Citations

Background: App-based technologies could enhance patient and caregiver communication and provide alerts that potentially reducing readmissions. However, the burden of App alerts needs to be optimized to reduce provider burnout. Aim: The purpose of this study was to determine subjective and objective burden of using the Patient Buddy App, a health information technology (HIT) on providers in a randomized multicenter trial, who completed a semi-quantitative Likert scale survey regarding training procedures, data and privacy concerns, follow-up details, and technical support. This randomized multicenter trial recruits cirrhosis inpatients and their caregivers, and randomizes them into standard-of-care, HIT (communication only via App) and HIT+visits (App+phone calls/visits) for 30 days after discharge. The alerts are monitored by providers through a central iPad. The reason(s) and number of alerts were recorded as the objective burden. A total of 1442 messages were sent as alerts from the 103 dyads (patient + caregiver) (n=206) randomized to HIT arms. The most common messages related to Hepatic Encephalopathy (HE) (high or low bowel movement=50% or orientation tests=37%). Twelve providers completed the surveys reflecting the following themes—92% and 100%, felt adequately trained and confident about educating the patients and caregivers before roll out of App and had no concerns related to data and privacy; 70%, felt that appropriate time was spent on pursuing reason for data not being logged; 60% each, had issues with availability of adequate technical support and connectivity. Conclusion: The Patient Buddy App randomized multicenter trial till date shows an overall favorable rating regarding training procedures/education, privacy concerns, and ease of message follow-up, from providers. However, it is important to gauge and address subjective and objective burdens of monitoring human resources in current and future HIT studies to avoid burnout and to ensure successful study completion.

Abstract Digital pathology (DP) has transformative potential, especially for Alzheimer disease and related disorders. However, infrastructure barriers may limit adoption. To provide benchmarks and insights into implementation barriers, a survey was conducted in 2019 within National Institutes of Health’s Alzheimer’s Disease Centers (ADCs). Questions covered infrastructure, funding sources, and data management related to digital pathology. Of the 35 ADCs to which the survey was sent, 33 responded. Most respondents (81%) stated that their ADC had digital slide scanner access, with the most frequent brand being Aperio/Leica (62.9%). Approximately a third of respondents stated there were fees to utilize the scanner. For DP and machine learning (ML) resources, 41% of respondents stated none was supported by their ADC. For scanner purchasing and operations, 50% of respondents stated they received institutional support. Some were unsure of the file size of scanned digital images (37%) and total amount of storage space files occupied (50%). Most (76%) were aware of other departments at their institution working with ML; a similar (76%) percentage were unaware of multiuniversity or industry partnerships. These results demonstrate many ADCs have access to a digital slide scanner; additional investigations are needed to further understand hurdles to implement DP and ML workflows.

Abstract Background The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC. Methods LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source. Results LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes. Conclusions LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

Importance Both tumor-infiltrating lymphocytes (TILs) assessment and immune-related gene expression signatures by RNA profiling predict higher pathologic complete response (pCR) and improved event-free survival (EFS) in patients with early-stage ERBB2/HER2-positive breast cancer. However, whether these 2 measures of immune activation provide similar or additive prognostic value is not known. Objective To examine the prognostic ability of TILs and immune-related gene expression signatures, alone and in combination, to predict pCR and EFS in patients with early-stage ERBB2/HER2-positive breast cancer treated in 2 clinical trials. Design, Setting, and Participants In this prognostic study, a correlative analysis was performed on the Cancer and Leukemia Group B (CALGB) 40601 trial and the PAMELA trial. In the CALGB 40601 trial, 305 patients were randomly assigned to weekly paclitaxel with trastuzumab, lapatinib, or both for 16 weeks. The primary end point was pCR, with a secondary end point of EFS. In the PAMELA trial, 151 patients received neoadjuvant treatment with trastuzumab and lapatinib for 18 weeks. The primary end point was the ability of the HER2-enriched subtype to predict pCR. The studies were conducted from October 2013 to November 2015 (PAMELA) and from December 2008 to February 2012 (CALGB 40601). Data analyses were performed from June 1, 2020, to January 1, 2022. Main Outcomes and Measures Immune-related gene expression profiling by RNA sequencing and TILs were assessed on 230 CALGB 40601 trial pretreatment tumors and 138 PAMELA trial pretreatment tumors. The association of these biomarkers with pCR (CALGB 40601 and PAMELA) and EFS (CALGB 40601) was studied by logistic regression and Cox analyses. Results The median age of the patients was 50 years (IQR, 42-50 years), and 305 (100%) were women. Of 202 immune signatures tested, 166 (82.2%) were significantly correlated with TILs. In both trials combined, TILs were significantly associated with pCR (odds ratio, 1.01; 95% CI, 1.01-1.02; P = .02). In addition to TILs, 36 immune signatures were significantly associated with higher pCR rates. Seven of these signatures outperformed TILs for predicting pCR, 6 of which were B-cell related. In a multivariable Cox model adjusted for clinicopathologic factors, including PAM50 intrinsic tumor subtype, the immunoglobulin G signature, but not TILs, was independently associated with EFS (immunoglobulin G signature–adjusted hazard ratio, 0.63; 95% CI, 0.42-0.93; P = .02; TIL-adjusted hazard ratio, 1.00; 95% CI, 0.98-1.02; P = .99). Conclusions and Relevance Results of this study suggest that multiple B-cell–related signatures were more strongly associated with pCR and EFS than TILs, which largely represent T cells. When both TILs and gene expression are available, the prognostic value of immune-related signatures appears to be superior.

Abstract TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a co-inhibitory receptor, highly expressed by Tregs, and contributes to the suppressive function of Tregs by limiting pro-inflammatory Th1 and Th17 cell responses. Herein, we report that subsets of human regulatory B cells (Bregs) express surface TIGIT and can thus play a critical role in immune regulation. Using data from human B cell surface arrays and RNA-seq, we identified two major TIGIT+ human Bregs subsets, exhibiting CD24hiCD27+CD39hiIgD+IgMhiCD1chi marginal zone (MZ)-like and CD24hiCD27+CD39+IgD−IgM+CD1c+ memory Bregs. We further demonstrated that TIGIT+ Bregs were also capable of suppressing immune responses by their ability to express not only IL-10 and PD-L1, but also granzyme B and TGFb1. In addition, TIGIT+ Bregs can also suppress immune responses by altering dendritic cell functions. In line with these observations, liver allograft recipients with donor-specific alloantibody (DSA) had significantly lower numbers of TIGIT+ Bregs than those without DSA. Moreover, the frequency of TIGIT+ Bregs correlated with that of CD4+CD25+CD127lo Tregs, while it inversely correlated with the frequency of follicular helper T cells. We thus concluded that TIGIT+ Bregs play critical roles in immune regulation in liver allograft recipients.

Abstract Background: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10−8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20–1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10−8) and 8q24.23 (rs7005722, P = 2.88 × 10−8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09–1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07–1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. Impact: These findings can guide potential prevention treatments.

AbstractChildhood spinal tumors are rare. Tumors can involve the spinal cord, the meninges, bony spine, and the paraspinal tissue. Optimized imaging should be utilized to evaluate tumors arising from specific spinal compartments. This paper provides consensus‐based recommendations for optimized imaging of tumors arising from specific spinal compartments at diagnosis, follow‐up during and after therapy, and response assessment.

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

AbstractImaging in hematopoietic stem cell transplantation patients is not targeted at evaluating the transplant per se. Rather, imaging is largely confined to evaluating peri‐procedural and post‐procedural complications. Alternatively, imaging may be performed to establish a baseline study for comparison should the patient develop certain post‐procedural complications. This article looks to describe the various imaging modalities available with recommendations for which imaging study should be performed in specific complications. We also provide select imaging protocols for different indications and modalities for the purpose of establishing a set minimal standard for imaging in these complex patients.