Early Experience With Novel Molded Allograft Anchors for the Management of Screw Loosening in Elderly Patients With Reduced Bone Density in Primary and Revision Lumbar Surgery.

BACKGROUND: Various strategies have been used to reduce pedicle screw loosening following lumbar instrumented fusion, but all strategies have limitations. In this prospective multicenter cohort study, outcomes of elderly patients with reduced bone density who underwent primary or revision fusion surgery using a novel technique of pedicle screw augmentation with demineralized bone fiber (DBF) anchors were evaluated. METHODS: This study included elderly patients (aged >65 years) with dual-energy x-ray absorptiometry-confirmed reduced bone density who required lumbar pedicle screw fixation and were treated with supplemental DBF allograft anchors during primary or revision surgery. The need for DBF anchors was determined by evaluating preoperative computed tomography (CT) scans (for revision surgery) and by the surgeons' tactile feedback intraoperatively during pedicle screw insertion and removal. After determining the pedicle screw void diameter with a sizing instrument, DBF anchors and pedicle screws of the same diameter were placed into the void. CT scans were obtained on postoperative day 2 to assess pedicle breach, pedicle fracture, or anchor material extrusion and at 6 and 12 months postoperatively to assess screw loosening. Thereafter, to minimize radiation exposure, CT scans were only performed for recurrence of pain. RESULTS: Twenty-three patients (79% women; mean age, 74 years) received 50 lumbosacral pedicle screws augmented with DBF anchors. Most surgeries (n = 18, 78%) were revisions, and most anchors were inserted into revision pedicle screw trajectories (n = 33, 66%). Day-2 CT scans revealed no pedicle breach/fracture or extrusion of anchor material. During a mean follow-up of 15 months (12-20 months), no screw loosening was detected, and no patient required pedicle screw revision surgery. There were no adverse events attributable to DBF allografts. CONCLUSIONS: DBF allograft anchors appear to be safe and effective for augmenting pedicle screws during revision surgeries in female elderly patients with reduced bone density. CLINICAL RELEVANCE: Clinically, DBF reduced the rate of pedicle screw loosening in patients with reduced bone density. A significant reduction in screw loosening can decrease the need for revision surgeries, which are costly and carry additional risks. Enhanced bone integration from the DBF may promote better healing and long-term stability.

Impact of Insurance Status and Region on Angiotensin Receptor-Neprilysin Inhibitor Prescription During Heart Failure Hospitalizations.

BACKGROUND: An angiotensin receptor-neprilysin inhibitor (ARNI) is the preferred renin-angiotensin system (RAS) inhibitor for heart failure with reduced ejection fraction (HFrEF). Among eligible patients, insurance status and prescriber concern regarding out-of-pocket costs may constrain early initiation of ARNI and other new therapies. OBJECTIVES: In this study, the authors sought to evaluate the association of insurance and other social determinants of health with ARNI initiation at discharge from HFrEF hospitalization. METHODS: The authors analyzed ARNI initiation from January 2017 to June 2020 among patients with HFrEF eligible to receive RAS inhibitor at discharge from hospitals in the Get With The Guidelines-Heart Failure registry. The primary outcome was the proportion of ARNI prescription at discharge among those prescribed RAS inhibitor who were not on ARNI on admission. A logistic regression model was used to determine the association of insurance status, U.S. region, and their interaction, as well as self-reported race, with ARNI initiation at discharge. RESULTS: From 42,766 admissions, 24,904 were excluded for absolute or relative contraindications to RAS inhibitors. RAS inhibitors were prescribed for 16,817 (94.2%) of remaining discharges, for which ARNI was prescribed in 1,640 (9.8%). Self-reported Black patients were less likely to be initiated on ARNI compared to self-reported White patients (OR: 0.64; 95% CI: 0.50-0.81). Compared to Medicare beneficiaries, patients with third-party insurance, Medicaid, or no insurance were less likely to be initiated on ARNI (OR: 0.47 [95% CI: 0.31-0.72], OR: 0.41 [95% CI: 0.25-0.67], and OR: 0.20 [95% CI: 0.08-0.47], respectively). ARNI therapy varied by hospital region, with lowest utilization in the Mountain region. An interaction was demonstrated between the impact of insurance disparities and hospital region. CONCLUSIONS: Among patients hospitalized between 2017 and 2020 for HFrEF who were prescribed RAS inhibitor therapy at discharge, insurance status, geographic region, and self-reported race were associated with ARNI initiation.

Feasibility of precision smoking treatment in a low-income community setting: results of a pilot randomized controlled trial in The Southern Community Cohort Study.

BACKGROUND: The feasibility of precision smoking treatment in socioeconomically disadvantaged communities has not been studied. METHODS: Participants in the Southern Community Cohort Study who smoked daily were invited to join a pilot randomized controlled trial of three smoking cessation interventions: guideline-based care (GBC), GBC plus nicotine metabolism-informed care (MIC), and GBC plus counseling guided by a polygenic risk score (PRS) for lung cancer. Feasibility was assessed by rates of study enrollment, engagement, and retention, targeting > 70% for each. Using logistic regression, we also assessed whether feasibility varied by age, sex, race, income, education, and attitudes toward precision smoking treatment. RESULTS: Of 92 eligible individuals (79.3% Black; 68.2% with household income < $15,000), 67 (72.8%; 95% CI 63.0-80.9%) enrolled and were randomized. Of these, 58 (86.6%; 95% CI 76.4-92.8%) engaged with the intervention, and of these engaged participants, 43 (74.1%; 95% CI 61.6-83.7%) were retained at 6-month follow-up. Conditional on enrollment, older age was associated with lower engagement (OR 0.83, 95% CI 0.73-0.95, p = 0.008). Conditional on engagement, retention was significantly lower in the PRS arm than in the GBC arm (OR 0.18, 95% CI 0.03-1.00, p = 0.050). No other selection effects were observed. CONCLUSIONS: Genetically informed precision smoking cessation interventions are feasible in socioeconomically disadvantaged communities, exhibiting high enrollment, engagement, and retention irrespective of race, sex, income, education, or attitudes toward precision smoking treatment. Future smoking cessation interventions in this population should take steps to engage older people and to sustain participation in interventions that include genetic risk counseling. TRIAL REGISTRATION: ClinicalTrials.gov No. NCT03521141, Registered 27 April 2018, https://www. CLINICALTRIALS: gov/study/NCT03521141.

Recurrence After Atrial Fibrillation Ablation and Investigational Biomarkers of Cardiac Remodeling.

BACKGROUND: Recurrence after atrial fibrillation (AF) ablation remains common. We evaluated the association between recurrence and levels of biomarkers of cardiac remodeling, and their ability to improve recurrence prediction when added to a clinical prediction model. METHODS AND RESULTS: Blood samples collected before de novo catheter ablation were analyzed. Levels of bone morphogenetic protein-10, angiopoietin-2, fibroblast growth factor-23, insulin-like growth factor-binding protein-7, myosin-binding protein C3, growth differentiation factor-15, interleukin-6, N-terminal pro-brain natriuretic peptide, and high-sensitivity troponin T were measured. Recurrence was defined as ≥30 seconds of an atrial arrhythmia 3 to 12 months postablation. Multivariable logistic regression was performed using biomarker levels along with clinical covariates: APPLE score (Age >65 years, Persistent AF, imPaired eGFR [<60 ml/min/1.73m2], LA diameter ≥43 mm, EF <50%; which includes age, left atrial diameter, left ventricular ejection fraction, persistent atrial fibrillation, and estimated glomerular filtration rate), preablation rhythm, sex, height, body mass index, presence of an implanted continuous monitor, year of ablation, and additional linear ablation. A total of 1873 participants were included. A multivariable logistic regression showed an association between recurrence and levels of angiopoietin-2 (odds ratio, 1.08 [95% CI, 1.02-1.15], P=0.007) and interleukin-6 (odds ratio, 1.02 [95% CI, 1.003-1.03]; P=0.02). The area under the receiver operating characteristic curve of a model that only contained clinical predictors was 0.711. The addition of any of the 9 studied biomarkers to the predictive model did not result in a statistically significant improvement in the area under the receiver operating characteristic curve. CONCLUSIONS: Higher angiopoietin-2 and interleukin-6 levels were associated with recurrence after atrial fibrillation ablation in multivariable modeling. However, the addition of biomarkers to a clinical prediction model did not significantly improve recurrence prediction.

LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation.

AIMS: The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic disorders, including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress. We hypothesized that Lnk-/- mice are susceptible to atrial fibrillation (AF) and that rs3184504 is associated with AF and AF-related stroke in humans. During inflammation, reactive lipid dicarbonyls are the major components of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice. METHODS AND RESULTS: Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared with WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current, increased late Na+ current, and reduced peak Na+ current, pro-arrhythmic effects that were inhibited by 2-HOBA. Mitochondrial dysfunction, especially for Complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumour necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1ß) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodelling in vitro. Inhibition of soluble TNF-α prevented electrical remodelling and AF susceptibility, while IL-1ß inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In a large database of genotyped patients, rs3184504 was associated with AF, as well as AF-related stroke. CONCLUSION: These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the pro-arrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodelling.

A prognostic molecular signature of hepatic steatosis is spatially heterogeneous and dynamic in human liver.

Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is increasing in parallel with an obesity pandemic, calling for novel strategies for prevention and treatment. We defined a circulating proteome of human MASLD across ≈7000 proteins in ≈5000 individuals from diverse, at-risk populations across the metabolic health spectrum, demonstrating reproducible diagnostic performance and specifying both known and novel metabolic pathways relevant to MASLD (central carbon and amino acid metabolism, hepatocyte regeneration, inflammation, fibrosis, insulin sensitivity). A parsimonious proteomic signature of MASLD was associated with a protection from MASLD and its related multi-system metabolic consequences in >26000 free-living individuals, with an additive effect to polygenic risk. The MASLD proteome was encoded by genes that demonstrated transcriptional enrichment in liver, with spatial transcriptional activity in areas of steatosis in human liver biopsy and dynamicity for select targets in human liver across stages of steatosis. We replicated several top relations from proteomics and spatial tissue transcriptomics in a humanized "liver-on-a-chip" model of MASLD, highlighting the power of a full translational approach to discovery in MASLD. Collectively, these results underscore utility of blood-based proteomics as a dynamic "liquid biopsy" of human liver relevant to clinical biomarker and mechanistic applications.

Clinical characteristics and one-year all-cause mortality outcomes in Africans with dilated cardiomyopathy.

AIMS: Dilated cardiomyopathy (DCM) is a common cause of heart failure in sub-Saharan Africa (SSA). The affected individuals present with new-onset heart failure with reduced ejection fraction and no identifiable primary or secondary aetiology. We aim to describe the clinical characteristics of participants with heart failure of unknown origin. METHODS: We screened 161 participants with heart failure of unknown origin and prospectively excluded primary and secondary causes of DCM. All study participants were subjected to laboratory biochemical testing, echocardiography, cardiovascular magnetic resonance (CMR) imaging and invasive coronary angiography. RESULTS: The study comprised 93 participants with a mean age of 47.5 SD 13.1 years. Forty-six (56.1%) participants had evidence of late gadolinium enhancement (LGE) on imaging, and LGE was visualised in the mid wall in 28 (61.0%) of these participants. After a median duration of 13.4 months [interquartile range (IQR): 8.8-28.9 months], 18 (19%) participants died. Non-survivors had a higher median left atrial volume index (44.9 mL/m2 (IQR: 34.4-58.7) compared to survivors [32.9 mL/m2 (IQR: 24.5-47.0), p = 0.017)]. The rate of all-cause rehospitalisation was 29.3%, of which 17 of the 22 re-hospitalisations were heart failure related. CONCLUSION: Dilated cardiomyopathy in Africans primarily affects young males. In our cohort, this disease was associated with an all-cause mortality of 19% in one year. In SSA, large multicenter studies are required to investigate this disease's pathogenesis and outcomes.

Can Treatment Support Mitigate Nicotine Metabolism-Based Disparities in Smoking Abstinence? Secondary Analysis of the Helping HAND 4 Trial.

INTRODUCTION: The nicotine metabolite ratio (NMR), a biomarker of CYP2A6-mediated nicotine metabolism, predicts the efficacy of nicotine replacement therapy (NRT), with fast metabolizers benefiting less than slow metabolizers. Whether treatment support to optimize NRT use (henceforth "treatment support") modifies this pharmacogenetic relationship is unknown. METHODS: Hospitalized adult daily smokers were assigned to one of two post-discharge smoking cessation interventions offering NRT and counseling: (1) Transitional Tobacco Care Management, which delivered enhanced treatment support via free combination NRT at discharge and automated counseling, and (2) a quitline-based approach representing usual care (UC). The primary outcome was biochemically verified 7-day point prevalence abstinence 6 months after discharge. Secondary outcomes were the use of NRT and counseling during the 3-month intervention period. Logistic regression models tested for interactions between NMR and intervention, controlling for sex, race, alcohol use, and BMI. RESULTS: Participants (N = 321) were classified as slow (n = 80) or fast (n = 241) metabolizers relative to the first quartile of NMR (0.012-0.219 vs. 0.221-3.455, respectively). Under UC, fast (vs. slow) metabolizers had lower odds of abstinence at 6 months (aOR 0.35, 95% CI 0.13-0.95) and similar odds of NRT and counseling use. Compared to UC, enhanced treatment support increased abstinence (aOR 2.13, 95% CI 0.98-4.64) and use of combination NRT (aOR 4.62, 95% CI 2.57-8.31) in fast metabolizers, while reducing abstinence in slow metabolizers (aOR 0.21, 95% CI 0.05-0.87; NMR-by-intervention interaction p = .004). CONCLUSIONS: Treatment support increased abstinence and optimal use of NRT among fast nicotine metabolizers, thereby mitigating the gap in abstinence between fast and slow metabolizers. IMPLICATIONS: In this secondary analysis of two smoking cessation interventions for recently hospitalized smokers, fast nicotine metabolizers quit at lower rates than slow metabolizers, but providing fast metabolizers with enhanced treatment support doubled the odds of quitting in this group and mitigated the disparity in abstinence between fast and slow metabolizers. If validated, these findings could lead to personalized approaches to smoking cessation treatment that improve outcomes by targeting treatment support to those who need it most.

Association of Sex and Race With Incident Peripheral Artery Disease Among Veterans With Normal Ankle-Brachial Indices.

Importance: Reported risk of incident peripheral artery disease (PAD) by sex and race varies significantly and has not been reported in national cohorts among individuals free of baseline PAD. Objective: To evaluate the association of sex and race, as well as prevalent cardiovascular risk factors, with limb outcomes in a national cohort of people with normal baseline ankle-brachial indices (ABIs). Design, setting, and participants: This cohort study was conducted using data from participants in the Veterans Affairs Birth Cohort Study (born 1945-1965), with follow-up data between January 1, 2000, and December 31, 2016. Baseline demographics were collected from 77 041 participants receiving care from the Veterans Health Administration with baseline ABIs of 0.90 to 1.40 and no history of PAD. Data were analyzed from October 2019 through September 2022. Exposures: Sex, race, diabetes, and smoking status. Main Outcomes and Measures: Incident PAD, defined as subsequent ABI less than 0.90, surgical or percutaneous revascularization, or nontraumatic amputation. Results: Of 77 041 participants with normal ABIs (73 822 [95.8%] men; mean [SD] age, 60.2 [5.9] years; 13 080 Black [18.2%] and 54 377 White [75.6%] among 71 911 participants with race and ethnicity data), there were 6692 incident PAD events over a median [IQR] of 3.9 [1.7-6.9] years. Incidence rates were lower for women than men (incidence rates [IRs] per 1000 person-years, 7.4 incidents [95% CI, 6.2-8.8 incidents] vs 19.2 incidents [95% CI, 18.7-19.6 incidents]), with a lower risk of incident PAD (adjusted hazard ratio [aHR], 0.49 [95% CI, 0.41-0.59]). IRs per 1000 person-years of incident PAD were similar for Black and White participants (18.9 incidents [95% CI, 17.9-20.1 incidents] vs 18.8 incidents [95% CI, 18.3-19.4]). Compared with White participants, Black participants had increased risk of total PAD (aHR, 1.09 [95% CI, 1.02-1.16]) and nontraumatic amputation (aHR, 1.20 [95% CI, 1.06-1.36]) but not surgical or percutaneous revascularization (aHR, 1.10 [95% CI, 0.98-1.23]) or subsequent ABI less than 0.90 (aHR, 1.04 [95% CI, 0.95-1.13]). Diabetes (aHR, 1.62 [95% CI, 1.53-1.72]) and smoking (eg, current vs never: aHR, 1.76 [95% CI, 1.64-1.89]) were associated with incident PAD. Incident PAD was rare among individuals without a history of smoking or diabetes (eg, among 632 women: IR per 1000 people-years, 2.1 incidents [95% CI, 1.0-4.5 incidents]) despite an otherwise-high-risk cardiovascular profile (eg, 527 women [83.4%] with hypertension). Conclusions and Relevance: This study found that the risk of PAD was approximately 50% lower in women than men and less than 10% higher for Black vs White participants, while the risk of nontraumatic amputation was 20% higher among Black compared with White participants.

Expression of CD70 Modulates Nitric Oxide and Redox Status in Endothelial Cells.

BACKGROUND: Endothelial dysfunction is a critical component in the pathogenesis of cardiovascular diseases and is closely associated with nitric oxide (NO) levels and oxidative stress. Here, we report on novel findings linking endothelial expression of CD70 (also known as CD27 ligand) with alterations in NO and reactive oxygen species. METHODS: CD70 expression was genetically manipulated in human aortic and pulmonary artery endothelial cells. Intracellular NO and hydrogen peroxide (H2O2) were measured using genetically encoded biosensors, and cellular phenotypes were assessed. RESULTS: An unbiased phenome-wide association study demonstrated that polymorphisms in CD70 associate with vascular phenotypes. Endothelial cells treated with CD70-directed short-interfering RNA demonstrated impaired wound closure, decreased agonist-stimulated NO levels, and reduced eNOS (endothelial nitric oxide synthase) protein. These changes were accompanied by reduced NO bioactivity, increased 3-nitrotyrosine levels, and a decrease in the eNOS binding partner heat shock protein 90. Following treatment with the thioredoxin inhibitor auranofin or with agonist histamine, intracellular H2O2 levels increased up to 80% in the cytosol, plasmalemmal caveolae, and mitochondria. There was increased expression of NADPH oxidase 1 complex and gp91phox; expression of copper/zinc and manganese superoxide dismutases was also elevated. CD70 knockdown reduced levels of the H2O2 scavenger catalase; by contrast, glutathione peroxidase 1 expression and activity were increased. CD70 overexpression enhanced endothelial wound closure, increased NO levels, and attenuated the reduction in eNOS mRNA induced by TNFα. CONCLUSIONS: Taken together, these data establish CD70 as a novel regulatory protein in endothelial NO and reactive oxygen species homeostasis, with implications for human vascular disease.

Negotiating for new technologies: guidelines for the procurement of assistive technologies in spinal surgery: a narrative review.

Background and Objective: This is a narrative review with the objective to discuss available assistive technologies for spinal surgery. Characteristics, costs, and compatibility of the different systems are summarized and recommendations made regarding acquiring these technologies. The availability of assistive technologies in spine surgery continues to evolve rapidly. The literature is lacking a collective summary of the available technologies and guidelines for acquisition. This is a narrative review which (I) presents an up-to-date summary of the currently available assistive technologies in spinal surgery; (II) makes comment on the utility of imaging, navigation, and robotics; (III) makes recommendations for the utility of the platform based on hospital size and (IV) discuss factors involved in negotiating for the purchase of these new technologies. Methods: We assemble the most up-to-date collection of description, characteristics and pricing of assistive technologies in spinal surgery. We compare and contrast these technologies and make recommendations regarding acquisition. Key Content and Findings: These technologies require a learning-curve for the surgeon and the operating room staff to understand how to use them efficiently. Surgeons need to be involved in the process of purchase decisions. Surgeons occupy a unique position in the health care infrastructure as their approach to care has significant ramifications on both the quality and cost of care. Surgeons should maintain conviction that their training and practice has allowed the use of these technologies to provide safer and more effective care for patients. Conclusions: Assistive technologies and prostheses for spinal fusion are evolving rapidly. This article serves as an encompassing reference to the current technologies. These technologies will play a significant role in the delivery of spinal health care in the future. All stakeholders stand to benefit from the increased value these technologies bring to patient care.

Dispositional optimism and optimistic bias: Associations with cessation motivation, confidence, and attitudes.

OBJECTIVE: To test whether 2 conceptually overlapping constructs, dispositional optimism (generalized positive expectations) and optimistic bias (inaccurately low risk perceptions), may have different implications for smoking treatment engagement. METHOD: Predominantly Black, low-income Southern Community Cohort study smokers (n = 880) self-reported dispositional optimism and pessimism (Life Orientation Test-Revised subscales: 0 = neutral, 12 = high optimism/pessimism), comparative lung cancer risk (Low/Average/High), and information to calculate objective lung cancer risk (Low/Med/High). Perceived risk was categorized as accurate (perceived = objective), optimistically-biased (perceived < objective), or pessimistically-biased (perceived > objective). One-way ANOVAs tested associations between dispositional optimism/pessimism and perceived risk accuracy. Multivariable logistic regressions tested independent associations of optimism/pessimism and perceived risk accuracy with cessation motivation (Low/High), confidence (Low/High), and precision treatment attitudes (Favorable/Unfavorable), controlling for sociodemographics and nicotine dependence. RESULTS: Mean dispositional optimism/pessimism scores were 8.41 (SD = 2.59) and 5.65 (SD = 3.02), respectively. Perceived lung cancer risk was 38% accurate, 27% optimistically-biased, and 35% pessimistically-biased. Accuracy was unrelated to dispositional optimism (F(2, 641) = 1.23, p = .29), though optimistically-biased (vs. pessimistically-biased) smokers had higher dispositional pessimism (F(2, 628) = 3.17, p = .043). Dispositional optimism was associated with higher confidence (Adjusted odds ratio [AOR] = 1.71, 95% CI [1.42, 2.06], p < .001) and favorable precision treatment attitudes (AOR = 1.66, 95% CI [1.37, 2.01], p < .001). Optimistically-biased (vs. accurate) risk perception was associated with lower motivation (AOR = .64, 95% CI [.42, .98], p = .041) and less favorable precision treatment attitudes (AOR = .59, 95% CI [.38, .94], p = .029). CONCLUSIONS: Dispositional optimism and lung cancer risk perception accuracy were unrelated. Dispositional optimism was associated with favorable engagement-related outcomes and optimistically-biased risk perception with unfavorable outcomes, reinforcing the distinctiveness of these constructs and their implications for smoking treatment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality.

Rationale: A common MUC5B gene polymorphism, rs35705950-T, is associated with idiopathic pulmonary fibrosis (IPF), but its role in severe acute respiratory syndrome coronavirus 2 infection and disease severity is unclear. Objectives: To assess whether rs35705950-T confers differential risk for clinical outcomes associated with coronavirus disease (COVID-19) infection among participants in the Million Veteran Program (MVP). Methods: The MUC5B rs35705950-T allele was directly genotyped among MVP participants; clinical events and comorbidities were extracted from the electronic health records. Associations between the incidence or severity of COVID-19 and rs35705950-T were analyzed within each ancestry group in the MVP followed by transancestry meta-analysis. Replication and joint meta-analysis were conducted using summary statistics from the COVID-19 Host Genetics Initiative (HGI). Sensitivity analyses with adjustment for additional covariates (body mass index, Charlson comorbidity index, smoking, asbestosis, rheumatoid arthritis with interstitial lung disease, and IPF) and associations with post-COVID-19 pneumonia were performed in MVP subjects. Measurements and Main Results: The rs35705950-T allele was associated with fewer COVID-19 hospitalizations in transancestry meta-analyses within the MVP (Ncases = 4,325; Ncontrols = 507,640; OR = 0.89 [0.82-0.97]; P = 6.86 × 10-3) and joint meta-analyses with the HGI (Ncases = 13,320; Ncontrols = 1,508,841; OR, 0.90 [0.86-0.95]; P = 8.99 × 10-5). The rs35705950-T allele was not associated with reduced COVID-19 positivity in transancestry meta-analysis within the MVP (Ncases = 19,168/Ncontrols = 492,854; OR, 0.98 [0.95-1.01]; P = 0.06) but was nominally significant (P < 0.05) in the joint meta-analysis with the HGI (Ncases = 44,820; Ncontrols = 1,775,827; OR, 0.97 [0.95-1.00]; P = 0.03). Associations were not observed with severe outcomes or mortality. Among individuals of European ancestry in the MVP, rs35705950-T was associated with fewer post-COVID-19 pneumonia events (OR, 0.82 [0.72-0.93]; P = 0.001). Conclusions: The MUC5B variant rs35705950-T may confer protection in COVID-19 hospitalizations.

Genome-wide association study reveals novel genetic loci: a new polygenic risk score for mitral valve prolapse.

AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-ß signalling molecules and spectrin ß. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Surface landmarks for anterior lumbar access: is fluoroscopy necessary?

BACKGROUND CONTEXT: Anterior lumbar fusion surgery is increasing by an estimated 24% annually in the United States. There is a paucity of precise anatomic guidelines to help surgeons determine the appropriate anterior access incision site. PURPOSE: The purpose of this study is to compare the available anterior surface landmarks for the L4/L5 and L5/S1 disk levels to the disk levels determined by fluoroscopy, with the goal of creating a guide for surgical incision sites in anterior lumbar access surgery. STUDY DESIGN: A prospective, observational cohort study of consecutive patients undergoing anterior lumbar spinal exposure for anterior lumbar interbody fusion (ALIF), total disk replacement (TDR), or a combination of the two procedures at levels L4/L5 and/or L5/S1. PATIENT SAMPLE: All patients (n=183) undergoing primary ALIF and/or TDR surgery from June 2018 to April 2021 at the study sites were assessed for inclusion, and 18 patients were excluded. The remaining 165 patients were included in the study, and a total of 208 surgical levels were exposed. OUTCOME MEASURES: Mean, standard deviation, and 95% confidence interval (CI) were calculated. At each level, the distance from the symphysis pubis to the target disk level (SD distance) and the distance from the symphysis pubis to the umbilicus (SU distance) were measured, and the SD/SU ratio was calculated. Paired 2-tailed t tests were used to assess significant differences (p<.05). An R2 (coefficient of determination) test was used to assess variability of the SD distance, SU distance, and SD/SU ratio at each level. METHODS: All physiologic and anatomic measures were collected prospectively by the investigators, including intraoperative measurements of SD and SU. Demographic and previous health history data were collected at the time of study enrollment. RESULTS: The mean age of the 165 study participants was 48±14 years (range 18-80 years), and 97 (61%) were male. A total of 208 disk levels were exposed: 140 at L5/S1 and 68 at L4/L5. For the L5/S1, the SD ranged from 0 to 12.5 cm, with a mean of 5.2±1.9 cm (95% CI 4.88-5.52). For the L4/L5 level, the SD ranged from 6 to 15.5 cm, with a mean of 10.7±2.3 cm (95% CI 10.2-11.2). SD/SU ratios at both levels were lower in overweight (body mass index [BMI] 25-29.9) and obese (BMI 30-34.9) groups than in normal body mass index groups. There was no significant difference in SD/SU ratios between females and males at either L5/S1 (p=.39) or L4/L5 (p=.66). CONCLUSION: Clinically important variability in SD distances (≥9.5 cm) was observed for both the L5/S1 and L4/L5 disk levels. SD/SU ratios provided more consistent estimates of disk location than SD distance alone, but they still displayed substantial variability. Thus, intraoperative fluoroscopy remains mandatory to accurately plan the surgical incision for anterior lumbar access surgery.

Using genetics to detangle the relationships between red cell distribution width and cardiovascular diseases: a unique role for body mass index.

OBJECTIVE: Red cell distribution width (RDW) is an enigmatic biomarker associated with the presence and severity of multiple cardiovascular diseases (CVDs). It is unclear whether elevated RDW contributes to, results from, or is pleiotropically related to CVDs. We used contemporary genetic techniques to probe for evidence of aetiological associations between RDW, CVDs, and CVD risk factors. METHODS: Using an electronic health record (EHR)-based cohort, we built and deployed a genetic risk score (GRS) for RDW to test for shared genetic architecture between RDW and the cardiovascular phenome. We also created GRSs for common CVDs (coronary artery disease, heart failure, atrial fibrillation, peripheral arterial disease, venous thromboembolism) and CVD risk factors (body mass index (BMI), low-density lipoprotein, high-density lipoprotein, systolic blood pressure, diastolic blood pressure, serum triglycerides, estimated glomerular filtration rate, diabetes mellitus) to test each for association with RDW. Significant GRS associations were further interrogated by two-sample Mendelian randomisation (MR). In a separate EHR-based cohort, RDW values from 1-year pre-gastric bypass surgery and 1-2 years post-gastric bypass surgery were compared. RESULTS: In a cohort of 17 937 subjects, there were no significant associations between the RDW GRS and CVDs. Of the CVDs and CVD risk factors, only genetically predicted BMI was associated with RDW. In subsequent analyses, BMI was associated with RDW by multiple MR methods. In subjects undergoing bariatric surgery, RDW decreased postsurgery and followed a linear relationship with BMI change. CONCLUSIONS: RDW is unlikely to be aetiologically upstream or downstream of CVDs or CVD risk factors except for BMI. Genetic and clinical association analyses support an aetiological relationship between BMI and RDW.

Polygenic Risk Score to Identify Subclinical Coronary Heart Disease Risk in Young Adults.

BACKGROUND: Polygenic risk scores (PRS) may enhance risk stratification for coronary heart disease among young adults. Whether a coronary heart disease PRS improves prediction beyond modifiable risk factors in this population is not known. METHODS: Genotyped adults aged 18 to 35 years were selected from the CARDIA study (Coronary Artery Risk Development in Young Adults; n=1132) and FOS (Framingham Offspring Study; n=663). Systolic blood pressure, total and HDL (high-density lipoprotein) cholesterol, triglycerides, smoking, and waist circumference or body mass index were measured at the visit 1 exam of each study, and coronary artery calcium, a measure of coronary atherosclerosis, was assessed at year 15 (CARDIA) or year 30 (FOS). A previously validated PRS for coronary heart disease was computed for each subject. The C statistic and integrated discrimination improvement were used to compare improvements in prediction of elevated coronary artery calcium between models containing the PRS, risk factors, or both. RESULTS: There were 62 (5%) and 93 (14%) participants with a coronary artery calcium score >20 (CARDIA) and >300 (FOS), respectively. At these thresholds, the C statistic changes of adding the PRS to a risk factor-based model were 0.015 (0.004-0.028) and 0.020 (0.001-0.039) in CARDIA and FOS, respectively. When adding risk factors to a PRS-based model, the respective changes were 0.070 (0.033-0.109) and 0.051 (0.017-0.079). The integrated discrimination improvement, when adding the PRS to a risk factor model, was 0.027 (-0.006 to 0.054) in CARDIA and 0.039 (0.0005-0.072) in FOS. CONCLUSIONS: Among young adults, a PRS improved model discrimination for coronary atherosclerosis, but improvements were smaller than those associated with modifiable risk factors.

Low Prevalence of Clinically Apparent Cardiac Amyloidosis Among Carriers of Transthyretin V122I Variant in a Large Electronic Medical Record.

BACKGROUND: Transthyretin (TTR) gene mutations are the most common cause of hereditary amyloidosis. Valine replaced by isoleucine in position 122 (V122I) variant is common, particularly in the black population. Carriers of V122I have increased risk for developing cardiac amyloidosis. Despite a relatively high prevalence, the penetrance of V122I is not firmly established. This study sought to determine the prevalence of clinically apparent cardiac amyloidosis among carriers of the TTR V122I variant. METHODS: BioVU, a Vanderbilt University resource linking DNA samples and pre-existing genetic data to de-identified electronic medical records was used to identify TTR V122I mutation carriers. Automated billing code queries (International Classification of Diseases, 9th revision codes), problem list searches, and manual chart reviews were used to identify subjects with clinically diagnosed cardiac amyloidosis. RESULTS: Among 28,429 subjects with available genotype data, 129 were V122I carriers. Carriers had a median age of 42 years (interquartile range 16-64). Noncarriers had a median age of 62 years, (interquartile range 41-77). The carrier rate was 3.7% in blacks and 0.02% in whites. Overall, the prevalence of clinically apparent cardiac amyloidosis was 0.8% in carriers and 0.04% in noncarriers (P = .05). Above age 60, the prevalence of cardiac amyloidosis was 2.6% in carriers and 0.06% in noncarriers (P = .03). CONCLUSION: Carriers of the TTR V122I variant are at a higher risk for development of cardiac amyloidosis, particularly at age>60 years. However, clinically apparent cardiac amyloidosis in this population was uncommon. These results support that the penetrance of TTR V122I is age dependent and suggest it may be significantly lower than previously reported.

A retrospective approach to evaluating potential adverse outcomes associated with delay of procedures for cardiovascular and cancer-related diagnoses in the context of COVID-19.

OBJECTIVE: During the COVID-19 pandemic, health systems postponed non-essential medical procedures to accommodate surge of critically-ill patients. The long-term consequences of delaying procedures in response to COVID-19 remains unknown. We developed a high-throughput approach to understand the impact of delaying procedures on patient health outcomes using electronic health record (EHR) data. MATERIALS AND METHODS: We used EHR data from Vanderbilt University Medical Center's (VUMC) Research and Synthetic Derivatives. Elective procedures and non-urgent visits were suspended at VUMC between March 18, 2020 and April 24, 2020. Surgical procedure data from this period were compared to a similar timeframe in 2019. Potential adverse impact of delay in cardiovascular and cancer-related procedures was evaluated using EHR data collected from January 1, 1993 to March 17, 2020. For surgical procedure delay, outcomes included length of hospitalization (days), mortality during hospitalization, and readmission within six months. For screening procedure delay, outcomes included 5-year survival and cancer stage at diagnosis. RESULTS: We identified 416 surgical procedures that were negatively impacted during the COVID-19 pandemic compared to the same timeframe in 2019. Using retrospective data, we found 27 significant associations between procedure delay and adverse patient outcomes. Clinician review indicated that 88.9% of the significant associations were plausible and potentially clinically significant. Analytic pipelines for this study are available online. CONCLUSION: Our approach enables health systems to identify medical procedures affected by the COVID-19 pandemic and evaluate the effect of delay, enabling them to communicate effectively with patients and prioritize rescheduling to minimize adverse patient outcomes.