Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.

BACKGROUND: Major histocompatibility complex class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression. METHODS: We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single-cell neighborhoods from mIF images followed by multivariate discriminant analysis. RESULTS: Spatial quantitation of tumor cell MHC-I expression revealed intratumoral and intertumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56+ cell numbers in patient tumors were positively associated with disease-free survival (HR=0.58, p=0.064) and overall survival (OS) (HR=0.496, p=0.041). The OS association strengthened with high counts of both CD56+ and CD8+ cells (HR=0.199, p<1×10-3). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3+CD8+ T cells and CD3-CD56+ NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single-cell neighborhood profiles to delineate the cellular environments of IFNγ+/- NK cells and T cells. We discovered that both IFNγ+ NK and CD8 T cells were more frequently associated with other IFNγ+ lymphocytes in comparison to IFNγ- NK cells and CD8 T cells (p<1×10-30). Moreover, IFNγ+ lymphocytes were most often found clustered near MHC-I+ tumor cells. CONCLUSIONS: Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Coassociation of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent colocalization of IFNγ+ NK cells with other IFNγ+ lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated.

Peripheral blood interferon responses to toll-like receptor 1/2 signaling associate with longer survival in men with metastatic prostate cancer treated with Sipleucel-T.

Mounting evidence links systemic innate immunity with cancer immune surveillance. In advanced metastatic castration resistant prostate cancer (mCRPC), Black patients have been found to have increased inflammatory markers and longer survival after sipuleucel-T (sip-T) therapy, an FDA-approved, autologous cell therapy. We hypothesized these differences may be explained by previously reported ancestral differences in pattern recognition receptor (PRR) signaling, which broadly governs innate inflammation to control adaptive immune cell activation, chemotaxis, and functionality. We discovered that PBMC interferon (IFN)-ß responses to TLR1/2, a sensor of bacterial and gut microbiome constituents, associated with significantly longer survival after sip-T therapy in two separate cohorts of men with mCRPC (discovery cohort: n=106, HR=0.12, p=0.019; validation cohort: n=28, HR<0.01, p=0.047). Higher IFN-ß induction after TLR1/2 stimulation was associated with lower hazard ratios compared to biomarkers of vaccine potency and other prognostic factors in mCRPC. TLR1/2 dependent cytokine induction was stronger in Black individuals (1.2-fold higher for IFN-ß; p=0.04) but was associated with survival independently of race or numbers of vaccine-induced tumor antigen-specific T cells. IFN-ß responses to TLR1/2 signaling correlated with increased numbers of IFN-ß producing T cells after broad, tumor antigen independent stimulation. Thus, peripheral innate immunity differs by race, may predict survival after sip-T, and associates with peripheral T cell functionality in men with mCRPC.

A signal-seeking phase 2 study of Trastuzumab emtansine in tumours harbouring HER2 amplification or mutation.

This single-arm phase II non-randomised trial (ACTRN12619001265167) evaluated trastuzumab emtansine in solid cancers with HER2 amplification or mutation detected by comprehensive genomic profiling. The primary objective was objective response (OR), while secondary objectives included the time to progression (TTP) on study to TTP on prior therapy ratio, progression-free survival (PFS) and overall survival (OS). The cohort included 16 tumours with HER2 mutations (group 1) and 16 with HER2 amplification (group 2). After 17 months median follow-up, ORs occurred in 19% of group 1 (1 salivary gland carcinoma (SGC), 2 lung cancers) and 25% of group 2 (3 SGCs, 1 uterine carcinoma). Fourteen of 29 TTP-evaluable patients achieved a TTP ratio ≥1.3, including 10 without an OR. Median PFS and OS were 4.5 (95% CI 2.1-7.0) and 18.2 months (95% CI 8.1-not reached) respectively. Trastuzumab emtansine showed modest ORs and a favourable change in disease trajectory in select HER2-altered solid cancers.

Phosphorylation of Insig-2 mediates inhibition of fatty acid synthesis by polyunsaturated fatty acids.

Insig-1 and Insig-2 are endoplasmic reticulum (ER) proteins that inhibit lipid synthesis by blocking transport of sterol regulatory element-binding proteins (SREBP-1 and SREBP-2) from ER to Golgi. In the Golgi, SREBPs are processed proteolytically to release their transcription-activating domains, which enhance the synthesis of fatty acids, triglycerides, and cholesterol. Heretofore, the two Insigs have redundant functions, and there is no rationale for two isoforms. The current data identify a specific function for Insig-2. We show that eicosapentaenoic acid (EPA), a polyunsaturated fatty acid, inhibits fatty acid synthesis in human fibroblasts and rat hepatocytes by activating adenylate cyclase, which induces protein kinase A (PKA) to phosphorylate serine-106 in Insig-2. Phosphorylated Insig-2 inhibits the proteolytic processing of SREBP-1, thereby blocking fatty acid synthesis. Phosphorylated Insig-2 does not block the processing of SREBP-2, which activates cholesterol synthesis. Insig-1 lacks serine-106 and is not phosphorylated at this site. EPA inhibition of SREBP-1 processing was reduced by the replacement of serine-106 in Insig-2 with alanine or by treatment with KT5720, a PKA inhibitor. Inhibition did not occur in mutant human fibroblasts that possess Insig-1 but lack Insig-2. These data provide an Insig-2-specific mechanism for the long-known inhibition of fatty acid synthesis by polyunsaturated fatty acids.

Spatial colocalization and combined survival benefit of natural killer and CD8 T cells despite profound MHC class I loss in non-small cell lung cancer.

Background: MHC class I (MHC-I) loss is frequent in non-small cell lung cancer (NSCLC) rendering tumor cells resistant to T cell lysis. NK cells kill MHC-I-deficient tumor cells, and although previous work indicated their presence at NSCLC margins, they were functionally impaired. Within, we evaluated whether NK cell and CD8 T cell infiltration and activation vary with MHC-I expression. Methods: We used single-stain immunohistochemistry (IHC) and Kaplan-Meier analysis to test the effect of NK cell and CD8 T cell infiltration on overall and disease-free survival. To delineate immune covariates of MHC-I-disparate lung cancers, we used multiplexed immunofluorescence (mIF) imaging followed by multivariate statistical modeling. To identify differences in infiltration and intercellular communication between IFNγ-activated and non-activated lymphocytes, we developed a computational pipeline to enumerate single cell neighborhoods from mIF images followed by multivariate discriminant analysis. Results: Spatial quantitation of tumor cell MHC-I expression revealed intra- and inter-tumoral heterogeneity, which was associated with the local lymphocyte landscape. IHC analysis revealed that high CD56+ cell numbers in patient tumors were positively associated with disease-free survival (DFS) (HR=0.58, p=0.064) and overall survival (OS) (HR=0.496, p=0.041). The OS association strengthened with high counts of both CD56+ and CD8+ cells (HR=0.199, p<1×10-3). mIF imaging and multivariate discriminant analysis revealed enrichment of both CD3+CD8+ T cells and CD3-CD56+ NK cells in MHC-I-bearing tumors (p<0.05). To infer associations of functional cell states and local cell-cell communication, we analyzed spatial single cell neighborhood profiles to delineate the cellular environments of IFNγ+/- NK cells and T cells. We discovered that both IFNγ+ NK and CD8 T cells were more frequently associated with other IFNγ+ lymphocytes in comparison to IFNγ- NK cells and CD8 T cells (p<1×10-30). Moreover, IFNγ+ lymphocytes were most often found clustered near MHC-I+ tumor cells. Conclusions: Tumor-infiltrating NK cells and CD8 T cells jointly affected control of NSCLC tumor progression. Co-association of NK and CD8 T cells was most evident in MHC-I-bearing tumors, especially in the presence of IFNγ. Frequent co-localization of IFNγ+ NK cells with other IFNγ+ lymphocytes in near-neighbor analysis suggests NSCLC lymphocyte activation is coordinately regulated.

Endogenous bystander killing mechanisms enhance the activity of novel FAP-specific CAR-T cells against glioblastoma.

Objectives: CAR-T cells are being investigated as a novel immunotherapy for glioblastoma, but clinical success has been limited. We recently described fibroblast activation protein (FAP) as an ideal target antigen for glioblastoma immunotherapy, with expression on both tumor cells and tumor blood vessels. However, CAR-T cells targeting FAP have never been investigated as a therapy for glioblastoma. Methods: We generated a novel FAP targeting CAR with CD3ζ and CD28 signalling domains and tested the resulting CAR-T cells for their lytic activity and cytokine secretion function in vitro (using real-time impedance, flow cytometry, imaging and bead-based cytokine assays), and in vivo (using a xenograft mimicking the natural heterogeneity of human glioblastoma). Results: FAP-CAR-T cells exhibited target specificity against model cell lines and potent cytotoxicity against patient-derived glioma neural stem cells, even when only a subpopulation expressed FAP, indicating a bystander killing mechanism. Using co-culture assays, we confirmed FAP-CAR-T cells mediate bystander killing of antigen-negative tumor cells, but only after activation by FAP-positive target cells. This bystander killing was at least partially mediated by soluble factors and amplified by IL-2 which activated the non-transduced fraction of the CAR-T product. Finally, a low dose of intravenously administered FAP-CAR-T cells controlled, without overt toxicity, the growth of subcutaneous tumors created using a mixture of antigen-negative and antigen-positive glioblastoma cells. Conclusions: Our findings advance FAP as a leading candidate for clinical CAR-T therapy of glioblastoma and highlight under-recognised antigen nonspecific mechanisms that may contribute meaningfully to the antitumor activity of CAR-T cells.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to 23 genes. Investigating these genes' functional implications shed light on neurological, thyroidal, bone metabolism, and hematopoietic pathways that necessitate future investigation for blood pressure management that caters to sleep health lifestyle. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausible nature of distinct influences of both sleep duration extremes in cardiovascular health. Several of our loci are specific towards a particular population background or sex, emphasizing the importance of addressing heterogeneity entangled in gene-environment interactions, when considering precision medicine design approaches for blood pressure management.

High Area Deprivation Index is Associated With Discharge to Foster Care in Pediatric Patients With Non-accidental Trauma.

BACKGROUND: Outcomes after non-accidental trauma (NAT) have been shown to be impacted by social determinants of health. Our study aims to investigate the association between NAT, patient demographics, neighborhood disadvantage as measured by the Area Deprivation Index (ADI), and patient disposition. METHODS: An 8-year retrospective chart review was conducted in pediatric patients presenting to our level I trauma center with suspected NAT. Patient demographics, ADI, injury severity score (ISS), Glasgow coma scale (GCS), length of stay, and discharge disposition were analyzed using univariate and multivariate techniques to evaluate associations between patient demographics, injury severity, and patient outcomes. RESULTS: A total of 84 patients were admitted with suspected NAT. Of our study population, 45% of patients were White and 26% were Black. Black children were overrepresented in this cohort compared to general population means, while White children were underrepresented (p < 0.05). Median ADI was 6.5 (IQR 4.0-8.0). Of our cohort, 65 patients were discharged home, and 18 patients to foster care. One patient in our cohort died. An ADI >6 was the only factor significantly associated with discharge to foster care. This association held on both univariate (OR 1.4; 95% CI 1.07-1.84, p = 0.02) and multivariate (OR 1.4; 95% CI 1.05-1.86, p = 0.02) analyses. CONCLUSION: Our study found that neighborhood disadvantage, as measured by ADI, is an independent predictor of discharge to foster care. Additionally, Black children remain over-represented in the NAT population referred to our institution, including those discharged to foster care. Efforts to address healthcare disparities and community-based NAT prevention and reunification programs are necessary. TYPE OF STUDY: Prognosis Study (Retrospective Case-Control Study). LEVEL OF EVIDENCE: Level III.

Inflammation and Macrophage Loss Mark Increased Susceptibility in a Genetic Model of Acute Viral Infection-Induced Tissue Damage.

M.R2k/b mice are identical to the MA/My parent strain aside from a 5.58-Mb C57L-derived region on chromosome 17 (Cmv5s) that causes increased susceptibility to acute murine CMV (MCMV) infection and the development of significant spleen tissue damage. Spleen pathology begins at the marginal zone (MZ), apparent by 2 d postinfection (dpi), and progresses throughout the red pulp by 4 dpi. To better understand how M.R2k/b mice respond to infection and how Cmv5s contributes to tissue damage in the spleen, we assessed the regulation of myeloid cells and inflammation during acute MCMV infection in MA/My and M.R2k/b mice. We found that Cmv5s drove increased neutrophil accumulation and cell death at the MZ, which corresponded with evidence of localized oxidative stress and increased overall spleen IL-6 and TGF-ß1 early during infection. Further assessment of MCMV infection dynamics at the early MZ revealed infected SIGNR1+ MZ macrophages as the first apparent cell type lost during infection in these mice and the likely target of early neutrophil recruitment. Spleen macrophages were also identified as the mediators of differential spleen IL-6 and TGF-ß1 between MA/My and M.R2k/b mice. Interrogation of MCMV progression past 2 dpi revealed substantial M.R2k/b F480+ red pulp macrophage loss along with buildup of oxidative stress and MZ macrophage debris that was not neutrophil dependent. Together we identify Cmv5s-driven macrophage loss and inflammation during acute MCMV infection corresponding with the spatial and temporal development of spleen tissue damage.

Examining patient demographics and major adverse cardiac events following noncardiac surgery: Applying a health equity lens.

BACKGROUND: Major adverse cardiac events (MACE) are a major contributor to postoperative complications. This study employed a health equity lens to examine rates of postoperative MACE by race and ethnicity. METHODS: This single-center, retrospective observational cohort study followed patients with and without pre-existing coronary artery stents from 2008 to 2018 who underwent non-cardiac surgery. MACE was the primary outcome (death, acute MI, repeated coronary revascularization, in-stent thrombosis) and self-reported race and ethnicity was the primary predictor. A propensity score model of a 1:1 cohort of non-Hispanic White (NHW) patients and all other racial and ethnic minority populations (Hispanic and Black) was used to compare the rate of perioperative MACE in this cohort. RESULTS: During the study period, 79,686 cases were included in the analytic sample; 950 patients (1.2 %) had pre-existing coronary artery stents. <1 % of patients experienced MACE within 30 days following non-cardiac surgery (0.8 %). After confounder adjustment and propensity score matching, there were no statistically significant differences in MACE among racial and ethnic minority patients compared to NHW patients (OR = 0.77; 95 % CI: 0.48, 1.25). In our sensitivity analyses, stratifying by sex, there were no differences in MACE by race and ethnicity. CONCLUSIONS: The study found no statistically significant differences in MACE by race and ethnicity among patients who underwent non-cardiac surgery. Access to a high-volume, high-quality hospital such as the one studied may reduce the presence of healthcare disparities and may explain why our findings are not consistent with previous studies.

Safety and biological outcomes following a phase 1 trial of GD2-specific CAR-T cells in patients with GD2-positive metastatic melanoma and other solid cancers.

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapies specific for the CD19 and B-cell maturation antigen have become an approved standard of care worldwide for relapsed and refractory B-cell malignancies. If CAR-T cell therapy for non-hematological malignancies is to achieve the same stage of clinical development, then iterative early-phase clinical testing can add value to the clinical development process for evaluating CAR-T cell products containing different CAR designs and manufactured under differing conditions. METHODS: We conducted a phase 1 trial of third-generation GD2-specific CAR-T cell therapy, which has previously been tested in neuroblastoma patients. In this study, the GD2-CAR-T therapy was evaluated for the first time in metastatic melanoma patients in combination with BRAF/MEK inhibitor therapy, and as a monotherapy in patients with colorectal cancer and a patient with fibromyxoid sarcoma. Feasibility and safety were determined and persistence studies, multiplex cytokine arrays on sera and detailed immune phenotyping of the original CAR-T products, the circulating CAR-T cells, and, in select patients, the tumor-infiltrating CAR-T cells were performed. RESULTS: We demonstrate the feasibility of manufacturing CAR-T products at point of care for patients with solid cancer and show that a single intravenous infusion was well tolerated with no dose-limiting toxicities or severe adverse events. In addition, we note significant improvements in CAR-T cell immune phenotype, and expansion when a modified manufacturing procedure was adopted for the latter 6 patients recruited to this 12-patient trial. We also show evidence of CAR-T cell-mediated immune activity and in some patients expanded subsets of circulating myeloid cells after CAR-T cell therapy. CONCLUSIONS: This is the first report of third-generation GD2-targeting CAR-T cells in patients with metastatic melanoma and other solid cancers such as colorectal cancer, showing feasibility, safety and immune activity, but limited clinical effect. TRIAL REGISTRATION NUMBER: ACTRN12613000198729.

Diabetes and Hearing Impairment: Knowledge, Attitudes, and Practices Among Providers and Patients.

PURPOSE: The purpose of this study was to assess the knowledge, attitudes, and practices among providers and patients regarding hearing impairment and screening referrals in people with diabetes. METHODS: A cross-sectional survey design among health care providers and patients at an academic medical center in Oklahoma was used to gather knowledge, attitudes, and practices data. RESULTS: Only 25.6% of providers selected hearing impairment as a complication of diabetes, whereas 96.7% selected retinopathy, kidney dysfunction, and foot infection. Reported barriers to referring patients for hearing impairment screenings were being unfamiliar with recommended screening frequency (57.3%) and existence of higher priorities (35.4%). When asked to select parts of the body affected by diabetes, 21.0% of patients surveyed selected ears, 88.0% selected feet, and 85.0% selected eyes and kidneys. Fewer patients reported being told hearing impairment is a complication of diabetes compared to retinopathy (8.1% vs 85.9%). Additionally, 24.2% of patients reported having a hearing impairment screening, and 96.0% reported having a dilated eye exam. CONCLUSIONS: Most providers and patients at an academic medical center are unaware of the relationship between diabetes and hearing impairment. Providers reported there are several barriers that need to be overcome to refer patients to audiologists.

An approach to identify gene-environment interactions and reveal new biological insight in complex traits.

There is a long-standing debate about the magnitude of the contribution of gene-environment interactions to phenotypic variations of complex traits owing to the low statistical power and few reported interactions to date. To address this issue, the Gene-Lifestyle Interactions Working Group within the Cohorts for Heart and Aging Research in Genetic Epidemiology Consortium has been spearheading efforts to investigate G × E in large and diverse samples through meta-analysis. Here, we present a powerful new approach to screen for interactions across the genome, an approach that shares substantial similarity to the Mendelian randomization framework. We identify and confirm 5 loci (6 independent signals) interacted with either cigarette smoking or alcohol consumption for serum lipids, and empirically demonstrate that interaction and mediation are the major contributors to genetic effect size heterogeneity across populations. The estimated lower bound of the interaction and environmentally mediated heritability is significant (P < 0.02) for low-density lipoprotein cholesterol and triglycerides in Cross-Population data. Our study improves the understanding of the genetic architecture and environmental contributions to complex traits.

A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management.

Access to an Educational Video Preoperatively Has No Effect on Postoperative Opioid Use After Arthroscopic Partial Meniscectomy of the Knee: A Prospective Cohort Study.

Purpose: To determine whether access to a website with an educational video would decrease postoperative opioid use in patients undergoing arthroscopic partial meniscectomy. Methods: Enrolled patients who underwent arthroscopic partial meniscectomy at a single center were randomized to either the intervention or control group prior to surgery. The intervention group received a card with access to an online educational video regarding opioids with their postoperative instructions; the control group did not. The online video was just over 5 minutes long and contained general information about the dangers of opioid use, how to safely dispose of unused opioids, and local support contact information. Data were collected by telephone 10 to 14 days postoperatively and analyzed with GraphPad Prism version 9.5.0. Patient characteristics including age, sex, body mass index, allergies, smoking, depression, alcohol abuse, American Society of Anesthesiologists level, diagnosis of chronic obstructive pulmonary disease, hypertension, diabetes, substance abuse, employment status, workers' compensation, and sports participation were analyzed and correlated with postoperative opioid use. Results: A total of 166 patients were included in this study, with 78 in the control group and 88 in the intervention group. Mean number of pills consumed was 3 in the control group and 2.2 in the intervention group. This difference did not reach statistical significance. Patients who were obese, smokers, or diagnosed with depression both consumed more opioids and were less likely to take no narcotics postoperatively. Patients who participated in sports consumed fewer total opioids on average than those who did not. Subgroup analysis of patients with higher risk factors did not show a difference between the control and intervention groups in the average amount of opioid used or the likelihood of using no narcotics. Among all patients, 82 (49%) used no narcotics postoperatively and 90% used 8 or fewer tablets. Conclusions: Directing patients to an educational website and video is not an effective tool in decreasing opioid consumption. Patients undergoing arthroscopic meniscectomy who are obese, active smokers, and clinically depressed or do not participate in sports are likely to use more postoperative narcotics. Regardless of access to the online educational video, half of patients used no narcotics. Level of Evidence: Level II, prospective cohort.

A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.

ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Risk of Fractures and Falls in Men with Advanced or Metastatic Prostate Cancer Receiving Androgen Deprivation Therapy and Treated with Novel Androgen Receptor Signalling Inhibitors: A Systematic Review and Meta-analysis of Randomised Controlled Trials.

CONTEXT: The addition of androgen receptor signalling inhibitors (ARSIs) to standard androgen deprivation therapy (ADT) has improved survival outcomes in patients with advanced prostate cancer (PCa). Advanced PCa patients have a higher incidence of osteoporosis, compounded by rapid bone density loss upon commencement of ADT resulting in an increased fracture risk. The effect of treatment intensification with ARSIs on fall and fracture risk is unclear. OBJECTIVE: To assess the risk of falls and fractures in men with PCa treated with ARSIs. EVIDENCE ACQUISITION: A systematic review of EMBASE, MEDLINE, The Cochrane Library, and The Health Technology Assessment Database for randomised control trials between 1990 and June 2023 was conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-analyses guidance. Risk ratios were estimated for the incidence of fracture and fall events. Subgroup analyses by grade of event and disease state were conducted. EVIDENCE SYNTHESIS: Twenty-three studies were eligible for inclusion. Fracture outcomes were reported in 17 studies (N = 18 811) and fall outcomes in 16 studies (N = 16 537). A pooled analysis demonstrated that ARSIs increased the risk of fractures (relative risk [RR] 2.32, 95% confidence interval [CI] 2.00-2.71; p < 0.01) and falls (RR 2.22, 95% CI 1.81-2.72; p < 0.01) compared with control. A subgroup analysis demonstrated an increased risk of both fractures (RR 2.13, 95% CI 1.70-2.67; p < 0.01) and falls (RR 2.19, 95% CI 1.53-3.12; p < 0.0001) in metastatic hormone-sensitive PCa patients, and an increased risk of fractures in the nonmetastatic (RR 2.27, 95% CI 1.60-3.20; p < 0.00001) and metastatic castrate-resistant (RR 2.85, 95% CI 2.16-3.76; p < 0.00001) settings. The key limitations include an inability to distinguish fragility from pathological fractures and potential for a competing risk bias. CONCLUSIONS: Addition of an ARSI to standard ADT significantly increases the risk of fractures and falls in men with prostate cancer. PATIENT SUMMARY: We found a significantly increased risk of both fractures and falls with a combination of novel androgen signalling inhibitors and traditional forms of hormone therapy.

Cervical Disc Arthroplasty: Rationale, Designs, and Results of Randomized Controlled Trials.

BACKGROUND: This review outlines clinical data and characteristics of current Food and Drug Administration (FDA)-approved implants in cervical disc replacement/cervical disc arthroplasty (CDR/CDA) to provide a centralized resource for spine surgeons. METHODS: Randomized controlled trials (RCTs) on CDR/CDA were identified using a search of the PubMed, Web of Science, and Google Scholar databases. The initial search identified 69 studies. Duplicates were removed, and the following inclusion criteria were applied when determining eligibility of RCTs for the current review: (1) discussing CDR/CDA prosthesis and (2) published within between 2010 and 2020. Studies without clinical data or that were not RCTs were excluded. All articles were reviewed independently by 2 authors, with the involvement of an arbitrator to facilitate consensus on any discrepancies. RESULTS: A total of 34 studies were included in the final review. Findings were synthesized into a comprehensive table describing key features and clinical results for each FDA-approved CDR/CDA implant and are overall suggestive of expanding indications and increasing utilization. CONCLUSIONS: RCTs have provided substantial evidence to support CDR/CDA for treating single- and 2-level cervical degenerative disc disease in place of conventional anterior cervical discectomy and fusion. CLINICAL RELEVANCE: This review provides a resource that consolidates relevant clinical data for current FDA-approved implants to help spine surgeons make an informed decision during preoperative planning.