Faculty Bibliography

INTRODUCTION/BACKGROUND:Family caregivers of people with advanced Parkinson's Disease (PD) are at high risk of caregiver strain, which independently predicts adverse patient outcomes. We tested the effects of one year of interdisciplinary, telehealth-enhanced home visits (IN-HOME-PD) with 16 weeks of peer mentoring on caregiver strain compared with usual care. METHODS:We enrolled homebound people with advanced PD (PWPD) and their primary caregiver as IN-HOME-PD dyads. We trained experienced PD family caregivers as peer mentors. Dyads received four structured home visits focused on advanced symptom management, home safety, medications, and psychosocial needs. Starting at approximately four months, caregivers spoke weekly with a peer mentor for 16 weeks. We compared one-year change in caregiver strain (MCSI, range 0-72) with historical controls, analyzed intervention acceptability, and measured change in anxiety, depression, and self-efficacy. RESULTS:Longitudinally, IN-HOME-PD caregiver strain was unchanged (n = 51, 23.34 (SD 9.43) vs. 24.32 (9.72), p = 0.51) while that of controls worsened slightly (n = 154, 16.45 (10.33) vs. 17.97 (10.88), p = 0.01). Retention in peer mentoring was 88.2%. Both mentors and mentees rated 100% of mentoring calls useful, with mean satisfaction of 91/100 and 90/100, respectively. There were no clinically significant improvements in anxiety, depression, or self-efficacy. CONCLUSIONS:Interdisciplinary telehealth-enhanced home visits combined with peer mentoring mitigated the worsening strain observed in caregivers of less advanced individuals. Mentoring was met with high satisfaction. Future caregiver-led peer mentoring interventions are warranted given the growing, unmet needs of PD family caregivers. TRIAL REGISTRATION/BACKGROUND:NCT03189459.

INTRODUCTION/BACKGROUND:Oral cancer patients suffer severe chronic and mechanically-induced pain at the site of the cancer. Our clinical experience is that oral cancer patients report new sensitivity to spicy foods. We hypothesized that in cancer patients, mechanical and chemical sensitivity would be greater when measured at the cancer site compared to a contralateral matched normal site. METHODS:We determined mechanical pain thresholds (MPT) on the right and left sides of the tongue of 11 healthy subjects, and at the cancer and contralateral matched normal site in 11 oral cancer patients in response to von Frey filaments in the range of 0.008 to 300 g (normally not reported as painful). We evaluated chemical sensitivity in 13 healthy subjects and seven cancer patients, who rated spiciness/pain on a visual analog scale in response to exposure to six paper strips impregnated with capsaicin (0-10 mM). RESULTS:Mechanical detection thresholds (MDT) were recorded for healthy subjects, but not MPTs. By contrast, MPTs were measured at the site of the cancer in oral cancer patients (7/11 patients). No MPTs were measured at the cancer patients' contralateral matched normal sites. Measured MPTs were correlated with patients' responses to the University of California Oral Cancer Pain Questionnaire. Capsaicin sensitivity at the site of the cancer was evident in cancer patients by a leftward shift of the cancer site capsaicin dose-response curve compared to that of the patient's contralateral matched normal site. We detected no difference in capsaicin sensitivity on the right and left sides of tongues of healthy subjects. CONCLUSIONS:Mechanical and chemical sensitivity testing was well tolerated by the majority of oral cancer patients. Sensitivity is greater at the site of the cancer than at a contralateral matched normal site.

In light of the National Institute of Mental Health (NIMH)'s Research Domain Criteria (RDoC), the advent of functional neuroimaging, novel technologies and methods provide new opportunities to develop precise and personalized prognosis and diagnosis of mental disorders. Machine learning (ML) and artificial intelligence (AI) technologies are playing an increasingly critical role in the new era of precision psychiatry. Combining ML/AI with neuromodulation technologies can potentially provide explainable solutions in clinical practice and effective therapeutic treatment. Advanced wearable and mobile technologies also call for the new role of ML/AI for digital phenotyping in mobile mental health. In this review, we provide a comprehensive review of ML methodologies and applications by combining neuroimaging, neuromodulation, and advanced mobile technologies in psychiatry practice. We further review the role of ML in molecular phenotyping and cross-species biomarker identification in precision psychiatry. We also discuss explainable AI (XAI) and neuromodulation in a closed human-in-the-loop manner and highlight the ML potential in multi-media information extraction and multi-modal data fusion. Finally, we discuss conceptual and practical challenges in precision psychiatry and highlight ML opportunities in future research.

Mechanisms of Alzheimer's disease (AD) and its putative prodromal stage, amnestic mild cognitive impairment (aMCI), involve the dysregulation of multiple candidate molecular pathways that drive selective cellular vulnerability in cognitive brain regions. However, the spatiotemporal overlap of markers for pathway dysregulation in different brain regions and cell types presents a challenge for pinpointing causal versus epiphenomenal changes characterizing disease progression. To approach this problem, we performed Weighted Gene Co-expression Network Analysis and STRING interactome analysis of gene expression patterns quantified in frontal cortex samples (Brodmann area 10) from subjects who died with a clinical diagnosis of no cognitive impairment, aMCI, or mild/moderate AD. Frontal cortex was chosen due to the relatively protracted involvement of this region in AD, which might reveal pathways associated with disease onset. A co-expressed network correlating with clinical diagnosis was functionally associated with insulin signaling, with insulin (INS) being the most highly connected gene within the network. Co-expressed networks correlating with neuropathological diagnostic criteria (e.g., NIA-Reagan Likelihood of AD) were associated with platelet-endothelium-leucocyte cell adhesion pathways and hypoxia-oxidative stress. Dysregulation of these functional pathways may represent incipient alterations impacting disease progression and the clinical presentation of aMCI and AD.

Numerous applications in molecular biology and genomics require characterization of mutant DNA molecules present at low levels within a larger sample of non-mutant DNA. This is often achieved either by selectively amplifying mutant DNA, or by sequencing all the DNA followed by computational identification of the mutant DNA. However, selective amplification is challenging for insertions and deletions (indels). Additionally, sequencing all the DNA in a sample may not be cost effective when only the presence of a mutation needs to be ascertained rather than its allelic fraction. The MutS protein evolved to detect DNA heteroduplexes in which the two DNA strands are mismatched. Prior methods have utilized MutS to enrich mutant DNA by hybridizing mutant to non-mutant DNA to create heteroduplexes. However, the purity of heteroduplex DNA these methods achieve is limited because they can only feasibly perform one or two enrichment cycles. We developed a MutS-magnetic bead system that enables rapid serial enrichment cycles. With six cycles, we achieve complete purification of heteroduplex indel DNA originally present at a 5% fraction and over 40-fold enrichment of heteroduplex DNA originally present at a 1% fraction. This system may enable novel approaches for enriching mutant DNA for targeted sequencing. This article is protected by copyright. All rights reserved.

Purpose/Objective(s): To assess late gastrointestinal (GI) and genitourinary (GU) toxicities of intensity-modulated proton therapy (IMPT) targeting the prostate/seminal vesicles and regional pelvic lymph nodes for high risk (HR) or unfavorable intermediate risk (UIR) prostate cancer (Pca). Materials/Methods: A prospective study (ClinicalTrials.gov: NCTXXX) to evaluate a moderately hypofractionated regimen of IMPT for HR-Pca or UIR-Pca accrued a target sample size of 55 patients. The prostate/seminal vesicles and pelvic lymph nodes were treated simultaneously with 67.5 Gy (2.7 Gy/fraction) and 45 Gy (1.8 Gy/fraction), respectively, in 25 fractions over 5 weeks. IMPT plan was prepared with pre-defined dose-volume histogram objectives for target volumes and organs at risk. All received androgen deprivation therapy (ADT). GI and GU toxicities were prospectively assessed, using the CTCAEv.4, at baseline (before IMPT); 3-, 6-, and 12-month post-RT and then every 6 months thereafter. Late toxicity was defined as toxicity persisting for > 3 months, or developing > 3 months post-RT. Late GI and GU toxicity rates were computed using Kaplan-Meier estimates, and log-rank tests were utilized for comparisons of time-to-event distributions.
Result(s): Median age was 75 years (range: 55-87). Median PSA was 10.5 ng/mL (range: 0.65 -97.3). Fifty-three patients had HR-Pca; 2 had UIR-Pca. Median duration of ADT was 18 months. Fifty-four patients were available for late toxicity assessment. Median follow-up was 46 months (range: 16-66). 29% and 6% experienced late grade 1 and 2 GI toxicity, respectively. One patient (2%) had late grade 3 GI toxicity (proctitis). The actuarial rate of late grade >= 2 GI toxicity was 7% (95% CI: 0.2-14%) at both 2 and 3 years. The actuarial rate of late grade 3 GI toxicity was 2% (95% CI: 0-5%) at both 2 and 3 years. 76% and 24% experienced late grade 1 and 2 GU toxicity, respectively. None had late grade >= 3 GU toxicity. The actuarial rate of late grade 2 GU toxicity was 21% (95% CI: 9-31%) at 2 years, and 29% (95% CI: 15-40%) at 3 years. None had late grade >= 4 GI or GU toxicity. The presence of baseline GU symptom was associated with a greater likelihood of experiencing late grade 2 GU toxicity. Of 44 patients with baseline GU symptoms, late grade 2 GU toxicity rate at 3 years was 36% (95%: 19-49%), compared to 0% among 10 patients with no baseline GU symptoms (p=0.02).
Conclusion(s): A moderately hypofractionated regimen of IMPT targeting prostate/seminal vesicles and pelvic lymph nodes for HR-Pca or UIR-Pca yielded very acceptable late GI and GU toxicity.
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OBJECTIVE:Abnormal cerebellar development has been implicated in Attention-Deficit/Hyperactivity Disorder (ADHD), although cerebro-cerebellar functional connectivity (FC) has yet to be examined in ADHD. Our objective is to investigate the disturbed cerebro-cerebellar FC in children and adolescents with ADHD. METHOD/METHODS:We analyzed the dataset of 106 individuals with ADHD (68 children, 38 adolescents) and 62 healthy comparisons (34 children, 28 adolescents) from the publicly available ADHD-200 dataset. We identified seven cerebellar sub-regions based on cerebro-cerebellar FC and subsequently obtained the FC maps of cerebro-cerebellar networks. Main effects of ADHD and age and their interaction were examined using two-way analysis of variance. RESULTS:Compared to comparisons, ADHD showed higher cerebro-cerebellar FC in superior temporal gyrus within the somatomotor network. Interactions of diagnosis and age were identified in the supplementary motor area and postcentral gyrus within the somatomotor network and middle temporal gyrus within the ventral attention network. Follow-up Pearson correlation analysis revealed decreased cerebro-cerebellar FC in these regions with increasing age in comparisons, while the opposite pattern of increased cerebro-cerebellar FC occurred in ADHD. CONCLUSION/CONCLUSIONS:Increased cerebro-cerebellar FC in superior temporal gyrus within the somatomotor network could underlie impairments in cognitive control and somatic motor function in ADHD. In addition, increasing cerebro-cerebellar FC in older participants with ADHD suggests that enhanced cerebellar involvement may compensate for dysfunctions of the cerebral cortex in ADHD.

Ammonium is a major urinary buffer that is necessary for the normal excretion of the daily acid load. Its urinary rate of excretion (UNH₄) may be increased several fold in the presence of extrarenal metabolic acidosis. Therefore, measurement of UNH₄ can provide important clues about causes of metabolic acidosis. Because UNH₄ is not commonly measured in clinical laboratories, the urinary anion gap (UAG) was proposed as its surrogate about four decades ago and it is still frequently used for that purpose. Several published studies strongly suggest that UAG is not a good index of UNH₄ and support the concept that direct measurement of UNH₄ is an important parameter to define in clinical nephrology. Low UNH₄ levels have recently been found to be associated with a higher risk of metabolic acidosis, loss of kidney function, and death in persons with chronic kidney disease, while surrogates like the UAG do not recapitulate this risk. In order to advance the field it is necessary for the medical community to become more familiar with UNH₄ levels in a variety of clinical settings. Herein, we have reviewed the literature, searching for available data on UNH₄ under normal and various pathological conditions, in an attempt to establish reference values to interpret UNH₄ results if and when UNH₄ measurements become available as a routine clinical test. In addition, we present original data in two large populations which provide further evidence that the UAG is not a good predictor of UNH₄. Measurement of urine NH₄ holds promise to aid clinicians in the care of patients and we encourage further research to determine its best diagnostic usage.