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Objective: The goal of this study was to partner with community organizations to understand the research experiences of communities who speak languages other than English (LOE). Methods: We conducted semi-structured qualitative interviews in Spanish, Nepali, Mandarin, French, or Kizigua with LOE community members and community leaders who completed recruitment and data collection. Audio-recordings of the interviews were transcribed and translated. We conducted qualitative coding using a mixed deductive-inductive analysis approach and thematic analyses using three rounds of affinity clustering. This study occurred in partnership with an established community-academic collaboration. Results: Thirty community members and six community leaders were interviewed. 83% of LOE participants were born outside of the US and most participants (63%) had never participated in a prior research study. Six themes emerged from this work. Many participants did not understand the concept of research, but those that did thought that inclusion of LOE communities is critical for equity. Even when research was understood as a concept, it was often inaccessible to LOE individuals, particularly because of the lack of language services. When LOE participants engaged in research, they did not always understand their participation. Participants thought that improving research trust was essential and recommended partnering with community organizations and disseminating research results to the community. Conclusion: This study's results can serve as an important foundation for researchers seeking to include LOE communities in future research to be more inclusive and scientifically rigorous. [ABSTRACT FROM AUTHOR]

This study aims to optimize the utilization of whey, a significant dairy by-product from paneer production, in whey-based yogurt preparation. The primary goal is to identify the optimal ratio of skim milk powder and stabilizer (pectin) to minimize syneresis, a critical quality parameter, while preserving sensory attributes. Six formulations varying in skim milk powder (5-8%) and pectin (0-1%) were meticulously crafted and underwent sensory analysis alongside a control yogurt. The findings reveal that the inclusion of skim milk powder markedly influences syneresis reduction, showcasing a quadratic relationship. By employing response surface methodology and sensory evaluation, an optimal formulation comprising 8% skim milk powder and 0.06% stabilizer emerged, boasting superior sensory properties and mitigated syneresis. Furthermore, the study meticulously analyzed the composition of the optimized formulation, unveiling specific content percentages for total solid, pH, acidity, protein, fat, total ash, and lactose. Additionally, the research assessed the storage stability of the optimized product over a 10-day refrigerated period, tracking alterations in pH, acidity, and syneresis. Results indicated a gradual decline in pH coupled with an increase in acidity and syneresis, highlighting the importance of monitoring product attributes during storage. This investigation contributes valuable insights into maximizing whey utilization in yogurt production, ensuring both product quality and stability. The optimized formulation not only minimizes syneresis but also maintains sensory excellence, offering a promising avenue for the valorization of dairy by-products and enhancing sustainability within the dairy industry. [ABSTRACT FROM AUTHOR]

In this community-partnered study we conducted focus groups with non-English speaking immigrant and refugee communities of color in 4 languages to understand their perspectives on COVID-19 vaccines, barriers to accessing vaccines, and recommendations for healthcare providers. We used a mixed deductive-inductive thematic analysis approach and human centered design to guide data analysis. 66 individuals participated; 85% were vaccinated. The vaccination experience was often positive; however, participants described language inaccessibility, often relying on family members for interpretation. Community-based organizations played a role in connecting participants to vaccines. Unvaccinated participants expressed fear of side effects and belief in natural immunity. Participants shared recommendations to providers around increasing vaccine access, improving language accessibility, and building trust. Results from our study show numerous barriers immigrant and refugee communities of color faced getting their COVID-19 vaccine, but also highlights opportunities to engage with community partners. Future implications for research, policy, and practice are described. [ABSTRACT FROM AUTHOR]

Background: Brain metabolism is critical for the pathological mechanism of neurodegeneration. However, most metabolite quantitative trait loci (MQTL) studies have used tissues other than brain or cerebrospinal fluid (CSF) and are not ideal for neurodegeneration. We therefore pursued a large‐scale brain and CSF study to identify metabolites contributing to 27 brain‐related diseases. Method: We obtained 440 metabolites in 2311 CSF samples and 962 metabolites in 1016 brain samples (WashU, ROSMAP, MAYO). We identified MQTL and performed metabolome‐wide association study (MWAS) to identify metabolites affecting diseases. Mendelian randomization (MR) and colocalization was performed for causality and shared genetic regulations. Result: We identified 192 associations for 144 CSFmetabolites at 102 loci. Of those, 122 associations and 24 loci were novel, indicating tissue specificity. The brain study found 35 associations at 27 loci. Through MWAS, we identified 57 metabolites associated with 17 traits, in which 21 colocalized. Of the eight metabolites associated with AD, succinylcarnitine and adenine were causal. Succinylcarnitine was associated with AD risk gene LACTB, which product regulates lipid metabolism in mitochondrial, where succinylcarnitine generates energy. Both succinylcarnitine and LACTB have been implicated in obesity, a risk factor for AD. For Parkinson disease (PD), low galactosylglycerol level was causal, with signal colocalized at GALC with PD. The knockout of GALC gene prevented alpha‐synuclein accumulation in PD mice model, indicating that galactosylceramidase contributed to the development of PD. For cognitive performance, high levels of three metabolites (6‐oxopiperidine‐2‐carboxylate, 3‐hydroxyisobutyrate and argininosuccinate) were causal for low cognition, with additional support from colocalization and literature evidences. Pyridoxine‐dependent epilepsy patients, often with impaired cognition, had increased level of 6‐oxopiperidine‐2‐carboxylate. AD patients who underwent medium chain triglycerides treatment and improved cognition had changed level of beta‐hydroxybutyrate, related to 3‐hydroxyisobutyrate. Moreover, argininosuccinate lyase deficiency patients often develop severe cognitive impairment and seizures. Conclusion: Our large‐scale CSF and brain MQTL study identified tissue‐specific MQTLs and multiple metabolites contributing to neurodegenerative disorders. Our results expand the knowledge on neurodegeneration, providing insights to neurodegeneration etiology, including AD, PD, and cognitive function. [ABSTRACT FROM AUTHOR]

Background: Leucine‐rich repeat kinase 2 (LRRK2) common gene variants (tagged by rs76904798) are associated with Parkinson's disease (PD) risk. In a previous study, we found that rs76904798 was associated with CSF GRN levels, but a comprehensive unbiased analysis of associated proteins remains incomplete due to prior focus on cis‐protein quantitative trait loci (pQTL). Using the largest aptamer‐based CSF proteomics study to date (7,006 aptamers (6,138 unique proteins) in 3,107 individuals), we performed a trans‐pQTL study to identify proteins associated with the LRRK2 variants and used additional mediation and pathway analyses to better understand downstream effects (Figure 1). Method: SNP selection using Conditional and Joint Association Analysis (GTCA‐COJO) and PLINK LD r2 scores identified 11 other independently associated SNPs. Fine mapping was performed between each significant aptamer and PD GWAS via proteome‐wide association studies (PWAS) and Mendelian randomization (MR). These aptamers were further analyzed based on PD risk association, brain cell‐type specificity, and gene pathway annotations. Result: Overall, 26 proteins passed FDR correction and eleven were implicated in PD prior like GRN and GPNMB. PWAS analyses using TWAS/FUSION also indicate 12 proteins were significant and positively associated with PD risk, such as novel proteins C1QTNF1 and SDCBP2, and half were validated by the PPMI data. MR analyses indicate that GRN, GPNMB, HLA‐DQA2, CD68, and LCT are also causal for PD risk (Table 1). Cell‐type enrichment analyses indicate microglia‐specific protein enrichment (Fold change: 7.35, P = 4.91×10−5). Enrichment analyses indicate enrichment for leukocyte activation (GO:0045321, P = 0.002) and microglial cell activation (GO:0001774, P = 0.003) pathways. Conclusion: Trans‐pQTL can identify novel protein interactions in an unbiased manner. This study linked LRRK2 variants with both PD implicated (GRN, GPNMB) and novel (ITGB2, C1QTNF1) proteins that have support in our PWAS, MR, and PPMI differential protein level analyses. Microglia and lysosome enrichment support the previous observations regarding the importance of microglia and immune system function in the underlying pathobiology of PD (Figure 2). Our results suggest that the CSF concentrations of these proteins (such as GRN, GPNMB, C1QTNF1, and ITGB2) have potential as biomarkers for target engagement and disease progression modification in clinical trials that target LRRK2. [ABSTRACT FROM AUTHOR]

Weight recurrence (WR) after bariatric surgery occurs in nearly 20% of patients. Revisional bariatric surgery (RBS) may benefit this population but remains controversial among surgeons. Explore surgeon perspectives and practices for patients with WR after primary bariatric surgery (PBS). Web-based survey of bariatric surgeons. A 21-item survey was piloted and posted on social media closed groups (Facebook) utilized by bariatric surgeons. Survey items included demographic information, questions pertaining to the definition of suboptimal and satisfactory response to bariatric surgery, and general questions related to different WR management options. One hundred ten surgeons from 19 countries responded to the survey. Ninety-eight percent responded that WR was multifactorial, including behavioral and biological factors. Failure of PBS was defined as excess weight loss < 50% by 31.4%, as excess weight loss <25% by 12.8%, and as comorbidity recurrence by 17.4%. Surgeon responses differed significantly by gender (P =.036). 29.4% believed RBS was not successful, while 14.1% were unsure. Nevertheless, 73% reported that they would perform RBS if sufficient evidence of benefit existed. Most frequently performed revisional procedures included conversion of sleeve gastrectomy to Roux-en-Y gastric bypass (RYGB), adjustable gastric band to RYGB, and RYGB revision (21.9% versus 18.2% versus 15.3%, respectively). This survey demonstrates significant variability in surgeon perception regarding causes and the effectiveness of RBS. Moreover, they disagree on what constitutes a nonsatisfactory response to PBS and to whom they offer RBS. These findings may relate to limited available clinical evidence on best management options for this patient population. Clinical trials investigating the comparative effectiveness of various treatment options are needed. • Ninety-eight percent of surgeons suggested that WR is multifactorial. • Conversion of sleeve gastrectomy to RYGB was the most common RBS (22%). • Failure of PBS was defined as EWL<50% by 31%. • The definition of failure of PBS differed significantly by surgeon gender. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of prolonged length of stay (LOS) after esophagectomy on long term survival. Background: Complications after esophagectomy have a significant impact in short-term survival. The specific effect of prolonged LOS after esophagectomy is unclear. We hypothesized that postoperative complications that occur after esophagectomy, resulting in prolonged LOS, have a detrimental effect on long term survival. Methods: All patients undergoing esophagectomy between 2004 and 2014 were identified in the National Cancer Database. To eliminate the confounding effect of short-term mortality, we included only patients who survived at least 90 days postoperatively. Demographics, disease characteristics, and perioperative outcomes were analyzed. Postoperative LOS was used as a surrogate for postoperative complications. The highest quintile of LOS was defined as excessive LOS (ELOS). Kaplan-Meier and Cox proportional hazards survival analyses were performed to examine survival. Results: A total of 20,719 patients were identified. Of those 3826 had ELOS, with median LOS 26days (range 18-168days). Their median survival was 30.6 months compared to 53.6 months in the entire non-ELOS group (P < 0.0001). After multivariate analysis ELOS (odds ratio 1.56, 95% confidence interval 1.46–1.67) was an independent predictor of overall mortality. Higher disease stage, higher age, male sex, higher Charlson/Deyo comorbidity score, and readmission after discharge were also significant negative predictors of long-term survival, whereas surgery in an academic institution, being at the highest income quartile and having private or Medicare insurance predicted longer survival (all P < 0.001). Conclusions and Relevance: Postoperative complications after esophagectomy, resulting in ELOS, predict lower long-term survival independent of other factors. Counseling patients about surgery should include the detrimental long-term effects of postoperative complications and ELOS. Avoiding ELOS (LOS exceeding 18 days) could be considered a quality metric after esophagectomy. [ABSTRACT FROM AUTHOR]

Objective: To demonstrate the feasibility of implementing a CBE curriculum within a general surgery residency program and to evaluate its effectiveness in improving resident skill. Summary of Background Data: Operative skill variability affects residents and practicing surgeons and directly impacts patient outcomes. CBE can decrease this variability by ensuring uniform skill acquisition. We implemented a CBE LC curriculum to improve resident performance and decrease skill variability. Methods: PGY-2 residents completed the curriculum during monthly rotations starting in July 2017. Once simulator proficiency was reached, residents performed elective LCs with a select group of faculty at 3 hospitals. Performance at curriculum completion was assessed using LC simulation metrics and intraoperative operative performance rating system scores and compared to both baseline and historical controls, comprised of rising PGY-3s, using a 2-sample Wilcoxon rank-sum test. PGY-2 group's performance variability was compared with PGY-3s using Levene robust test of equality of variances; P < 0.05 was considered significant. Results: Twenty-one residents each performed 17.52 ± 4.15 consecutive LCs during the monthly rotation. Resident simulated and operative performance increased significantly with dedicated training and reached that of more experienced rising PGY-3s (n = 7) but with significantly decreased variability in performance (P = 0.04). Conclusions: Completion of a CBE rotation led to significant improvements in PGY-2 residents' LC performance that reached that of PGY-3s and decreased performance variability. These results support wider implementation of CBE in resident training. [ABSTRACT FROM AUTHOR]

Objective: To determine if distinct financial trajectories exist and if they are associated with quality-of-life outcomes. Summary of Background Data: Financial hardship after injury measurably impacts Health-Related Quality of Life outcomes. Financial hardship, encompassing material losses, financial worry, and poor coping mechanisms, is associated with lower quality of life and increased psychological distress. However, recovery is dynamic and financial hardship may change over time. Methods: This is a secondary analysis of a cohort of 500 moderate-to-severe nonneurologic injured patients in which financial hardship and Health-related Quality of Life outcomes were measured at 1, 2, 4, and 12 months after injury using survey instruments (Short Form-36). Enrollment occurred at an urban, academic, Level 1 trauma center in Memphis, Tennessee during January 2009 to December 2011 and follow-up completed by December 2012. Results: Four hundred seventy-four patients had sufficient data for Group- Based Trajectory Analysis. Four distinct financial hardship trajectories were identified: Financially Secure patients (8.6%) had consistently low hardship over time; Financially Devastated patients had a high degree of hardship immediately after injury and never recovered (51.6%); Financially Frail patients had increasing hardship over time (33.6%); and Financially Resilient patients started with a high degree of hardship but recovered by year end (6.2%). At 12-months, all trajectories had poor Short Form-36 physical component scores and the Financial Frail and Financially Devastated trajectories had poor mental health scores compared to US population norms. Conclusions and Relevance: The Financially Resilient trajectory demonstrates financial hardship after injury can be overcome. Further research into understanding why and how this occurs is needed. [ABSTRACT FROM AUTHOR]

Women in Thoracic Surgery (WTS) has previously reported on the status of women in cardiothoracic (CT) surgery. We sought to provide a 10-year update on women in CT surgery. An anonymous research electronic data capture survey link was emailed to female diplomats of the American Board of Thoracic Surgery. Survey questions queried respondents regarding demographics, training, accolades, practice details, and career satisfaction. The survey link was open for 30 days. Results were compared with The Society of Thoracic Surgeons 2019 workforce survey. Descriptive analyses were performed using frequency and proportions. Comparisons were performed using Student's t tests, Fisher's exact tests, and χ2 tests. Of 354 female diplomats, 309 were contacted and 176 (57%) responded. The majority of respondents were aged 36 to 50 years (59%), white (67.4%), and had graduated from traditional-track programs (91.4%). Most respondents reported practicing in an urban (64%) and academic setting (73.1%). 36.4% and 23.9% reported a general thoracic and adult cardiac practice (22.7% mixed practice, 9.6% congenital). Fifty percent of respondents reported salaries between $400,000 and $700,000 annually; 37.7% reported salaries less than 90% of their male colleagues; 21.6% of respondents in academia are full professor; 53.4% reported having a leadership role. Whereas 74.1% would pursue a career in CT surgery again, only 27.3% agreed that CT surgery is a healthy and positive environment for women. The number of women in CT surgery has steadily increased. Although women are rising in academic rank and into leadership positions, salary disparities and the CT surgery work environment remain important issues in achieving a diverse work force. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: The American College of Surgeons (ACS) conducts a robust quality improvement program for ACS-verified trauma centers, yet many injured patients receive care at non-accredited facilities. This study tested for variation in outcomes across non-trauma hospitals and characterized hospitals associated with increased mortality. Summary Background Data: The study included state trauma registry data of 37,670 patients treated between January 1, 2013, and December 31, 2015. Clinical data were supplemented with data from the American Hospital Association and US Department of Agriculture, allowing comparisons among 100 nontrauma hospitals. Methods: Using Bayesian techniques, risk-adjusted and reliability-adjusted rates of mortality and interfacility transfer, as well as Emergency Departments length-of-stay (ED-LOS) among patients transferred from EDs were calculated for each hospital. Subgroup analyses were performed for patients ages >55 years and those with decreased Glasgow coma scores (GCS). Multiple imputation was used to address missing data. Results: Mortality varied 3-fold (0.9%–3.1%); interfacility transfer rates varied 46-fold (2.1%–95.6%); and mean ED-LOS varied 3-fold (81–231 minutes). Hospitals that were high and low statistical outliers were identified for each outcome, and subgroup analyses demonstrated comparable hospital variation. Metropolitan hospitals were associated increased mortality [odds ratio (OR) 1.7, P = 0.004], decreased likelihood of interfacility transfer (OR 0.7, P ≤ 0.001), and increased ED-LOS (coef. 0.1, P ≤ 0.001) when compared with nonmetropolitan hospitals and risk-adjusted. Conclusions: Wide variation in trauma outcomes exists across nontrauma hospitals. Efforts to improve trauma quality should include engagement of nontrauma hospitals to reduce variation in outcomes of injured patients treated at those facilities. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: We hypothesized that failure to achieve protein goals early in the critical care course via enteral nutrition is associated with increased complications. Background: Although robust randomized controlled trials are lacking, present data suggest that early, adequate nutrition is associated with improved outcomes in critically ill patients. Injured patients are at risk of accumulating significant protein debt due to interrupted feedings and intolerance. Methods: Critically injured adults who were unable to be volitionally fed were included in this retrospective review. Data collected included demographics, injury characteristics, number and types of operations, total prescribed and delivered protein and calories during the first 7 days of critical care admission, complications, and outcomes. Group-based trajectory modeling was applied to identify subgroups with similar feeding trajectories in the cohort. Results: There were 274 patients included (71.2% male). Mean age was 50.56  ± 19.76 years. Group-based trajectory modeling revealed 5 Groups with varying trajectories of protein goal achievement. Group 5 fails to achieve protein goals, includes more patients with digestive tract injuries (33%, P = 0.0002), and the highest mean number of complications (1.52, P = 0.0086). Group 2, who achieves protein goals within 4 days, has the lowest mean number of complications (0.62, P = 0.0086) and operations (0.74, P = 0.001). Conclusions: There is heterogeneity in the trajectory of protein goal achievement among various injury pattern Groups. There is a sharp decline in complication rates when protein goals are reached within 4 days of critical care admission, calling into question the application of current guidelines to healthy trauma patients to tolerate up to 7 days of nil per os status and further reinforcing recommendations for early enteral nutrition when feasible. [ABSTRACT FROM AUTHOR]

Background: Sex and age are major risk factors for several chronic diseases. Recent human and mouse studies of age‐related molecular changes in blood provided new insights into age‐related disease biology. Cerebrospinal fluid (CSF) is more closely related to brain than blood and can provide additional insights to sex and age‐related brain diseases. Method: We measured over 7000 proteins in CSF from 998 healthy individuals representing middle and old age (43‐91) across four multiple cohorts. After stringent QC, we performed weighted gene co‐expression network analysis (WGCNA) to group CSF proteins with similar sex and age trajectories. Each cluster was then tested for aging and sex differences. Cell‐type enrichment and disease ontology enrichment was also performed. Result: Co‐expression network analysis identified 24 modules for CSF 4926 proteins. Sex difference was detected for 2949 proteins (1730 were higher in females; 1219 were higher in males). Aging signature was detected for 4480 proteins (2999 increasing; 1481 decreasing with age). The pink module (containing SERPINA3, TREML2, and additional 197 proteins) had proteins higher in males and increasing with ages and were enriched in endothelial cell (P = 0.04). Cardiovascular diseases (FDR = 2.6E‐9), ischemic stroke (FDR = 1.7E‐7) and Alzheimer's disease (AD) (FDR = 7.3E‐3) were significantly enriched in this module. The blue module (containing APOE, APP and additional 681 proteins) had proteins higher in females and decreasing with ages, were enriched in microglia and macrophage (P = 0.01). AD (FDR = 0.043) and vascular dementia (FDR = 0.025) were enriched. The yellow module (containing SMPD1, GNS, CTSB and additional 331 proteins) had proteins higher in females and non‐linear aging trajectory (increasing until 70 years old and decreasing) were enriched in neurons (P = 4.6E‐9). Lysosomal storage diseases (FDR = 3.4E‐03) showed enrichment for them. Among the 46 plasma proteins showing conserved aging signature in mice and humans (Lehallier et al 2019), 20 proteins including TNFSF15 and PPBP were also conserved in CSF. In addition, nine of them show the sex‐specific signature conserved across all three datasets. Conclusion: Our study in CSF proteomic signatures identified clusters of proteins in distinct patterns and their relation to Alzheimer's disease and other neurodegeneration. More detailed characterization of proteomic signatures for other age‐related chronic diseases is underway. [ABSTRACT FROM AUTHOR]

Background: Sporadic Alzheimer's disease (AD) is a highly heterogeneous multifactorial disease in which females have a higher risk. Among 5.3 million senior Americans diagnosed with AD, over 60% are female. Despite the well‐established sex differences, sex‐specific molecular findings in AD are still limited. We therefore examined the role of sex in the proteomic alterations due to AD to elucidate potential protein markers of AD heterogeneity. Method: In the discovery cohort, 599 preclinical AD and 435 controls underwent lumbar puncture. Over 7,000 proteins in cerebrospinal fluid (CSF) were measured using SomaLogic assay. Amyloid/tau positivity (AT classification) was determined using ELISA Aβ42 and pTau181 levels in CSF. Proteins with sex‐specific effects were identified through linear models focusing on the interaction term between AT classification and sex. Results were tested in the independent cohort (N = 732) using the identical approaches. We analyzed brain proteomics and transcriptomics data to validate the replicated sex‐specific proteins. We performed pathway enrichment, interaction network using ConsensusPathDB and drug‐target prediction. Result: We identified 594 proteins with sex‐specific effects in discovery (P<0.05 and permutation FDR <0.05). Among them, 36 were validated in replication (P<0.05 and consistent direction). These proteins were found to be involved in neurologic disorders and highly enriched in axon regeneration (fold enrichment = 9.38 and FDR = 2.8×10−4). Among the 36 proteins identified, 13 were classified as female‐specific and 23 as male‐specific. These 36 proteins strongly predicted amyloid/tau positivity (AUC = 0.926) for all individuals as well as 13 female‐specific proteins for females (AUC = 0.929). The interaction network identified CCN2 as a hub and contained 10 additional proteins including JAG1 and DLL4 of Notch signaling pathway and CTSB, an amyloid precursor protein secretase, among others. The results of 36 proteins in brain proteomics and transcriptomics confirmed the sex‐specific effect of CCN2 and others on AD in different tissues. Drug target prediction suggests minocycline and etoposide as potential treatments for females as well amitriptyline and verteporfin for males. Conclusion: We robustly identified 36 proteins that showed significant sex‐specific alterations by preclinical AD. Several proteins involved in AD and neurodegeneration were highlighted. Our findings facilitate mechanistic understanding of sex differences for AD risk and progression. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD), the most common form of dementia, is characterized by the accumulation of Amyloid‐β (Aβ42) and hyperphosphorylated Tau 181 (p‐tau181) proteins in the brain. Changes in these proteins in AD brains and cerebrospinal fluid (CSF) are detected years before AD symptoms. Studying AD proteome in CSF can reflect its diverse underlying pathophysiology and pave the way for reliable diagnostic and therapeutic advancements. Method: We present one of the largest CSF AD proteomic profiles (7,029 protein analytes) in CSF of 3,065 individuals in three stages. Discovery was performed in 836 samples from the Knight ADRC and 618 samples from the FACE cohorts using the ATN framework (AT‐ = 680 and AT+ = 490). The identified proteins were tested in 832 individuals (AT‐ = 235 and AT+ = 358) from the ADNI and Barcelona‐1 cohorts. The proteins that passed multiple Bonferroni corrections on the meta‐analysis were utilized for AD prediction models and pathway enrichment analysis to gain mechanistic insights into AD pathophysiology. Result: In discovery, we identified 3,565 proteins to be significantly (FDR < 0.05) altered. Of these, 2,543 passed FDR in replication with a consistent direction. In the meta‐analysis, we identified 2,233 proteins to be significantly (P‐Bonferroni < 0.05) altered in the AD CSF proteome. Some of the highly significant proteins included YWHAG (P‐Bonf < 4.5×10−219), SMOC1 (P‐Bonf < 5.8×10−208), NRGN (P‐Bonf < 3.2×10−119), and NEFL (P‐Bonf < 1.8×10−37). By using lasso, we identified a set of 39 proteins with high predictive power (Discovery AUC = 1.0; Replication AUC = 0.99) representing a robust and precise AD diagnostic biomarker. Enrichment analysis highlighted several neurological disorders (e.g. AD, tauopathy, and synucleinopathy) and neuronal functions (neuron projection morphogenesis, synapse assembly and organization, and neuron differentiation) as significantly enriched in the altered AD CSF proteome. Conclusion: Our findings show the promising potential of AD CSF proteomics as a reliable and robust AD prediction model. We identified proteins and biological pathways that are compromised in AD, thereby, increasing our understanding of AD biology. Our findings may accelerate the development of effective intervention therapies that target the earliest molecular triggers of AD. [ABSTRACT FROM AUTHOR]

Background: Both sporadic and dominantly inherited Alzheimer's disease (DIAD) present with similar pathobiology and symptoms. A loss of proteostasis in AD has been identified with recent studies highlighting the role of ubiquitin‐dependent mechanisms in brain homeostasis and neurodegenerative diseases. The Ubiquitin Proteasome System (UPS) is responsible for the degradation of misfolded or aggregated proteins via an ATP‐dependent proteolytic mechanism. This process involves a cascade of ubiquitin transfer steps from E1 to E2 to E3 ligase. However, the role of the UPS in AD progression and symptom onset remains unknown. Method: In this cross‐sectional study we aimed to examine changes in cerebral spinal fluid (CSF) levels of UPS proteins in individuals with DIAD enrolled in the Dominantly Inherited Alzheimer Network. Sample size included 176 asymptomatic mutation carriers (MC) (Clinical Dementia Rating® [CDR®] = 0), 103 symptomatic mutation carriers [CDR®>0] and 172 non‐carriers (NC). CSF levels of UPS proteins were measured using the SOMAscan high‐throughput proteomics assay. AD biomarkers (Aβ42, Aβ40, Tau, phospho‐Tau181, phospho‐Tau205, phospho‐Tu217, and Aβ‐ PET), imaging measures of neurodegeneration (MRI, FDG PET) and clinical data (estimated years from symptom onset (EYO), CDR® score, age, sex, ApoE status) were assessed. Result: The ubiquitin‐fold modifier‐conjugating enzyme1, ubiquitin‐conjugating enzyme E2 K, E2 N, E3 ubiquitin‐protein ligase SMURF1, and small ubiquitin‐related protein modifier 2 and 3 levels were increased in MCs up to 10‐5 years before EYO, Figure 1, with highest levels found in symptomatic MCs. E3 ubiquitin‐protein ligase SMURF1 levels began increasing up to 10‐15 years before symptoms onset. Proteasome subunit beta type‐3 (PSMB3), 4 (PSMB4) and 9 (PSMB9) showed a similar pattern as ubiquitin ligase which significantly increased in symptomatic mutation carrier group. All the above ubiquitin enzymes positively correlated with Aβ‐ PET, CSF phospho‐Tau181, phospho‐Tau205, phospho‐Tau217 and negatively correlated with FDG PET, Figure 2. Conclusion: Our study revealed E1, E2, E3 ligase, ubiquitin‐related modifiers (SUMOs), and proteasome components were involved in DIAD pathophysiology and correlated with AD biomarkers with some increasing over 10 years before symptom onset. Further investigation of the role of UPS will be needed to explore the molecular mechanism in the progression of DIAD. [ABSTRACT FROM AUTHOR]

Background: Quantitative trait loci (QTL) are successful at identifying the functional gene for many loci identified through GWAS. While expression QTL (eQTL) studies robustly examine tissue‐specificity, most protein QTL (pQTL) studies have been limited to plasma. We have previously demonstrated that pQTL associations are highly tissue‐specific. Given the relevance of cerebrospinal fluid (CSF) to Alzheimer's disease (AD) and other forms of neurodegeneration, we developed a CSF‐specific pQTL atlas and integrated it with AD GWAS to identify novel causal proteins for AD. Method: We generated CSF proteomics (Somalogic, 7,584 analytes) data for 3,107 individuals. pQTL mapping was performed using a three‐stage approach: discovery, replication, and meta‐analysis. We analyzed the tissue‐ and molecule‐specificity of our associations by comparing to plasma & brain pQTLs and various eQTLs. We performed a proteome‐wide association study (PWAS) and Mendelian randomization (MR) to prioritize proteins affecting AD. We determined shared protein‐disease genetic regulation using colocalization. Using AD‐associated proteins, we built risk models of disease status. Result: We identified 2,316 significant pQTL (1,247 in cis and 1,069 in trans) for 1,960 proteins, of which 1,720 were novel and not reported in the largest currently available pQTL studies in plasma or brain. Through PWAS, we identified 440 proteins associated with AD risk, which show enrichment in neurons (with APOE region) or microglia/macrophages (without APOE). MR prioritized 37 proteins as causal and colocalization identified 153 proteins that share genetic etiology with AD. Seventeen of these proteins overlap between all three methods and multiple (including PILRA, PRSS8, and SIRPA) represent novel causal proteins for AD. A protein risk score using PWAS‐identified proteins outperformed a polygenic risk score (PRS) at predicting amyloid/tau positivity across ages (AUC: 0.852‐0.906 vs. 0.724‐0.806, P<0.002) and across APOE genotypes (AUC: 0.809‐0.893 vs. 0.70‐0.80, P<0.027). Conclusion: We reported the largest CSF pQTL analysis to date and confirmed that CSF pQTLs are largely tissue‐specific. We identified proteins involved in AD that confirm reported candidate genes and prioritize new ones at GWAS loci. We developed accurate prediction models using prioritized proteins. Our findings offer insights into AD biology undetected with plasma pQTL analyses, supporting proteogenomic databases in neurologically‐relevant tissues. [ABSTRACT FROM AUTHOR]

Background: Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer's disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). Here, we pursued the largest CSF study to identify additional novel genetic modifiers of sTREM2. Method: We performed the genome‐wide association study (GWAS) of CSF sTREM2 in 3350 individuals of European ancestry from eight cohorts. To identify functional genes, we performed multi‐ethnic fine mapping with 250 non‐European individuals. Functional validation using peripheral blood mononuclear cell‐derived macrophages was performed. Colocalization and Mendelian randomization (MR) was performed for the causality of sTREM2 in AD. Result: The known MS4A locus and three novel loci were identified at genome‐wide significance. In the MS4A locus, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drove the association through multi‐ethnic fine mapping. They showed an epistatic effect for sTREM2 and AD risk. The novel TREM2 locus on chromosome 6 contained two rare missense variants (rs142232675 p.D87N, P = 2.71×10‐10; rs75932628 p.R47H, P = 7.16×10‐19) associated with sTREM2 and AD risk. Another novel locus in the intergenic region between TGFBR2 and RBMS3 (rs73823326, P = 3.86×10‐9) included a regulatory variant with a microglia‐specific chromatin loop for promoters of TGFBR2. Using cell‐ based assays we demonstrate that TGFBR2, but not RBMS3, modify sTREM2 levels. The last novel locus NECTIN2 on chromosome 19 (rs11666329, P = 2.52×10‐8) was independent of APOE genotype and colocalized with cis‐eQTL of NECTIN2 in the brain cortex and cis‐pQTL of NECTIN2 in CSF (PP.H4 = 0.83). This variant was also associated with AD risk (P = 1.52×10‐66) and age at onset (P = 3.26×10‐5). Our MR results confirmed the significant protective effect of sTREM2 on reducing AD risk. Conclusion: To our knowledge, this is the largest study to date aiming at identifying genetic modifiers of CSF sTREM2. We provided novel insights for MS4A and TREM2, the two well‐ known gens for AD risk. We also identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology. Our findings provide new insight to unravel sTREM2 modulators and their role in AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer disease (AD) has different prevalence across different ancestries. However, the genetic factors underlying AD pathogenesis between diverse populations are largely unknown. The recent AD genome‐wide association study (GWAS) (Bellenguez et al 2022) reported 75 significant genetic loci in European ancestry, while the latest African‐based AD GWAS (Kunkle et al 2021) only reported two loci. It will be important to map these genetic loci into the functional molecular traits, e.g. RNA expression, protein abundance, metabolite levels. Multiple studies integrated such molecular traits with AD risk and termed them as TWAS, PWAS, and MWAS. However, few studies reported more than one molecular trait and in multiple ancestries. Method: We first identified the plasma proteomic (SomaScan 7K) and metabolomic (Metabolon HD4) QTLs (quantitative trait loci) from participants with African (AFR, N = 400) and European (EUR, N = 2,300) ancestry, respectively. We next associated the genetic variants with the AD risk GWAS (EUR‐Bellenguez‐2022 & AFR‐Kunkle‐2021) using the protein or metabolite as the intermediate molecular trait. We extended the TWAS framework to test the disease association with the genetically predicted levels of proteins (PWAS) and metabolites (MWAS). Result: We identified over 3,000 pQTLs and 400 mQTLs. Out of these findings, approximately 40% were novel QTLs compared to the previous studies. We found ancestry‐specific proteins and metabolites associated with AD risk. For example, proteins BIN1, TREM2, APOE, were only significant in EUR‐PWAS results but not AFR‐PWAS using the ancestry‐matched disease associations. Conversely, Spondin‐1 and RNF24 were only nominally significant in AFR‐PWAS. Similarly, metabolites glucuronide and sphingosine were only significant in EUR‐MWAS, whereas ethylmalonate was only nominally significant in AFR‐MWAS. There were 146 and 10 proteins associated with AD‐risk in EUR and AFR, respectively. 55 proteins can be used as drug targets. 119 proteins were not nominated by previous AD risk GWAS. Three and one metabolites were associated with AD‐risk in EUR and AFR, respectively. One metabolite can be used as drug target. Conclusion: We uncovered ancestry‐specific genetic architectures for proteomics and metabolomics. Our study serves as the first multi‐omic genetic study on multi‐ancestries for AD and can help guide the future ancestry‐specific therapy. [ABSTRACT FROM AUTHOR]

Background: Quantitative trait loci (QTL) are successful at identifying the functional gene for many loci identified through GWAS. While expression QTL (eQTL) studies robustly examine tissue‐specificity, most protein QTL (pQTL) studies have been limited to plasma. We have previously demonstrated that pQTL associations are highly tissue‐specific. Given the relevance of cerebrospinal fluid (CSF) to Alzheimer's disease (AD) and other forms of neurodegeneration, we developed a CSF‐specific pQTL atlas and integrated it with AD GWAS to identify novel causal proteins for AD. Method: We generated CSF proteomics (Somalogic, 7,584 analytes) data for 3,107 individuals. pQTL mapping was performed using a three‐stage approach: discovery, replication, and meta‐analysis. We analyzed the tissue‐ and molecule‐specificity of our associations by comparing to plasma & brain pQTLs and various eQTLs. We performed a proteome‐wide association study (PWAS) and Mendelian randomization (MR) to prioritize proteins affecting AD. We determined shared protein‐disease genetic regulation using colocalization. Using AD‐associated proteins, we built risk models of disease status. Result: We identified 2,316 significant pQTL (1,247 in cis and 1,069 in trans) for 1,960 proteins, of which 1,720 were novel and not reported in the largest currently available pQTL studies in plasma or brain. Through PWAS, we identified 440 proteins associated with AD risk, which show enrichment in neurons (with APOE region) or microglia/macrophages (without APOE). MR prioritized 37 proteins as causal and colocalization identified 153 proteins that share genetic etiology with AD. Seventeen of these proteins overlap between all three methods and multiple (including PILRA, PRSS8, and SIRPA) represent novel causal proteins for AD. A protein risk score using PWAS‐identified proteins outperformed a polygenic risk score (PRS) at predicting amyloid/tau positivity across ages (AUC: 0.852‐0.906 vs. 0.724‐0.806, P<0.002) and across APOE genotypes (AUC: 0.809‐0.893 vs. 0.70‐0.80, P<0.027). Conclusion: We reported the largest CSF pQTL analysis to date and confirmed that CSF pQTLs are largely tissue‐specific. We identified proteins involved in AD that confirm reported candidate genes and prioritize new ones at GWAS loci. We developed accurate prediction models using prioritized proteins. Our findings offer insights into AD biology undetected with plasma pQTL analyses, supporting proteogenomic databases in neurologically‐relevant tissues. [ABSTRACT FROM AUTHOR]

Background: Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer's disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). Here, we pursued the largest CSF study to identify additional novel genetic modifiers of sTREM2. Method: We performed the genome‐wide association study (GWAS) of CSF sTREM2 in 3350 individuals of European ancestry from eight cohorts. To identify functional genes, we performed multi‐ethnic fine mapping with 250 non‐European individuals. Functional validation using peripheral blood mononuclear cell‐derived macrophages was performed. Colocalization and Mendelian randomization (MR) was performed for the causality of sTREM2 in AD. Result: The known MS4A locus and three novel loci were identified at genome‐wide significance. In the MS4A locus, we identified two independent missense variants (p.M178V in MS4A4A and p.A112T in MS4A6A) that drove the association through multi‐ethnic fine mapping. They showed an epistatic effect for sTREM2 and AD risk. The novel TREM2 locus on chromosome 6 contained two rare missense variants (rs142232675 p.D87N, P = 2.71×10‐10; rs75932628 p.R47H, P = 7.16×10‐19) associated with sTREM2 and AD risk. Another novel locus in the intergenic region between TGFBR2 and RBMS3 (rs73823326, P = 3.86×10‐9) included a regulatory variant with a microglia‐specific chromatin loop for promoters of TGFBR2. Using cell‐ based assays we demonstrate that TGFBR2, but not RBMS3, modify sTREM2 levels. The last novel locus NECTIN2 on chromosome 19 (rs11666329, P = 2.52×10‐8) was independent of APOE genotype and colocalized with cis‐eQTL of NECTIN2 in the brain cortex and cis‐pQTL of NECTIN2 in CSF (PP.H4 = 0.83). This variant was also associated with AD risk (P = 1.52×10‐66) and age at onset (P = 3.26×10‐5). Our MR results confirmed the significant protective effect of sTREM2 on reducing AD risk. Conclusion: To our knowledge, this is the largest study to date aiming at identifying genetic modifiers of CSF sTREM2. We provided novel insights for MS4A and TREM2, the two well‐ known gens for AD risk. We also identified TGFBR2 and NECTIN2 as additional modulators involved in TREM2 biology. Our findings provide new insight to unravel sTREM2 modulators and their role in AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer disease (AD) has different prevalence across different ancestries. However, the genetic factors underlying AD pathogenesis between diverse populations are largely unknown. The recent AD genome‐wide association study (GWAS) (Bellenguez et al 2022) reported 75 significant genetic loci in European ancestry, while the latest African‐based AD GWAS (Kunkle et al 2021) only reported two loci. It will be important to map these genetic loci into the functional molecular traits, e.g. RNA expression, protein abundance, metabolite levels. Multiple studies integrated such molecular traits with AD risk and termed them as TWAS, PWAS, and MWAS. However, few studies reported more than one molecular trait and in multiple ancestries. Method: We first identified the plasma proteomic (SomaScan 7K) and metabolomic (Metabolon HD4) QTLs (quantitative trait loci) from participants with African (AFR, N = 400) and European (EUR, N = 2,300) ancestry, respectively. We next associated the genetic variants with the AD risk GWAS (EUR‐Bellenguez‐2022 & AFR‐Kunkle‐2021) using the protein or metabolite as the intermediate molecular trait. We extended the TWAS framework to test the disease association with the genetically predicted levels of proteins (PWAS) and metabolites (MWAS). Result: We identified over 3,000 pQTLs and 400 mQTLs. Out of these findings, approximately 40% were novel QTLs compared to the previous studies. We found ancestry‐specific proteins and metabolites associated with AD risk. For example, proteins BIN1, TREM2, APOE, were only significant in EUR‐PWAS results but not AFR‐PWAS using the ancestry‐matched disease associations. Conversely, Spondin‐1 and RNF24 were only nominally significant in AFR‐PWAS. Similarly, metabolites glucuronide and sphingosine were only significant in EUR‐MWAS, whereas ethylmalonate was only nominally significant in AFR‐MWAS. There were 146 and 10 proteins associated with AD‐risk in EUR and AFR, respectively. 55 proteins can be used as drug targets. 119 proteins were not nominated by previous AD risk GWAS. Three and one metabolites were associated with AD‐risk in EUR and AFR, respectively. One metabolite can be used as drug target. Conclusion: We uncovered ancestry‐specific genetic architectures for proteomics and metabolomics. Our study serves as the first multi‐omic genetic study on multi‐ancestries for AD and can help guide the future ancestry‐specific therapy. [ABSTRACT FROM AUTHOR]

Cardiac risk stratification and coronary angiography are routinely performed as part of kidney and liver transplant candidacy evaluation. There are limited data on the outcomes of surgical coronary revascularization in this patient population. This study investigated outcomes in patients with end- stage renal or hepatic disease who were undergoing coronary artery bypass grafting (CABG) to attain kidney or liver transplant candidacy. This study was a retrospective analysis of all patients who underwent isolated CABG at our institution, Indiana University School of Medicine (Indianapolis, IN), between 2010 and 2016. Patients were divided into 2 cohorts: pretransplant (those undergoing surgery to attain renal or hepatic transplant candidacy) and nontransplant (all others). Baseline characteristics and postoperative outcomes were compared between the groups. A total of 1801 patients were included: 28 in the pretransplant group (n = 22, kidney; n = 7, liver) and 1773 in the nontransplant group. Major adverse postoperative outcomes were significantly greater in the pretransplant group compared with the nontransplant group: 30-day mortality (14.3% vs 2.8%; P =.009), neurologic events (17.9% vs 4.8%; P =.011), reintubation (21.4% vs 5.8%; P =.005), and total postoperative ventilation (5.2 hours vs 5.0 hours; P =.0124). The 1- and 5-year mortality in the pretransplant group was 17.9% and 53.6%, respectively. Of the pretransplant cohort, 3 patients (10.7%) underwent organ transplantation (all kidney) at a mean 436 days after CABG. No patients underwent liver transplantation. Outcomes after CABG in pre–kidney transplant and pre–liver transplant patients are poor. Despite surgical revascularization, most patients do not ultimately undergo organ transplantation. Revascularization strategies and optimal management in this high-risk population warrant further study. [ABSTRACT FROM AUTHOR]

Objective: Malnutrition among hospital patients, a frequent, yet under-diagnosed problem is associated with adverse impact on patient outcome and health care costs. Development of highly accurate malnutrition screening tools is, therefore, essential for its timely detection, for providing nutritional care, and for addressing the concerns related to the suboptimal predictive value of the conventional screening tools, such as the Malnutrition Universal Screening Tool (MUST). We aimed to develop a machine learning (ML) based classifier (MUST-Plus) for more accurate prediction of malnutrition.Method: A retrospective cohort with inpatient data consisting of anthropometric, lab biochemistry, clinical data, and demographics from adult (≥ 18 years) admissions at a large tertiary health care system between January 2017 and July 2018 was used. The registered dietitian (RD) nutritional assessments were used as the gold standard outcome label. The cohort was randomly split (70:30) into training and test sets. A random forest model was trained using 10-fold cross-validation on training set, and its predictive performance on test set was compared to MUST.Results: In all, 13.3% of admissions were associated with malnutrition in the test cohort. MUST-Plus provided 73.07% (95% confidence interval [CI]: 69.61%-76.33%) sensitivity, 76.89% (95% CI: 75.64%-78.11%) specificity, and 83.5% (95% CI: 82.0%-85.0%) area under the receiver operating curve (AUC). Compared to classic MUST, MUST-Plus demonstrated 30% higher sensitivity, 6% higher specificity, and 17% increased AUC.Conclusions: ML-based MUST-Plus provided superior performance in identifying malnutrition compared to the classic MUST. The tool can be used for improving the operational efficiency of RDs by timely referrals of high-risk patients. [ABSTRACT FROM AUTHOR]