Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease.

The genetics of complex disease produce alterations in the molecular interactions of cellular pathways whose collective effect may become clear through the organized structure of molecular networks. To characterize molecular systems associated with late-onset Alzheimer's disease (LOAD), we constructed gene-regulatory networks in 1,647 postmortem brain tissues from LOAD patients and nondemented subjects, and we demonstrate that LOAD reconfigures specific portions of the molecular interaction structure. Through an integrative network-based approach, we rank-ordered these network structures for relevance to LOAD pathology, highlighting an immune- and microglia-specific module that is dominated by genes involved in pathogen phagocytosis, contains TYROBP as a key regulator, and is upregulated in LOAD. Mouse microglia cells overexpressing intact or truncated TYROBP revealed expression changes that significantly overlapped the human brain TYROBP network. Thus the causal network structure is a useful predictor of response to gene perturbations and presents a framework to test models of disease mechanisms underlying LOAD.

Influence of lamina propria invasion extension on T1 high-grade non-muscle-invasive bladder cancer in patients undergoing BCG or radical cystectomy.

OBJECTIVE: To evaluate the prognostic value of T1 substaging in patients treated with bacillus Calmette-Guérin (BCG) or immediate radical cystectomy (iRC). MATERIALS AND METHODS: We performed an institutional review board-approved retrospective study analysing non-muscle-invasive bladder cancer (NMIBC) patients with pT1 disease treated with either BCG or iRC between 2000 and 2020. Lamina propria (LP) invasion characteristics were extracted from the pathology report. The Kaplan-Meier method was used to calculate overall survival (OS), cancer-specific survival (CSS) and metastasis-free survival (MFS). Multivariable Cox models were used to determine the association between progression-free survival (PFS) and characteristics in the BCG cohort. A logistic regression model explored the relationship between T1 substaging and upstaging to >pT2 at iRC. RESULTS: A total of 411 T1 high-grade patients were identified. LP invasion characteristics were as follows: not specified: 115 (28%); focal/superficial (F/S): 147 (35.8%); and extensive/multifocal (E/M): 149 (36.2%). Overall, 303 patients (73.7%) received BCG, and 108 patients (26.3%) underwent iRC. The median (interquartile range) follow-up was 53 (32-96) months. Patients with E/M LP invasion were significantly more likely to undergo iRC (34% vs. 19%; P = 0.003). Patients with E/M LP invasion showed poorer MFS and CSS compared to those with F/S LP invasion when treated with BCG but not when treated with iRC. Among BCG-treated patients, progression occurred in 41 patients and E/M LP invasion was independently associated with progression after BCG (hazard ratio 5.3, 95% confidence interval [CI] 2.2-13.1; P < 0.001). T1 substaging was not associated with upstaging at RC (odds ratio 3.15, 95% CI 0.82-12.12; P = 0.095). CONCLUSIONS: Extensive/multifocal LP invasion was associated with poor PFS, MFS and CSS in patients treated with BCG. T1 substaging provides valuable prognostic information and should be reported in pathology reports.

Barriers and Facilitators to Accessing and Utilizing Medicaid Smartphone Services: Perspectives of Peer Support Specialists and Patients with a Diagnosis of a Serious Mental Illness.

Access to smartphone and data plan services may impact levels of connection and opportunities for health management for patients with a diagnosis of a serious mental illness. Such smartphone-based services provide opportunities that extend the reach of physical and mental health care programs. The purpose of this study was to explore barriers and facilitators faced by individuals with mental health challenges when accessing Medicaid SafeLink smartphones and data plans. Interview guides were developed using the Consolidated Framework for Implementation Research. Individual semi-structured interviews were conducted to collect qualitative data on 18 participants' experiences with SafeLink services. Two main themes were identified- barriers and facilitators. Sub-themes included monthly data limits, followed by account management (barriers), opportunities for safety, and connection (facilitators). Massachusetts SafeLink policies provide individuals with an opportunity for smartphone ownership. However, results imply that expanding the current policy's usage limits may provide additional opportunities for connection and access to health services.

Intraoperative Blood Transfusion Is Associated With Increased Risk of Venous Thromboembolism After Radical Cystectomy.

PURPOSE: Our objective was to examine whether perioperative blood transfusion is associated with venous thromboembolism following radical cystectomy adjusting for both patient- and disease-related factors. MATERIALS AND METHODS: Patients who underwent radical cystectomy for bladder cancer from 1980-2020 were identified in the Mayo Clinic cystectomy registry. Blood transfusion during the initial postoperative hospitalization was analyzed as a 3-tiered variable: no transfusion, postoperative transfusion alone, or intraoperative with or without postoperative transfusion. The primary outcome was venous thromboembolism within 90 days of radical cystectomy. Associations between clinicopathological variables and 90-day venous thromboembolism were assessed using multivariable logistic regression, with transfusion analyzed as both a categorical and a continuous variable. RESULTS: A total of 3,755 radical cystectomy patients were identified, of whom 162 (4.3%) experienced a venous thromboembolism within 90 days of radical cystectomy. Overall, 2,112 patients (56%) received a median of 1 (IQR: 0-3) unit of blood transfusion, including 811 (38%) with intraoperative transfusion only, 572 (27%) with postoperative transfusion only, and 729 (35%) with intraoperative and postoperative transfusion. On multivariable analysis, intraoperative with or without postoperative blood transfusion was associated with a significantly increased risk of venous thromboembolism (adjusted OR 1.73, 95% CI 1.17-2.56, P = .002). Moreover, when analyzed as a continuous variable, each unit of blood transfused intraoperatively was associated with 7% higher odds of venous thromboembolism (adjusted OR 1.07, 95% CI 1.01-1.13, P = .03). CONCLUSIONS: Intraoperative blood transfusion was significantly associated with venous thromboembolism within 90 days of radical cystectomy. To ensure optimal perioperative outcomes, continued effort to limit blood transfusion in radical cystectomy patients is warranted.

Assessing the Feasibility, Acceptability, and Preliminary Effectiveness of a School-Aged Program that Supports Physical Activity and Wellness.

The prevalence of anxiety symptoms in children and adolescents aged 4 to 18 years has nearly doubled after the first year of the pandemic. However, only one in five adolescents diagnosed with anxiety is treated. We R H.O.P. E. is a school-based mental health program that includes evidence-based principles designed to engage children and adolescents in anxiety treatment, including wellness and emotional regulation, and the emotional CPR method. We R H.O.P. E. augments traditional services provided by school administrators, school social workers, school teachers, and school nurses. The purpose of this study was to examine the feasibility, acceptability, and preliminary effectiveness of We R H.O.P. E.

Integration of peripheral transcriptomics, genomics, and interactomics following trauma identifies causal genes for symptoms of post-traumatic stress and major depression.

Posttraumatic stress disorder (PTSD) is a debilitating syndrome with substantial morbidity and mortality that occurs in the aftermath of trauma. Symptoms of major depressive disorder (MDD) are also a frequent consequence of trauma exposure. Identifying novel risk markers in the immediate aftermath of trauma is a critical step for the identification of novel biological targets to understand mechanisms of pathophysiology and prevention, as well as the determination of patients most at risk who may benefit from immediate intervention. Our study utilizes a novel approach to computationally integrate blood-based transcriptomics, genomics, and interactomics to understand the development of risk vs. resilience in the months following trauma exposure. In a two-site longitudinal, observational prospective study, we assessed over 10,000 individuals and enrolled >700 subjects in the immediate aftermath of trauma (average 5.3 h post-trauma (range 0.5-12 h)) in the Grady Memorial Hospital (Atlanta) and Jackson Memorial Hospital (Miami) emergency departments. RNA expression data and 6-month follow-up data were available for 366 individuals, while genotype, transcriptome, and phenotype data were available for 297 patients. To maximize our power and understanding of genes and pathways that predict risk vs. resilience, we utilized a set-cover approach to capture fluctuations of gene expression of PTSD or depression-converting patients and non-converting trauma-exposed controls to find representative sets of disease-relevant dysregulated genes. We annotated such genes with their corresponding expression quantitative trait loci and applied a variant of a current flow algorithm to identify genes that potentially were causal for the observed dysregulation of disease genes involved in the development of depression and PTSD symptoms after trauma exposure. We obtained a final list of 11 driver causal genes related to MDD symptoms, 13 genes for PTSD symptoms, and 22 genes in PTSD and/or MDD. We observed that these individual or combined disorders shared ESR1, RUNX1, PPARA, and WWOX as driver causal genes, while other genes appeared to be causal driver in the PTSD only or MDD only cases. A number of these identified causal pathways have been previously implicated in the biology or genetics of PTSD and MDD, as well as in preclinical models of amygdala function and fear regulation. Our work provides a promising set of initial pathways that may underlie causal mechanisms in the development of PTSD or MDD in the aftermath of trauma.

Peer Support Specialists and Service Users' Perspectives on Privacy, Confidentiality, and Security of Digital Mental Health.

As the digitalization of mental health systems progresses, the ethical and social debate on the use of these mental health technologies has seldom been explored among end-users. This article explores how service users (e.g., patients and users of mental health services) and peer support specialists understand and perceive issues of privacy, confidentiality, and security of digital mental health interventions. Semi-structured qualitative interviews were conducted among service users (n = 17) and peer support specialists (n = 15) from a convenience sample at an urban community mental health center in the United States. We identified technology ownership and use, lack of technology literacy including limited understanding of privacy, confidentiality, and security as the main barriers to engagement among service users. Peers demonstrated a high level of technology engagement, literacy of digital mental health tools, and a more comprehensive awareness of digital mental health ethics. We recommend peer support specialists as a potential resource to facilitate the ethical engagement of digital mental health interventions for service users. Finally, engaging potential end-users in the development cycle of digital mental health support platforms and increased privacy regulations may lead the field to a better understanding of effective uses of technology for people with mental health conditions. This study contributes to the ongoing debate of digital mental health ethics, data justice, and digital mental health by providing a first-hand experience of digital ethics from end-users' perspectives.

Effectiveness of a Digital Peer Support Training Program Designed for Rapid Uptake Among Peer Support Specialists Pilot Study.

Peer telemental health recently became Medicaid reimbursable during the COVID-19 crisis, increasing the need for standardized training on digital peer support (DPS) services. DPS has the potential to reduce barriers to services and expand the reach of peer support specialists. The 4-h Digital Peer Support Training program was developed to train peer support specialists for rapid uptake in providing digital peer support during the COVID-19 crisis. The purpose of this study was to examine the impact of the 4-h DPS course for peer support specialists. Surveys were administered to examine pre-post changes in DPS course for participants (N = 75) related to attitudes/ beliefs towards DPS, ability to use/ engage in DPS, and organizational readiness to implement DPS. Data were analyzed by conducting paired samples t-tests. Linear mixed models were used to explore significant results further. Statistically significant (< .05) changes were observed related to readiness to use DPS, attitudes/ beliefs towards DPS, and ability to use/ engage in DPS. The 4-h DPS course may be beneficial in providing diverse groups of peer support specialists with a standardized training framework. Widespread dissemination of the DPS short course may be beneficial in rapidly equipping peer support specialists with the skills and resources needed to expand the reach of peer support services during the COVID-19 crisis and beyond.

Effectiveness of a Digital Peer Support Training Program Designed for Rapid Uptake Among Peer Support Specialists Pilot Study.

Peer telemental health recently became Medicaid reimbursable during the COVID-19 crisis, increasing the need for standardized training on digital peer support (DPS) services. DPS has the potential to reduce barriers to services and expand the reach of peer support specialists. The 4-h Digital Peer Support Training program was developed to train peer support specialists for rapid uptake in providing digital peer support during the COVID-19 crisis. The purpose of this study was to examine the impact of the 4-h DPS course for peer support specialists. Surveys were administered to examine pre-post changes in DPS course for participants (N = 75) related to attitudes/ beliefs towards DPS, ability to use/ engage in DPS, and organizational readiness to implement DPS. Data were analyzed by conducting paired samples t-tests. Linear mixed models were used to explore significant results further. Statistically significant (< .05) changes were observed related to readiness to use DPS, attitudes/ beliefs towards DPS, and ability to use/ engage in DPS. The 4-h DPS course may be beneficial in providing diverse groups of peer support specialists with a standardized training framework. Widespread dissemination of the DPS short course may be beneficial in rapidly equipping peer support specialists with the skills and resources needed to expand the reach of peer support services during the COVID-19 crisis and beyond.

Feasibility, Acceptability, and Potential Utility of Peer-supported Ecological Momentary Assessment Among People with Serious Mental Illness: a Pilot Study.

To examine the feasibility, acceptability, and initial validity of using smartphone-based peer-supported ecological momentary assessment (EMA) as a tool to assess loneliness and functioning among adults with a serious mental illness diagnosis. Twenty-one adults with a diagnosis of a serious mental illness (i.e., schizophrenia, schizoaffective disorder, bipolar disorder, or treatment-refractory major depressive disorder) and at least one medical comorbidity (i.e., cardiovascular disease, obesity, diabetes, chronic obstructive pulmonary disease, hypertension, and/or high cholesterol) aged 18 years and older completed EMA surveys via smartphones once per day for 12-weeks. Nine peer support specialists prompted patients with SMI to complete the EMA surveys. Data were collected at baseline and 12-weeks. EMA acceptability (15.9%) was reported, and participants rated their experience with EMA methods positively. EMA responses were correlated with higher social support at 3 months. Higher levels of EMA-measured loneliness were significantly correlated with levels of social support, less hope, and less empowerment at 3 months. Lastly, those who contacted their peer specialist reported higher levels of loneliness and lower levels of functioning on that day suggesting that participants were able to use their peers for social support. Peer-supported EMA via smartphones is a feasible and acceptable data collection method among adults with SMI and appears to be a promising mobile tool to assess loneliness and functioning. These preliminary findings indicate EMA-measured loneliness and functioning are significantly predicted by baseline variables and such variables may impact engagement in EMA. EMA may contribute to future research examining the clinical utility of peer support specialists to alleviate feelings of loneliness and improve functioning.

Advancing the Science of Recovery: The Utility of the Recovery Assessment Scale in the Prediction of Self-Directed Health and Wellness Outcomes in Adults with a Diagnosis of a Serious Mental Illness.

Adults with serious mental illness commonly experience comorbid chronic physical conditions and experience a reduced life expectancy of 10-25 years compared to the general population (Saha et al. in Arch Gen Psychiatry 64(10):1123-31.  2007; Hayes et al. in Acta Psychiatr Scand 131(6):417-25. 2015; Walker et al. in JAMA Psychiatry 72(4):334-41. 2015). Dimensions of personal recovery may have real-world implications that extend beyond functional and mental health outcomes to impact the self-directed health and wellness of adults with serious mental illness. This study examined the predictive utility of the Recovery Assessment Scale with respect to medical self-efficacy, self-management, psychiatric symptoms, and community functioning for adults with serious mental illness. Data were derived from a secondary analysis of baseline and 10-month data collected from a randomized control trial with adults aged 18 years and older with a diagnosis of bipolar disorder, schizoaffective disorder, schizophrenia, or major depressive disorder (N=56). A linear regression was conducted to examine the predictive value of total baseline RAS scores on self-efficacy at 10 months while controlling for study group. This model significantly predicted self-efficacy (F (2, 53) = 13.28, p < .001) and accounted for 36.1% of the variance. Total baseline RAS scores significantly predicted self-efficacy (ß = 059, p < .001); specifically, higher baseline RAS scores were associated with greater self-efficacy. A greater degree of recovery may facilitate greater medical self-efficacy in managing chronic disease in people diagnosed with a serious mental illness. Future intervention approaches may consider recovery-focused therapeutic targets such as peer support to promote self-efficacy to manage chronic diseases in people with serious mental illness.

Assessing a digital peer support self-management intervention for adults with serious mental illness: feasibility, acceptability, and preliminary effectiveness.

OBJECTIVE: To assess the feasibility, acceptability, and preliminary effectiveness of digital peer support integrated medical and psychiatric self-management intervention ("PeerTECH") for adults with a serious mental illness. METHODS: Twenty-one adults with a chart diagnosis of a serious mental illness (i.e., schizophrenia, schizoaffective disorder, bipolar disorder, or treatment-refractory major depressive disorder) and at least one medical comorbidity (i.e., cardiovascular disease, obesity, diabetes, chronic obstructive pulmonary disease, hypertension, and/or high cholesterol) aged 18 years and older received the PeerTECH intervention in the community. Nine peer support specialists were trained to deliver PeerTECH. Data were collected at baseline and 12-weeks. RESULTS: This pilot study demonstrated that a 12-week, digital peer support integrated medical and psychiatric self-management intervention for adults with serious mental illness was feasible and acceptable among peer support specialists and patients and was associated with statistically significant improvements in self-efficacy to manage chronic disease and personal empowerment. In addition, pre/post non-statistically significant improvements were observed in psychiatric self-management, medical self-management skills, and feelings of loneliness. CONCLUSIONS: This single-arm pre/post pilot study demonstrated preliminary evidence peer support specialists could offer a fidelity-adherent digital peer support self-management intervention to adults with serious mental illness. These findings build on the evidence that a digital peer support self-management intervention for adults with serious mental illness designed to improve medical and psychiatric self-management is feasible, acceptable, and shows promising evidence of improvements in clinical outcomes. The use of technology among peer support specialists may be a promising tool to facilitate the delivery of peer support and guided evidence-based self-management support.People with serious mental illness (SMI; defined as individuals diagnosed with schizophrenia spectrum disorder, bipolar disorder, or treatment-refractory major depressive disorder) are increasingly utilizing peer support services to support their health and recovery. Peer support is defined as shared knowledge, experience, emotional, social, and/or practical assistance to support others with similar lived experiences (Solomon, 2004). Most recently the definition also includes the provision of evidence-based peer-supported self-management services (Fortuna et al., 2020). Mental health peer support can augment the traditional mental health treatment system through providing support services to maintain recovery between clinical encounters (Solomon, 2004) and is classified by the World Health Organization as an essential element of recovery (World, Health, and Organization, About social determinants of health, 2017).

Independent external validation of a nomogram to define risk categories for a significant decline in estimated glomerular filtration rate after robotic-assisted partial nephrectomy.

OBJECTIVE: To validate the Martini nomogram predicting the decline in estimated glomerular filtration rate after robotic-assisted partial nephrectomy. METHODS: Estimated glomerular filtration rate of 406 patients from a single surgeon series was calculated before robotic-assisted partial nephrectomy and at postoperative intervals. To determine the risk group, we calculated the total score and corresponding risk of significant estimated glomerular filtration rate reduction at 15 months using the Martini nomogram. The primary outcome was a reduction in estimated glomerular filtration rate of ≥25% from preoperative levels between 1 and 12 months after surgery. RESULTS: The median length of follow up for this study was 12 months (interquartile range 6-12 months). Overall, 134 (33%) patients were in the low-, 143 (35%) in the intermediate-, 119 (29%) in the high- and 10 (2%) in the very high-risk groups. The Kaplan-Meier estimates for the probability of significant estimated glomerular filtration rate reduction by 12 months after robotic-assisted partial nephrectomy was 12.9% in the low-risk group, 24.0% in the intermediate-risk group, 49.7% in the high-risk group and 40.0% in the very high-risk group. Harrell's C-index for discriminating between those with and without a significant reduction in estimated glomerular filtration rate 1-12 months after robotic-assisted partial nephrectomy was 0.73 (95% confidence interval 0.68-0.78). CONCLUSIONS: The risk groups proposed by the Martini nomogram are accurate in predicting those at higher risk for a >25% decline in postoperative estimated glomerular filtration rate after robotic-assisted partial nephrectomy at 12 months.

Spontaneous extrusion of renal calculi presenting as a retroperitoneal abscess.

Spontaneous extrusion of a kidney stone is an extremely rare event with few reported cases. We present the unusual case of a 62-year-old female who presented with worsening of fever and flank pain over a 5 day period. Imaging revealed retroperitoneal and abdominal wall abscesses that upon evaluation of prior imaging were attributed to spontaneously extruded kidney stones. Prior reports suggest surgical exploration and extraction is the preferred treatment option for extruded renal calculi. Based on the experience presented here, conservative management may be an attractive first-line treatment option for patients with extruded renal stones and associated retroperitoneal abscesses.

The atypical MAPK ERK3 potently suppresses melanoma cell growth and invasiveness.

Mitogen-activated protein kinase 6 (MAPK6) represents an atypical MAPK also known as extracellular signal-regulated kinase 3 (ERK3), which has been shown to play roles in cell motility and metastasis. ERK3 promotes migration and invasion of lung cancer cells and head and neck cancer cells by regulating the expression and/or activity of proteins involved in cancer progression. For instance, ERK3 upregulates matrix metallopeptidases and thereby promotes cancer cell invasiveness, and it phosphorylates tyrosyl-DNA phosphodiesterase 2, thereby enhancing chemoresistance in lung cancer. Here we discovered that ERK3 plays a converse role in melanoma. We observed that BRAF, an oncogenic Ser/Thr kinase, upregulates ERK3 expression levels by increasing both ERK3 messenger RNA levels and protein stability. Interestingly, although BRAF's kinase activity was required for upregulating ERK3 gene transcription, BRAF stabilized ERK3 protein in a kinase-independent fashion. We further demonstrate that ERK3 inhibits the migration, proliferation and colony formation of melanoma cells. In line with this, high level of ERK3 predicted increased survival among patients with melanomas. Taken together, these results indicate that ERK3 acts as a potent suppressor of melanoma cell growth and invasiveness.

The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target.

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes.10.1093/brain/awy215_video1awy215media15824729224001.

Polygenic risk score analysis of pathologically confirmed Alzheimer disease.

Previous estimates of the utility of polygenic risk score analysis for the prediction of Alzheimer disease have given area under the curve (AUC) estimates of <80%. However, these have been based on the genetic analysis of clinical case-control series. Here, we apply the same analytic approaches to a pathological case-control series and show a predictive AUC of 84%. We suggest that this analysis has clinical utility and that there is limited room for further improvement using genetic data. Ann Neurol 2017;82:311-314.