Endoscopic Posterior Cervical Foraminotomy Under Lateral Decubitus Position with Local Anesthesia.

BACKGROUND: Endoscopic posterior cervical foraminotomy is gaining popularity among endoscopic spine surgeons for the treatment of radiculopathy caused by foraminal stenosis. METHODS: This study describes a technique using the lateral decubitus position for endoscopic posterior cervical foraminotomy under monitored anesthesia care and local anesthesia only. RESULTS: A total of 10 patients with contraindications to general anesthesia underwent the procedure, resulting in improvement in cervical radicular pain with no perioperative complications. CONCLUSIONS: The findings suggest that this approach is a viable alternative for patients at high risk of general anesthesia care, expanding the surgical options for the treatment of radiculopathy.

Concomitant Biceps Tenodesis Does Not Compromise Arthroscopic Rotator Cuff Repair Outcomes.

PURPOSE: To compare outcomes of patients who underwent rotator cuff repair (RCR) with concomitant biceps tenodesis with those who underwent an isolated RCR. METHODS: Exclusion criteria included previous ipsilateral shoulder surgery, irreparable rotator cuff tears, rotator cuff arthropathy, calcific tendinitis, adhesive capsulitis requiring a capsular release, or advanced osteoarthritis of the glenohumeral joint. Patients were indicated for biceps tenodesis if they had any degree of tendon tearing, moderate-to-severe tenosynovitis, instability, or a significant degenerative SLAP tear. Primary outcome measures included American Shoulder and Elbow Surgeons score, Simple Shoulder Test, EuroQoL 5-Dimension 5-Level visual analog scale, EuroQoL 5-Dimension 5-Level, and a site-specific questionnaire, which focused on surgical expectations, satisfaction, and complications. Multivariate analysis of variance to analyze descriptive statistics and determine significant differences between the patient groups for subjective and objective outcome measures were performed. RESULTS: There were no significant differences for pain/visual analog scale (0.34 ± 0.09 vs 0.47 ± 0.09, P = .31), American Shoulder and Elbow Surgeons score (96.69 ± 0.87 vs 94.44 ± 0.91, P = .07), and Simple Shoulder Test (11.42 ± 0.17 vs 10.95 ± 0.18, P = .06) between the RCR with concomitant biceps tenodesis and isolated RCR at a minimum of 2 years' postoperatively. This is despite the RCR with concomitant biceps tenodesis group having significantly larger rotator cuff tears (4.25 ± 0.30 cm2 vs 2.80 ± 0.32 cm2, P = .001) than the isolated RCR group. CONCLUSIONS: This study revealed that concomitant biceps tenodesis does not compromise outcomes when compared with an isolated RCR at 2-year follow-up, despite this group having larger rotator cuff tears. LEVEL OF EVIDENCE: Level III, retrospective case study.

Machine Learning-Driven Design Optimization of Buckling-Induced Quasi-Zero Stiffness Metastructures for Low-Frequency Vibration Isolation.

Metastructures, artificial arrangements of micro/macrostructures, possess unique properties and are of significant interest in aerospace, stealth technology, and various other applications. Recent studies have focused on quasi-zero stiffness metastructures, providing an outstanding vibration isolation capability. However, existing methods are constrained to low preloads and lack the consideration of structural analysis, despite their intended use in practical structures. This study introduces metastructures with quasi-zero stiffness characteristics under high preloads by inducing local buckling. An optimization framework combining deep reinforcement learning and finite-element analysis is employed to derive an optimal model that considers both structural safety and quasi-zero stiffness characteristics. To validate the optimization results, quasi-zero stiffness metastructures are fabricated via 3D printing, and compression and vibration experiments are conducted. The fabricated metastructures exhibit quasi-zero stiffness characteristics under a high target preload along with outstanding vibration reduction performance, even in the low-frequency range.

Determination of the Nutrient and Toxic Element Content of Wild-Collected and Cultivated Seaweeds from Hawai'i.

For centuries, Hawaiians have gathered seaweed for food, medicine, and ceremonial purposes. Seaweed contains nutrients, but some varieties can accumulate toxic elements. We measured target macrominerals (Na, Mg, P, K, Ca), microminerals (B, V, Mn, Co, Cu, Zn, Mo), and nonessential/toxic elements (As, Sr, Cd, Sn, Hg, Pb, and U) in a sample of wild-collected and cultivated seaweeds from Hawai'i. The samples consisted of brown (Sargassum aquifolium, Sargassum echinocarpum), red (Gracilaria parvispora, Halymenia formosa, Halymenia hawaiiana), and green (Ulva ohnoi) seaweed. Elemental composition was determined by inductively coupled plasma (ICP)-atomic emission spectroscopy and ICP-mass spectrometry (MS). Speciation of As was conducted by using liquid chromatography-ICP-MS. S. echinocarpum per 80 g serving was high in Ca (~37% daily value [DV]), U. ohnoi was high in Mg (~40%DV), H. formosa was high in Fe (~40%DV), and G. parvispora was high in Mn (~128%DV). In this study, the highest amounts of toxic elements were observed in S. aquifolium and S. echinocarpum (27.6 mg inorganic As/kg fdw), G. parvispora (43.3 mg Pb/kg fdw) and H. formosa (46.6 mg Pb/kg fdw). These results indicate that although seaweeds from Hawai'i contain a variety of nutrients, some species can accumulate high amounts of toxic elements.

Practicality and Safety of Electrical Pulmonary Vein Isolation and Left Atrial Appendage Ligation in Lung Transplant Recipients With Pretransplant Atrial Fibrillation.

Background: Lung transplant surgery creates surgical pulmonary vein isolation (PVI) as a routine part of the procedure. However, many patients with pretransplant atrial fibrillation continue to have atrial fibrillation at 1 y. We hypothesized that the addition of electrical PVI and left atrial appendage isolation/ligation (LAL) to the lung transplant procedure restores sinus rhythm at 1 y in patients with pretransplant atrial fibrillation. Methods: We retrospectively reviewed all adult lung transplant recipients at the University of California Los Angeles from April 2006 to August 2021. All patients with pretransplant atrial fibrillation underwent concomitant PVI/LAL and were compared with lung transplant recipients without preoperative atrial fibrillation. In-hospital outcomes; 1-y survival; and the incidence of stroke, cardiac readmissions, repeat ablations, and sinus rhythm (composite endpoint) were examined at 1 y for the PVI/LAL cohort. Results: Sixty-one lung transplant recipients with pretransplant atrial fibrillation underwent concomitant PVI/LAL. No patient in the PVI/LAL cohort required cardiac-related readmission or catheter ablation for atrial fibrillation within 1 y of transplantation. Freedom from the composite endpoint of death, stroke, cardiac readmission, and repeat ablation for atrial fibrillation at 1 y was 85% (95% confidence interval, 73%-92%) for lung transplant recipients treated with PVI/LAL. Conclusions: The addition of PVI/LAI to the lung transplant operation in patients with pretransplant atrial fibrillation was safe and effective in maintaining sinus rhythm and baseline risk of stroke at 1 y.

Role for Caspase-8 in the Release of IL-1ß and Active Caspase-1 from Viable Human Monocytes during Toxoplasma gondii Infection.

Monocytes are actively recruited to sites of infection and produce the potent proinflammatory cytokine IL-1ß. We previously showed that IL-1ß release during Toxoplasma gondii infection of primary human monocytes requires the NLRP3 inflammasome and caspase-1 but is independent of gasdermin D and pyroptosis. To investigate mechanisms of IL-1ß release, we generated caspase-1, -4, -5, or -8 knockout (KO) THP-1 monocytic cells. Genetic ablation of caspase-1 or -8, but not caspase-4 or -5, decreased IL-1ß release during T. gondii infection without affecting cell death. In contrast, TNF-α and IL-6 secretion were unperturbed in caspase-8 KO cells during T. gondii infection. Dual pharmacological inhibition of caspase-8 and RIPK1 in primary monocytes also decreased IL-1ß release without affecting cell viability or parasite infection. Caspase-8 was also required for the release of active caspase-1 from T. gondii-infected cells and for IL-1ß release during infection with the related apicomplexan parasite Neospora caninum. Surprisingly, caspase-8 deficiency did not impair synthesis or cleavage of pro-IL-1ß, but resulted in the retention of mature IL-1ß within cells. Generation of gasdermin E KO and ATG7 KO THP-1 cells revealed that the release of IL-1ß was not dependent on gasdermin E or ATG7. Collectively, our data indicate that during T. gondii Infection of human monocytes, caspase-8 functions in a novel gasdermin-independent mechanism controlling IL-1ß release from viable cells. This study expands on the molecular pathways that promote IL-1ß in human immune cells and provides evidence of a role for caspase-8 in the mechanism of IL-1ß release during infection.

Leveraging single-cell ATAC-seq and RNA-seq to identify disease-critical fetal and adult brain cell types.

Prioritizing disease-critical cell types by integrating genome-wide association studies (GWAS) with functional data is a fundamental goal. Single-cell chromatin accessibility (scATAC-seq) and gene expression (scRNA-seq) have characterized cell types at high resolution, and studies integrating GWAS with scRNA-seq have shown promise, but studies integrating GWAS with scATAC-seq have been limited. Here, we identify disease-critical fetal and adult brain cell types by integrating GWAS summary statistics from 28 brain-related diseases/traits (average N = 298 K) with 3.2 million scATAC-seq and scRNA-seq profiles from 83 cell types. We identified disease-critical fetal (respectively adult) brain cell types for 22 (respectively 23) of 28 traits using scATAC-seq, and for 8 (respectively 17) of 28 traits using scRNA-seq. Significant scATAC-seq enrichments included fetal photoreceptor cells for major depressive disorder, fetal ganglion cells for BMI, fetal astrocytes for ADHD, and adult VGLUT2 excitatory neurons for schizophrenia. Our findings improve our understanding of brain-related diseases/traits and inform future analyses.

Prognostic Value of Metastatic Lymph Node Ratio and Identification of Factors Influencing the Lymph Node Yield in Patients Undergoing Curative Colon Cancer Resection.

Due to the impact of nodal metastasis on colon cancer prognosis, adequate regional lymph node resection and accurate pathological evaluation are required. The ratio of metastatic to examined nodes may bring an additional prognostic value to the actual staging system. This study analyzes the identification of factors influencing a high lymph node yield and its impact on survival. The lymph node ratio was determined in patients with fewer than 12 or at least 12 evaluated nodes. The study included patients after radical colon cancer resection in UICC stages II and III. For the lymph node ratio (LNR) analysis, node-positive patients were divided into four categories: i.e., LNR 1 (<0.05), LNR 2 (≥0.05; <0.2), LNR 3 (≥0.2; <0.4), and LNR 4 (≥0.4), and classified into two groups: i.e., those with <12 and ≥12 evaluated nodes. The study was conducted on 7012 patients who met the set criteria and were included in the data analysis. The mean number of examined lymph nodes was 22.08 (SD 10.64, median 20). Among the study subjects, 94.5% had 12 or more nodes evaluated. These patients were more likely to be younger, women, with a lower ASA classification, pT3 and pN2 categories. Also, they had no risk factors and frequently had a right-sided tumor. In the multivariate analysis, a younger age, ASA classification of II and III, high pT and pN categories, absence of risk factors, and right-sided location remained independent predictors for a lymph node yield ≥12. The univariate survival analysis of the entire cohort demonstrated a better five-year overall survival (OS) in patients with at least 12 lymph nodes examined (68% vs. 63%, p = 0.027). The LNR groups showed a significant association with OS, reaching from 75.5% for LNR 1 to 33.1% for LNR 4 (p < 0.001) in the ≥12 cohort, and from 74.8% for LNR2 to 49.3% for LNR4 (p = 0.007) in the <12 cohort. This influence remained significant and independent in multivariate analyses. The hazard ratios ranged from 1.016 to 2.698 for patients with less than 12 nodes, and from 1.248 to 3.615 for those with at least 12 nodes. The LNR allowed for a more precise estimation of the OS compared with the pN classification system. The metastatic lymph node ratio is an independent predictor for survival and should be included in current staging and therapeutic decision-making processes.

Chemical Localization With Robotic Bronchoscopy: Can It Aid Resection of Subsolid Lung Nodules?

INTRODUCTION: Subsolid nodules or those located deep in lung parenchyma are difficult to localize using minimally invasive thoracic surgery. While image-guided percutaneous needle localization has been performed, it is inconvenient and has potential complications. In this study, the role of chemical localization using robotic bronchoscopy to facilitate resection was evaluated. METHODS: Consecutive patients undergoing surgical resection for lung nodules between 8/2019-3/2022 were included. Patients with subsolid lung nodules, or small nodules deep in lung parenchyma that were deemed difficult to localize, were chemically localized (CL) using robotic bronchoscopy before resection. Clinico-demographic data were obtained retrospectively using a prospectively maintained database. RESULTS: Localization of lung nodules before resection was performed in 139 patients while 110 patients were not localized. Daily activity score was higher for localized patients. Nodules in the localized group were smaller (P < 0.001) and had similar solid:ground glass ratio. In the localized group, larger margins were observed, and no re-resection of the parenchymal margin was required. Twenty patients in the non-localized group required re-resection intraoperatively due to close pathological margins or inability to locate the nodule in the resected specimen. Operative time was a median of 10-15 min longer for localized patients, P < 0.001. Length of stay was shorter in the localized group (P < 0.05). CONCLUSIONS: Chemical localization of lung nodules using robotic bronchoscopy appears to be a safe and effective method of identifying the location of nodules with small size and less density and aids increased tumor margins intraoperatively.

Temporal correlation between postreperfusion complement deposition and severe primary graft dysfunction in lung allografts.

Growing evidence implicates complement in the pathogenesis of primary graft dysfunction (PGD). We hypothesized that early complement activation postreperfusion could predispose to severe PGD grade 3 (PGD-3) at 72 hours, which is associated with worst posttransplant outcomes. Consecutive lung transplant patients (n = 253) from January 2018 through June 2023 underwent timed open allograft biopsies at the end of cold ischemia (internal control) and 30 minutes postreperfusion. PGD-3 at 72 hours occurred in 14% (35/253) of patients; 17% (44/253) revealed positive C4d staining on postreperfusion allograft biopsy, and no biopsy-related complications were encountered. Significantly more patients with PGD-3 at 72 hours had positive C4d staining at 30 minutes postreperfusion compared with those without (51% vs 12%, P < .001). Conversely, patients with positive C4d staining were significantly more likely to develop PGD-3 at 72 hours (41% vs 8%, P < .001) and experienced worse long-term outcomes. In multivariate logistic regression, positive C4d staining remained highly predictive of PGD-3 (odds ratio 7.92, 95% confidence interval 2.97-21.1, P < .001). Hence, early complement deposition in allografts is highly predictive of PGD-3 at 72 hours. Our data support future studies to evaluate the role of complement inhibition in patients with early postreperfusion complement activation to mitigate PGD and improve transplant outcomes.

Heart Retransplantation Under the 2018 Adult Heart Allocation Policy.

BACKGROUND: The purpose of the present study was to characterize the impact of the 2018 adult heart allocation policy change on waiting list and posttransplant outcomes of heart retransplantation in the United States. METHODS: All adults listed for heart retransplantation from May 2015 to June 2022 were identified using the United Network for Organ Sharing database. Patients were stratified into eras (era 1 and era 2) based on the heart allocation change on October 18, 2018. Competing risks regressions and Cox proportional hazards models were used to assess differences across eras in waiting list outcomes and 1-year posttransplant survival, respectively. RESULTS: The analysis included 356 repeat heart transplant recipients, with 207 (58%) receiving retransplantation during era 2. Patients who received a retransplant in era 2 were more commonly bridged with extracorporeal membrane oxygenation (21% vs 8%, P < .01) and intra-aortic balloon pump (29% vs 13%, P < .001) and had a lower likelihood of death/deterioration on the waiting list (subdistribution hazard ratio, 0.52; 95% CI, 0.33-0.82) compared with those in era 1. Rates of 30-day mortality (7% vs 7%, P = .99) and 1-year survival (82% vs 87%, P = .27) were not significantly different among retransplantation recipients across eras. After adjustment, retransplantation in era 2 was not associated with an increased hazard of mortality (adjusted hazard ratio, 1.13; 95% CI, 0.55-2.30). The gap in 1-year mortality between primary transplant and retransplant recipients increased from era 1 to 2. CONCLUSIONS: Heart retransplantation candidates have experienced improved waiting list outcomes after the 2018 adult heart allocation policy, without significant changes to posttransplant survival.

Characteristics and outcomes of lung transplants performed with ex-situ lung perfusion.

BACKGROUND: Ex-situ lung perfusion (ESLP) can be used to assess and rehabilitate donor lungs, potentially expanding the donor pool. We examined the characteristics and outcomes of lung transplants performed with ESLP in the United States. METHODS: Retrospective review of the United Network for Organ Sharing registry of primary adult lung transplant recipients from February 28, 2018, to June 30, 2021, was performed, comparing baseline characteristics, in-hospital outcomes, and 1-year survival of ESLP vs no ESLP lung transplants. RESULTS: Of 8204 lung transplants, 426 (5.2%) were performed with ESLP. ESLP donors were older, more donation after circulatory death (DCD), and had lower PaO2:FiO2 (P:F) ratios. Recipients had lower lung allocation scores. ESLP lungs traveled further, had longer preservation times, and were more likely double lung transplants. Reintubation rates, extracorporeal membrane oxygenation at 72 hours, and hospital length of stay were greater in the ESLP group. On multivariable analysis, ESLP was not an independent predictor of 1-year survival. However, further analysis showed that DCD lungs managed on ESLP had worse 1-year survival compared to DCD lungs preserved with standard cold storage or with donation after brain death donor lungs. CONCLUSIONS: ESLP is used in a small percentage of lung transplants in the US and is not independently associated with 1-year survival. ESLP combined with DCD lungs, however, is associated with worse 1-year survival and warrants further investigation.

Rapid Discharge After Anatomic Lung Resection: Is Ambulatory Surgery for Early Lung Cancer Possible?

BACKGROUND: Given resource constraints during the coronavirus disease 2019 pandemic, we explored whether minimally invasive anatomic lung resections for early-stage lung cancer could undergo rapid discharge. METHODS: All patients with clinical stage I-II non-small cell lung cancer from September 2019 to June 2022 who underwent minimally invasive anatomic lung resection at a single institution were included. Patients discharged without a chest tube <18 hours after operation, meeting preset criteria, were considered rapid discharge. Demographics, comorbidities, operative details, and 30-day outcomes were compared between rapid discharge patients and nonrapid discharge "control" patients. Multivariable logistic regression was performed for predictors of nonrapid discharge. RESULTS: Overall, 430 patients underwent resection (200 lobectomies and 230 segmentectomies); 162 patients (37%) underwent rapid discharge and 268 patients (63%) were controls. The rapid discharge group was younger (66.5 vs 70.0 years; P < .001), was assigned to lower American Society of Anesthesiologists class (P = .02), had more segmentectomies than lobectomies (P = .003), and had smaller tumors (P < .001). There were no differences between groups in distance from home to hospital (P = .335) or readmission rates (P = .39). Increasing age had higher odds for nonrapid discharge (odds ratio, 1.04; 95% CI, 1.02-1.07), whereas segmentectomy had decreased odds (odds ratio, 0.46; 95% CI, 0.28-0.75). CONCLUSIONS: Approximately 37% of the patients underwent rapid discharge after operation with similar readmission rate to controls. Increasing age had higher odds for nonrapid discharge; segmentectomy was likely to lead to rapid discharge. Consideration of rapid discharge minimally invasive lung resection for early-stage lung cancer can result in significant reduction in inpatient resources without adverse patient outcomes.

Lung Transplantation from hepatitis C+ donor lungs: Reassuring midterm outcomes.

BACKGROUND: The development of modern antiviral therapy for hepatitis C virus (HCV) has allowed for the transplantation of HCV nucleic acid amplification testing-positive (NAT+) donor lungs with acceptable short-term outcomes. We sought to evaluate trends and midterm outcomes of lung transplant recipients of HCV NAT+ donor allografts. METHODS: All adults undergoing isolated lung transplantation in the United Network for Organ Sharing database from January 2016 to December 2022 were included in the study. Lung transplant recipients were stratified based on donor HCV status (HCV NAT+ vs NAT-). Propensity score matching was used to adjust for differences between groups. Several outcomes, including acute rejection by 1 year, early (30-day and in-hospital) mortality, and both 1- and 3-year survival, were compared between matched groups. RESULTS: A total of 16,725 patients underwent lung transplantation during the study period, with 489 (3%) receiving HCV NAT+ donor lungs. Regions 1 (18%) and 6/8 (both 0%) had the highest and lowest proportions, respectively, of HCV NAT+ donor transplants. Utilization of HCV NAT+ donors increased throughout the study period from 2 (0.1%) in 2016 to a peak of 117 (5%) in 2019. Donors who were HCV NAT+ were younger (34 vs 36 years, p < 0.001), more often female (44% vs 39%, p < 0.01), and more commonly died due to drug intoxication (56% vs 15%, p < 0.001). Recipients of HCV NAT+ donor lungs were similar in age (62 vs 62 years, p = 0.69) and female gender (43% vs 39%, p = 0.15) but had lower lung allocation scores (38 vs 41, p < 0.001) compared to others. Rates of acute rejection (13% vs 17%, p = 0.09), early mortality (30-day: 2% vs 1%, p = 0.59, in-hospital: 3% vs 4%, p = 0.38), as well as 1-year (90% vs 92%, p = 0.29) and 3-year survival (69% vs 75%, p = 0.13) were not significantly different between matched groups. CONCLUSIONS: Lung transplant recipients of HCV NAT+ donor allografts experience similar rates of acute rejection, early mortality, and 3-year survival compared to all other lung recipients. Increased use of HCV NAT+ donor allografts may help to expand the donor pool and alleviate donor shortages.

Ligand-Mediated Mechanical Enhancement in Protein Complexes at Nano- and Macro-Scale.

Protein self-assembly plays a vital role in a myriad of biological functions and in the construction of biomaterials. Although the physical association underlying these assemblies offers high specificity, the advantage often compromises the overall durability of protein complexes. To address this challenge, we propose a novel strategy that reinforces the molecular self-assembly of protein complexes mediated by their ligand. Known for their robust noncovalent interactions with biotin, streptavidin (SAv) tetramers are examined to understand how the ligand influences the mechanical strength of protein complexes at the nanoscale and macroscale, employing atomic force microscopy-based single-molecule force spectroscopy, rheology, and bioerosion analysis. Our study reveals that biotin binding enhances the mechanical strength of individual SAv tetramers at the nanoscale. This enhancement translates into improved shear elasticity and reduced bioerosion rates when SAv tetramers are utilized as cross-linking junctions within hydrogel. This approach, which enhances the mechanical strength of protein-based materials without compromising specificity, is expected to open new avenues for advanced biotechnological applications, including self-assembled, robust biomimetic scaffolds and soft robotics.

Predicting Development of Chronic Obstructive Pulmonary Disease and its Risk Factor Analysis.

Chronic Obstructive Pulmonary Disease (COPD) is an irreversible airway obstruction with a high societal burden. Although smoking is known to be the biggest risk factor, additional components need to be considered. In this study, we aim to identify COPD risk factors by applying machine learning models that integrate sociodemographic, clinical, and genetic data to predict COPD development.Clinical relevance- This study assessed the risk factors of COPD in sociodemographic, clinical, and genetic data. We have determined that sociodemographic factors are highly associate to the development of COPD.

Proprotein convertase subtilisn/kexin type 9 inhibitors and small interfering RNA therapy for cardiovascular risk reduction: A systematic review and meta-analysis.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality worldwide. Atherosclerosis occurs due to accumulation of low-density lipoprotein cholesterol (LDL-c) in the arterial system. Thus, lipid lowering therapy is essential for both primary and secondary prevention. Proprotein convertase subtilisn/kexin type 9 (PCSK9) inhibitors (Evolocumab, Alirocumab) and small interfering RNA (siRNA) therapy (Inclisiran) have been demonstrated to lower LDL-c and ASCVD events in conjunction with maximally tolerated statin therapy. However, the degree of LDL-c reduction and the impact on reducing major adverse cardiac events, including their impact on mortality, remains unclear. OBJECTIVE: The purpose of this study is to examine the effects of PCSK9 inhibitors and small interfering RNA (siRNA) therapy on LDL-c reduction and major adverse cardiac events (MACE) and mortality by conducting a meta-analysis of randomized controlled trials. METHODS: Using Pubmed, Embase, Cochrane Library and clinicaltrials.gov until April 2023, we extracted randomized controlled trials (RCTs) of PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) for lipid lowering and risk of MACE. Using random-effects models, we pooled the relative risks and 95% CIs and weighted least-squares mean difference in LDL-c levels. We estimated odds ratios with 95% CIs among MACE subtypes and all-cause mortality. Fixed-effect model was used, and heterogeneity was assessed using the I2 statistic. RESULTS: In all, 54 studies with 87,669 participants (142,262 person-years) met criteria for inclusion. LDL-c percent change was reported in 47 studies (n = 62,634) evaluating two PCSK9 inhibitors and siRNA therapy. Of those, 21 studies (n = 41,361) included treatment with Evolocumab (140mg), 22 (n = 11,751) included Alirocumab (75mg), and 4 studies (n = 9,522) included Inclisiran (284mg and 300mg). Compared with placebo, after a median of 24 weeks (IQR 12-52), Evolocumab reduced LDL-c by -61.09% (95% CI: -64.81, -57.38, p<0.01) and Alirocumab reduced LDL-c by -46.35% (95% CI: -51.75, -41.13, p<0.01). Inclisiran 284mg reduced LDL-c by -54.83% (95% CI: -59.04, -50.62, p = 0.05) and Inclisiran 300mg reduced LDL-c by -43.11% (95% CI: -52.42, -33.80, p = 0.01). After a median of 8 months (IQR 6-15), Evolocumab reduced the risk of myocardial infarction (MI), OR 0.72 (95% CI: 0.64, 0.81, p<0.01), coronary revascularization, 0.77 (95% CI: 0.70, 0.84, p<0.01), stroke, 0.79 (95% CI: 0.66, 0.94, p = 0.01) and overall MACE 0.85 (95% CI: 0.80, 0.89, p<0.01). Alirocumab reduced MI, 0.57 (0.38, 0.86, p = 0.01), cardiovascular mortality 0.35 (95% CI: 0.16, 0.77, p = 0.01), all-cause mortality 0.60 (95% CI: 0.43, 0.84, p<0.01), and overall MACE 0.35 (0.16, 0.77, p = 0.01). CONCLUSION: PCSK9 inhibitors (Evolocumab, Alirocumab) and siRNA therapy (Inclisiran) significantly reduced LDL-c by >40% in high-risk individuals. Additionally, both Alirocumab and Evolocumab reduced the risk of MACE, and Alirocumab reduced cardiovascular and all-cause mortality.

Pervasive correlations between causal disease effects of proximal SNPs vary with functional annotations and implicate stabilizing selection.

The genetic architecture of human diseases and complex traits has been extensively studied, but little is known about the relationship of causal disease effect sizes between proximal SNPs, which have largely been assumed to be independent. We introduce a new method, LD SNP-pair effect correlation regression (LDSPEC), to estimate the correlation of causal disease effect sizes of derived alleles between proximal SNPs, depending on their allele frequencies, LD, and functional annotations; LDSPEC produced robust estimates in simulations across various genetic architectures. We applied LDSPEC to 70 diseases and complex traits from the UK Biobank (average N=306K), meta-analyzing results across diseases/traits. We detected significantly nonzero effect correlations for proximal SNP pairs (e.g., -0.37±0.09 for low-frequency positive-LD 0-100bp SNP pairs) that decayed with distance (e.g., -0.07±0.01 for low-frequency positive-LD 1-10kb), varied with allele frequency (e.g., -0.15±0.04 for common positive-LD 0-100bp), and varied with LD between SNPs (e.g., +0.12±0.05 for common negative-LD 0-100bp) (because we consider derived alleles, positive-LD and negative-LD SNP pairs may yield very different results). We further determined that SNP pairs with shared functions had stronger effect correlations that spanned longer genomic distances, e.g., -0.37±0.08 for low-frequency positive-LD same-gene promoter SNP pairs (average genomic distance of 47kb (due to alternative splicing)) and -0.32±0.04 for low-frequency positive-LD H3K27ac 0-1kb SNP pairs. Consequently, SNP-heritability estimates were substantially smaller than estimates of the sum of causal effect size variances across all SNPs (ratio of 0.87±0.02 across diseases/traits), particularly for certain functional annotations (e.g., 0.78±0.01 for common Super enhancer SNPs)-even though these quantities are widely assumed to be equal. We recapitulated our findings via forward simulations with an evolutionary model involving stabilizing selection, implicating the action of linkage masking, whereby haplotypes containing linked SNPs with opposite effects on disease have reduced effects on fitness and escape negative selection.

Short stature is a risk factor for heart transplant morbidity and mortality.

BACKGROUND: Short stature is associated with mortality after cardiac surgery and may increase size mismatch risk among transplant recipients. Yet, stature's impact on heart transplant outcomes is not well-characterized. METHODS: The Scientific Registry of Transplant Recipients was queried for data on all adult heart transplants in the United States from 2000 to 2022. Recipients were stratified into five cohorts by sex-corrected stature. Morbidity was assessed with Kruskal-Wallis and chi-squared tests. Mortality was analyzed using Kaplan-Meier estimation. Risk factors for mortality were assessed with multivariable Cox regression. RESULTS: Among 43,420 transplant recipients, 5321 (12.2%) had short stature (females >4'11″ & ≤5'1″; males >5'4″ & ≤5'7″) and 765 (1.8%) had very short stature (females ≤4'11″; males ≤5'4″). Very short stature patients had higher waitlist status (1A and 1), more congenital heart disease, and received more oversized donor hearts than other cohorts (all p < 0.05). Very short stature patients had decreased 30-day, 1-, 5-, and 10-year survival (94.6%, 84.3%, 69.3% and 52.5%, respectively, all p < 0.001), but less acute rejection (p = 0.005) and comparable stroke rates (p = 0.107). On multivariable regression adjusting for congenital heart disease and oversized donor hearts, very short and short stature were associated with 10-year mortality (hazard ratios: 1.40 and 1.12, respectively, both p < 0.005). CONCLUSIONS: Short stature confers increased mortality risk for heart transplant recipients and merits inclusion in prognostic models.