Impact of congestive heart failure on patients undergoing lumbar spine fusion for adult spine deformity.

Background: With the increasing amount of elective spine fusion patients presenting with cardiac disease and congestive heart failure, it is becoming difficult to assess when it is safe to proceed with surgery. Assessing the severity of heart failure (HF) through ejection fraction may provide insight into patients' short- and long-term risks. Purpose: The purpose of this study was to assess the severity of HF on perioperative outcomes of spine fusion surgery patients. Study Design/Setting: This was a retrospective cohort study of the PearlDiver database. Patient Sample: We enrolled 670,526 patients undergoing spine fusion surgery. Outcome Measures: Thirty-day and 90-day complication rates, discharge destination, length of stay (LOS), physician reimbursement, and hospital costs. Methods: Patients undergoing elective spine fusion surgery were isolated and stratified by preoperative HF with preserved ejection fraction (P-EF) or reduced ejection fraction (R-EF) (International Classification of Diseases-9: 428.32 [chronic diastolic HF] and 428.22 [chronic systolic HF]). Means comparison tests (Chi-squared and independent samples t-tests, as appropriate) compared differences in demographics, diagnoses, comorbidities, procedural characteristics, LOS, 30-day and 90-day complication outcomes, and total hospital charges between those diagnosed with P-EF and those not R-EF. Binary logistic regression assessed the odds of complication associated with HF, controlling for levels fused (odds ratio [OR] [95% confidence interval]). Statistical significance was set at P < 0.05. Results: Totally 670,526 elective spine fusion patients were included. Four thousand and seventy-seven were diagnosed with P-EF and 2758 R-EF. Overall, P-EF patients presented with higher rates of morbid obesity, chronic kidney disease, chronic obstructive pulmonary disease, diabetes mellitus, and hypertension (all P < 0.001). In relation to No-HF, P-EF patients had higher rates of 30-day major complications including pulmonary embolism, pneumonia, cerebrovascular accident (CVA), myocardial infarctions (MI), sepsis, and death (all P < 0.001). Furthermore, P-EF was associated significantly with increased odds of pneumonia (OR: 2.07 [1.64-2.56], P < 0.001) and sepsis (OR: 2.09 [1.62-2.66], P < 0.001). Relative to No-HF, R-EF was associated with significantly higher odds of MI (OR: 3.66 [2.34-5.47]), CVA (OR: 2.70 [1.67-4.15]), and pneumonia (OR: 1.85 [1.40-2.40]) (all P < 0.001) postoperative within 30 days. Adjusting for prior history of MI, CAD, and the presence of a pacemaker R-EF was a significant predictor of an MI 30 days postoperatively (OR: 2.2 [1.14-4.32], P = 0.021). Further adjusting for history of CABG or stent placement, R-EF was associated with higher odds of CVA (OR: 2.11 [1.09-4.19], P = 0.028) and MI (OR: 2.27 [1.20-4.43], P = 0.013). Conclusions: When evaluating the severity of HF before spine surgery, R-EF was associated with a higher risk of major complications, especially the occurrence of a myocardial infarction 30 days postoperatively. During preoperative risk assessment, congestive HF should be considered thoroughly when thinking of postoperative outcomes with emphasis on R-EF.

Targeting HER2/HER3 co-mutations in metastatic breast cancer: Case reports of exceptional responders to trastuzumab and pertuzumab therapy.

BACKGROUND: Overexpression of HER2 plays an important role in cancer progression and is the target of multiple therapies in HER2-positive breast cancer. Recent studies have also highlighted the presence of activating mutations in HER2, and HER3 that are predicted to enhance HER2 downstream pathway activation in a HER2-dependent manner. METHODS: In this report, we present two exceptional responses in hormone receptor-positive, HER2-nonamplified, HER2/HER3 co-mutated metastatic breast cancer patients who were treated with the anti-HER2-directed monoclonal antibodies, trastuzumab and pertuzumab. RESULTS: Both patients acheived exceptional responses to treatment, suggesting that combined trastuzumab, pertuzumab, and endocrine therapy could be a highly effective therapy for these patients and our observations could help prioritize trastuzumab deruxtecan as an early therapeutic choice for patients whose cancers have activating mutations in HER2.

Life course plasma metabolomic signatures of genetic liability to Alzheimer's disease.

Mechanisms through which most known Alzheimer's disease (AD) loci operate to increase AD risk remain unclear. Although Apolipoprotein E (APOE) is known to regulate lipid homeostasis, the effects of broader AD genetic liability on non-lipid metabolites remain unknown, and the earliest ages at which metabolic perturbations occur and how these change over time are yet to be elucidated. We examined the effects of AD genetic liability on the plasma metabolome across the life course. Using a reverse Mendelian randomization framework in two population-based cohorts [Avon Longitudinal Study of Parents and Children (ALSPAC, n = 5648) and UK Biobank (n ≤ 118,466)], we estimated the effects of genetic liability to AD on 229 plasma metabolites, at seven different life stages, spanning 8 to 73 years. We also compared the specific effects of APOE ε4 and APOE ε2 carriage on metabolites. In ALSPAC, AD genetic liability demonstrated the strongest positive associations with cholesterol-related traits, with similar magnitudes of association observed across all age groups including in childhood. In UK Biobank, the effect of AD liability on several lipid traits decreased with age. Fatty acid metabolites demonstrated positive associations with AD liability in both cohorts, though with smaller magnitudes than lipid traits. Sensitivity analyses indicated that observed effects are largely driven by the strongest AD instrument, APOE, with many contrasting effects observed on lipids and fatty acids for both ε4 and ε2 carriage. Our findings indicate pronounced effects of the ε4 and ε2 genetic variants on both pro- and anti-atherogenic lipid traits and sphingomyelins, which begin in childhood and either persist into later life or appear to change dynamically.

Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes.

BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.

Risk of spinal surgery among individuals who have been re-vascularized for coronary artery disease.

HYPOTHESIS: Revascularization is a more effective intervention to reduce future postop complications. METHODS: Patients undergoing elective spine fusion surgery were isolated in the PearlDiver database. Patients were stratified by having previous history of vascular stenting (Stent), coronary artery bypass graft (CABG), and no previous heart procedure (No-HP). Means comparison tests (chi-squared and independent samples t-tests, as appropriate) compared differences in demographics, diagnoses, and comorbidities. Binary logistic regression assessed the odds of 30-day and 90-day postoperative (postop) complications associated with each heart procedure (Odds Ratio [95 % confidence interval]). Statistical significance was set p < 0.05. RESULTS: 731,173 elective spine fusion patients included. Overall, 8,401 pts underwent a CABG, 24,037 pts Stent, and 698,735 had No-HP prior to spine fusion surgery. Compared to Stent and No-HP patients, CABG patients had higher rates of morbid obesity, chronic kidney disease, and diabetes (p < 0.001 for all). Meanwhile, stent patients had higher rates of PVD, hypertension, and hyperlipidemia (all p < 0.001). 30-days post-op, CABG patients had significantly higher complication rates including pneumonia, CVA, MI, sepsis, and death compared to No-HP (all p < 0.001). Stent patients vs. No-HF had higher 30-day post-op complication rates including pneumonia, CVA, MI, sepsis, and death. Furthermore, adjusting for age, comorbidities, and sex Stent was significantly predictive of a MI 30-days post-op (OR: 1.90 [1.53-2.34], P < 0.001). Additionally, controlling for levels fused, stent patients compared to CABG patients had 1.99x greater odds of a MI within 30-days (OR: 1.99 [1.26-3.31], p = 0.005) and 2.02x odds within 90-days postop (OR: 2.2 [1.53-2.71, p < 0.001). CONCLUSION: With regards to spine surgery, coronary artery bypass graft remains the gold standard for risk reduction. Stenting does not appear to minimize risk of experiencing a post-procedure cardiac event as dramatically as CABG.

Identifying metabolic features of colorectal cancer liability using Mendelian randomization.

Background: Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. Methods: To investigate whether changes in circulating metabolites characterize the early stages of colorectal cancer (CRC) development, we examined the associations between a genetic risk score (GRS) associated with CRC liability (72 single-nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N = 6221). Linear regression models were applied to examine the associations between genetic liability to CRC and circulating metabolites measured in the same individuals at age 8 y, 16 y, 18 y, and 25 y. Results: The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P < 0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N = 118,466, median age 58 y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk. Conclusions: These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism and suggest that fatty acids may play an important role in CRC development. Funding: This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.

Colorectal cancer, or bowel cancer, is the fourth most common cause of death from cancer worldwide. Understanding how the cancer develops and recognizing early signs is essential, as people who receive treatment early on have higher survival rates. One way to boost early detection and disease survival rates is through identifying early colorectal cancer biomarkers. For example, metabolites produced when cells process nutrients have been shown to play a role in the development of colon cancer. Certain metabolites could therefore serve as biomarkers, which can be detected in routine blood tests. But first, scientists need to identify the exact metabolic processes involved in cancer development. Bull, Hazelwood et al. show that fat metabolites during early adulthood may help predict colorectal cancer risk. In the experiments, the team assessed the link between an individual's genetic risk for developing colorectal cancer and metabolites in their blood. By looking at data from over 6,000 individuals living in the UK, followed from early life into adulthood, they found higher fatty acid and low-density lipoprotein levels in young adults at risk of colorectal cancer. However, the results could not be replicated in a separate cohort study of middle-aged adults. Bull, Hazelwood et al. noted that many individuals in this older age group use fat-targeting drugs called statins, which may have obscured this connection. The study of Bull, Hazelwood et al. shows that colorectal cancer risk indicators may be present from adolescence to around 40 years, before most individuals are diagnosed. The results suggest this may be a window for early detection and preventive interventions. It also highlights that differences in fat metabolism, possibly linked to genetic differences, may underlie colorectal cancer risk. More studies are needed to better understand how and whether interventions targeting fat levels may help prevent colorectal cancer development.

Childhood socioeconomic position and sex-specific trajectories of metabolic traits across early life: prospective cohort study.

BACKGROUND: Socioeconomic inequalities in cardiovascular disease risk begin early in life and are more pronounced in females than males later in life. Causal atherogenic traits explaining this are not well understood. We explored sex-specific associations between childhood socioeconomic position (SEP) and molecular measures of systemic metabolism across early life. METHODS: Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based birth cohort in southwest England. Pregnant women with an expected delivery date between 1991 and 1992 were invited to participate. Maternal education was the primary indicator of SEP. Concentrations of 148 metabolic traits from targeted metabolomics (nuclear magnetic resonance spectroscopy) from research clinics at ages 7, 15, 18 and 25 years were analysed. The sex-specific slope index of inequality (SII) in trajectories of metabolic traits was estimated using multilevel models. FINDINGS: Total number of participants included was 6537 (12,543 repeated measures). Lower maternal education was associated with more adverse levels of several atherogenic lipids and key metabolic traits among females at age 7 years, but not males. For instance, SII for very small very-low-density lipoprotein (VLDL) concentrations was 0.16SD (95% CI: 0.01, 0.30) among females and -0.02SD (95% CI: -0.16, 0.13) among males. Between 7 and 25 years, inequalities widened among females and emerged among males particularly for VLDL particle concentrations, apolipoprotein-B concentrations, and inflammatory glycoprotein acetyls. For instance, at 25 years, SII for very small VLDL concentrations was 0.36SD (95% CI: 0.20, 0.52) and 0.22SD (95% CI: 0.04, 0.40) among females and males respectively. INTERPRETATION: Prevention of socioeconomic inequalities in cardiovascular disease risk requires a life course approach beginning at the earliest opportunity, especially among females. FUNDING: The UK Medical Research Council and Wellcome (grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). KON is supported by a Health Research Board (HRB) of Ireland Investigator Led Award (ILP-PHR-2022-008). JB, GDS and KT work in a unit funded by the UK MRC (MC_UU_00011/1 and MC UU 00011/3) and the University of Bristol. OR is supported by a UKRI Future Leaders Fellowship (MR/S03532X/1). These funding sources had no role in the design and conduct of this study. This publication is the work of the authors and KON will serve as guarantor for the contents of this paper.

Knowing your boundaries: no effect of tool-use on body representation following a gather-and-sort task.

Internal representations of the body have received considerable attention in recent years, particularly in the context of tool-use. Results have supported the notion that these representations are plastic and tool-use engenders an extension of the internal representation of the arm. However, the limitations of the literature underlying this tool embodiment process have not been adequately considered or tested. For example, there is some evidence that tool-use effects do not extend beyond simplistic tool-use tasks. To further clarify this issue, 66 participants engaged in a period of tool-augmented reaches in a speeded gather-and-sort task. If task characteristics inherent to simplistic tasks are relevant to putative embodiment effects, it was predicted that there would be no effect of tool-use on tactile distance judgments or forearm bisections. A Bayesian analysis found considerable support for the null hypothesis in both outcome measures, suggesting that some of the evidence for tool embodiment may be based in task characteristics inherent in the narrow range of tool-use tasks used to study them, rather than a tool incorporation process. Potential sources of influence stemming from these characteristics are discussed.

Molecular profiling of a real-world breast cancer cohort with genetically inferred ancestries reveals actionable tumor biology differences between European ancestry and African ancestry patient populations.

BACKGROUND: Endocrine-resistant HR+/HER2- breast cancer (BC) and triple-negative BC (TNBC) are of interest for molecularly informed treatment due to their aggressive natures and limited treatment profiles. Patients of African Ancestry (AA) experience higher rates of TNBC and mortality than European Ancestry (EA) patients, despite lower overall BC incidence. Here, we compare the molecular landscapes of AA and EA patients with HR+/HER2- BC and TNBC in a real-world cohort to promote equity in precision oncology by illuminating the heterogeneity of potentially druggable genomic and transcriptomic pathways. METHODS: De-identified records from patients with TNBC or HR+/HER2- BC in the Tempus Database were randomly selected (N = 5000), with most having stage IV disease. Mutations, gene expression, and transcriptional signatures were evaluated from next-generation sequencing data. Genetic ancestry was estimated from DNA-seq. Differences in mutational prevalence, gene expression, and transcriptional signatures between AA and EA were compared. EA patients were used as the reference population for log fold-changes (logFC) in expression. RESULTS: After applying inclusion criteria, 3433 samples were evaluated (n = 623 AA and n = 2810 EA). Observed patterns of dysregulated pathways demonstrated significant heterogeneity among the two groups. Notably, PIK3CA mutations were significantly lower in AA HR+/HER2- tumors (AA = 34% vs. EA = 42%, P < 0.05) and the overall cohort (AA = 28% vs. EA = 37%, P = 2.08e-05). Conversely, KMT2C mutation was significantly more frequent in AA than EA TNBC (23% vs. 12%, P < 0.05) and HR+/HER2- (24% vs. 15%, P = 3e-03) tumors. Across all subtypes and stages, over 8000 genes were differentially expressed between the two ancestral groups including RPL10 (logFC = 2.26, P = 1.70e-162), HSPA1A (logFC = - 2.73, P = 2.43e-49), ATRX (logFC = - 1.93, P = 5.89e-83), and NUTM2F (logFC = 2.28, P = 3.22e-196). Ten differentially expressed gene sets were identified among stage IV HR+/HER2- tumors, of which four were considered relevant to BC treatment and were significantly enriched in EA: ERBB2_UP.V1_UP (P = 3.95e-06), LTE2_UP.V1_UP (P = 2.90e-05), HALLMARK_FATTY_ACID_METABOLISM (P = 0.0073), and HALLMARK_ANDROGEN_RESPONSE (P = 0.0074). CONCLUSIONS: We observed significant differences in mutational spectra, gene expression, and relevant transcriptional signatures between patients with genetically determined African and European ancestries, particularly within the HR+/HER2- BC and TNBC subtypes. These findings could guide future development of treatment strategies by providing opportunities for biomarker-informed research and, ultimately, clinical decisions for precision oncology care in diverse populations.

Suspected focal nodular hyperplasia in male adults: 10-year experience from a large liver centre.

PURPOSE: Focal nodular hyperplasia (FNH) is commonly found in females of reproductive age. In males, the diagnosis is made more cautiously due to its lower incidence and higher incidence of hepatocellular carcinoma, which can have overlapping imaging features. Follow-up or biopsy is sometimes required. This retrospective study aims to assess management of suspected FNH in male adult patients at our institution over a 10-year period. METHODS: Male adults (≥ 18 years) suspected of having FNH from January 2010-June 2020 were identified using a departmental radiology information system search. Data was collected from radiology reports and patient pathway manager. RESULTS: Of 342 patients with suspected FNH, 62 were male (18.1%; F:M of 4.5:1). We only included patients investigated and followed up by MRI, total of 57 patients. Median age was 40 years (range 18-74 years). Background liver disease present in 21/57 (36.8%), majority with hepatic steatosis. Average number of lesions per patient 1.7. 22/57 (38.6%) had at least one MRI follow-up using liver-specific contrast with 7 lesions demonstrating variation in size (range growth: -3.27 mm/year to + 4 mm/year). In 7 cases, MRI was not definitive; 6 required biopsy and 1 resection. Only 2/7 demonstrated malignancy. Of the total 57 patients, 6 have deceased and none due to a misdiagnosed or mismanaged hepatic lesion. CONCLUSION: FNH is relatively uncommon in males, however, our data suggests that lesions with typical MRI characteristics do not require follow-up and diagnosis can be made confidently, similar to females. Any atypical features should prompt a biopsy.

Distinct metabolic features of genetic liability to type 2 diabetes and coronary artery disease: a reverse Mendelian randomization study.

BACKGROUND: Type 2 diabetes (T2D) and coronary artery disease (CAD) both have known genetic determinants, but the mechanisms through which their associated genetic variants lead to disease onset remain poorly understood. METHODS: We used large-scale metabolomics data in a two-sample reverse Mendelian randomization (MR) framework to estimate effects of genetic liability to T2D and CAD on 249 circulating metabolites in the UK Biobank (N = 118,466). We examined the potential for medication use to distort effect estimates by conducting age-stratified metabolite analyses. FINDINGS: Using inverse variance weighted (IVW) models, higher genetic liability to T2D was estimated to decrease high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) (e.g. , HDL-C:  -0.05 SD; 95% CI -0.07 to -0.03, per doubling of liability), whilst increasing all triglyceride groups and branched chain amino acids (BCAAs). IVW estimates for CAD liability suggested an effect on reducing HDL-C as well as raising very-low density lipoprotein cholesterol (VLDL-C) and LDL-C. In pleiotropy-robust models, T2D liability was still estimated to increase BCAAs, but several estimates for higher CAD liability reversed and supported decreased LDL-C and apolipoprotein-B. Estimated effects of CAD liability differed substantially by age for non-HDL-C traits, with higher CAD liability lowering LDL-C only at older ages when statin use was common. INTERPRETATION: Overall, our results support largely distinct metabolic features of genetic liability to T2D and CAD, illustrating both challenges and opportunities for preventing these commonly co-occurring diseases. FUNDING: Wellcome Trust [218495/Z/19/Z], UK MRC [MC_UU_00011/1; MC_UU_00011/4], the University of Bristol, Diabetes UK [17/0005587], World Cancer Research Fund [IIG_2019_2009].

Sex-specific trajectories of molecular cardiometabolic traits from childhood to young adulthood.

BACKGROUND: The changes which typically occur in molecular causal risk factors and predictive biomarkers for cardiometabolic diseases across early life are not well characterised. METHODS: We quantified sex-specific trajectories of 148 metabolic trait concentrations including various lipoprotein subclasses from age 7 years to 25 years. Data were from 7065 to 7626 offspring (11 702 to14 797 repeated measures) of the Avon Longitudinal Study of Parents and Children birth cohort study. Outcomes were quantified using nuclear magnetic resonance spectroscopy at 7, 15, 18 and 25 years. Sex-specific trajectories of each trait were modelled using linear spline multilevel models. RESULTS: Females had higher very-low-density lipoprotein (VLDL) particle concentrations at 7 years. VLDL particle concentrations decreased from 7 years to 25 years with larger decreases in females, leading to lower VLDL particle concentrations at 25 years in females. For example, females had a 0.25 SD (95% CI 0.20 to 0.31) higher small VLDL particle concentration at 7 years; mean levels decreased by 0.06 SDs (95% CI -0.01 to 0.13) in males and 0.85 SDs (95% CI 0.79 to 0.90) in females from 7 years to 25 years, leading to 0.42 SDs (95% CI 0.35 to 0.48) lower small VLDL particle concentrations in females at 25 years. Females had lower high-density lipoprotein (HDL) particle concentrations at 7 years. HDL particle concentrations increased from 7 years to 25 years with larger increases among females leading to higher HDL particle concentrations in females at 25 years. CONCLUSION: Childhood and adolescence are important periods for the emergence of sex differences in atherogenic lipids and predictive biomarkers for cardiometabolic disease, mostly to the detriment of males.

Racial Disparities in Pathological Complete Response Among Patients Receiving Neoadjuvant Chemotherapy for Early-Stage Breast Cancer.

Importance: Among patients with breast cancer, inconsistent findings have been published on racial disparities in achieving pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT). Objective: To investigate whether racial disparities exist in achieving pCR and what factors contribute to them. Design, Setting, and Participants: Within the ongoing Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), which consists of a prospectively ascertained cohort of patients with breast cancer, 690 patients with stage I to III breast cancer receiving NACT were identified for this single-institution study at the University of Chicago Medicine. Patients diagnosed between 2002 and 2020 (median follow-up: 5.4 years) were included; next-generation sequencing data on tumor-normal tissue pairs were available from 186 ChiMEC patients, including both primary and residual tumor samples. Statistical analysis was performed from September 2021 to September 2022. Exposures: Demographic, biological, and treatment factors that could contribute to disparities in achieving pCR. Main Outcomes and Measures: pCR was defined as the absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ. Results: The study included 690 patients with breast cancer, with a mean (SD) age of 50.1 (12.8) years. Among the 355 White patients, 130 (36.6%) achieved pCR compared to 77 of the 269 Black patients (28.6%; P = .04). Not achieving pCR was associated with significantly worse overall survival (adjusted hazard ratio, 6.10; 95% CI, 2.80-13.32). Black patients had significantly lower odds of achieving pCR compared with White patients in the hormone receptor-negative/ERBB2+ subtype (adjusted odds ratio, 0.30; 95% CI, 0.11-0.81). Compared with White patients with ERBB2+ disease, Black patients were more likely to have MAPK pathway alterations (30.0% [6 of 20] vs 4.6% [1 of 22]; P = .04), a potential mechanism of anti-ERBB2 therapy resistance. Tumor mutational burden and somatic alterations in several genes (eg, FGF4, FGF3, CCND1, MCL1, FAT1, ERCC3, PTEN) were significantly different between the primary and residual tumors. Conclusions and Relevance: In this cohort study of patients with breast cancer, racial disparities in response to NACT were associated with disparities in survival and varied across different breast cancer subtypes. This study highlights the potential benefits of better understanding the biology of primary and residual tumors.

Life course effects of genetic susceptibility to higher body size on body fat and lean mass: prospective cohort study.

BACKGROUND/OBJECTIVES: Different genetic variants are associated with larger body size in childhood vs adulthood. Whether and when these variants predominantly influence adiposity are unknown. We examined how genetic variants influence total body fat and total lean mass trajectories. METHODS: Data were from the Avon Longitudinal Study of Parents and Children birth cohort (N = 6926). Sex-specific genetic risk scores (GRS) for childhood and adulthood body size were generated, and dual-energy X-ray absorptiometry scans measured body fat and lean mass six times between the ages of 9 and 25 years. Multilevel linear spline models examined associations of GRS with fat and lean mass trajectories. RESULTS: In males, the sex-specific childhood and adulthood GRS were associated with similar differences in fat mass from 9 to 18 years; 8.3% [95% confidence interval (CI) 5.1, 11.6] and 7.5% (95% CI 4.3, 10.8) higher fat mass at 18 years per standard deviation (SD) higher childhood and adulthood GRS, respectively. In males, the sex-combined childhood GRS had stronger effects at ages 9 to 15 than the sex-combined adulthood GRS. In females, associations for the sex-specific childhood GRS were almost 2-fold stronger than the adulthood GRS from 9 to 18 years: 10.5% (95% CI 8.5, 12.4) higher fat mass at 9 years per SD higher childhood GRS compared with 5.1% (95% CI 3.2, 6.9) per-SD higher adulthood GRS. In females, the sex-combined GRS had similar effects, with slightly larger effect estimates. Lean mass effect sizes were much smaller. CONCLUSIONS: Genetic variants for body size are more strongly associated with adiposity than with lean mass. Sex-combined childhood variants are more strongly associated with increased adiposity until early adulthood. This may inform future studies that use genetics to investigate the causes and impact of adiposity at different life stages.

Identifying metabolic features of colorectal cancer liability using Mendelian randomization.

Background: Recognizing the early signs of cancer risk is vital for informing prevention, early detection, and survival. Methods: To investigate whether changes in circulating metabolites characterise the early stages of colorectal cancer (CRC) development, we examined associations between a genetic risk score (GRS) associated with CRC liability (72 single nucleotide polymorphisms) and 231 circulating metabolites measured by nuclear magnetic resonance spectroscopy in the Avon Longitudinal Study of Parents and Children (N=6,221). Linear regression models were applied to examine associations between genetic liability to colorectal cancer and circulating metabolites measured in the same individuals at age 8, 16, 18 and 25 years. Results: The GRS for CRC was associated with up to 28% of the circulating metabolites at FDR-P<0.05 across all time points, particularly with higher fatty acids and very-low- and low-density lipoprotein subclass lipids. Two-sample reverse Mendelian randomization (MR) analyses investigating CRC liability (52,775 cases, 45,940 controls) and metabolites measured in a random subset of UK Biobank participants (N=118,466, median age 58y) revealed broadly consistent effect estimates with the GRS analysis. In conventional (forward) MR analyses, genetically predicted polyunsaturated fatty acid concentrations were most strongly associated with higher CRC risk. Conclusions: These analyses suggest that higher genetic liability to CRC can cause early alterations in systemic metabolism, and suggest that fatty acids may play an important role in CRC development. Funding: This work was supported by the Elizabeth Blackwell Institute for Health Research, University of Bristol, the Wellcome Trust, the Medical Research Council, Diabetes UK, the University of Bristol NIHR Biomedical Research Centre, and Cancer Research UK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work used the computational facilities of the Advanced Computing Research Centre, University of Bristol - http://www.bristol.ac.uk/acrc/.

Attitudes and uses of archival materials among science-based anthropologists.

While archival user studies have largely focused on humanities (and adjacent) scholars, this paper focuses on anthropologists engaged in scientific research. Based on qualitative results from an open-ended survey, we investigate how science-based anthropologists perceive and use archives in their work. We ask: How are science-based anthropologists and archaeologists reusing archival data in their research? What difficulties or barriers do they encounter in reusing archival data in scientific contexts? What attitudes or understandings about archival research are held by science-based anthropologists and archaeologists? Our findings primarily add to the body of literature about user experience in archives and more broadly to the emerging literature on archival data reuse. Major findings include (1) barriers and gatekeeping legacies that impact archival research and the ability of researchers to reuse data and (2) mixed perceptions about archives among researchers. We also discuss suggestions made by these communities of practice, and the ways that barriers to archival data reuse may stem from a lack of knowledge about core archival and information infrastructures among researcher communities. Together, this research showcases possible (re)uses of important primary source data in archives among scientific communities but highlights that barriers to access and misperceptions create a gap in exploiting that potential. We argue for a "re-imagining" of anthropological archives as relevant to contemporary communities and scientific pursuits toward a richer scientific research environment.

Failure to Normalize Risk Profile of Spine Fusion Patients With Coronary Artery Disease Previously Treated With Percutaneous Stent Revascularization.

BACKGROUND: The impact of an initially less invasive cardiac intervention on outcomes of future surgical spine procedures has been understudied; therefore, we sought to investigate the effect of coronary stents on postoperative outcomes in an elective spine fusion cohort. METHODS: Elective spine fusion patients were isolated with International Classification of Diseases-Ninth Edition and current procedural terminology procedure codes in the PearlDiver database. Patients were stratified by number of coronary stents: (1) 1 to 2 stents (ST12); (2) 3 to 4 stents (ST34); (3) no stents. Mean comparison tests compared differences in demographics, diagnoses, comorbidities, and 30-day and 90-day complication outcomes. Logistic regression assessed the odds of complications associated with coronary stents, controlling for levels fused, age, sex, and comorbidities (odds ratio [95% confidence interval]). Statistical significance was P < 0.05. RESULTS: A total of 726,061 elective spine fusion patients were isolated. Of those patients, 707,396 patients had no stent, 17,087 ST12, and 1578 ST34. At baseline (BL), ST12 patients had higher rates of morbid obesity, chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, and diabetes mellitus compared with no stent and ST34 patients (all P < 0.001). Relative to no stent patients, ST12 patients had a longer length of stay and, at 30 days, significantly higher complication rates, including pneumonia, myocardial infarction (MI), sepsis, acute kidney injury, urinary tract infection (UTI), wound complications, transfusions, and 30-day readmissions (P < 0.05). Controlling for age, sex, comorbidities, and levels fused, ST12 was a significant predictor of MI within 30 days (OR 2.15 [95% CI 1.7-2.7], P < 0.001) and 90 days postoperatively (OR 1.87 [95% CI 1.6-2.2], P < 0.001). ST34 patients compared with no stent patients at 30 days presented with increased rates of complication, including pneumonia, MI, sepsis, UTI, wound complications, and 30-day readmissions. Regression analysis showed no significant differences in complications between ST12 vs ST34 at 30 days, but at 90 days, ST34 was associated with significantly increased rate and odds of death (1.1% vs 0.3%, P = 0.021; OR 1.94 [95% CI 1.13-3.13], P = 0.01). CONCLUSION: Cardiac stents failed to normalize risk profile of patients with coronary artery disease. Postoperatively at 90 days, elective spine fusion patients with 3 or more stents were significantly at risk of mortality compared with patients with fewer or no stents.

Strategies to investigate and mitigate collider bias in genetic and Mendelian randomisation studies of disease progression.

Genetic studies of disease progression can be used to identify factors that may influence survival or prognosis, which may differ from factors that influence on disease susceptibility. Studies of disease progression feed directly into therapeutics for disease, whereas studies of incidence inform prevention strategies. However, studies of disease progression are known to be affected by collider (also known as "index event") bias since the disease progression phenotype can only be observed for individuals who have the disease. This applies equally to observational and genetic studies, including genome-wide association studies and Mendelian randomisation (MR) analyses. In this paper, our aim is to review several statistical methods that can be used to detect and adjust for index event bias in studies of disease progression, and how they apply to genetic and MR studies using both individual- and summary-level data. Methods to detect the presence of index event bias include the use of negative controls, a comparison of associations between risk factors for incidence in individuals with and without the disease, and an inspection of Miami plots. Methods to adjust for the bias include inverse probability weighting (with individual-level data), or Slope-Hunter and Dudbridge et al.'s index event bias adjustment (when only summary-level data are available). We also outline two approaches for sensitivity analysis. We then illustrate how three methods to minimise bias can be used in practice with two applied examples. Our first example investigates the effects of blood lipid traits on mortality from coronary heart disease, while our second example investigates genetic associations with breast cancer mortality.

Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study.

BACKGROUND: Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. METHODS: We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. RESULTS: Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98-1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00-1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04-1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77-1.22) and colon cancer (OR: 0.97, 95% CI: 0.76-1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90-1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). CONCLUSIONS: Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.

Should an Age Cutoff Be Considered for Elective Total Knee Arthroplasty Patients? An Analysis of Operative Success Based on Patient-Reported Outcomes.

Total knee arthroplasty (TKA) is increasing in the elderly population; however, some patients, family members, and surgeons raise age-related concerns over expected improvement and risks. This study aimed to (1) evaluate the relationship between age and change in patient-reported outcome measures (PROMs); (2) model how many patients would be denied improvements in PROMs if hypothetical age cutoffs were implemented; and (3) assess length of stay (LOS), readmission, reoperation, and mortality per age group. A prospective cohort of 4,396 primary TKAs (August 2015-August 2018) was analyzed. One-year PROMs were evaluated via Knee injury and Osteoarthritis Outcome Score (KOOS)-pain, -physical function short form (-PS), and -quality of life (-QOL), as well as Veterans Rand-12 (VR-12) physical (-PCS) and mental component (-MCS) scores. Positive predictive values (PPVs) of the number of postoperative "failures" (i.e., unattained minimal clinically important difference in PROMs) relative to number of hypothetically denied "successes" from a theoretical age-group restriction was estimated. KOOS-PS and QOL median score improvements were equivalent among all age groups (p = 0.946 and p = 0.467, respectively). KOOS-pain improvement was equivalent for ≥80 and 60-69-year groups (44.4 [27.8-55.6]). Median VR-12 PCS improvements diminished as age increased (15.9, 14.8, and 13.4 for the 60-69, 70-79, and ≥80 groups, respectively; p = 0.002) while improvement in VR-12 MCS was similar among age groups (p = 0.440). PPV for failure was highest in the ≥80 group, yet remained <34% for all KOOS measures. Overall mortality was highest in the ≥80 group (2.14%, n = 9). LOS >2, non-home discharge, and 90-day readmission were highest in the ≥80 group (8.11% [n = 24], p < 0.001; 33.7% [n = 109], p < 0.001; and 34.4% [n = 111], p = 0.001, respectively). Elderly patients exhibited similar improvement in PROMs to younger counterparts despite higher LOS, non-home discharge, and 90-day readmission. Therefore, special care pathways should be implemented for those age groups.