Heckman, Michael G.

Abstract Background: The CaPTC prostate cancer (CaP) Familial Cohort study (CaPFCS) was launched in 2017 to explore the CaP risk factors of African Black men (ABM). The study design is a prospective study that observes and follows healthy ABM and ABM diagnosed with CaP. Aim: The specific aim is to provide recommendations on statistical considerations for cohort studies focused on cancer disparities, based on lessons learned from the CaPTC CaPFCS. Methodology: Study participants were ABM in Cameroon, Nigeria, and the US. Using validated measures, data were collected mostly by self-administered or research assistant administered survey using paper survey (especially in Cameroon and Nigeria) with the responses transferred to REDCap by research coordinators. The statistical analysis for the CaPTC CaPFCS focused on the baseline epidemiological, behavioral, clinical and anthropometric measures of Black men. A total of 819 participants were included in the analyses. Statistical analyses included descriptive statistics (sample median, range, frequency and percentages) and unadjusted logistic regression models. Results: Data collection for the CaPTC CaPFCS were by multiple investigators/research coordinators at multiple sites in Cameroon, Nigeria, and the US. In preparation for the data analyses, we noted data entry errors and/or misinterpretation of data entry, which required extensive cleaning of the database prior to the analyses. The biostatisticians spent significant effort cleaning and ensuring data validity prior to the analyses. Confounding variables is another statistical consideration for cohort studies, such as the CaPTC CaPFCS. There was variability observed across age, education levels, employment status, household income and CaP diagnosis based on country of residence. CaP diagnosis was not reported by any of the ABM in the US, which may be due to the fact that they were all recruited within the community and no recruitment took place in the clinic. Finally, the CaPTC CaPFCS has several variables. Performing a lot of statistical tests may result in false-positive findings at P<0.05. Conclusion: The advantage of the CaPFCS is that it allows the CaPTC investigators to study epidemiological, behavioral, clinical and anthropometric variables associated with CaP over time. Being a longitudinal cohort study, investigators can track the changes in exposure and outcomes over time.However, statistical considerations need to be at the fore-front of multi-center, transatlantic cancer disparity studies such as the CaPTC CaPFCS, from data collection to data entry. The use of web-based survey with the ability to enter data directly into REDCaP will significantly reduce (if not totally eliminate) the need for database cleaning. There are multiple strategies that can be used to reduce confounder effect, including statistical adjustment and multivariate analysis to adjust for the confounders. The use of propensity score methods have especially been found to be effective in controlling baseline confounding factors. Citation Format: Daniel Lee, Michael Heckman, Zhongwei Peng, Emeka Iweala, Ademola Popoola, Paul Jibrin, Mohammed Faruk, Anthonia Sowumi, Omolara Fatiregun, Nkegoum Blaise, Catherine Oladoyinbo, Ifeoma Okoye, Abdulkadir Ayo Salako, Abidemi Omonisi, Iya Eze Bassey, Kayode Adeniji, Nggada Haruna Asura, Ernest Kaninjing, Oluwole Kukoyi, Fathi Parisa, Ruth Enuka, Oluwaseyi Toye, Jennifer Crook, CaPTC Investigators, Folakemi Odedina. Importance of statistical considerations in multi-center, transatlantic cancer disparity studies: Lessons learned from the CaPTC prostate cancer familial cohort study [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C004.

ObjectiveRecent evidence supports a link between increased TDP‐43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP‐43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP‐43 pathology and related neurodegeneration in the absence of typical AD pathologies.MethodsWe overexpressed human TDP‐43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe‐knockout (Apoe‐KO) mice. Behavior tests were performed across ages. Animals were harvested at 11 months of age and TDP‐43 overexpression‐related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP‐43 pathology in 160 postmortem brains from autopsy‐confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD‐MND) in the Mayo Clinic Brain Bank.ResultsWe found that TDP‐43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe‐KO mice. In the motor cortex of the ALS and FTLD‐MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP‐43‐positive dystrophic neurites.InterpretationOur data suggest a genotype‐specific effect of APOE on TDP‐43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. ANN NEUROL 2023;93:830–843

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often measured by Thal phase and Braak stage, respectively. Frequently, Aβ also deposits in the brain vasculature with severity categorized by a cerebral amyloid angiopathy (CAA) score. Assessment of these and related endophenotypes can reveal biological insights into the phenotypic variability in AD. We hypothesize that, amongst AD patients, severity of neuropathology and brain levels of AD‐related proteins are influenced by variation in DNA methylation (DNAm), the identification of which may uncover biological pathways for AD pathogenesis. To test this, we performed epigenome‐wide association studies (EWAS) using DNAm from the temporal cortex (TCX) and cerebellum (CER) with AD‐related neuropathology measures (Braak, Thal, and CAA) and brain levels of five proteins (apoE, Aβ40, Aβ42, tau, and p‐tau).MethodsDNAm from autopsy‐confirmed AD cases available through the Mayo Clinic Brain Bank was measured by reduced representation bisulfite sequencing (RRBS) from 471 brain samples, 200 of which had both TCX and CER measures. Bisulfite converted reads were sequenced on the Illumina High Seq4000 and quality filtered. Neuropathology scoring was performed by an experienced neuropathologist. TCX levels of five AD‐related proteins from three fractions (buffer‐soluble, detergent‐soluble, and insoluble) were measured by ELISA (Liu et al. 2020). Individual CpG methylation ratios were tested for association with each neuropathological and biochemical measure using the R package CpGassoc.ResultsWe identified multiple epigenome‐wide significant CpGs unique to each AD‐related measure. Comparisons between the TCX and CER revealed region specific CpG associations. The effects of sex, age at death, APOE genotype, and presence of genetic variants for each significant CpG association were also identified.ConclusionsAlthough all neuropathological and biochemical measures tested reflect core AD pathologies, our results demonstrate unique associations of epigenetic factors with these individual phenotypes, suggesting that their variability may be governed by distinct epigenetic processes. Discovery of DNAm changes that underlie specific neuropathological or biochemical outcomes can enhance our understanding of AD pathophysiology and may lead to the identification of novel gene or pathway targets for the different facets of this complex condition.

AbstractBackgroundInter‐cellular communication within the gliovascular unit (GVU) is critical for cerebral blood flow regulation, maintenance of the blood‐brain‐barrier (BBB) properties, and brain energy metabolism. Although numerous cell biology studies demonstrate the role of the GVU for BBB breakdown in Alzheimer’s disease (AD), the precise molecular changes contributing to its pathophysiology are unclear.MethodWe performed single nucleus RNA sequencing (snRNAseq) of temporal cortex tissue in 24 AD and control brains to understand the transcriptional changes in the cells of GVU. We acquired the snRNAseq profile of 79,751 total brain cells that comprise 6,541 astrocytes and 2,210 vascular cells. The latter formed three distinct vascular clusters characterized as activated pericytes, endothelia and resting pericytes. We identified differentially expressed genes (DEGs) and their enriched pathways in these clusters and detected the most transcriptional changes within activated pericytes. Using our data and a knowledge‐based predictive algorithm, we discovered and prioritized molecular interactions between vascular and astrocyte clusters, the main cell types of the GVU of the BBB.ResultsVascular targets predicted to interact with astrocytic ligands have biological functions in signalling, angiogenesis, amyloid ß metabolism and cytoskeletal structure. Top astrocytic and vascular interacting molecules include both novel and known AD risk genes such as APOE, APP and ECE1. We validated gene expression changes using qPCR. We are in the process of evaluating these gene expression changes in antemortem blood from AD and control participants.ConclusionOur findings provide valuable information into the transcriptional changes in predicted vascular‐astrocytic partners at the GVU, highlighting insights into the molecular mechanisms of BBB breakdown in AD.

Mutations in the CSF1R gene are the most common cause of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a neurodegenerative disease with rapid progression and ominous prognosis. Hematopoietic stem cell transplantation (HSCT) has been increasingly offered to patients with CSF1R-ALSP. However, different therapy results were observed, and it was not elucidated which patient should be referred for HSCT. This study aimed to determine predictors of good and bad HSCT outcomes in CSF1R-ALSP. We retrospectively analyzed 15 patients, 14 symptomatic and 1 asymptomatic, with CSF1R-ALSP that underwent HSCT. Median age of onset was 39 years, and the median age of HSCT was 43 years. Cognitive impairment was the most frequent initial manifestation (43%), followed by gait problems (21%) and neuropsychiatric symptoms (21%). Median post-HSCT follow-up was 26 months. Good outcomes were associated with gait problems as initial (p = 0.041) and predominant (p = 0.017) manifestation and younger age at HSCT (p = 0.044). Cognitive impairment as first manifestation was a predictor of a bad outcome (p = 0.016) and worsening of cognition post-HSCT (p = 0.025). In conclusion, gait problems indicated a milder phenotype with better response to HSCT and good therapy outcomes. In contrast, patients with a higher burden of cognitive symptoms were most likely not to benefit from HSCT.

Abstract Purpose: The purpose of this pilot study was to examine the clinical efficacy and safety of serial triamcinolone injections for the treatment of desmoid tumors. Patients and Methods: Nine patients were enrolled into this prospective study and underwent three serial ultrasound-guided triamcinolone injections (120 mg) at 6-week intervals. MRI was compared at baseline and every 6 months, out to 24 months. Safety and tolerability were assessed by clinical evaluation and questionnaires, including the 12-item short form survey (SF-12), visual analog scale (VAS), and desmoid patient-reported outcome (PRO) tool. Results: At 24 months, 8 (88.9%) patients demonstrated a reduction in the volume of their tumor while 1 (11.1%) enlarged. Median tumor volume change was −26.9% (−81.1% to 34.6%; P = 0.055) All 9 tumors remained stable based on World Health Organization criteria, whereas 2 (22.2%) demonstrated partial response based on RECIST. There was a significant decrease in the tumor:muscle postcontrast mean signal intensity ratio at 6 months (P = 0.008) and 24 months (P = 0.004). There was a similar decrease in the tumor:muscle T2 mean signal intensity ratio at 24 months (P = 0.02). We found no difference in the SF-12 and VAS scores, but there were significant improvements in the desmoid PRO. Conclusions: Treatment of desmoid tumors with serial triamcinolone injections appears safe and well tolerated by patients, with a 22% partial response based on RECIST. Further research is needed to confirm our results and determine factors predictive of response.

Introduction: Urinary tract infections (UTI) are one of the most common infections encountered in the emergency department (ED) with an estimated 2-3 million annual visits. Commonly prescribed antibiotics for UTIs have shown growing rates of resistance. Previous studies lack direction on improving UTI treatment based on the labs available to the bedside clinician. Methods: We sought to determine if antibiotic resistance in UTIs was related to demographics, urinalysis, and history of renal failure or kidney stones. We conducted an analysis of 892 women ≥18 years of age discharged from the ED with a UTI diagnosis. We assessed predictors of nitrofurantoin resistance, cefazolin resistance, ciprofloxacin resistance, and trimethoprim-sulfamethoxazole resistance using unadjusted and multivariable logistic regression models. Results: Antibiotic resistance was 13.6% for nitrofurantoin, 11.9% for cefazolin, 12.8% for ciprofloxacin, and 17.1% for trimethoprim-sulfamethoxazole. In multivariable analysis, significant independent associations with an increased likelihood of resistance to nitrofurantoin were observed for less urine blood (OR [per 1 category increase of score] 0.81; P = 0.02); greater mucous (OR [per 1 category increase of score] 1.22; P = 0.02); less specific gravity urine (OR [per 1 category increase] 0.87; P = 0.04), and presence of any history of kidney stones (OR 3.24; P = 0.01). There were no significant predictors for cefazolin resistance (all P ≥0.06); age was the only significant predictor of ciprofloxacin resistance (OR per 10 year increase] 1.10, P = 0.05), and lower specific gravity urine was significantly associated with an increased risk of resistance to trimethoprim- sulfamethoxazole (OR [per 1 category increase] 0.88, P = 0.04). Conclusion: Women with any history of kidney stones may have bacteriuria resistant to nitrofurantoin, suggesting that providers might consider alternative antibiotic therapies in this scenario.

Introduction Total knee arthroplasty is a common operation performed to relieve pain and restore functional activity. While overall widely successful, a subset of patients has continued pain postoperatively with no identifiable cause. Neuroma formation has been identified as a possible contributor to this unexplained pain, often necessitating an additional procedure for neuroma removal. The purpose of our study was to evaluate if prophylactic neurectomy could reduce the occurrence of postoperative pain. Methods A total of 112 patients were compared, 44 control patients and 68 neurectomy patients. Demographic information, Numerical rating pain scale (NRS) and Knee Society Scores (KSS) were collected pre- and post-operatively. Patients were additional asked if they were overall satisfied with the operation. Results There were no differences between groups with respect to age (Median: 71 vs 69 years, p = 0.28), male sex (41% vs 44%, p = 0.85), or body mass index (Median: 32.2 vs 31.3, p = 0.80). When comparing the degree of change following surgery there were no statistically significant differences observed in NRS pain scores (Median change: −7 vs −6, p = 0.89) or KSS scores (Median change: +44 vs +40, p = 0.14). Similarly, there was no statistically significant difference in overall patient-reported satisfaction with the knee replacement (82.5% vs 86.6%, p = 0.59). Conclusion We did not find a statistically significant difference in NRS, KSS, or overall patient satisfaction between the prophylactic neurectomy and control patient groups. Larger studies with evaluation of the nerve diameter will be needed to determine which patients are at risk for symptomatic neuroma development following total knee arthroplasty.