Faculty Bibliography

Rheumatoid arthritis (RA) is hypothesized to be associated with cognitive impairment and dementia, including Alzheimer's disease, through shared biological processes related to inflammation. It is important to elucidate this potential relationship as both conditions confer increased morbidity and even mortality among older adults. This narrative review provides a survey of recent epidemiologic studies, examining the association between rheumatoid arthritis and either dementia or cognitive impairment. Sixteen studies were included after searching in PubMed and EMBASE. All were published between 2012 and 2022 and were characterized as epidemiologic studies (either cohort, cross-sectional, or case-control). Studies varied in location, design, measures of exposure and outcome, and covariates considered. Of the 16 studies included, only five found statistically significant positive associations between RA and dementia or cognitive impairment. One study found an inverse relationship, while five studies found no associations at all. The remaining five studies found variable statistically significant associations between demographic or RA disease characteristics and cognitive measures. Given these mixed findings, further studies at both the mechanistic and population level are needed to clarify the possible shared biological underpinnings of these two conditions.

BACKGROUND:Spectral-domain (SD-) optical coherence tomography (OCT) can reliably measure axonal (peripapillary retinal nerve fiber layer [pRNFL]) and neuronal (macular ganglion cell + inner plexiform layer [GCIPL]) thinning in the retina. Measurements from 2 commonly used SD-OCT devices are often pooled together in multiple sclerosis (MS) studies and clinical trials despite software and segmentation algorithm differences; however, individual pRNFL and GCIPL thickness measurements are not interchangeable between devices. In some circumstances, such as in the absence of a consistent OCT segmentation algorithm across platforms, a conversion equation to transform measurements between devices may be useful to facilitate pooling of data. The availability of normative data for SD-OCT measurements is limited by the lack of a large representative world-wide sample across various ages and ethnicities. Larger international studies that evaluate the effects of age, sex, and race/ethnicity on SD-OCT measurements in healthy control participants are needed to provide normative values that reflect these demographic subgroups to provide comparisons to MS retinal degeneration. METHODS:Participants were part of an 11-site collaboration within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. SD-OCT was performed by a trained technician for healthy control subjects using Spectralis or Cirrus SD-OCT devices. Peripapillary pRNFL and GCIPL thicknesses were measured on one or both devices. Automated segmentation protocols, in conjunction with manual inspection and correction of lines delineating retinal layers, were used. A conversion equation was developed using structural equation modeling, accounting for clustering, with healthy control data from one site where participants were scanned on both devices on the same day. Normative values were evaluated, with the entire cohort, for pRNFL and GCIPL thicknesses for each decade of age, by sex, and across racial groups using generalized estimating equation (GEE) models, accounting for clustering and adjusting for within-patient, intereye correlations. Change-point analyses were performed to determine at what age pRNFL and GCIPL thicknesses exhibit accelerated rates of decline. RESULTS:The healthy control cohort (n = 546) was 54% male and had a wide distribution of ages, ranging from 18 to 87 years, with a mean (SD) age of 39.3 (14.6) years. Based on 346 control participants at a single site, the conversion equation for pRNFL was Cirrus = -5.0 + (1.0 × Spectralis global value). Based on 228 controls, the equation for GCIPL was Cirrus = -4.5 + (0.9 × Spectralis global value). Standard error was 0.02 for both equations. After the age of 40 years, there was a decline of -2.4 μm per decade in pRNFL thickness ( P < 0.001, GEE models adjusting for sex, race, and country) and -1.4 μm per decade in GCIPL thickness ( P < 0.001). There was a small difference in pRNFL thickness based on sex, with female participants having slightly higher thickness (2.6 μm, P = 0.003). There was no association between GCIPL thickness and sex. Likewise, there was no association between race/ethnicity and pRNFL or GCIPL thicknesses. CONCLUSIONS:A conversion factor may be required when using data that are derived between different SD-OCT platforms in clinical trials and observational studies; this is particularly true for smaller cross-sectional studies or when a consistent segmentation algorithm is not available. The above conversion equations can be used when pooling data from Spectralis and Cirrus SD-OCT devices for pRNFL and GCIPL thicknesses. A faster decline in retinal thickness may occur after the age of 40 years, even in the absence of significant differences across racial groups.

PURPOSE OF REVIEW/OBJECTIVE:Toxic metal exposures have been associated with cardiovascular disease in adults and growing evidence suggests metal exposures also adversely affect cardiovascular phenotypes in childhood and adolescence. However, to our knowledge, the influence of perinatal metals exposure, particularly metal mixtures, in relation to cardiovascular-related outcomes have not been comprehensively reviewed. RECENT FINDINGS/RESULTS:We summarized 17 contemporary studies (2017-2021) that investigated the impact of perinatal metal exposures on measures of cardiovascular health in children. Accumulating evidence supports a potential adverse impact of perinatal Pb exposure on BP in children. Fewer recent studies have focused on perinatal As, Hg, and Cd; thus, the cardiovascular impacts of these metals are less clear. Studies of metal mixtures demonstrate that interactions between metals may be complex and have identified numerous understudied elements and essential metals, including Mo, Co, Ni, Se, Zn, and Mn, which may influence cardiovascular risk. A key question that remains is whether perinatal metals exposure influences cardiovascular health into adulthood. Comparisons across studies remain challenging due to several factors, including differences in the timing of exposure/outcome assessments and exposure biomarkers, as well as variability in exposure levels and mixture compositions across populations. Future studies longitudinally investigating trajectories of cardiovascular outcomes could help determine the influence of perinatal metals exposure on long-term effects of clinical relevance in later life and whether interventions, which reduce metals exposures during this key developmental window, could alter disease development.

The incidence of esophageal adenocarcinoma (EA) has drastically increased in the United States since 1970s for unclear reasons. We hypothesized that the widespread usage of antibiotics has increased the procarcinogenic potential of the orodigestive microbiota along the sequence of gastroesophageal reflux (GR), Barrett's esophagus (BE) and EA phenotypes. This case control study included normal controls (NC) and three disease phenotypes GR, BE and EA. Microbiota in the mouth, esophagus, and stomach, and rectum were analyzed using 16S rRNA gene sequencing. Overall, we discovered 44 significant pairwise differences in abundance of microbial taxa between the four phenotypes, with 12 differences in the mouth, 21 in the esophagus, two in the stomach, and nine in the rectum. Along the GR→BE→EA sequence, oral and esophageal microbiota were more diversified, the dominant genus Streptococcus was progressively depleted while six other genera Atopobium, Actinomyces, Veillonella, Ralstonia, Burkholderia and Lautropia progressively enriched. In NC, Streptococcus appeared to control populations of other genera in the foregut via numerous negative and positive connections, while in disease states, the rich network was markedly simplified. Inferred gene functional content showed a progressive enrichment through the stages of EA development in genes encoding antibiotic resistance, ligands of Toll-like and NOD-like receptors, nitrate-nitrite-nitric oxide pathway and acetaldehyde metabolism. The orodigestive microbiota is in a progressive dysbiotic state along the GR-BE-EA sequence. The increasing dysbiosis and antibiotic and procarcinogenic genes in the disease states warrants further study to define their roles in EA pathogenesis.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Recent studies have suggested that inter-eye differences (IEDs) in peripapillary retinal nerve fiber layer (pRNFL) or ganglion cell+inner plexiform (GCIPL) thickness by spectral-domain optical coherence tomography (SD-OCT) may identify people with a history of unilateral optic neuritis (ON). However, this requires further validation. Machine learning classification may be useful for validating thresholds for OCT IEDs and for examining added utility for visual function tests, such as low-contrast letter acuity (LCLA), in the diagnosis of people with multiple sclerosis (PwMS) and for unilateral ON history. METHODS:Participants were from 11 sites within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. pRNFL and GCIPL thicknesses were measured using SD-OCT. A composite score combining OCT and visual measures was compared individual measurements to determine the best model to distinguish PwMS from controls. These methods were also used to distinguish those with history of ON among PwMS. ROC curve analysis was performed on a training dataset (2/3 of cohort), then applied to a testing dataset (1/3 of cohort). Support vector machine (SVM) analysis was used to assess whether machine learning models improved diagnostic capability of OCT. RESULTS:Among 1,568 PwMS and 552 controls, variable selection models identified GCIPL IED, average GCIPL thickness (both eyes), and binocular 2.5% LCLA as most important for classifying PwMS vs. controls. This composite score performed best, with AUC=0.89 (95% CI 0.85, 0.93), sensitivity=81% and specificity=80%. The composite score ROC curve performed better than any of the individual measures from the model (p<0.0001). GCIPL IED remained the best single discriminator of unilateral ON history among PwMS (AUC=0.77, 95% CI 0.71,0.83, sensitivity=68%, specificity=77%). SVM analysis performed comparably to standard logistic regression models. CONCLUSIONS:A composite score combining visual structure and function improved the capacity of SD-OCT to distinguish PwMS from controls. GCIPL IED best distinguished those with history of unilateral ON. SVM performed as well as standard statistical models for these classifications. CLASSIFICATION OF EVIDENCE/METHODS:The study provides Class III evidence that SD-OCT accurately distinguishes multiple sclerosis from normal controls as compared to clinical criteria.

BACKGROUND:Neighborhood walkability (NW) has been linked to increased physical activity, which in turn is associated with lower concentrations of sex hormones and higher concentration of SHBG in women. However, no study has directly examined the association of NW with female sex hormone levels. OBJECTIVE:We conducted a cross-sectional study to evaluate the association between NW and circulating levels of sex hormones and SHBG in pre- and post-menopausal women. METHODS:We included 797 premenopausal and 618 postmenopausal women from the New York University Women's Health Study (NYUWHS) who were healthy controls in previous nested case-control studies in which sex hormones (androstenedione, testosterone, DHEAS, estradiol and estrone) and SHBG had been measured in serum at enrollment. Baseline residential addresses were geo-coded and the Built Environment and Health Neighborhood Walkability Index (BEH-NWI) was calculated. Generalized Estimating Equations were used to assess the association between BEH-NWI and sex hormone and SHBG concentrations adjusting for individual- and neighborhood-level factors. RESULTS:In premenopausal women, a one standard deviation (SD) increment in BEH-NWI was associated with a 3.5% (95% CI 0.9%-6.1%) lower DHEAS concentration. In postmenopausal women, a one SD increment in BEH-NWI was related to an 8.5% (95% CI 5.4%-11.5%) lower level of DHEAS, a 3.7% (95% CI 0.5%-6.8%) lower level of testosterone, a 1.8% (95% CI 0.5%-3.0%) lower level of estrone, and a 4.2% (95% CI 2.7%-5.7%) higher level of SHBG. However, the associations with respect to DHEAS and estrone became apparent only after adjusting for neighborhood-level variables. Sensitivity analyses using fixed effects meta-analysis and inverse probability weighting accounting for potential selection bias yielded similar results. CONCLUSION/CONCLUSIONS:Our findings suggest that NW is associated with lower concentrations of androgens and estrone, and increased SHBG, in postmenopausal women, and lower levels of DHEAS in premenopausal women.

BACKGROUND:This study was performed to investigate the association between body mass index (BMI) and gastric cancer (GC) in East and Southeast Asia where most of GC is non-cardia GC. METHODS:Based on 8,997 GC cases among the Asia Cohort Consortium participants from China, Japan, Korea, and Singapore (N=538,835), we assessed GC risk according to BMI by calculating hazard ratios (HRs) and 95% confidence intervals (CIs) using the Cox proportional hazard regression model. RESULTS:A U-shaped associations between BMI and GC risk were observed. GC risks in underweight group (<18.5 kg/m2) and in obesity group (≥27.5 kg/m2) were higher than reference BMI group (23-24.9 kg/m2) (HR=1.15, 95% CI 1.05-1.25 for underweight; HR=1.12, 95% CI 1.03-1.22 for obesity, respectively). The associations of underweight and obesity with GC risk were consistent in the analyses for non-cardia GC, intestinal type GC, and late onset GC. No significant association of underweight and obesity with the risk of cardia GC, diffuse type GC, and early onset GC was observed. Additionally, we found that the U-shaped association between BMI and GC risk remained in non-smokers, while only underweight was related to increased GC risk in smokers. CONCLUSIONS:BMI has a U-shaped association with GC risk in East and Southeast Asian population, especially for the non-cardia GC, intestinal type GC, and late onset GC. IMPACT/CONCLUSIONS:Future studies with consideration of anatomical location and histology of GC are needed to establish the association of underweight as well as obesity with GC risk.

BACKGROUND:The association between body mass index (BMI) and oesophageal cancer (OC) has been consistently negative among Asians, whereas different associations based on histological OC subtypes have been observed in Europeans and North Americans. We examined the association between BMI and OC mortality in the Asia Cohort Consortium. METHODS:We performed a pooled analysis to evaluate the association between BMI and OC mortality among 842 630 Asians from 18 cohort studies. Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS:A wide J-shaped association between BMI and overall OC mortality was observed. The OC mortality risk was increased for underweight (BMI <18.5 kg/m2: HR = 2.20, 95% CI 1.80-2.70) and extreme obesity (BMI ≥35 kg/m2: HR = 4.38, 95% CI 2.25-8.52) relative to the reference BMI (23-25 kg/m2). This association pattern was confirmed by several alternative analyses based on OC incidence and meta-analysis. A similar wide J-shaped association was observed in oesophageal squamous cell carcinoma (OSCC). Smoking and alcohol synergistically increased the OC mortality risk in underweight participants (HR = 6.96, 95% CI 4.54-10.67) relative to that in reference BMI participants not exposed to smoking and alcohol. CONCLUSION/CONCLUSIONS:Extreme obesity and being underweight were associated with an OC mortality risk among Asians. OC mortality and BMI formed a wide J-shaped association mirrored by OSCC mortality. Although the effect of BMI on OSCC and oesophageal adenocarcinoma mortality can be different in Asians, further research based on a large case-control study is recommended.

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer with limited meaningful treatment options. NEPC lesions uniquely express delta-like ligand 3 (DLL3) on their cell surface. Taking advantage of DLL3 overexpression, we developed and evaluated lutetium-177 (¹⁷⁷Lu)-labeled DLL3-targeting antibody SC16 (¹⁷⁷Lu-DTPA-SC16) as a treatment for NEPC. SC16 was functionalized with DTPA-CHX-A" chelator and radiolabeled with ¹⁷⁷Lu to produce ¹⁷⁷Lu-DTPA-SC16. Specificity and selectivity of ¹⁷⁷Lu-DTPA-SC16 were evaluated in vitro and in vivo using NCI-H660 (NEPC, DLL3-positive) and DU145 (adenocarcinoma, DLL3-negative) cells and xenografts. Dose-dependent treatment efficacy and specificity of ¹⁷⁷Lu-DTPA-SC16 radionuclide therapy were evaluated in H660 and DU145 xenograft-bearing mice. Safety of the agent was assessed by monitoring hematologic parameters. ¹⁷⁷Lu-DTPA-SC16 showed high tumor uptake and specificity in H660 xenografts, with minimal uptake in DU145 xenografts. At all three tested doses of ¹⁷⁷Lu-DTPA-SC16 (4.63, 9.25, and 27.75 MBq/mouse), complete responses were observed in H660-bearing mice; 9.25 and 27.75 MBq/mouse doses were curative. Even the lowest tested dose proved curative in five (63%) of eight mice, and recurring tumors could be successfully re-treated at the same dose to achieve complete responses. In DU145 xenografts, ¹⁷⁷Lu-DTPA-SC16 therapy did not inhibit tumor growth. Platelets and hematocrit transiently dropped, reaching nadir at 2 to 3 wk. This was out of range only in the highest-dose cohort and quickly recovered to normal range by week 4. Weight loss was observed only in the highest-dose cohort. Therefore, our data demonstrate that ¹⁷⁷Lu-DTPA-SC16 is a potent and safe radioimmunotherapeutic agent for testing in humans with NEPC.