The relationship between personality and cognition in older adults with and without early-onset depression.

Introduction: It is well established that personality traits impact cognition, as certain personality factors are associated with performance in specific cognitive domains. However, the findings on the relationships between the Big Five traits and cognition are mixed. Additionally, few studies have explored these relationships in older adults with a history of depression. The present study aimed to (a) evaluate the impact of the Big Five personality traits in older adults with and without a lifetime history of depression; and (b) test the hypotheses that higher trait neuroticism would correlate negatively with cognitive performance, while openness to experience would correlate positively with cognition. Methods: The sample consisted of 138 participants between the ages of 55 and 78 (M = 65.56, SD = 6.36). Sixty-two participants met criteria for current or remitted Major Depressive Disorder, while 76 had no history of depression or other mental health disorders. Participants underwent comprehensive neuropsychological testing. Personality was assessed using the NEO Personality Inventory-Revised (NEO-PI-R), while depression status was determined using the Structured Clinical Interview for DSM-5 (SCID-5). Following a series of Pearson correlations of cognitive variables and the five personality factors, linear regression models were estimated for each significant correlation. Demographic variables (i.e., age, education and sex) were entered in block 1, depression status (never vs. ever) was entered in block 2, and the personality factor score, or sub-facet was entered in block 3. Results: Neuroticism was not associated with cognitive performance on any outcome measure. The facets Openness to Feelings and Openness to Values were positively related to phonemic fluency. Further Openness to Values was positively related to cognitive flexibility. Discussion: Our results suggest that older people who are (a) more capable of identifying and understanding their feelings and the feelings of others, and (b) who are more willing to re-examine social, political, and religious values perform stronger on tasks measuring verbal fluency and cognitive flexibility, which are aspects of executive functioning. Interventions that aim to enhance open mindedness in older adults may have a parallel impact on improving executive functioning, though this would need to be examined prospectively.

Assembly of respiratory syncytial virus matrix protein lattice and its coordination with fusion glycoprotein trimers.

Respiratory syncytial virus (RSV) is an enveloped, filamentous, negative-strand RNA virus that causes significant respiratory illness worldwide. RSV vaccines are available, however there is still significant need for research to support the development of vaccines and therapeutics against RSV and related Mononegavirales viruses. Individual virions vary in size, with an average diameter of ~130 nm and ranging from ~500 nm to over 10 µm in length. Though the general arrangement of structural proteins in virions is known, we use cryo-electron tomography and sub-tomogram averaging to determine the molecular organization of RSV structural proteins. We show that the peripheral membrane-associated RSV matrix (M) protein is arranged in a packed helical-like lattice of M-dimers. We report that RSV F glycoprotein is frequently observed as pairs of trimers oriented in an anti-parallel conformation to support potential interactions between trimers. Our sub-tomogram averages indicate the positioning of F-trimer pairs is correlated with the underlying M lattice. These results provide insight into RSV virion organization and may aid in the development of RSV vaccines and anti-viral targets.

Pulmonary matrix-derived hydrogels from patients with idiopathic pulmonary fibrosis induce a proinflammatory state in lung fibroblasts in vitro.

Idiopathic pulmonary fibrosis (IPF), one of the most common forms of interstitial lung disease, is a poorly understood, chronic, and often fatal fibroproliferative condition with only two FDA-approved medications. Understanding the pathobiology of the fibroblast in IPF is critical to evaluating and discovering novel therapeutics. Using a decellularized lung matrix derived from patients with IPF, we generate three-dimensional hydrogels as in vitro models of lung physiology and characterize the phenotype of fibroblasts seeded into the hydrogels. When cultured in IPF extracellular matrix hydrogels, IPF fibroblasts display differential contractility compared with their normal counterparts, lose the classical myofibroblast marker α-smooth muscle actin, and increase expression of proinflammatory cytokines compared with fibroblasts seeded two-dimensionally on tissue culture dishes. We validate this proinflammatory state in fibroblast-conditioned media studies with monocytes and monocyte-derived macrophages. These findings add to a growing understanding of the lung microenvironment effect on fibroblast phenotypes, shed light on the potential role of fibroblasts as immune signaling hubs during lung fibrosis, and suggest intervention in fibroblast-immune cell cross-talk as a possible novel therapeutic avenue.

Surgeons' dominant surgical modality: Impacts on wellbeing, burnout, and interventions for neuromusculoskeletal disorders.

BACKGROUND: This study investigated the impact of surgical modalities on surgeon wellbeing with a focus on burnout, job satisfaction, and interventions used to address neuromusculoskeletal disorders (NMSDs). METHODS: An electronic survey was sent to surgeons across an academic integrated multihospital system. The survey consisted of 47 questions investigating different aspects of surgeons' wellbeing. RESULTS: Out of 245 thoracic and abdominopelvic surgeons, 79 surgeons (32.2 â€‹%) responded, and 65 surgeons (82 â€‹%) were able to be categorized as having a dominant surgical modality. Compared to robotic surgeons, laparoscopic (p â€‹= â€‹0.042) and open (p â€‹= â€‹0.012) surgeons reported more frequent feelings of burnout. The number of surgeons who used any treatment/intervention to minimize the operative discomfort/pain was lower for robotic surgeons than the other three modalities (all p â€‹< â€‹0.05). CONCLUSIONS: NMSDs affect different aspects of surgeons' lives and occupations. Robotic surgery was associated with decreased feelings of burnout than the other modalities.

An ALK2 inhibitor, BLU-782, prevents heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disease driven by gain-of-function variants in activin receptor-like kinase 2 (ALK2), the most common variant being ALK2R206H. In FOP, ALK2 variants display increased and dysregulated signaling through the bone morphogenetic protein (BMP) pathway resulting in progressive and permanent replacement of skeletal muscle and connective tissues with heterotopic bone, ultimately leading to severe debilitation and premature death. Here, we describe the discovery of BLU-782 (IPN60130), a small-molecule ALK2R206H inhibitor developed for the treatment of FOP. A small-molecule library was screened in a biochemical ALK2 binding assay to identify potent ALK2 binding compounds. Iterative rounds of structure-guided drug design were used to optimize compounds for ALK2R206H binding, ALK2 selectivity, and other desirable pharmacokinetic properties. BLU-782 preferentially bound to ALK2R206H with high affinity, inhibiting signaling from ALK2R206H and other rare FOP variants in cells in vitro without affecting signaling of closely related homologs ALK1, ALK3, and ALK6. In vivo efficacy of BLU-782 was demonstrated using a conditional knock-in ALK2R206H mouse model, where prophylactic oral dosing reduced edema and prevented cartilage and heterotopic ossification (HO) in both muscle and bone injury models. BLU-782 treatment preserved the normal muscle-healing response in ALK2R206H mice. Delayed dosing revealed a short 2-day window after injury when BLU-782 treatment prevented HO in ALK2R206H mice, but dosing delays of 4 days or longer abrogated HO prevention. Together, these data suggest that BLU-782 may be a candidate for prevention of HO in FOP.

Treatment resistant late-life depression: A narrative review of psychosocial risk factors, non-pharmacological interventions, and the role of clinical phenotyping.

BACKGROUND: Treatment resistant depression (TRD) is a subset of major depressive disorder (MDD) in which symptoms do not respond to front line therapies. In older adults, the assessment and treatment of TRD is complicated by psychosocial risk factors unique to this population, as well as a relative paucity of research. METHODS: Narrative review aimed at (1) defining TRLLD for clinical practice and research; (2) describing psychosocial risk factors; (3) reviewing psychological and non-pharmacological treatments; (4) discussing the role of clinical phenotyping for personalized treatment; and (5) outlining research priorities. RESULTS: Our definition of TRLLD centers on response to medication and neuromodulation in primary depressive disorders. Psychosocial risk factors include trauma and early life adversity, chronic physical illness, social isolation, personality, and barriers to care. Promising non-pharmacological treatments include cognitive training, psychotherapy, and lifestyle interventions. The utility of clinical phenotyping is highlighted by studies examining the impact of comorbidities, symptom dimensions (e.g., apathy), and structural/functional brain changes. LIMITATIONS: There is a relative paucity of TRLLD research. This limits the scope of empirical data from which to derive reliable patterns and complicates efforts to evaluate the literature quantitatively. CONCLUSIONS: TRLLD is a complex disorder that demands further investigation given our aging population. While this review highlights the promising breadth of TRLLD research to date, more research is needed to help elucidate, for example, the optimal timing for implementing risk mitigation strategies, the value of collaborative care approaches, specific treatment components associated with more robust response, and phenotyping to help inform treatment decisions.

Introducing the Pi-CON Methodology to Overcome Usability Deficits during Remote Patient Monitoring.

The adoption of telehealth has soared, and with that the acceptance of Remote Patient Monitoring (RPM) and virtual care. A review of the literature illustrates, however, that poor device usability can impact the generated data when using Patient-Generated Health Data (PGHD) devices, such as wearables or home use medical devices, when used outside a health facility. The Pi-CON methodology is introduced to overcome these challenges and guide the definition of user-friendly and intuitive devices in the future. Pi-CON stands for passive, continuous, and non-contact, and describes the ability to acquire health data, such as vital signs, continuously and passively with limited user interaction and without attaching any sensors to the patient. The paper highlights the advantages of Pi-CON by leveraging various sensors and techniques, such as radar, remote photoplethysmography, and infrared. It illustrates potential concerns and discusses future applications Pi-CON could be used for, including gait and fall monitoring by installing an omnipresent sensor based on the Pi-CON methodology. This would allow automatic data collection once a person is recognized, and could be extended with an integrated gateway so multiple cameras could be installed to enable data feeds to a cloud-based interface, allowing clinicians and family members to monitor patient health status remotely at any time.

Return of the Living Dead Gut - A Case Report of Ischemic Colitis Identified on Point of Care Ultrasound.

Ischemic colitis is the most common form of gastrointestinal ischemia 1. The diagnosis of ischemic colitis is made by clinical data and computed tomography (CT) imaging of the abdomen and pelvis 1. While colonoscopy is considered the gold standard for diagnosis, this is not performed in the emergency department (ED) 2. Few studies have been performed to describe the sonographic findings of ischemic colitis using point of care ultrasound (POCUS). We report a case that highlights the sonographic findings of ischemic colitis in a patient who had two separate visits to the ED, showcasing the utility of POCUS in making this diagnosis. POCUS can be used as a diagnostic tool for early detection of ischemic colitis leading to prompt treatment with antibiotics, CT imaging, and surgical consultation.

A Comparative Study of Machine Learning and Algorithmic Approaches to Automatically Identify the Yield Point in Normal and Aneurysmal Human Aortic Tissues.

The stress-strain curve of biological soft tissues helps characterize their mechanical behavior. The yield point on this curve is when a specimen breaches its elastic range due to irreversible microstructural damage. The yield point is easily found using the offset yield method in traditional engineering materials. However, correctly identifying the yield point in soft tissues can be subjective due to its nonlinear material behavior. The typical method for yield point identification is visual inspection, which is investigator-dependent and does not lend itself to automation of the analysis pipeline. An automated algorithm to identify the yield point objectively assesses soft tissues' biomechanical properties. This study aimed to analyze data from uniaxial extension testing on biological soft tissue specimens and create a machine learning (ML) model to determine a tissue sample's yield point. We present a trained machine learning model from 279 uniaxial extension curves from testing aneurysmal/nonaneurysmal and longitudinal/circumferential oriented tissue specimens that multiple experts labeled through an adjudication process. The ML model showed a median error of 5% in its estimated yield stress compared to the expert picks. The study found that an ML model could accurately identify the yield point (as defined) in various aortic tissues. Future studies will be performed to validate this approach by visually inspecting when damage occurs and adjusting the model using the ML-based approach.

Precision Oncology in Gastrointestinal and Colorectal Cancer Surgery.

Precision medicine is used to treat gastrointestinal malignancies including esophageal, gastric, small bowel, colorectal, and pancreatic cancers. Cutting-edge assays to detect and treat these cancers are active areas of research and will soon become standard of care. Colorectal cancer is a prime example of precision oncology as disease site is no longer the final determinate of treatment. Here, the authors describe how leveraging an understanding of tumor biology translates to individualized patient care using evidence-based practices.

Evaluation of a Photo Captioning Cognitive Empathy Intervention for Dementia Caregivers.

OBJECTIVES: The goal of this study was to develop and evaluate an intervention aimed at increasing cognitive empathy, improving mental health, and reducing inflammation in dementia caregivers, and to examine the relevant neural and psychological mechanisms. METHODS: Twenty dementia caregivers completed an intervention that involved taking 3-5 daily photographs of their person living with dementia (PLWD) over a period of 10 days and captioning those photos with descriptive text capturing the inner voice of the PLWD. Both before and after the intervention, participants completed questionnaires, provided a blood sample for measures of inflammation, and completed a neuroimaging session to measure their neural response to viewing photographs of their PLWD and others. RESULTS: 87% of enrolled caregivers completed the intervention. Caregivers experienced pre- to post-intervention increases in cognitive empathy (i.e. Perspective-Taking) and decreases in both burden and anxiety. These changes were paralleled by an increased neural response to photographs of their PLWD within brain regions implicated in cognitive empathy. CONCLUSION: These findings warrant a larger replication study that includes a control condition and follows participants to establish the duration of the intervention effects. CLINICAL IMPLICATIONS: Cognitive empathy interventions may improve caregiver mental health and are worthy of further investigation.

Circulating Tumor DNA Dynamics Fail to Predict Efficacy of Poly(ADP-ribose) Polymerase/VEGFR Inhibition in Patients With Heavily Pretreated Advanced Solid Tumors.

PURPOSE: Cell-free circulating tumor DNA (ctDNA) has shown its potential as a quantitative biomarker for longitudinal monitoring of response to anticancer therapies. However, ctDNA dynamics have not been studied in patients with heavily pretreated, advanced solid tumors, for whom therapeutic responses can be weak. We investigated whether changes in ctDNA could predict clinical outcomes in such a cohort treated with combined poly(ADP-ribose) polymerase/vascular endothelial growth factor receptor inhibitor therapy. MATERIALS AND METHODS: Patients with metastatic pancreatic ductal adenocarcinoma (PDAC), triple-negative breast cancer (TNBC), small-cell lung cancer (SCLC), or non-small-cell lung cancer (NSCLC) received up to 7 days of cediranib 30 mg orally once daily monotherapy lead-in followed by addition of olaparib 200 mg orally twice daily. Patients had progressed on a median of three previous lines of therapy. Plasma samples were collected before and after cediranib monotherapy lead-in and on combination therapy at 7 days, 28 days, and every 28 days thereafter. ctDNA was quantified from plasma samples using a multigene mutation-based assay. Radiographic assessment was performed every 8 weeks. RESULTS: ctDNA measurements were evaluable in 63 patients. The median baseline ctDNA variant allele fractions (VAFs) were 20%, 28%, 27%, and 34% for PDAC, TNBC, SCLC, and NSCLC, respectively. No association was observed between baseline VAF and radiographic response, progression-free survival, or overall survival (OS). Similarly, no association was found between ctDNA decline and radiographic response or survival. However, an increase in ctDNA at 56 days of combination therapy was associated with disease progression and inferior OS in a landmark analysis. CONCLUSION: ctDNA levels or dynamics did not correlate with radiographic response or survival outcomes in patients with advanced metastatic malignancies treated with olaparib and cediranib.

The Immune Suppressor IGSF1 as a Potential Target for Cancer Immunotherapy.

The development of first-generation immune-checkpoint inhibitors targeting PD-1/PD-L1 and CTLA-4 ushered in a new era in anticancer therapy. Although immune-checkpoint blockade therapies have shown clinical success, a substantial number of patients yet fail to benefit. Many studies are under way to discover next-generation immunotherapeutic targets. Immunoglobulin superfamily member 1 (IGSF1) is a membrane glycoprotein proposed to regulate thyroid function. Despite containing 12 immunoglobin domains, a possible role for IGSF1, in immune response, remains unknown. Here, our studies revealed that IGSF1 is predominantly expressed in tumors but not normal tissues, and increased expression is observed in PD-L1low non-small cell lung cancer (NSCLC) cells as compared with PD-L1high cells. Subsequently, we developed and characterized an IGSF1-specific human monoclonal antibody, WM-A1, that effectively promoted antitumor immunity and overcame the limitations of first-generation immune-checkpoint inhibitors, likely via a distinct mechanism of action. We further demonstrated high WM-A1 efficacy in humanized peripheral blood mononuclear cells (PBMC), and syngeneic mouse models, finding additive efficacy in combination with an anti-PD-1 (a well-characterized checkpoint inhibitor). These findings support IGSF1 as an immune target that might complement existing cancer immunotherapeutics.

Feasibility and Clinical Utility of Reporting Hereditary Cancer Predisposition Pathogenic Variants Identified in Research Germline Sequencing: A Prospective Interventional Study.

PURPOSE: Patients with cancer frequently undergo research-grade germline sequencing but clinically actionable results are not routinely disclosed. The objective of this study is to evaluate the feasibility of reporting clinically relevant secondary findings (SF) identified in germline research sequencing using the institutional molecular tumor board (MTB) and the treating oncology physician. METHODS: This prospective, interventional cohort study enrolled Total Cancer Care participants with any cancer diagnosis at a single institution. Patients underwent research-grade germline whole-exome sequencing, with bioinformatic analysis in a Clinical Laboratory Improvement Amendments-certified laboratory to verify pathogenic/likely pathogenic germline variants (PGVs) in any American College of Medical Genomics and Genetics SF v2.0 genes. After a protocol modification in consenting patients, the MTB reported PGVs to treating oncology physicians with recommendations for referral to a licensed genetic counselor and clinical confirmatory testing. RESULTS: Of the 781 enrolled participants, 32 (4.1%) harbored cancer predisposition PGVs, 24 (3.1%) were heterozygous carriers of an autosomal recessive cancer predisposition syndrome, and 14 (1.8%) had other hereditary disease PGVs. Guideline-directed testing would have missed 37.5% (12/32) of the inherited cancer predisposition PGVs, which included BRCA1, BRCA2, MSH6, SDHAF2, SDHB, and TP53 variants. Three hundred fifteen participants consented to reporting results; results for all living patients were reported to the clinical team with half referred to a licensed genetic counselor. There was concordance between all research variants identified in patients (n = 9) who underwent clinical confirmatory sequencing. CONCLUSION: MTB reporting of research-grade germline sequencing to the clinical oncology team is feasible. Over a third of PGVs identified using a universal testing strategy would have been missed by guideline-based approach, suggesting a role for expanding germline testing.

Phase I Safety and Feasibility Pilot of Hepatic Artery Infusion Chemotherapy in a Rural Catchment Area Using The Codman Vascular Catheter with The Medtronic SynchroMed II Pump for Intrahepatic Cancers.

BACKGROUND: Discontinuation of the Codman 3000 pump in 2018 left no Food and Drug Administration (FDA)-approved hepatic artery infusion (HAI) device for unresectable colorectal liver metastases (uCLM) and intrahepatic cholangiocarcinoma (uIHC). Historically, HAI has been performed at academic medical centers in large metropolitan areas, which are often inaccessible to rural patients. Consequently, feasibility of dissemination of HAI to rural populations is unknown. PATIENTS AND METHODS: Under an FDA investigational device exemption, we opened the only HAI program in Kentucky and enrolled patients with uCLM and uIHC in a phase I clinical trial. The trial examined the safety of the hybrid Codman catheter/Medtronic SynchroMed II pump (hCMP) combination, defined as successful completion of one cycle of HAI chemotherapy. Rural feasibility was assessed by number of missed pump fills appointments. RESULTS: A total of 21 patients (n = 17 uCLM, n = 4 uIHC) underwent hCMP implantation before accrual was stopped early owing to FDA approval of the Intera 3000 pump. 20/21 (95%) patients met the primary safety endpoint. Serious adverse events (AEs) included a grade 5 coronavirus disease 2019 (COVID-19) infection (n = 1) and a grade 3 catheter erosion into the bowel (n = 1). Biliary sclerosis developed in two patients (9.5%). Median distance to infusion center was 47.6 miles (2-138 miles), and 62% were from Appalachia, yet there were no missed pump fill appointments. The 2-year overall survival was 82.4% (uCLM) and 50% (uIHC). CONCLUSIONS: The hCMP device had an acceptable safety profile. Despite the complexity of starting a new HAI program, early results showed feasibility for HAI delivery in a rural catchment area and comparable outcomes to larger urban-based HAI centers.

Effectiveness of Bio-K+ for the prevention of Clostridioides difficile infection: Stepped-wedge cluster-randomized controlled trial.

OBJECTIVE: To evaluate the impact of administering probiotics to prevent Clostridioides difficile infection (CDI) among patients receiving therapeutic antibiotics. DESIGN: Stepped-wedge cluster-randomized trial between September 1, 2016, and August 31, 2019. SETTING: This study was conducted in 4 acute-care hospitals across an integrated health region. PATIENTS: Hospitalized patients, aged ≥55 years. METHODS: Patients were given 2 probiotic capsules daily (Bio-K+, Laval, Quebec, Canada), containing 50 billion colony-forming units of Lactobacillus acidophilus CL1285, L. casei LBC80R, and L. rhamnosus CLR2. We measured hospital-acquired CDI (HA-CDI) and the number of positive C. difficile tests per 10,000 patient days as well as adherence to administration of Bio-K+ within 48 and 72 hours of antibiotic administration. Mixed-effects generalized linear models, adjusted for influenza admissions and facility characteristics, were used to evaluate the impact of the intervention on outcomes. RESULTS: Overall adherence of Bio-K+ administration ranged from 76.9% to 84.6% when stratified by facility and periods. Rates of adherence to administration within 48 and 72 hours of antibiotic treatment were 60.2% -71.4% and 66.7%-75.8%, respectively. In the adjusted analysis, there was no change in HA-CDI (incidence rate ratio [IRR], 0.92; 95% confidence interval [CI], 0.68-1.23) or C. difficile positivity rate (IRR, 1.05; 95% CI, 0.89-1.24). Discharged patients may not have received a complete course of Bio-K+. Our hospitals had a low baseline incidence of HA-CDI. Patients who did not receive Bio-K+ may have differential risks of acquiring CDI, introducing selection bias. CONCLUSIONS: Hospitals considering probiotics as a primary prevention strategy should consider the baseline incidence of HA-CDI in their population and timing of probiotics relative to the start of antimicrobial administration.

Anatomically distributed neural representations of instincts in the hypothalamus.

Artificial activation of anatomically localized, genetically defined hypothalamic neuron populations is known to trigger distinct innate behaviors, suggesting a hypothalamic nucleus-centered organization of behavior control. To assess whether the encoding of behavior is similarly anatomically confined, we performed simultaneous neuron recordings across twenty hypothalamic regions in freely moving animals. Here we show that distinct but anatomically distributed neuron ensembles encode the social and fear behavior classes, primarily through mixed selectivity. While behavior class-encoding ensembles were spatially distributed, individual ensembles exhibited strong localization bias. Encoding models identified that behavior actions, but not motion-related variables, explained a large fraction of hypothalamic neuron activity variance. These results identify unexpected complexity in the hypothalamic encoding of instincts and provide a foundation for understanding the role of distributed neural representations in the expression of behaviors driven by hardwired circuits.