interquartile range [IQR]: 48.5-65.5; 53% males) and 39 839 DPP-4i users (median age 63.4, IQR: 54.6-71.8; 61% males). The number of GLP-1 RA and DPP-4i users according to achieved HbA1c levels were as follows: HbA1c ≤ 53 mmol/mol (≤7.0%): 3026 (22%) versus 4824 (12%); HbA1c > 53 mmol/mol (>7.0%): 6577 (48%) versus 17 508 (44%); missing HbA1c: 4031 (30%) versus 17 507 (44%). During a median follow-up of 5 years (IQR: 2.6-5.0), 954 GLP-1 RA users experienced the primary outcome compared to 7093 DPP-4i users. The 5-year risk (95% confidence interval [CI]) of the outcome associated with GLP1-RA versus DPP-4i according to HbA1c categories was as follows: HbA1c ≤ 53 mmol/mol: 10.3% (8.2-12.3) versus 24.3% (22.7-25.8); HbA1c > 53 mmol/mol: 16.0% (14.3-17.6) versus 21.1% (20.3-21.9); missing HbA1c: 17.1% (15.7-18.5) versus 25.6% (24.9-26.3). The preventive effect associated with GLP-1 RA versus DPP-4i was significantly enhanced when achieving lower HbA1c levels: HbA1c ≤ 53 mmol/mol: 0.65 (0.52-0.80); HbA1c > 53 mmol/mol: 0.92 (0.83-1.03); missing HbA1c: 0.92 (0.84-1.02) (p value for interaction <.001). CONCLUSION: GLP-1 RA use was associated with a lower rate of major adverse cardiovascular outcomes. The association was stronger in patients achieving the target glycemic level and weaker in patients not achieving the target glycemic level, suggestive of an interaction between achieved HbA1c level and GLP-1 RA.

Incidence of depression in patients with cardiovascular disease and type 2 diabetes: a nationwide cohort study.

BACKGROUND: Estimating how type 2 diabetes (T2D) affects the rate of depression in cardiovascular disease (CVD) can help identify high-risk patients. The aim is to investigate how T2D affects the rate of depression according to specific subtypes of CVD. METHODS: Incident CVD patients, free of psychiatric disease, with and without T2D, were included from nationwide registries between 2010 and 2020. We followed patients from CVD diagnosis until the first occurrence of depression, emigration, death, 5 years, or end of study (December 31, 2021). We used time-dependent Poisson regression to estimate the incidence rates and rate ratios (IRR) of depression following subtypes of CVD with and without T2D. The model included age, sex, comorbidities, calendar year, T2D duration, educational level, and living situation as covariates. RESULTS: A total of 165,096 patients were included; 45,845 had a myocardial infarction (MI), 63,691 had a stroke, 19,959 had peripheral artery disease (PAD), 35,568 had heart failure (HF), and 979 were diagnosed with 2 or more CVD subtypes (= > 2 CVD's). Baseline T2D in each CVD subtype ranged from 11 to 17%. The crude incidence rate of depression per 1000 person-years (95% confidence intervals) was: MI + T2D: 131.1 (109.6;155.6), MI: 82.1 (65.3;101.9), stroke + T2D: 287.4 (255.1;322.6), stroke: 222.4(194.1;253.6), PAD + T2D: 173.6 (148.7;201.4), PAD:137.5 (115.5;162.5), HF + T2D: 244.3 (214.6;276.9), HF: 199.2 (172.5;228.9), = > 2 CVD's + T2D: 427.7 (388.1;470.2), = > 2 CVD's: 372.1 (335.2;411.9). The adjusted IRR of depression in MI, stroke, PAD, HF, and = > 2 CVD's with T2D compared to those free of T2D was: 1.29 (1.23;1.35), 1.09 (1.06;1.12), 1.18 (1.13;1.24), 1.05 (1.02;1.09), and 1.04 (0.85;1.27) (p-value for interaction < 0.001). CONCLUSION: The presence of T2D increased the rate of depression differently among CVD subtypes, most notable in patients with MI and PAD.

Cervical Disc Arthroplasty for Axial Neck Pain: Comparison of Outcomes to 2 Other Common Cervical Conditions.

BACKGROUND: Cervical disc arthroplasty (CDA) is an established treatment for degenerative disc disease with radiculopathy and/or myelopathy. There is, however, little published evidence of its effectiveness to relieve pain and improve function in patients with a primary diagnosis of axial neck pain. Such patients were excluded from all previous Food and Drug Administration clinical trials for CDA. We compare the outcomes of patients who underwent CDA for 3 common cervical conditions from 2003 to 2018. METHODS: Seven hundred and eighty-two CDA patients at a single site were grouped by primary diagnosis: predominant axial neck pain (ANP) (n = 257), predominant radiculopathy (RAD) (n = 331), or a combination of both (ANP + RAD) (n = 195). Mixed models for repeated measures predicted and analyzed scores at all time points, adjusting for diagnosis group, time point, and, if statistically significant, number of operative levels and demographic characteristics. Outcome measures included the Neck Disability Index, numerical pain scales (intensity plus frequency), the Veterans RAND 12 Item Health Survey (VR-12) Physical Component Score, the Mental Component Score, and reoperations. Patients were assessed preoperatively and postoperatively at 6 weeks, 3 months, 6 months, 1 year, and annually thereafter. RESULTS: At baseline, arm pain scores in the ANP group were statistically lower (P = .0002) than in the RAD and ANP + RAD groups, consistent with preoperative diagnoses. Surgeries included 40.8% 1-level, 41.6% 2-level, 14.7% 3-level, and 2.9% 4-level. For all outcome measures, improvements were statistically significant from baseline to each postoperative time point without statistical difference between the 3 diagnosis groups. In total, 45/782 patients (5.8%) underwent a secondary surgery: 3.5% ANP, 5.8% RAD, and 8.7% ANP + RAD. Days to reoperation did not statistically differ between groups (P = .489). CONCLUSIONS: Appropriately selected patients with predominant axial neck pain treated with CDA may achieve clinical and functional outcomes comparable to patients with a primary diagnosis of radiculopathy or of axial neck pain with concomitant radiculopathy. CLINICAL RELEVANCE: This study provides information that should help clinicians decide whether to offer CDA for patients with a primary diagnosis of axial neck pain and to appropriately counsel such patients about expected outcomes. LEVEL OF EVIDENCE: 4.

Multilevel Cervical Disc Arthroplasty: Long-Term Outcomes at 3 and 4 Levels.

BACKGROUND: Multilevel cervical degenerative disc disease in 2 or more segments poses treatment challenges. Anterior cervical discectomy and fusion is a viable treatment option, but one with high rates of adjacent segment disease and pseudoarthrosis. Cervical disc arthroplasty (CDA) is approved by the US Food and Drug Administration for the treatment of 1- and 2-level cervical pathology, with established long-term safety and effectiveness. Limited evidence exists for CDA at more than 2 levels. This study investigates the long-term outcomes of 3- and 4-level CDA out to 7 years. METHODS: In a retrospective review of prospectively collected data, patient demographics and surgical characteristics were collected. Patient-reported outcomes (PROs) were collected preoperatively and at 6 weeks, 3 months, 6 months, and 12 months postoperatively, and annually thereafter, including: Neck Disability Index (NDI), numeric rating scales for neck pain and arm pain, the Veterans Rand 12-item Health Survey physical component summary (PCS) score and mental component summary (MCS) score, and patient satisfaction scores. Secondary surgery data were also collected. Predictive methods using mixed-effects regression models were used to analyze the data. RESULTS: Data for 139 CDAs were available for evaluation (n = 116 three-level and n = 23 four-level). Statistical improvement was shown for all PRO scores at all postoperative intervals (P < .001). From preoperatively to 7 years postoperatively, mean NDI decreased from 57.9 to 31.3 (45.9% improvement), mean neck pain decreased from 15.6 to 7.9 (49.4% improvement), mean arm pain decreased from 12.2 to 5.6 (54.1% improvement), mean PCS increased from 29.2 to 41.4 (41.8% improvement), and mean MCS increased from 37.1 to 44.5 (19.9% improvement). Five (3.6%) 3-level patients underwent secondary surgery. Patient satisfaction exceeded 88% 7 years after surgery. CONCLUSION: Statistical improvement in PROs, with a low rate of secondary surgeries out to 7 years, demonstrates that 3- and 4-level CDA may be performed safely and effectively in appropriately selected patients. LEVEL OF EVIDENCE: 4.

Reversing the "Risk-Treatment Paradox" of Bleeding in Patients Undergoing Percutaneous Coronary Intervention: Risk-Concordant Use of Bleeding Avoidance Strategies Is Associated With Reduced Bleeding and Lower Costs.

Background Bleeding is a common, morbid, and costly complication of percutaneous coronary intervention. While bleeding avoidance strategies ( BAS ) are effective, they are used paradoxically less in patients at high risk of bleeding. Whether a patient-centered approach to specifically increase the risk-concordant use of BAS and, thus, reverse the risk-treatment paradox is associated with reduced bleeding and costs is unknown. Methods and Results We implemented an intervention to reverse the bleeding risk-treatment paradox at Barnes-Jewish Hospital, St. Louis, MO, and examined: (1) the temporal trends in BAS use and (2) the association of risk-concordant BAS use with bleeding and hospital costs of percutaneous coronary intervention. Among 3519 percutaneous coronary interventions, there was a significantly increasing trend ( P=0.002) in risk-concordant use of BAS . The bleeding incidence was 2% in the risk-concordant group versus 9% in the risk-discordant group (absolute risk difference, 7%; number needed to treat, 14). Risk-concordant BAS use was associated with a 67% (95% confidence interval, 52-78%; P<0.001) reduction in the risk of bleeding and a $4738 (95% confidence interval, 3353-6122; P<0.001) reduction in per-patient percutaneous coronary intervention hospitalization costs (21.6% cost-savings). Conclusions In this study, patient-centered care directly aimed to make treatment-related decisions based on predicted risk of bleeding, led to more risk-concordant use of BAS and reversal of the risk-treatment paradox. This, in turn, was associated with a reduction in bleeding and hospitalization costs. Larger multicentered studies are needed to corroborate these results. As clinical medicine moves toward personalization, both patients and hospitals can benefit from a simple practice change that encourages objectivity and mitigates variability in care.

Assessment of health-related quality of life in spine treatment: conversion from SF-36 to VR-12.

BACKGROUND CONTEXT: Health-related quality-of-life outcomes have been collected with the Medical Outcomes Study (MOS) Short Form 36 (SF-36) survey. Boston University School of Public Health has developed algorithms for the conversion of SF-36 to Veterans RAND 12-Item Health Survey (VR-12) Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. PURPOSE: The purpose of the present study is to investigate the conversion of the SF-36 to VR-12 PCS and MCS scores. STUDY DESIGN: Preoperative and postoperative SF-36 were collected from patients who underwent lumbar or cervical surgery from a single surgeon between August 1998 and January 2013. METHODS: Short Form 36 PCS and MCS scores were calculated following their original instructions. The SF-36 answers were then converted to VR-12 PCS and MCS scores following the algorithm provided by the Boston University School of Public Health. The mean score, preoperative to postoperative change, and proportions of patients who reach the minimum detectable change were compared between SF-36 and VR-12. RESULTS: A total of 1,968 patients (1,559 lumbar and 409 cervical) had completed preoperative and postoperative SF-36. The values of the SF-36 and VR-12 mean scores were extremely similar, with score differences ranging from 0.77 to 1.82. The preoperative to postoperative improvement was highly significant (p<.001) for both SF-36 and VR-12 scores. The mean change scores were similar, with a difference of up to 0.93 for PCS and up to 0.37 for MCS. Minimum detectable change (MDC) values were almost identical for SF-36 and VR-12, with a difference of 0.12 for PCS and up to 0.41 for MCS. The proportions of patients whose change in score reached MDC were also nearly identical for SF-36 and VR-12. About 90% of the patients above SF-36 MDC were also above VR-12 MDC. CONCLUSIONS: The converted VR-12 scores, similar to the SF-36 scores, detect a significant postoperative improvement in PCS and MCS scores. The calculated MDC values and the proportions of patients whose score improvement reach MDC are similar for both SF-36 and VR-12.

Novel Patient-Centered Approach to Facilitate Same-Day Discharge in Patients Undergoing Elective Percutaneous Coronary Intervention.

BACKGROUND: Same-day discharge (SDD) after elective percutaneous coronary intervention is safe, less costly, and preferred by patients, but it is usually performed in low-risk patients, if at all. To increase the appropriate use of SDD in more complex patients, we implemented a "patient-centered" protocol based on risk of complications at Barnes-Jewish Hospital. METHODS AND RESULTS: Our objectives were as follows: (1) to evaluate time trends in SDD; (2) to compare (a) mortality, bleeding, and acute kidney injury, (b) patient satisfaction, and (c) hospital costs by SDD versus no SDD (NSDD); and (3) to compare SDD eligibility by our patient-centered approach versus Society for Cardiovascular Angiography and Interventions guidelines. Our patient-centered approach was based on prospectively identifying personalized bleeding, mortality, and acute kidney injury risks, with a personalized safe contrast limit and mitigating those risks. We analyzed Barnes-Jewish Hospital's National Cardiovascular Data Registry CathPCI Registry data from July 1, 2009 to September 30, 2015 (N=1752). SDD increased rapidly from 0% to 77% (P<0.001), independent of radial access. Although SDD patients were comparable to NSDD patients, SDD was not associated with adverse outcomes (0% mortality, 0% bleeds, and 0.4% acute kidney injury). Patient satisfaction was high with SDD. Propensity score-adjusted costs were $7331 lower/SDD patient (P<0.001), saving an estimated $1.8 million annually. Only 16 patients (6.95%) met the eligibility for SDD by Society for Cardiovascular Angiography and Interventions guidelines, implying our patient-centered approach markedly increased SDD eligibility. CONCLUSIONS: With a patient-centered approach, SDD rapidly increased and was safe in 75% of patients undergoing elective percutaneous coronary intervention, despite patient complexity. Patient satisfaction was high, and hospital costs were lower. Patient-centered decision making to facilitate SDD is an important opportunity to improve the value of percutaneous coronary intervention.

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections.

Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening disease in otherwise healthy people, but the immunological basis for this remains unexplained. We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity.

Neprilysin-like activity correlates with CSF-Tau and phospho-tau in patients with Alzheimer's disease.

A relation between amyloid-ß peptide (Aß) accumulation and neprilysin (NEP), an Aß degrading enzyme, has been proposed but studies of NEP and the levels of the pathological hallmarks of Alzheimer's disease (AD), Aß and tau, in cerebrospinal fluid (CSF) are scarce. In this study, we measured the level and enzyme activity of NEP in serum and CSF, using a sandwich enzyme-linked immunosorbent assay and a fluorescence resonance energy transfer assay, respectively, in patients with AD, frontotemporal dementia (FTD), Creutzfeldt-Jakob disease (CJD), and depression. Results were correlated with the levels of CSF AD biomarkers Aß42, hyperphosphorylated tau (p-tau), and total tau (t-tau). In serum, we found no differences in NEP-like activity or concentration between the groups and there were no correlations between NEP and AD biomarkers. In CSF, no influence of age or gender on NEP levels or enzyme activity was seen. However, NEP concentration was lower and the specific activity was higher in FTD compared to AD. Aß42 levels in CSF did not correlate with NEP concentration or activity in the AD, CJD, or depression groups, but NEP-like activity and Aß42 levels correlated significantly in the FTD group. In AD and depression, the NEP-like activity in CSF correlated with levels of p-tau, and, in the AD group, it also was correlated with t-tau levels. Our results suggest that the relation between the specific activity of NEP and t-tau and p-tau is a characteristic trait of AD. The correlation between NEP concentration and Aß42 in FTD is unexpected and warrants further investigation.