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Atypical antipsychotics are used in cardiac intensive care units (CICU) to treat delirium despite limited data on safety in patients with acute cardiovascular conditions. Patients treated with these agents may be at higher risk for adverse events such as QTc prolongation and arrhythmias. We performed a retrospective cohort study of 144 adult patients who were not receiving antipsychotics before admission and received olanzapine (n = 50) or quetiapine (n = 94) in the Michigan Medicine CICU. Data on baseline characteristics, antipsychotic dose and duration, length of stay, and adverse events were collected. Adverse events included ventricular tachycardia (sustained ventricular tachycardia attributed to the medication), hypotension (systolic blood pressure90 mm Hg attributed to the medication), and QTc prolongation (QTc increase by ≥60 ms or to an interval ≥500 ms). Twenty-six patients (18%) experienced an adverse event. Of those adverse events, 20 patients (14%) experienced QTc prolongation, 3 patients (2%) had ventricular tachycardia, and 3 patients (2%) had hypotension. Patients who received quetiapine had a higher rate of adverse events (25% vs 6%, p = 0.01) including QTc prolongation (18% vs 6%, p = 0.046). Intensive care unit length of stay was shorter in patients who received olanzapine (6.5 vs 9.5 days, p = 0.047). Eighteen patients (13%) had their antipsychotic continued at discharge from the hospital. In conclusion, QTc prolongation was more common in patients treated with quetiapine versus olanzapine although the number of events was relatively low with both agents in a CICU cohort.

Objective Negative symptoms and cognitive impairment in schizophrenia (SZ) remain unmet treatment needs as they are highly prevalent, associated with poor functional outcomes, and resistant to pharmacologic treatment. The current pilot randomized controlled trial examined the efficacy of an integrated Cognitive-Behavioral Social Skills Training and Compensatory Cognitive Training (CBSST-CCT) intervention compared to Goal-focused Supportive Contact (SC) on negative symptoms and cognitive performance. Methods Fifty-five adults with SZ or schizoaffective disorder with moderate-to-severe negative symptoms were randomized to receive 25 twice-weekly, 1-h manualized group sessions (12.5 weeks total duration) of either CBSST-CCT or SC delivered by master’s level clinicians in five community settings. Assessments of negative symptom severity (primary outcomes) and neuropsychological performance, functional capacity, social skills performance, and self-reported functional ability/everyday functioning, psychiatric symptom severity, and motivation (secondary outcomes) were administered at baseline, mid-treatment, post-treatment, and 6-month follow-up. Results Mixed-effects models using baseline, mid-treatment, and post-treatment data demonstrated significant CBSST-CCT-associated effects on negative symptom severity, as assessed by the Scale for the Assessment of Negative Symptoms (p = .049, r = 0.22), with improvements in diminished motivation driving this effect (p = .037, r = 0.24). The CBSST-CCT group also demonstrated improved verbal learning compared to SC participants (p = .026, r = 0.36). The effects of CBSST-CCT appeared to be durable at 6-month follow-up. Conclusions CBSST-CCT improved negative symptom severity and verbal learning in high-negative-symptom individuals relative to SC. CBSST-CCT warrants larger investigations to examine its efficacy in treating negative symptoms, along with other symptoms, cognition, and, ultimately, real-world functional outcomes. Clinical Trial registration number NCT02170051.

Neuromyths are commonly held misconceptions about the brain believed by both the general public and educators. While much research has investigated the prevalence of myths about the typically developing brain, less attention has been devoted to the pervasiveness of neuromyths about neurodevelopmental disorders, which have the potential to exacerbate stigma. This preregistered study investigated to what extent neuromyths about neurodevelopmental disorders (namely dyslexia, attention deficit hyperactivity disorder, autism spectrum disorders, and syndrome) are endorsed by two groups: the general public and those working in education. In an online survey, 366 members of the general public and 203 individuals working in education rated similar numbers of myths to be true, but more about neurodevelopmental disorders than general neuromyths. As the frequency of access to brain information emerged as a protective factor against endorsing myths in both populations, we argue that this problem may be addressed via provision of neuroeducational resources.

BACKGROUND Exception from informed consent (EFIC) enables the enrollment of research subjects with emergent conditions to clinical trials without prior consent. EFIC study approval requires community consultation and public disclosure. We hypothesized that the integration of social media with targeted emails and in-person outreach is an effective community consultation strategy. METHODS We utilized social media with targeted emails and in-person outreach for the community consultation of the ACCESS cardiac arrest trial. Study advertisements were disseminated using Facebook and Instagram, and targeted emails were sent to emergency medicine, prehospital, and cardiology providers. We also interviewed at-risk individuals with cardiac conditions, their caretakers, and patient advocacy groups. Participants were asked to complete a survey about their opinions about the study. RESULTS We collected 559 surveys over an 8-week period, and 70.5% of the surveys were obtained using social media. The median (IQR) age of survey respondents was 44 (33-57) years; 89.9% were White and 60.1% were women. A total of 91.3% believed ACCESS was an important study. Compared to the in-person group, more from social media (81.8% vs. 63.3%, p

OBJECTIVE: Many psychotropic medications used to treat schizophrenia have significant anticholinergic properties, which are linked to cognitive impairment and dementia risk in healthy subjects. Clarifying the impact of cognitive impairment attributable to anticholinergic medication burden may help optimize cognitive outcomes in schizophrenia. The aim of this study was to comprehensively characterize how this burden affects functioning across multiple cognitive domains in schizophrenia outpatients. METHODS: Cross-sectional data were analyzed using inferential statistics and exploratory structural equation modeling to determine the relationship between anticholinergic medication burden and cognition. Patients with a diagnosis of schizophrenia or schizoaffective disorder (N = 1,120) were recruited from the community at five U.S. universities as part of the Consortium on the Genetics of Schizophrenia–2. For each participant, prescribed medications were rated and summed according to a modified Anticholinergic Cognitive Burden (ACB) scale. Cognitive functioning was assessed by performance on domains of the Penn Computerized Neurocognitive Battery (PCNB). RESULTS: ACB score was significantly associated with cognitive performance, with higher ACB groups scoring worse than lower ACB groups on all domains tested on the PCNB. Similar effects were seen on other cognitive tests. Effects remained significant after controlling for demographic characteristics and potential proxies of illness severity, including clinical symptoms and chlorpromazine-equivalent antipsychotic dosage. CONCLUSIONS: Anticholinergic medication burden in schizophrenia is substantial, common, conferred by multiple medication classes, and associated with cognitive impairments across all cognitive domains. Anticholinergic medication burden from all medication classes—including psychotropics used in usual care—should be considered in treatment decisions and accounted for in studies of cognitive functioning in schizophrenia.

Loneliness is associated with increased morbidity and mortality. Deeper understanding of neurobiological mechanisms underlying loneliness is needed to identify potential intervention targets. We did not find any systematic review of neurobiology of loneliness. Using MEDLINE and PsycINFO online databases, we conducted a search for peer-reviewed publications examining loneliness and neurobiology. We identified 41 studies (n = 16,771 participants) that had employed various methods including computer tomography (CT), structural magnetic resonance imaging (MRI), functional MRI (fMRI), electroencephalography (EEG), diffusion tensor imaging (DTI), single-photon emission computed tomography (SPECT), positron emission tomography (PET), and post-mortem brain tissue RNA analysis or pathological analysis. Our synthesis of the published findings shows abnormal structure (gray matter volume or white matter integrity) and/or activity (response to pleasant versus stressful images in social versus nonsocial contexts) in the prefrontal cortex (especially medial and dorsolateral), insula (particularly anterior), amygdala, hippocampus, and posterior superior temporal cortex. The findings related to ventral striatum and cerebellum were mixed. fMRI studies reported links between loneliness and differential activation of attentional networks, visual networks, and default mode network. Loneliness was also related to biological markers associated with Alzheimer's disease (e.g., amyloid and tau burden). Although the published investigations have limitations, this review suggests relationships of loneliness with altered structure and function in specific brain regions and networks. We found a notable overlap in the regions involved in loneliness and compassion, the two personality traits that are inversely correlated in previous studies. We have offered recommendations for future research studies of neurobiology of loneliness.

Introduction The two week wait (2ww) colorectal referral pathway was introduced to expedite referrals where cancer is suspected, facilitating prompt diagnosis +/− intervention. Older frail patients are referred via this 2ww pathway even when invasive testing and intervention may not be appropriate. These patients may benefit more from holistic assessment than a universally surgical approach. A Colorectal and Geriatric Medicine (CGM) 2ww referral clinic was piloted, delivered by an urgent referral colorectal specialist nurse and an advanced clinical practitioner in geriatric medicine. Method Patients >65 years with a Clinical Frailty Scale (CFS) score of 5 or more at referral were directed to the CGM clinic. A telephone consultation was undertaken, incorporating both 2ww assessment and aspects of comprehensive geriatric assessment. Results 42-patients were reviewed in the clinic. Mean age was 86.1 years and mean CFS 6. 12-patients underwent CT, and 2 CT virtual colonoscopy. No patients underwent endoscopic investigation and 28-patients declined any investigation. Of those who underwent investigation, no cancers were identified. 1 patient was referred on for endosocpic mucosal resection of polyps. 5-patients had severe diverticular disease, which accounted for their symptoms. Medication recommendations were made for 30-patients, some of which led to symptom cessation. Onward referrals were made to a community geriatrician, diabetes and continence teams, and palliative care specialists. 9-patients were identified as meeting criteria for advance care planning. This was commenced during the consultation and communicated back to the referring clinician for further action. Conclusion Older, frail patients are often not able, nor wish to undergo, invasive investigations but should not be disadvantaged or delayed in their pathway. Further work is needed to determine the most appropriate referral pathway for this group of patients. Holistic assessment that leads to improvement in symptoms and future planning may not be achievable through a solely surgical assessment.

Introduction The prevalence and complications of biliary disease increase with age. We describe the prevalence of frailty in older patients hospitalised with benign biliary and pancreatic disease and establish its association with mortality and duration of hospital stay. Methods Prospective observational cohort study of patients aged 75 years and over admitted with a diagnosis of acute biliary disease to a surgical hospital unit between 17/09/2014 and 20/03/2017. Clinical Frailty Scale (CFS) score was recorded on admission. Results We included 200 patients with a median age of 82 (75–99), 60% females, 89% lived in their homes, 154 (77%) were independent for personal and 99 (49.5%) for instrumental ADLs, 95% mobilised independently, 17.5% had memory impairment and 8% low mood. Acute cholecystitis was the most common diagnosis (43%) followed by acute cholangitis (36%) and acute pancreatitis (21%). 99 patients were non-frail (NF = CFS 1–4) and 101 were frail (F = CFS ≥5). 104 patients received medical treatment only. Surgery was more common in non-frail (F 2% vs. NF 11%), percutaneous drainage more frequently carried out in frail patients (15% vs. NF 5%) and endoscopic cholangiopancreatography (ERCP) was similar in both groups (F 32%vs. NF 31%). Frailty was associated with worse clinical outcomes in F vs. NF: functional deconditioning (34% vs. 11%), increased care level (19% vs 3%), length of stay (12 vs. 7 days), 90-day (8% vs. 3%) and 1 year-mortality (48% vs. 24%). Conclusion Half of patients in our cohort of older adults hospitalised with acute biliary disease were frail. Higher scores of frailty are associated with increased mortality. Compared with non-frail patients, individuals living with frailty were less likely to undergo surgical treatment, spent longer in hospital and were less likely to remain alive at 12 months after hospital discharge.

Objectives:Wisdom is a personality trait comprising seven components: self-reflection, pro-social behaviors, emotional regulation, acceptance of diverse perspectives, decisiveness, social advising, and spirituality. Wisdom, a potentially modifiable trait, is strongly associated with well-being. We have published a validated 28-item San Diego Wisdom Scale, the SD-WISE-28. Brief scales are necessary for use in large population-based studies and in clinical practice. The present study aimed to create an abbreviated 7-item version of the SD-WISE.Method:Participants included 2093 people, aged 20-82 years, recruited and surveyed through the online crowdsourcing platform Amazon Mechanical Turk. The participants’ mean age was 46 years, with 55% women. Participants completed the SD-WISE-28 as well as validation scales for various positive and negative constructs. Psychometric analyses (factor analysis and item response theory) were used to select one item from each of the seven SD-WISE-28 subscales.Results:We selected a combination of items that produced acceptable unidimensional model fit and good reliability (ω = 0.74). Item statistics suggested that all seven items were strong indicators of wisdom, although the association was weakest for spirituality. Analyses indicated that the 28-item and 7-item SD-WISE are both very highly correlated (r = 0.92) and produce a nearly identical pattern of correlations with demographic and validity variables.Conclusion:The SD-WISE-7, and its derived Jeste-Thomas Wisdom Index (JTWI) score, balances reliability and brevity for research applications.

There is an urgent need for new treatments for visceral leishmaniasis (VL), a parasitic infection which impacts heavily large areas of East Africa, Asia, and South America. We previously reported on the discovery of GSK3494245/DDD01305143 (1) as a preclinical candidate for VL and, herein, we report on the medicinal chemistry program that led to its identification. A hit from a phenotypic screen was optimized to give a compound with in vivo efficacy, which was hampered by poor solubility and genotoxicity. The work on the original scaffold failed to lead to developable compounds, so an extensive scaffold-hopping exercise involving medicinal chemistry design, in silico profiling, and subsequent synthesis was utilized, leading to the preclinical candidate. The compound was shown to act via proteasome inhibition, and we report on the modeling of different scaffolds into a cryo-EM structure and the impact this has on our understanding of the series' structure-activity relationships.

Objective Evaluate reproductive function in nulligravid and gravid women after levonorgestrel 52 mg intrauterine system (IUS) discontinuation based on time to pregnancy. Study design We evaluated women participating in the ACCESS IUS multicenter, Phase 3, open-label clinical trial of the Liletta(®) levonorgestrel 52 mg IUS who discontinued the IUS within 60 months of use and desired pregnancy. Study staff contacted participants every three months after IUS discontinuation for up to 12 months to determine whether pregnancy occurred. We excluded women who opted to stop attempting to conceive before 12 months. We evaluated 12-month conception rates in participants 16–35 years at IUS placement, comparing dichotomous outcomes using Fisher’s exact test. We performed a multivariable analysis to assess the association of baseline characteristics, age at discontinuation, duration of IUS use, and positive sexually transmitted infection testing during IUS use with conception. Results Among 165 women who attempted to conceive, 142 (86.1%) did so within 12 months with a median time to conception of 92 days. The 12-month conception rates did not differ between nulligravid (66/76 [86.8%]) and gravid (76/89 [85.4%]) women (p = 0.83) and nulliparous (78/90 [86.7%]) and parous (64/75 [85.3%]) women (p = 0.83). In multivariable analysis, only obesity (aOR 0.3 [95% CI 0.1–0.8]) was associated with ability to conceive. Conclusions After levonorgestrel 52 mg IUS discontinuation, women have rapid return of fertility in the year post-removal. Fertility rates after IUS removal do not vary based on gravidity, parity, age at discontinuation, or duration of IUS use. Implications This contemporary IUS study included a large population of nulligravid and nulliparous women. IUS use over many years does not effect spontaneous fertility after IUS discontinuation, regardless of gravidity or parity. Providers and patients should have no concern about the impact of IUS use on future fertility.

BACKGROUND: Fractional myocardial blood volume (fMBV) estimated using ferumoxytol-enhanced MRI (FE-MRI) has the potential to capture a hemodynamic response to myocardial hypoperfusion during contrast steady state without reliance on gadolinium chelates. Ferumoxytol has a long intravascular half-life and its use for steady-state MRI is off-label. PURPOSE: To optimize and evaluate a two-compartment model for estimation of fMBV based on FE-MRI. STUDY TYPE: Prospective ANIMAL MODEL: Nine healthy swine; one swine with artificially-induced single-vessel coronary stenosis. FIELD STRENGTH/SEQUENCE: 3.0T clinical magnet using the 5(3)3(3)3 Modified Look-Locker Inversion Recovery (MOLLI) sequence. ASSESSMENT: Myocardial longitudinal spin-lattice relaxation rate (R1) was measured using the MOLLI sequence before and at contrast steady state following seven ferumoxytol infusions (0.125 – 4.0 mg/kg). fMBV and water exchange were estimated using a two-compartment model. Model-fitted fMBV was compared to simple fast-exchange fMBV approximation and percent change in pre and post-ferumoxytol R1. Dose under-sampling schemes were investigated to reduce acquisition duration. STATISTICAL TESTS: Variation in fMBV was assessed with a one-way analysis of variance (ANOVA). Fast-exchange fMBV and ferumoxytol dose under-sampling were evaluated using Bland-Altman analysis. RESULTS: Healthy normal swine showed a mean mid-ventricular fMBV of 7.2 ± 1.4% and water exchange rate of 11.3 ± 5.1 s(−1). There was inter-subject variation in fMBV (p

The purpose of this study was to evaluate adipose tissue distributions and hepatic and pancreatic fat contents using a 6-point Dixon MRI technique in type 2 diabetes mellitus (T2DM), and to assess associations between fat distributions and biochemical markers of insulin resistance. Intra-abdominal MRI was investigated in 14 T2DM patients, 13 age- and sex-matched healthy controls (HC) and 11 young HC using a 3 T Prisma MRI scanner. All T2DM subjects completed a fasting comprehensive metabolic panel, and demographic measurements were taken according to standardized methodologies. We observed excellent correlation (R2 = 0.94) between hepatic fat fraction quantified using 6-point Dixon MRI and gold standard MRS, establishing the accuracy and reliability of the Dixon technique. Significantly increased visceral adipose tissue (VAT) volumes were found in T2DM patients compared to age-matched HC (1569.81 ± 670.62 cm3 vs. 1106.60 ± 566.85 cm3, p = .04). We also observed a trend of increasing subcutaneous adipose tissues (SAT), and total abdominal fat (TAT) volumes in T2DM compared to age-matched HC. Hepatic fat fraction percentage (HFF%) was 44.6% higher in T2DM compared to age-matched HC and 64.4% higher compared to young HC. Pancreatic fat fractions in the head and body/tail were higher in T2DM patients compared to both healthy cohorts. We also observed correlations between fat contents of the liver and pancreas in T2DM patients, and association between biochemical markers of T2DM with HFF, indicating a risk for non-alcoholic fatty liver disease among T2DM. In summary, this study provides evidence of T2DM patients having increased liver and pancreatic fat, as well as increased adipose tissues.

Objective: To describe the types of intervention and determine patency and survival after arterial and venous reconstruction after surgical excision of sarcomas. Methods: Between November 2001 and July 2015, 42 patients with sarcomas and vascular involvement underwent surgical oncologic resection followed by arterial or venous reconstruction or preservation of the native vascular bundle. Univariate, multivariate, and Kaplan-Meier survival analyses were performed on abstracted data, which included demographics, risk factors, oncologic and vascular treatment modalities, postoperative complications, graft patency, and survival outcomes. Results: A total of 42 sarcomas required vascular assistance for oncologic removal. The majority of sarcomas were malignant fibrous histiocytoma (23.8%), and the most common anatomic location was the retroperitoneum (48%). A total of 12 revascularizations procedures were performed, including 5 arterial, 3 venous, and 2 concomitant arterial and venous. In 32 cases, a vascular surgeon was needed for vessel ligation, repair, or mobilization. The overall 2- and 5-year survival was 77.7% and 26.2%, respectively, with no significant survival difference between patients who underwent revascularization compared to those without revascularization. There was a 100% patency rate in all cases at last follow-up, regardless of the type of vascular reconstruction (median 18 months, range 1-29 months). On multivariate analysis, chronic obstructive pulmonary disease (COPD; P = .002) and positive surgical margins ( P = .003) were associated with decreased survival. Most cases were performed in the last 5 years of the study (n = 27, 64.3%). Conclusions: Vascular reconstruction is feasible after surgical oncologic resection of sarcomas with good mid-term patency and limb preservation. Factors independently associated with mortality included COPD and positive surgical margins.

Visceral leishmaniasis (VL) is a parasitic infection that results in approximately 26 000–65 000 deaths annually. The available treatments are hampered by issues such as toxicity, variable efficacy...

BackgroundAbnormalities in cortical excitation and inhibition (E/I) balance are thought to underlie sensory and information processing deficits in schizophrenia. Deficits in early auditory information processing mediate both neurocognitive and functional impairment and appear to be normalized by acute pharmacologic challenge with the NMDA antagonist memantine (MEM).MethodsThirty-six subjects with a diagnosis of schizophrenia and 31 healthy control subjects underwent electroencephalographic recordings. Subjects ingested either placebo or MEM (10 or 20 mg) in a double-blind, within-subject, crossover, randomized design. The aperiodic, 1/f-like scaling property of the neural power spectra, which is thought to index relative E/I balance, was estimated using a robust linear regression algorithm.ResultsPatients with schizophrenia had greater aperiodic components compared with healthy control subjects (p < .01, d= 0.64), which was normalized after 20 mg MEM. Analysis revealed a significant dose× diagnosis interaction (p < .0001, d= 0.82). Furthermore, the MEM effect (change in aperiodic component in MEM vs. placebo conditions) was associated with baseline attention and vigilance (r= .54, p < .05) and MEM-induced enhancements in gamma power (r=-.60, p < .01).ConclusionsFindings confirmed E/I balance abnormalities in schizophrenia that were normalized with acute MEM administration and suggest that neurocognitive profiles may predict treatment response based on E/I sensitivity. These data provide proof-of-concept evidence for the utility of E/I balance indices as metrics of acute pharmacologic sensitivity for central nervous system therapeutics.

Cellular membranes are not homogenous mixtures of proteins; rather, they are segregated into microdomains on the basis of preferential association between specific lipids and proteins. These microdomains, called lipid rafts, are well known for their role in receptor signaling on the plasma membrane (PM) and are essential to such cellular functions as signal transduction and spatial organization of the PM. A number of disease states, including atherosclerosis and other cardiovascular disorders, may be caused by dysfunctional maintenance of lipid rafts. Lipid rafts do not occur only in the PM but also have been found in intracellular membranes and extracellular vesicles (EVs). Here, we focus on discussing newly discovered functions of lipid rafts and microdomains in intracellular membranes, including lipid and protein trafficking from the ER, Golgi bodies, and endosomes to the PM, and we examine lipid raft involvement in the production and composition of EVs. Because lipid rafts are small and transient, visualization remains challenging. Future work with advanced techniques will continue to expand our knowledge about the roles of lipid rafts in cellular functioning.

Background and PurposeThe Health Risk Screening Tool (HRST) is a 22-item instrument specifically designed to assess the health risk of persons with developmental disabilities. The predictive validity of the HRST was investigated by examining its ability to predict mortality.MethodsThe sample consisted of 12,582 people with an intellectual or developmental disability residing in Georgia (U.S.). Data were analyzed using survival analysis (Kaplan–Meier estimate and Cox regression) and a binary logistic regression.ResultsAll models supported the prognostic value of the six-level health risk classification. The Kaplan–Meier procedure showed clear separation among functions. The Cox proportional hazard regression revealed that hazard is inversely related to the health risk level, even after controlling for potential confounding by gender, ethnicity, and race.ConclusionsThe HRST can predict mortality. Therefore, it can serve as a basis for establishing healthcare needs and determining nursing care acuity.

Available treatments for Chagas' disease and visceral leishmaniasis are inadequate, and there is a pressing need for new therapeutics. Drug discovery efforts for both diseases principally rely upon phenotypic screening. However, the optimization of phenotypically active compounds is hindered by a lack of information regarding their molecular target(s). To combat this issue we initiate target deconvolution studies at an early stage. Here, we describe comprehensive genetic and biochemical studies to determine the targets of three unrelated phenotypically active compounds. All three structurally diverse compounds target the Qi active-site of cytochrome b, part of the cytochrome bc1 complex of the electron transport chain. Our studies go on to identify the Qi site as a promiscuous drug target in Leishmania donovani and Trypanosoma cruzi with a propensity to rapidly mutate. Strategies to rapidly identify compounds acting via this mechanism are discussed to ensure that drug discovery portfolios are not overwhelmed with inhibitors of a single target.

Auditory-based targeted cognitive training (TCT) is an effective and well-validated intervention for the treatment of cognitive impairment in schizophrenia patients. Improvements in higher-order cognition, reductions in symptom severity, and increases in psychosocial functioning secondary to TCT are thought to be driven by “bottom-up” enhancement of early auditory information processing (EAIP). Despite strong evidence of efficacy at the group level, there is significant variability in response to TCT, with few well-delineated biomarkers for predicting individual benefit. EEG biomarkers of EAIP are indicators of early-treatment sensitivity that predict full-course TCT outcome; however, further characterization is necessary for biomarker-guided clinical trials. The current study examined baseline and early-treatment sensitivity (i.e., change from baseline after 1 h) in theta band oscillatory activity to deviant stimuli as moderators of full course (30 h) TCT response in treatment-refractory schizophrenia patients randomly assigned to receive either treatment-as-usual (TAU; n = 22) or TAU augmented with TCT (n = 30). Theta evoked power and phase locking at baseline predicted patient improvements in global cognitive function after 30 h of TCT. Decrease in theta activity to deviant stimuli after 1 h of TCT predicted improvements in verbal learning after 30 h. Exploratory analyses using EEG composite scores had high levels of sensitivity and specificity for identifying patients most likely to benefit from TCT. The integrity of baseline neurophysiologic activity associated with EAIP, as well as the sensitivity of the underlying circuity to change, likely reflects an intermediate therapeutic process underlying the effectiveness of TCT that can be used to predict patient response to treatment.

Visceral leishmaniasis (VL) affects millions of people across the world, largely in developing nations. It is fatal if left untreated and the current treatments are inadequate. As such, there is an urgent need for new, improved medicines. In this paper, we describe the identification of a 6-amino-N-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine scaffold and its optimization to give compounds which showed efficacy when orally dosed in a mouse model of VL.

Background Suicide is a serious public health problem, including among U.S. Army personnel. There is great interest in discovering objective predictors of suicide and non-fatal suicidal behaviors. The current study examined the association between neurocognitive functioning and pre-military history of suicide attempts (SA) and post-enlistment onset of SA. Methods: New Soldiers reporting for Basic Combat Training (N = 38,507) completed a comprehensive computerized neurocognitive assessment battery and self-report questionnaires. A subset of Soldiers (n = 6216) completed a follow-up survey, including assessment of lifetime SA, 3–7 years later. Results Six hundred eighty-nine Soldiers indicated lifetime SA at baseline and 210 Soldiers indicated new-onset SA at follow-up. Regression analyses, adjusted for demographic variables, revealed significant bivariate associations between neurocognitive performance on measures of sustained attention, impulsivity, working memory, and emotion recognition and lifetime SA at baseline. In a multivariable model including each of these measures as predictors, poorer impulse control and quicker response times on an emotion recognition measure were significantly and independently associated with increased odds of lifetime SA. A second model predicted new-onset SA at follow-up for Soldiers who did not indicate a history of SA at baseline. Poorer impulse control on a measure of sustained attention was predictive of new-onset SA. Limitations: Effect sizes are small and of unlikely clinical predictive utility. Conclusions We simultaneously examined multiple neurocognitive domains as predictors of SA in a large, representative sample of new Army Soldiers. Impulsivity most strongly predicted past and future SA over and beyond other implicated cognitive-emotional domains.

Objective To investigate whether rates of self-reported Woman's Condom (WC) clinical failure and semen exposure from a functionality study are comparable to results from a contraceptive efficacy substudy. Study design We structured our comparative analysis to assess whether functionality studies might credibly supplant contraceptive efficacy studies when evaluating new female condom products. Couples not at risk of pregnancy in the functionality (breakage/slippage/invagination/penile misdirection) study and women in the contraceptive efficacy study completed condom self-reports and collected precoital and postcoital vaginal samples for up to four uses of the WC. Both studies used nearly identical self-report questions and the same self-sampling procedures and laboratory for prostatic specific antigen (PSA), a well-studied semen biomarker. We compared condom failure and semen exposure proportions using generalized estimating equations methods accounting for within-couple correlation. Results Ninety-five (95) efficacy substudy participants used 334 WC and 408 functionality participants used 1572 WC. Based on self-report, 19.2% WC (64 condoms) clinically failed in the efficacy substudy compared to 12.3% WC (194 condoms) in the functionality study (p=.03). Of the 207 WC efficacy uses with evaluable postcoital PSA levels, 14.5% (30 uses) resulted in semen exposure compared to 14.2% (184 uses) of the 1293 evaluable WC functionality study uses. Conclusions When evaluating the ability of an experimental condom to prevent semen exposure, the rate of clinical condom failure reported by participants risking pregnancy in an efficacy substudy was significantly higher than the rate reported by participants not risking pregnancy in a functionality study. The rate of semen exposure, assessed by an objective biomarker was nearly identical for the two studies. Implications Our results suggest that an objective marker of semen exposure in functionality studies could provide a reasonable alternative to contraceptive efficacy studies in evaluating risk of unintended pregnancy and inferring protection from sexually transmitted infection than condom failure rates based on self-report.

Aims To study the prevalence and complications of biliary disease with increasing age. We describe the prevalence of frailty in older patients hospitalised with benign biliary and pancreatic disease and establish its association with mortality and duration of hospital stay. Methods Prospective observational cohort study of patients aged 75 years and over admitted with acute biliary disease between 17/09/2014 and 20/03/2017. Clinical Frailty Scale (CFS) score was recorded on admission. Results 200 patients with a median age of 82 (75-99), 60% females, 154 (77%) were independent for personal and 99 (49.5%) for instrumental activities of daily living. Acute cholecystitis was the most common diagnosis (43%), acute cholangitis (36%) and acute pancreatitis (21%). 99 patients were non-frail (NF = CFS 1-4) and 101 were frail (F= CFS ≥5). 104 patients received medical treatment only. Surgery was more common in non-frail (F 2% vs. NF 11%), percutaneous drainage more frequently carried out in frail patients (15% vs. NF 5%) and endoscopic cholangiopancreatography (ERCP) was similar in both groups (F 32%vs. NF 31%). Frailty was associated with worse clinical outcomes. F vs. NF: functional deconditioning (34% vs. 11%), increased care level (19% vs 3%), length of stay (12 vs. 7 days), 90-day (8% vs. 3%) and 1 year-mortality (48% vs. 24%). Conclusions : Higher frailty scoring is associated with increased mortality in acute biliary disease. Individuals living with frailty were less likely to undergo surgical treatment, spent longer in hospital and were less likely to remain alive at 12 months after hospital discharge.

White matter deterioration is associated with cognitive impairment in healthy aging and Alzheimer's disease. It is critical to identify interventions that can slow down white matter deterioration. So far, clinical trials have failed to demonstrate the benefits of aerobic exercise on the adult white matter using diffusion Magnetic Resonance Imaging. Here, we report the effects of a 6-month aerobic walking and dance interventions (clinical trial NCT01472744) on white matter integrity in healthy older adults (n = 180, 60–79 years) measured by changes in the ratio of calibrated T1- to T2-weighted images (T1w/T2w). Specifically, the aerobic walking and social dance interventions resulted in positive changes in the T1w/T2w signal in late-myelinating regions, as compared to widespread decreases in the T1w/T2w signal in the active control. Notably, in the aerobic walking group, positive change in the T1w/T2w signal correlated with improved episodic memory performance. Lastly, intervention-induced increases in cardiorespiratory fitness did not correlate with change in the T1w/T2w signal. Together, our findings suggest that white matter regions that are vulnerable to aging retain some degree of plasticity that can be induced by aerobic exercise training. In addition, we provided evidence that the T1w/T2w signal may be a useful and broadly accessible measure for studying short-term within-person plasticity and deterioration in the adult human white matter.

Background: Sensory processing abnormalities are common in schizophrenia (SZ) and impact everyday functions, such as speech perception in noisy environments. Auditory-based targeted cognitive training (TCT) is a “bottom up” cognitive remediation intervention designed to enhance the speed and accuracy of low-level auditory information processing. However, the effects of TCT on behavioral measures of central auditory processing (CAP) and the role of CAP function on verbal learning outcomes in SZ are unknown. Methods: SZ (n = 42) and healthy subjects (CTL; n = 18) underwent comprehensive clinical, neurocognitive, and auditory assessments, including tests of hearing sensitivity and speech recognition (Words-in-Noise (WIN), Quick Speech-in-Noise (SIN)). SZ patients were randomized to receive either treatment-as-usual (TAU); or 30-h of TCT + TAU using a stratified, parallel design. SZ patients repeated assessments ~10–12 weeks later. Results: Patients exhibited deficits in both WIN (p < 0.05, d = 0.50) and SIN (p < 0.01, d = 0.63). A treatment × time interaction on WIN (p < 0.05, d = 0.74), but not SIN discriminability, was seen in the TCT group relative to TAU. Specific enhancements in the 4-dB over background range drove gains in WIN performance. Moreover, SZ patients with greater CAP deficits experienced robust gains in verbal learning after 30-h of TCT relative to SZ patients without CAP impairment (p < 0.01, d = 1.28). Conclusion: Findings demonstrate that intensive auditory training enhances the fidelity of auditory processing and perception, such that specific CAP deficits were ‘normalized’ and were predictive of gains in verbal learning after TCT. It is conceivable that patients with deficiencies in CAP measures may benefit most from TCT and other interventions targeting auditory dysfunction in SZ.

Neurophysiological biomarkers of auditory processing show promise predicting outcomes following auditory-based targeted cognitive training (TCT) in schizophrenia, but the viability of the frequency following response (FFR) as a biomarker has yet to be examined, despite its ecological and face validity for auditory-based interventions. FFR is an event-related potential (ERP) that reflects early auditory processing. We predicted that schizophrenia patients would show acute- and longer-term FFR malleability in the context of TCT. Patients were randomized to either TCT (n = 30) or treatment as usual (TAU; n = 22), and electroencephalography was recorded during rapid presentation of an auditory speech stimulus before treatment, after one hour of training, and after 30 h of training. Whereas patients in the TCT group did not show changes in FFR after training, amplitude reductions were observed in the TAU. FFR was positively associated with performance on a measure of single word-in-noise perception in the TCT group, and with a measure of sentence-in-noise perception in both groups. Psychometric reliability analyses of FFR scores indicated high internal consistency but low one-hour and 12-week test-rest reliability. These findings support the dissociation between measures of speech discriminability along the hierarchy of cortical and subcortical early auditory information processing in schizophrenia.

There is growing interest in the role of compassion in promoting health and well-being, with cross-sectional data showing an inverse correlation with loneliness. This is the first longitudinal study examining both compassion toward others (CTO) and compassion toward self (CTS) as predictors of mental and physical health outcomes including loneliness, across adult lifespan. We followed 552 women and 538 men in San Diego County for up to 7.5 (mean 4.8 and SD 2.2) years, using validated rating scales for CTO, CTS, and loneliness. Linear mixed-effects models were employed to examine age- and sex-related trajectories of CTO and CTS over time. Linear regression models were used to evaluate baseline and longitudinal relationships of CTO and CTS with mental well-being, physical well-being, and loneliness. CTS and CTO were weakly intercorrelated. Women had higher baseline CTO than men. While CTO was stable over time and across the lifespan, CTS scores had an inverse U-shaped relationship with age, peaking around age 77. There were significant baseline × slope interactions of both CTO and CTS predicting improvements in physical well-being in adults

ObjectiveAssess the relationship between parity and prior route of delivery to levonorgestrel 52 mg intrauterine system (IUS) expulsion during the first 72 months of use.Study designWe evaluated women enrolled in the ACCESS IUS multicenter, Phase 3, open-label clinical trial of the Liletta levonorgestrel 52 mg IUS. Investigators evaluated IUS presence at 3 and 6 months after placement and then every 6 months and during unscheduled visits. We included women with successful placement and at least one follow-up assessment. We evaluated expulsion rates based on obstetric history; for prior delivery method subanalyses, we excluded 12 participants with missing delivery data. We determined predictors of expulsion using multivariable regression analyses.ResultsOf 1714 women with IUS placement, 1710 had at least one follow-up assessment. The total population included 986 (57.7%) nulliparous women. Sixty-five (3.8%) women experienced expulsion within 72 months, 50 (76.9%) within the first 12 months. Expulsion rates among nulliparous women (22/986 [2.2%]) or parous women with any pregnancy ending with a Cesarean delivery (6/195 [3.1%]) differed from parous women who only experienced vaginal deliveries (37/517 [7.2%]) (p < 0.001). In multivariable regression, obesity (adjusted odds ratio [aOR] 2.2, 95% confidence interval [CI] 1.3-3.7), parity (aOR 2.2, 95% CI 1.2-4.1), and non-white race (aOR 1.8, 95% CI 1.1-3.2) predicted expulsion. Among parous women, obesity (aOR 2.2, 95% CI 1.2-4.2) increased the odds and having ever had a cesarean delivery (aOR 0.4, 95% CI 0.1-0.9) decreased the odds of expulsion.ConclusionIUS expulsion occurs in less than 4% of users over the first 6 years of use and occurs mostly during the first year. Expulsion is more likely among obese and parous women.ImplicationsLevonorgestrel 52 mg intrauterine system expulsion occured more commonly in parous than nulliparous women; the increase in parous women is primarily in women who had vaginal deliveries only. The association between obesity, delivery route, and IUS expulsion needs further elucidation.

Objective:Cognitive tasks are used to probe neuronal activity during functional magnetic resonance imaging (fMRI) to detect signs of aberrant cognitive functioning in patients diagnosed with schizophrenia (SZ). However, nonlinear (inverted-U-shaped) associations between neuronal activity and task difficulty can lead to misinterpretation of group differences between patients and healthy comparison subjects (HCs). In this paper, we evaluated a novel method for correcting these misinterpretations based on conditional performance analysis.Method:Participants included 25 HCs and 27 SZs who performed a working memory (WM) task (N-back) with 5 load conditions while undergoing fMRI. Neuronal activity was regressed onto: 1) task load (i.e., parametric task levels), 2) marginal task performance (i.e., performance averaged over all load conditions), or 3) conditional task performance (i.e., performance within each load condition).Results:In most regions of interest, conditional performance analysis uniquely revealed inverted-U-shaped neuronal activity in both SZs and HCs. After accounting for conditional performance differences between groups, we observed few difference in both the pattern and level of neuronal activity between SZs and HCs within regions that are classically associated with WM functioning (e.g., posterior dorsolateral prefrontal and parietal association cortices). However, SZs did show aberrant activity within the anterior dorsolateral prefrontal cortex.Conclusions:Interpretations of differences in neuronal activity between groups, and of associations between neuronal activity and performance, should be considered within the context of task performance. Whether conditional performance-based differences reflect compensation, dedifferentiation, or other processes is not a question that is easily resolved by examining activation and performance data alone.

Social impairments are common across many psychiatric conditions. Standardized dyadic assessments intended to elicit social affiliation between unacquainted partners are used to elucidate mechanisms that disrupt relationship formation and inform possible treatment targets; however, the psychometric properties of such paradigms remain poorly understood. This study evaluated the psychometric properties of a controlled social affiliation paradigm intended to induce connectedness between a target participant and trained confederate. Individuals with an anxiety or depressive disorder diagnosis (clinical group; n = 132) and those without (control group; n = 35) interacted face-to-face with a trained confederate; partners took turns answering a series of increasingly intimate questions about themselves. Social connectedness, affect, and affiliative behavior measures were collected during the interaction. Participant symptom and social functioning measures were collected to examine validity. The paradigm elicited escalating social connectedness throughout the task for both participants and confederates. Parallel forms (i.e., different question sets) elicited similar affiliation outcomes. Self-reported (but not behavioral) affiliation differed across some demographic variables (e.g., participant gender, Hispanic ethnicity). Within-task affiliation measures were associated with one another and with global social connectedness and social anxiety symptom measures, but not with somatic anxiety measures. Clinical participants reported lower social affiliation and positive affect reactivity and higher negative affect reactivity than healthy participants. These findings provide initial psychometric support for a standardized and controlled dyadic affiliation paradigm that could be used to reliably probe social disconnection mechanisms across psychopathology. Keywords: social affiliation, psychometrics, reliability, validity, relationship formation, behavioral, social anxiety, anxiety, depression, reciprocal self-disclosure paradigm

Williams Syndrome (WS) is a rare neurodevelopmental disorder associated with a specific cognitive profile of strengths and impairments. It has been argued that studying cognitive development of this disorder would not only allow improved knowledge of WS but also provide insight into alternative pathways in development. However, due to the rarity and nature of the disorder, there are a number of challenges to collect longitudinal data. This letter describes a new multi-lab based approach to examine development in WS longitudinally and discusses some of the challenges and solutions that need to be taken into account when putting together either previously obtained or newly collected data from different labs.

Mobile health, or 'mHealth', is the application of mobile devices, their components and related technologies to healthcare. It is already improving patients' access to treatment and advice. Now, in combination with internet-connected diagnostic devices, it offers novel ways to diagnose, track and control infectious diseases and to improve the efficiency of the health system. Here we examine the promise of these technologies and discuss the challenges in realizing their potential to increase patients' access to testing, aid in their treatment and improve the capability of public health authorities to monitor outbreaks, implement response strategies and assess the impact of interventions across the world.

ObjectiveThe aim of this study was to determine whether post-traumatic stress disorder (PTSD) moderates treatment outcomes in Acceptance and Commitment Therapy for chronic pain.DesignLongitudinal.SettingVeterans Affairs San Diego Healthcare System.SubjectsA total of 126 veterans with chronic pain participating in an Acceptance and Commitment Therapy intervention for chronic pain. A structured clinical interview was used at baseline to designate PTSD-positive (N = 43) and -negative groups (N = 83).MethodsLinear mixed-effects models to determine whether PTSD moderated change in pain interference, pain severity, pain acceptance, depressive symptoms, or pain-related anxiety at post-treatment and six-month follow-up.ResultsParticipants with co-occurring PTSD reported greater pain interference, pain severity, depressive symptoms, and pain-related anxiety at baseline. PTSD status did not moderate treatment effects post-treatment. Rather, there were significant improvements on all study measures across groups (P < 0.001). PTSD status moderated change in depressive symptoms at six-month follow-up (P ConclusionsPTSD status did not significantly affect treatment outcomes, with the exception of depressive symptoms at six-month follow-up. Overall, Acceptance and Commitment Therapy for chronic pain appears helpful for improving outcomes among veterans with co-occurring PTSD; however, veterans with co-occurring PTSD may experience fewer long-term gains compared with those with chronic pain alone.

BACKGROUND Sacubitril-valsartan is an angiotensin receptor-neprilysin inhibitor indicated for the treatment of patients with symptomatic heart failure with reduced ejection fraction (HFrEF). Little is known about outcomes of HFrEF patients transitioned from sodium nitroprusside (SNP) to sacubitril-valsartan during an admission for acute decompensated heart failure. We sought to describe characteristics of patients initiated on sacubitril-valsartan while receiving SNP and, in particular, those patients who did and did not experience hypotension requiring interruption or discontinuation of sacubitril-valsartan. METHODS We performed a retrospective case series of adult patients (>18 years) with HFrEF (left ventricular ejection fraction ≤40%) admitted to the University of Michigan cardiac intensive care unit between July 2018 to September 2020 who received sacubitril-valsartan while on SNP. RESULTS A total of 15 patients with acute decompensated heart failure were initiated on sacubitril-valsartan while on SNP. The mean age was 57 ± 15.9 years. Seven (46.7%) patients experienced hypotension. The patients in the cohort who experienced hypotension were numerically older (60 ± 17 vs. 55 ± 15.5), and the majority were white (86%). Patients with hypotension had a numerically lower left ventricular ejection fraction (13 ± 4.2 vs. 18 ± 8.2) and higher serum creatinine (1.4 ± 0.54 vs. 0.88 ± 0.25). Seven (100%) patients received a diuretic on the day of sacubitril-valsartan initiation in those who experienced hypotension compared with 2 (25%) in those who did not experience hypotension. CONCLUSIONS In almost half of patients admitted to the cardiac intensive care unit with acutely decompensated HFrEF, significant hypotension was seen when initiating sacubitril-valsartan while on SNP. Future studies should evaluate appropriate patients for this transition and delineate appropriate titration parameters.

Nuclear magnetic resonance spectroscopy (MRS) allows for the determination of atomic structures and concentrations of different chemicals in a biochemical sample of interest. MRS is used in vivo clinically to aid in the diagnosis of several pathologies that affect metabolic pathways in the body. Typically, this experiment produces a one dimensional (1D) 1H spectrum containing several peaks that are well associated with biochemicals, or metabolites. However, since many of these peaks overlap, distinguishing chemicals with similar atomic structures becomes much more challenging. One technique capable of overcoming this issue is the localized correlated spectroscopy (L-COSY) experiment, which acquires a second spectral dimension and spreads overlapping signal across this second dimension. Unfortunately, the acquisition of a two dimensional (2D) spectroscopy experiment is extremely time consuming. Furthermore, quantitation of a 2D spectrum is more complex. Recently, artificial intelligence has emerged in the field of medicine as a powerful force capable of diagnosing disease, aiding in treatment, and even predicting treatment outcome. In this study, we utilize deep learning to: (1) accelerate the L-COSY experiment and (2) quantify L-COSY spectra. All training and testing samples were produced using simulated metabolite spectra for chemicals found in the human body. We demonstrate that our deep learning model greatly outperforms compressed sensing based reconstruction of L-COSY spectra at higher acceleration factors. Specifically, at four-fold acceleration, our method has less than 5% normalized mean squared error, whereas compressed sensing yields 20% normalized mean squared error. We also show that at low SNR (25% noise compared to maximum signal), our deep learning model has less than 8% normalized mean squared error for quantitation of L-COSY spectra. These pilot simulation results appear promising and may help improve the efficiency and accuracy of L-COSY experiments in the future.

Background Collaborative decision-making is an innovative decision-making approach that assigns equal power and responsibility to patients and providers. Most veterans with serious mental illnesses like schizophrenia want a greater role in treatment decisions, but there are no interventions targeted for this population. A skills-based intervention is promising because it is well-aligned with the recovery model, uses similar mechanisms as other evidence-based interventions in this population, and generalizes across decisional contexts while empowering veterans to decide when to initiate collaborative decision-making. Collaborative Decision Skills Training (CDST) was developed in a civilian serious mental illness sample and may fill this gap but needs to undergo a systematic adaptation process to ensure fit for veterans. Methods In aim 1, the IM Adapt systematic process will be used to adapt CDST for veterans with serious mental illness. Veterans and Veteran’s Affairs (VA) staff will join an Adaptation Resource Team and complete qualitative interviews to identify how elements of CDST or service delivery may need to be adapted to optimize its effectiveness or viability for veterans and the VA context. During aim 2, an open trial will be conducted with veterans in a VA Psychosocial Rehabilitation and Recovery Center (PRRC) to assess additional adaptations, feasibility, and initial evidence of effectiveness. Discussion This study will be the first to evaluate a collaborative decision-making intervention among veterans with serious mental illness. It will also contribute to the field’s understanding of perceptions of collaborative decision-making among veterans with serious mental illness and VA clinicians, and result in a service delivery manual that may be used to understand adaptation needs generally in VA PRRCs. Trial registration ClinicalTrials.gov Identifier: NCT04324944

Loss of the neuromuscular junction (NMJ) is an early and critical hallmark in all forms of ALS. The study design was to develop a functional NMJ disease model by integrating motoneurons (MNs) differentiated from multiple ALS-patients' induced pluripotent stem cells (iPSCs) and primary human muscle into a chambered system. NMJ functionality was tested by recording myotube contractions while stimulating MNs by field electrodes and a set of clinically relevant parameters were defined to characterize the NMJ function. Three ALS lines were analyzed, 2 with SOD1 mutations and 1 with a FUS mutation. The ALS-MNs reproduced pathological phenotypes, including increased axonal varicosities, reduced axonal branching and elongation and increased excitability. These MNs formed functional NMJs with wild type muscle, but with significant deficits in NMJ quantity, fidelity and fatigue index. Furthermore, treatment with the Deana protocol was found to correct the NMJ deficits in all the ALS mutant lines tested. Quantitative analysis also revealed the variations inherent in each mutant lines. This functional NMJ system provides a platform for the study of both fALS and sALS and has the capability of being adapted into subtype-specific or patient-specific models for ALS etiological investigation and patient stratification for drug testing.

Cognitive impairment is a hallmark of schizophrenia and a robust predictor of functional outcomes. Impairments are found in all phases of the illness and are only moderately attenuated by currently approved therapeutics. Neurophysiological indices of sensory discrimination (ie, mismatch negativity (MMN) and P3a amplitudes) and gamma-band auditory steady-state response (ASSR; power and phase locking) are translational biomarkers widely used in the development of novel therapeutics for neuropsychiatric disorders. It is unclear whether laboratory-based EEG measures add explanatory power to well-established models that use only cognitive, clinical, and functional outcome measures. Moreover, it is unclear if measures of sensory discrimination and gamma-band ASSR uniquely contribute to putative causal pathways linking sensory discrimination, neurocognition, negative symptoms, and functional outcomes in schizophrenia. To answer these questions, hierarchical associations among sensory processing, neurocognition, clinical symptoms, and functional outcomes were assessed via structural equation modeling in a large sample of schizophrenia patients (n = 695) and healthy comparison subjects (n = 503). The results showed that the neurophysiologic indices of sensory discrimination and gamma-band ASSR both significantly contribute to and yield unique hierarchical, “bottom-up” effects on neurocognition, symptoms, and functioning. Measures of sensory discrimination showed direct effects on neurocognition and negative symptoms, while gamma-band ASSR had a direct effect on neurocognition in patients. Continued investigation of the neural mechanisms underlying abnormal networks of MMN/P3a and gamma-band ASSR is needed to clarify the pathophysiology of schizophrenia and the development of novel therapeutic interventions.

Developing digital biomarkers that would enable reliable detection of autism–ASD early in life is challenging because of the variability in the presentation of the autistic disorder and the need for simple measurements that could be implemented routinely during checkups. Electroencephalography, widely known as EEG, is an electrophysiological monitoring method that has been explored as a potential clinical tool for monitoring atypical brain function. EEG measurements were collected from 101 infants, beginning at 12 to 15 months of age and continuing until 36 months of age. In contrast to previous work in the literature that analysed EEG signals, our approach considers EEG–as–an–image using an appropriate signal transformation that preserves the spatial location of the EEG signals to create RGB images. It employs Residual neural networks and transfer learning to detect atypical brain function. Prediction of the clinical diagnostic outcome of ASD or not ASD at 36 months was accurate from as early as 12 months of age. This shows that using end-to-end deep learning is a viable way of extracting useful digital biomarkers from EEG measurements for predicting autism in infants.

Objective Wisdom has gained increasing interest among researchers as a personality trait relevant to well-being and mental health. We previously reported development of a new 24-item San Diego Wisdom Scale (SD-WISE), with good to excellent psychometric properties, comprised of six subscales: pro-social behaviors, emotional regulation, self-reflection (insight), tolerance for divergent values (acceptance of uncertainty), decisiveness, and social advising. There is controversy about whether spirituality is a marker of wisdom. The present cross-sectional study sought to address that question by developing a new SD-WISE subscale of spirituality and examining its associations with various relevant measures. Methods Data were collected from a national-level sample of 1,786 community-dwelling adults age 20–82 years, as part of an Amazon M-Turk cohort. Participants completed the 24-item SD-WISE along with several subscales of a commonly used Brief Multidimensional Measure of Religiousness/Spirituality, along with validated scales for well-being, resilience, happiness, depression, anxiety, loneliness, and social network. Results Using latent variable models, we developed a Spirituality subscale, which demonstrated acceptable psychometric properties including a unidimensional factor structure and good reliability. Spirituality correlated positively with age and was higher in women than in men. The expanded 28-item, 7-subscale SD-WISE total score (called the Jeste-Thomas Wisdom Index or JTWI) demonstrated acceptable psychometric properties. The Spirituality subscale was positively correlated with good mental health and well-being, and negatively correlated with poor mental health. However, compared to other components of wisdom, the Spirituality factor showed weaker (i.e., small-to-medium vs. medium-to-large) association with the SD-WISE higher-order Wisdom factor (JTWI). Conclusion Similar to other components as well as overall wisdom, spirituality is significantly associated with better mental health and well-being, and may add to the predictive utility of the total wisdom score. Spirituality is, however, a weaker contributor to overall wisdom than components like pro-social behaviors and emotional regulation. Longitudinal studies of larger and more diverse samples are needed to explore mediation effects of these constructs on well-being and health.

Cognitive impairments are pervasive and disabling features of schizophrenia. Targeted cognitive training (TCT) is a “bottom-up” cognitive remediation intervention with efficacy for neurocognitive outcomes in schizophrenia, yet individual responses are variable. Gamma oscillatory measures are leading candidate biomarkers in the development of biologically informed pro-cognitive therapeutics. Forty-two schizophrenia patients were recruited from a long-term residential treatment facility. Participants were randomized to receive either 1 h of cognitive training (TCT, n = 21) or computer games (TAU, n = 21). All participants received standard-of-care treatment; the TCT group additionally completed 30 h of cognitive training. The auditory steady-state response paradigm was used to elicit gamma oscillatory power and synchrony during electroencephalogram recordings. Detailed clinical and cognitive assessments were collected at baseline and after completion of the study. Baseline gamma power predicted cognitive gains after a full course of TCT (MCCB, R2 = 0.31). A change in gamma power after 1-h TCT exposure predicted improvement in both positive (SAPS, R2 = 0.40) and negative (SANS, R2 = 0.30) symptoms. These relationships were not observed in the TAU group (MCCB, SAPS, and SANS, all R2

Introduction: Stimulating cardiomyocyte (CM) proliferation is a major strategy for achieving therapeutic heart regeneration. However, heart regeneration requires coordinated interactions of multiple cell types. Because a hallmark of advanced heart failure is vascular rarefaction, the requirement of cardiac endothelial cells (CECs) for cardiac growth and regeneration is of particular importance. Hypothesis: We hypothesized that CECs are required for CM proliferation during growth and regeneration. Methods and Results: We performed a large-scale histologic assessment of neonatal mouse hearts and found the rate of CEC proliferation to shadow CM proliferation over the first 10 days of life. Using a nearest neighbor analysis, we found the fraction of proliferating CECs to be significantly enriched around cycling CMs compared to non-cycling CMs, suggesting that CEC and CM expansion are coupled within a myovascular niche. Single cell sequencing of neonatal mouse hearts after cryoinjury revealed that a majority of these proliferating CECs also express Vegfr2 . To functionally link CEC and CM proliferation, we generated Cdh5-CreER T2 ; Vefgr2 flox/flox mice to genetically delete Vegfr2 from CECs. Compared to mice with intact Vegfr2 , loss of Vegfr2 from CECs in neonatal mice leads to loss of CECs and severely dampens CM proliferation by 4 days (7.01±0.88% vs 0.39±0.35%, p = 7.4x10-4, n = 9),. Interestingly, CM proliferation is attenuated when Vegfr2 is deleted from CECs despite an increase of hypoxia indicators in CMs, signifying that hypoxia-induced CM proliferation is dependent on CECs. In contrast to CEC depletion, treatment of cryoinjured neonatal hearts with AAV encoding the master angiogenic factor, Vegfa can enhance heart regeneration with increased CM cycling in the borderzone (12.6±2.2% vs 5.4±0.4%, p = 0.02, n = 8), reduced scarring of the left ventricle (3.4±1.4% vs 7.6±1.2%, p = 03, n = 16), and improved fractional shortening (51.7±2.5% vs 36.7±4.3%, p = 0.007, n = 14). Conclusions: CEC and CM expansion are spatiotemporally coupled in a myovascular niche during cardiac growth. CECs play a critical role to support CM proliferation and are likely to provide instructive cues that may be leveraged for therapeutic heart regeneration.

Introduction: Heart regeneration has been proposed as a treatment for heart failure. However, the challenge of detecting bona fide heart regeneration has complicated the validation of potential regenerative factors. We sought to develop a method for quantifying cardiomyogenesis in the mouse heart using multicolor lineage tracing. Hypothesis: We hypothesized that multicolor lineage tracing in combination with modeling of nearest neighbor distances could be used to quantify clonal expansion of cardiomyocytes (CMs) during growth and regeneration. Methods: Myh6- MerCreMer ; R26R-Rainbow bitransgenic mice underwent cryoinjury (CI) or sham injury on postnatal day 1 (P1). Tamoxifen was then administered such that limited numbers of CMs were randomly labeled with mCerulean, mOrange, or mCherry fluorophores. Hearts were collected at 21 days post CI. We analyzed a total of 81 sections, across 6 hearts (3 with sham injury and 3 with cryoinury). Images of entire cardiac sections were manually segmented to generate positional information for each labeled CM. Results: We used the nearest neighbor distributions of CMs carrying the same fluorophore and CMs carrying different fluorophores to develop a Bayesian model for estimating the probability that two CMs are clonally related. We found that, across a range of recombination efficiency, CMs carrying the same fluorophore within 30 μm are likely to be clonally related. By classifying CMs based on this distance threshold, we were able to confirm that clonally related CMs are smaller than non-clonally related CMs (165.20 ± 13.79 μm 2 vs 252.37 ± 20.51 μm 2 , p = 0.007, Welch t-test). We also confirmed that rates of cardiomyogenesis in cryoinjured and sham injured hearts are approximately the same (8.57 ± 2.69 % in cryoinjured hearts vs 9.45 ± 1.23 % in sham hearts, p=0.788). Conclusions: We have developed a robust and objective approach for quantifying cardiomyogenesis in the mouse heart. This method can be applied to studies of heart regeneration and can also be adapted to other tissues.

White matter (WM) deterioration is an important mechanism of cognitive decline in healthy aging and dementia. Engaging in aerobic exercise to improve cardiorespiratory fitness (CRF) is considered one of the most promising ways to improve cognitive and brain health in aging. Yet, no randomized controlled trials have reported benefits of aerobic exercise interventions on WM microstructure measured with diffusion tensor imaging. Here, we studied the effects of a 6-month exercise intervention (clinical trial NCT01472744) on WM of 180 cognitively healthy older adults (60–79 years) using the ratio of calibrated T1-weighted image to T2-weighted images (T1w/T2w). Participants were randomized to one of four groups including a low intensity activity with complex cognitive demands (Dance), Walking, Walking + nutritional supplement or an active control. Results showed that a 6-month aerobic walking and dance intervention produced positive changes in the T1w/T2w with significant time-by-group interactions in the total WM, the genu and splenium of the corpus callosum, forceps minor, cingulum, relative to an active control condition. In contrast, we observed a decline in T1w/T2w in the majority of WM regions in the active control group. Lastly, a positive change in the T1w/T2w in the genu of the corpus callosum correlated with a positive change in episodic memory in the Walking but not in the control group; however, there were no associations between change in the T1w/T2w and change in CRF. Together, our findings suggest that the T1w/T2w may be a sensitive metric to detect short-term within-person changes in the WM and intervention-induced WM plasticity in the adult human brain.