The Additive Effect of Social Anxiety Disorder on Learning in Veterans with Unipolar Depression

Differential patterns of punishment and reward responsivity are found in social anxiety disorder (SAD), which is highly comorbid with major depressive disorder (MDD). Individuals with either SAD or MDD react and respond differently to receipt of punishing and rewarding stimuli compared to healthy controls, suggesting a shared diathesis. Little is known, however, about punishment and reward responsivity in comorbid SAD and MDD compared to MDD-alone. In a sample of 80 veterans with unipolar depression, mixed model repeated measures analyses of variances (ANOVA) were conducted to explore the additive effect of co-occurring SAD and MDD on response bias (RB) in punishment and reward learning. For the punishment task, the SAD group demonstrated greater bias away from the more frequently punished stimuli and slower reaction times (RT). However, the interactions between Block and Group for RB and RT were not significant. For the reward task, no statistically significant main effects or interactions emerged, suggesting a unique effect of comorbid SAD on punishment responsivity in a depressed sample. Implications for etiology, maintenance, and treatment of comorbid SAD and MDD are reviewed as well as future directions for exploring this presentation

Successful Treatment of ANCA-Negative Wegener's Granulomatosis with Rituximab

Wegener's Granulomatosis (WG) is a systemic vasculitis typically associated with antineutrophil cytoplasmic antibodies (ANCAs). A small proportion of patients are ANCA negative, however, and this is more commonly found in individuals with disease limited to the ears, nose, throat, and lungs, who do not have renal involvement. Rituximab is a monoclonal anti-CD20 antibody that has been demonstrated to be effective in the treatment of autoantibody-associated rheumatic diseases, including systemic WG. We report the case of a patient with ANCA-negative WG who responded well to rituximab, illustrating that even in the absence of detectable autoantibodies, B-cell depletion can be effective

Decreasing delirium through music (DDM) in critically ill, mechanically ventilated patients in the intensive care unit: Protocol for a randomized controlled trial

Background Delirium is a highly prevalent and morbid syndrome in intensive care units (ICUs). Changing the stressful environment within the ICU via music may be an effective and a scalable way to reduce the burden of delirium. Methods/design The Decreasing Delirium through Music (DDM) study is a three-arm, single-blind, randomized controlled feasibility trial. Sixty patients admitted to the ICU with respiratory failure requiring mechanical ventilation will be randomized to one of three arms (20 participants per arm): (1) personalized music, (2) non-personalized relaxing music, or (3) attention-control. Music preferences will be obtained from all enrolled participants or their family caregivers. Participants will receive two 1-h audio sessions a day through noise-cancelling headphones and mp3 players. Our primary aim is to determine the feasibility of the trial design (recruitment, adherence, participant retention, design and delivery of the music intervention). Our secondary aim is to estimate the potential effect size of patient-preferred music listening in reducing delirium, as measured by the Confusion Assessment Method for the ICU (CAM-ICU). Participants will receive twice daily assessments for level of sedation and presence of delirium. Enrolled participants will be followed in the hospital until death, discharge, or up to 28 days, and seen in the Critical Care Recovery Clinic at 90 days. Discussion DDM is a feasibility trial to provide personalized and non-personalized music interventions for critically ill, mechanically ventilated patients. Our trial will also estimate the preliminary efficacy of music interventions on reducing delirium incidence and severity. Trial registration ClinicalTrials.gov, Identifier: NCT03095443. Registered on 23 March 2017

In Vivo Analysis of Trypanosoma cruzi Persistence Foci at Single-Cell Resolution.

Infections with Trypanosoma cruzi are usually lifelong despite generating a strong adaptive immune response. Identifying the sites of parasite persistence is therefore crucial to understanding how T. cruzi avoids immune-mediated destruction. However, this is a major technical challenge, because the parasite burden during chronic infections is extremely low. Here, we describe an integrated approach involving comprehensive tissue processing, ex vivo imaging, and confocal microscopy, which allowed us to visualize infected host cells in murine tissue with exquisite sensitivity. Using bioluminescence-guided tissue sampling, with a detection level of 200 parasites, which we term mega-nests. In contrast, during the acute stage, when the total parasite burden is considerably higher and many cells are infected, nests containing >50 parasites are rarely found. In C3H/HeN mice, but not BALB/c mice, we identified skeletal muscle as a major site of persistence during the chronic stage, with most parasites being found in large mega-nests within the muscle fibers. Finally, we report that parasites are also frequently found in the skin during chronic murine infections, often in multiple infection foci. In addition to being a site of parasite persistence, this anatomical reservoir could play an important role in insect-mediated transmission and have implications for drug development.IMPORTANCE Trypanosoma cruzi causes Chagas disease, the most important parasitic infection in Latin America. Major pathologies include severe damage to the heart and digestive tract, although symptoms do not usually appear until decades after infection. Research has been hampered by the complex nature of the disease and technical difficulties in locating the extremely low number of parasites. Here, using highly sensitive imaging technology, we reveal the sites of parasite persistence during chronic-stage infections of experimental mice at single-cell resolution. We show that parasites are frequently located in smooth muscle cells in the circular muscle layer of the colon and that skeletal muscle cells and the skin can also be important reservoirs. This information provides a framework for investigating how the parasite is able to survive as a lifelong infection, despite a vigorous immune response. It also informs drug development strategies by identifying tissue sites that must be accessed to achieve a curative outcome

Combat‐Related Posttraumatic Stress Disorder and Comorbid Major Depression in U.S. Veterans: The Role of Deployment Cycle Adversity and Social Support

Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) commonly co‐occur in combat veterans, and this comorbidity has been associated with higher levels of distress and more social and economic costs compared to one disorder alone. In a secondary analysis of a multisite randomized controlled trial of a sample of veterans with combat‐related PTSD, we examined the associations among pre‐, peri‐, and postdeployment adversity, social support, and clinician‐diagnosed comorbid MDD. Participants completed the Deployment Risk and Resilience Inventory and the Beck Depression Inventory–II as well as structured clinical interviews for diagnostic status. Among 223 U.S. veterans of the military operations in Iraq and Afghanistan (86.9% male) with primary combat‐related PTSD, 69.5% had current comorbid MDD. After adjustment for sex, a linear regression model indicated that more concerns about family disruptions during deployment, f2 = 0.065; more harassment during deployment, f2 = 0.020; and lower ratings of postdeployment social support, f2 = 0.154, were associated with more severe self‐reported depression symptoms. Interventions that enhance social support as well as societal efforts to foster successful postdeployment reintegration are critical for reducing the mental health burden associated with this highly prevalent comorbidity in veterans with combat‐related PTSD.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155948/1/jts22496_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155948/2/jts22496.pd

Deterministic evolution and stringent selection during preneoplasia

The earliest events during human tumour initiation, although poorly characterized, may hold clues to malignancy detection and prevention1. Here we model occult preneoplasia by biallelic inactivation of TP53, a common early event in gastric cancer, in human gastric organoids. Causal relationships between this initiating genetic lesion and resulting phenotypes were established using experimental evolution in multiple clonally derived cultures over 2 years. TP53 loss elicited progressive aneuploidy, including copy number alterations and structural variants prevalent in gastric cancers, with evident preferred orders. Longitudinal single-cell sequencing of TP53-deficient gastric organoids similarly indicates progression towards malignant transcriptional programmes. Moreover, high-throughput lineage tracing with expressed cellular barcodes demonstrates reproducible dynamics whereby initially rare subclones with shared transcriptional programmes repeatedly attain clonal dominance. This powerful platform for experimental evolution exposes stringent selection, clonal interference and a marked degree of phenotypic convergence in premalignant epithelial organoids. These data imply predictability in the earliest stages of tumorigenesis and show evolutionary constraints and barriers to malignant transformation, with implications for earlier detection and interception of aggressive, genome-instable tumours

A Hypermorphic Missense Mutation in PLCG2, Encoding Phospholipase Cγ2, Causes a Dominantly Inherited Autoinflammatory Disease with Immunodeficiency

Whole-exome sequencing was performed in a family affected by dominantly inherited inflammatory disease characterized by recurrent blistering skin lesions, bronchiolitis, arthralgia, ocular inflammation, enterocolitis, absence of autoantibodies, and mild immunodeficiency. Exome data from three samples, including the affected father and daughter and unaffected mother, were filtered for the exclusion of reported variants, along with benign variants, as determined by PolyPhen-2. A total of eight transcripts were identified as possible candidate genes. We confirmed a variant, c.2120C>A (p.Ser707Tyr), within PLCG2 as the only de novo variant that was present in two affected family members and not present in four unaffected members. PLCG2 encodes phospholipase Cγ2 (PLCγ2), an enzyme with a critical regulatory role in various immune and inflammatory pathways. The p.Ser707Tyr substitution is located in an autoinhibitory SH2 domain that is crucial for PLCγ2 activation. Overexpression of the altered p.Ser707Tyr protein and ex vivo experiments using affected individuals’ leukocytes showed clearly enhanced PLCγ2 activity, suggesting increased intracellular signaling in the PLCγ2-mediated pathway. Recently, our laboratory identified in individuals with cold-induced urticaria and immune dysregulation PLCG2 exon-skipping mutations resulting in protein products with constitutive phospholipase activity but with reduced intracellular signaling at physiological temperatures. In contrast, the p.Ser707Tyr substitution in PLCγ2 causes a distinct inflammatory phenotype that is not provoked by cold temperatures and that has different end-organ involvement and increased intracellular signaling at physiological temperatures. Our results highlight the utility of exome-sequencing technology in finding causal mutations in nuclear families with dominantly inherited traits otherwise intractable by linkage analysis

Clusters of Hantavirus Infection, Southern Argentina

Person-to-person transmission should be suspected when Andes virus case-patients are linked