Transmission from vaccinated individuals in a large SARS-CoV-2 Delta variant outbreak.

An outbreak of over 1,000 COVID-19 cases in Provincetown, Massachusetts (MA), in July 2021-the first large outbreak mostly in vaccinated individuals in the US-prompted a comprehensive public health response, motivating changes to national masking recommendations and raising questions about infection and transmission among vaccinated individuals. To address these questions, we combined viral genomic and epidemiological data from 467 individuals, including 40% of outbreak-associated cases. The Delta variant accounted for 99% of cases in this dataset; it was introduced from at least 40 sources, but 83% of cases derived from a single source, likely through transmission across multiple settings over a short time rather than a single event. Genomic and epidemiological data supported multiple transmissions of Delta from and between fully vaccinated individuals. However, despite its magnitude, the outbreak had limited onward impact in MA and the US overall, likely due to high vaccination rates and a robust public health response.

Interferon-ß acts directly on T cells to prolong allograft survival by enhancing regulatory T cell induction through Foxp3 acetylation.

Type I interferons (IFNs) are pleiotropic cytokines with potent antiviral properties that also promote protective T cell and humoral immunity. Paradoxically, type I IFNs, including the widely expressed IFNß, also have immunosuppressive properties, including promoting persistent viral infections and treating T-cell-driven, remitting-relapsing multiple sclerosis. Although associative evidence suggests that IFNß mediates these immunosuppressive effects by impacting regulatory T (Treg) cells, mechanistic links remain elusive. Here, we found that IFNß enhanced graft survival in a Treg-cell-dependent murine transplant model. Genetic conditional deletion models revealed that the extended allograft survival was Treg cell-mediated and required IFNß signaling on T cells. Using an in silico computational model and analysis of human immune cells, we found that IFNß directly promoted Treg cell induction via STAT1- and P300-dependent Foxp3 acetylation. These findings identify a mechanistic connection between the immunosuppressive effects of IFNß and Treg cells, with therapeutic implications for transplantation, autoimmunity, and malignancy.

Alignment of learning objectives, assessments, and active learning to promote critical thinking in a first-year medical physiology course: lessons learned.

Medical students must be adept at critical thinking to successfully meet the learning objectives of their preclinical coursework. To encourage student success on assessments, the course director of a first-year medical physiology course emphasized the use of learning objectives that were explicitly aligned with formative assessments in class. The course director introduced the physiology discipline, learning objectives, and evidence-based methods of studying to students on the first day of class. Thereafter, class sessions started with a review of the learning objectives for that session and included active learning opportunities such as retrieval practice. The instructor provided short answer formative assessments aligned with the learning objectives, intended to help the students apply and integrate the concepts. Midsemester, students received a link to an online survey with questions on studying habits, class attendance, and student engagement. After finals, students were invited to participate in focus groups about their class experience. A qualitative researcher moderated focus groups, recorded responses, and analyzed the narrative data. Of 175 students, 95 submitted anonymous online surveys. Student engagement was significantly correlated with in-person class attendance (r = 0.26, T = 2.5, P = 0.01) and the completion of open-ended formative assessments (r = 0.33, T = 3.3, P = 0.001). Focus groups were held via videoconference. From the class, 14 students participated in 4 focus groups; focus group participants were mostly women (11 of 14) and mostly in-class attendees (13 of 14). The students in this sample valued critical thinking but misunderstood expectations on exams and few students used learning objectives to study.NEW & NOTEWORTHY We introduced formative assessments and study techniques to first-year medical students in a physiology course. Mastery of learning objectives was emphasized as the key to success. We asked how they studied physiology through an anonymous online survey and focus group interviews. The students enjoyed physiology but had difficulty with exam expectations. Helping students use learning objectives to guide their study may lead to improved exam scores. It may also help administrators meet their curriculum goals.

Germline ERBB3 mutation in familial non-small-cell lung carcinoma: expanding ErbB's role in oncogenesis.

Lung cancer is the commonest cause of cancer deaths worldwide. Although strongly associated with smoking, predisposition to lung cancer is also heritable, with multiple common risk variants identified. Rarely, dominantly inherited non-small-cell lung cancer (NSCLC) has been reported due to somatic mutations in EGFR/ErbB1 and ERBB2. Germline exome sequencing was performed in a multi-generation family with autosomal dominant NSCLC, including an affected child. Tumour samples were also sequenced. Full-length wild-type (wtErbB3) and mutant ERBB3 (mutErbB3) constructs were transfected into HeLa cells. Protein expression, stability, and subcellular localization were assessed, and cellular proliferation, pAkt/Akt and pERK levels determined. A novel germline variant in ERBB3 (c.1946 T > G: p.Iso649Arg), coding for receptor tyrosine-protein kinase erbB-3 (ErbB3), was identified, with appropriate segregation. There was no loss-of-heterozygosity in tumour samples. Both wtErbB3 and mutErbB3 were stably expressed. MutErbB3-transfected cells demonstrated an increased ratio of the 80 kDa form (which enhances proliferation) compared with the full-length (180 kDa) form. MutErbB3 and wtErbB3 had similar punctate cytoplasmic localization pre- and post-epidermal growth factor stimulation; however, epidermal growth factor receptor (EGFR) levels decreased faster post-stimulation in mutErbB3-transfected cells, suggesting more rapid processing of the mutErbB3/EGFR heterodimer. Cellular proliferation was increased in mutErbB3-transfected cells compared with wtErbB3 transfection. MutErbB3-transfected cells also showed decreased pAkt/tAkt ratios and increased pERK/tERK 30 min post-stimulation compared with wtErbB3 transfection, demonstrating altered signalling pathway activation. Cumulatively, these results support this mutation as tumorogenic. This is the first reported family with a germline ERBB3 mutation causing heritable NSCLC, furthering understanding of the ErbB family pathway in oncogenesis.

Open Science in eating disorders: Using current evidence to inspire a plan for increasing the transparency of our research.

OBJECTIVE: There is increasing consensus that open science practices improve the transparency and quality of clinical science. However, several barriers impede the implementation of these practices at the individual, institutional, and field levels; understanding and addressing these barriers is critical to promoting targeted efforts in increasing effective uptake of open science. METHODS: Within this research forum, we drew from publicly available online information sources to identify initial characterizations of researchers engaged in several types of open science practices in the field of eating disorders. We use these observations to discuss potential barriers and recommendations for next steps in the promotion of these practices. RESULTS: Data from online open science repositories suggest that individuals using these publishing approaches with pre-prints and articles with eating-disorder-relevant content are predominantly non-male gender identifying, early to mid-career stage, and are more likely to be European-, United States-, or Canada-based. DISCUSSION: We outline recommendations for tangible ways that the eating disorder field can support broad, increased uptake of open science practices, including supporting initiatives to increase knowledge and correct misconceptions; and prioritizing the development and accessibility of open science resources. PUBLIC SIGNIFICANCE STATEMENT: The use of open science practices has the potential to increase the transparency and quality of clinical science. This Forum uses publicly sourced online data to characterize researchers engaged in open science practices in the field of eating disorders. These observations provide an important framework from which to discuss potential barriers to open science and recommendations for next steps in the promotion of these practices.

A randomized, controlled pilot study of positive affect treatment adapted for anorexia nervosa.

OBJECTIVE: Novel treatments for adults with anorexia nervosa (AN) are sorely needed. Although psychological interventions have been developed for AN, none have been identified as superior to one another or nonspecific treatments. Common comorbidities (e.g., mood and anxiety disorders) are rarely targeted in AN treatments, possibly impairing long-term clinical improvement. AN is associated with reward processing dysfunctions paralleling those identified in affective disorders; however, few treatments directly target these processes. METHOD: We adapted Positive Affect Treatment, a neuroscience-informed behavioral treatment developed for affective disorders, to the treatment of AN (PAT-AN). Adults with AN (N = 20) were randomized to 20 weeks of PAT-AN or waitlist to investigate the feasibility, acceptability, preliminary efficacy, and target engagement (on reward mechanisms) of PAT-AN. RESULTS: PAT-AN demonstrated strong retention (100%) and acceptability ratings (M = 5.67-5.95 on a 7-point scale). BMI (p = .006) and eating disorder symptoms (p < .001) improved over PAT-AN sessions. The PAT-AN group showed medium to large pre-to-post-treatment improvements in BMI, eating disorder symptoms and impairment, depressive and anxiety symptoms, and some reward indices (ds = .56-.87); changes were largely sustained at 3-month follow-up. Waitlist showed negligible changes (ds < .20) on nearly all measures. DISCUSSION: PAT-AN holds promise as an innovative treatment with capability to simultaneously improve eating disorder symptoms, affective symptoms, and underlying reward mechanisms. Findings should be interpreted cautiously due to small sample size and permitted concurrent enrollment in other treatments. Future, larger-scale research is warranted to establish the efficacy of PAT-AN. PUBLIC SIGNIFICANCE: This study provided a preliminary evaluation of Positive Affect Treatment for anorexia nervosa (PAT-AN), a novel, neuroscience-informed treatment aimed at increasing rewarding life experiences outside of one's eating disorder. Initial results suggest that PAT-AN is considered acceptable and may alleviate eating disorder, depressive, and anxiety symptoms. Therefore, this study presents promising data on a treatment that may hold potential for improving the lives of individuals with this disorder.

Causal discovery analysis: A promising tool in advancing precision medicine for eating disorders.

OBJECTIVE: Precision medicine (i.e., individually tailored treatments) represents an optimal goal for treating complex psychiatric disorders, including eating disorders. Within the eating disorders field, most treatment development efforts have been limited in their ability to identify individual-level models of eating disorder psychopathology and to develop and apply an individually tailored treatment for a given individual's personalized model of psychopathology. In addition, research is still needed to identify causal relationships within a given individual's model of eating disorder psychopathology. Addressing this limitation of the current state of precision medicine-related research in the field will allow us to progress toward advancing research and practice for eating disorders treatment. METHOD: We present a novel set of analytic tools, causal discovery analysis (CDA) methods, which can facilitate increasingly fine-grained, person-specific models of causal relations among cognitive, behavioral, and affective symptoms. RESULTS: CDA can advance the identification of an individual's causal model that maintains that individuals' eating disorder psychopathology. DISCUSSION: In the current article, we (1) introduce CDA methods as a set of promising analytic tools for developing precision medicine methods for eating disorders including the potential strengths and weaknesses of CDA, (2) provide recommendations for future studies utilizing this approach, and (3) outline the potential clinical implications of using CDA to generate personalized models of eating disorder psychopathology. PUBLIC SIGNIFICANCE STATEMENT: CDA provides a novel statistical approach for identifying causal relationships among variables of interest for a given individual. Person-specific causal models may offer a promising approach to individualized treatment planning and inform future personalized treatment development efforts for eating disorders.

Providing the choice of in-person or videoconference attendance in a clinical physiology course may harm learning outcomes for the entire cohort.

Clinical Physiology 1 and 2 are flipped classes in which students watch prerecorded videos before class. During the 3-h class, students take practice assessments, work in groups on critical thinking exercises, work through case studies, and engage in drawing exercises. Due to the COVID pandemic, these courses were transitioned from in-person classes to online classes. Despite the university's return-to-class policy, some students were reluctant to return to in-person classes; therefore during the 2021-2022 academic year, Clinical Physiology 1 and 2 were offered as flipped, hybrid courses. In a hybrid format, students either attended the synchronous class in person or online. Here we evaluate the learning outcomes and the perceptions of the learning experience for students who attended Clinical Physiology 1 and 2 either online (2020-2021) or in a hybrid format (2021-2022). In addition to exam scores, in-class surveys and end of course evaluations were compiled to describe the student experience in the flipped hybrid setting. Retrospective linear mixed-model regression analysis of exam scores revealed that a hybrid modality (2021-2022) was associated with lower exam scores when controlling for sex, graduate/undergraduate status, delivery method, and the order in which the courses were taken (F test: F = 8.65, df1 = 2, df2 = 179.28, P = 0.0003). In addition, being a Black Indigenous Person of Color (BIPOC) student is associated with a lower exam score, controlling for the same previous factors (F test: F = 4.23, df1 = 1, df2 = 130.28, P = 0.04), albeit with lower confidence; the BIPOC representation in this sample is small (BIPOC: n = 144; total: n = 504). There is no significant interaction between the hybrid modality and race, meaning that BIPOC and White students are both negatively affected in a hybrid flipped course. Instructors should consider carefully about offering hybrid courses and build in extra student support.NEW & NOTEWORTHY The transition from online to in-person teaching has been as challenging as the original transition to remote teaching with the onset of the pandemic. Since not all students were ready to return to the classroom, students could choose to take this course in person or online. This arrangement provided flexibility and opportunities for innovative class activities for students but introduced tradeoffs in lower test scores from the hybrid modality than fully online or fully in-person modalities.

Urine Residual Volume in Normal Dogs Determined by Direct Measurement and Comparison to Two-Dimensional Ultrasonographic Measurement.

Normal urine residual volume (URV) in dogs has not previously been established by direct measurement. Twenty-two client-owned normal healthy dogs (8 female spayed, 12 male castrated, 2 male intact) without history of urinary abnormalities were included. Dogs were walked outside for 5 min to allow for natural voiding, immediately followed by urinary bladder ultrasound and urinary catheterization. The URV was recorded, and the ultrasound images were used to estimate URV for each dog. There was no significant difference between male and female URV; therefore, all data were pooled. With a 90% confidence interval, URV was 0-0.47 mL/kg with a mean URV of 0.21 mL/kg and a median value of 0.175 mL/kg. There was no significant difference between the measured URV and the ultrasound-determined URV. This case series supports previously established normal URV in the dog; however, a reference interval based on a larger population of dogs with further evaluation of body size/weight, sex, and neuter status is recommended to be established for use in clinical setting to differentiate normal urination from urinary retention in patients.

Cerebrospinal fluid mutant huntingtin is a biomarker for huntingtin lowering in the striatum of Huntington disease mice.

Huntington disease (HD) is a neurodegenerative disease caused by a trinucleotide repeat expansion in the HTT gene encoding an elongated polyglutamine tract in the huntingtin (HTT) protein. Expanded mutant HTT (mHTT) is toxic and leads to regional atrophy and neuronal cell loss in the brain, which occurs earliest in the striatum. Therapeutic lowering of mHTT in the central nervous system (CNS) has shown promise in preclinical studies, with multiple approaches currently in clinical development for HD. Quantitation of mHTT in the cerebrospinal fluid (CSF) is being used as a clinical pharmacodynamic biomarker of target engagement in the CNS. We have previously shown that the CNS is a major source of mHTT in the CSF. However, little is known about the specific brain regions and cell types that contribute to CSF mHTT. Therefore, a better understanding of the origins of CSF mHTT and whether therapies targeting mHTT in the striatum would be expected to be associated with significant lowering of mHTT in the CSF is needed. Here, we use complementary pharmacological and genetic-based approaches to either restrict expression of mHTT to the striatum or selectively deplete mHTT in the striatum to evaluate the contribution of this brain region to mHTT in the CSF. We show that viral expression of a mHTT fragment restricted to the striatum leads to detectable mHTT in the CSF. We demonstrate that targeted lowering of mHTT selectively in the striatum using an antisense oligonucleotide leads to a significant reduction of mHTT in the CSF of HD mice. Furthermore, using a transgenic mouse model of HD that expresses full length human mHTT and wild type HTT, we show that genetic inactivation of mHTT selectively in the striatum results in a significant reduction of mHTT in the CSF. Taken together, our data supports the conclusion that the striatum contributes sufficiently to the pool of mHTT in the CSF that therapeutic levels of mHTT lowering in the striatum can be detected by this measure in HD mice. This suggests that CSF mHTT may represent a pharmacodynamic biomarker for therapies that lower mHTT in the striatum.

Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer.

BACKGROUND: Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling. METHODS: In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis. RESULTS: The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group. CONCLUSIONS: A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).

Micro-level de-coupling of negative affect and binge eating in relationship to macro-level outcomes in binge eating disorder treatment.

BACKGROUND: While negative affect reliably predicts binge eating, it is unknown how this association may decrease or 'de-couple' during treatment for binge eating disorder (BED), whether such change is greater in treatments targeting emotion regulation, or how such change predicts outcome. This study utilized multi-wave ecological momentary assessment (EMA) to assess changes in the momentary association between negative affect and subsequent binge-eating symptoms during Integrative Cognitive Affective Therapy (ICAT-BED) and Cognitive Behavior Therapy Guided Self-Help (CBTgsh). It was predicted that there would be stronger de-coupling effects in ICAT-BED compared to CBTgsh given the focus on emotion regulation skills in ICAT-BED and that greater de-coupling would predict outcomes. METHODS: Adults with BED were randomized to ICAT-BED or CBTgsh and completed 1-week EMA protocols and the Eating Disorder Examination (EDE) at pre-treatment, end-of-treatment, and 6-month follow-up (final N = 78). De-coupling was operationalized as a change in momentary associations between negative affect and binge-eating symptoms from pre-treatment to end-of-treatment. RESULTS: There was a significant de-coupling effect at follow-up but not end-of-treatment, and de-coupling did not differ between ICAT-BED and CBTgsh. Less de-coupling was associated with higher end-of-treatment EDE global scores at end-of-treatment and higher binge frequency at follow-up. CONCLUSIONS: Both ICAT-BED and CBTgsh were associated with de-coupling of momentary negative affect and binge-eating symptoms, which in turn relate to cognitive and behavioral treatment outcomes. Future research is warranted to identify differential mechanisms of change across ICAT-BED and CBTgsh. Results also highlight the importance of developing momentary interventions to more effectively de-couple negative affect and binge eating.

Gastrointestinal Interoception in Eating Disorders: Charting a New Path.

PURPOSE OF REVIEW: Abnormal interoception has been consistently observed across eating disorders despite limited inclusion in diagnostic conceptualization. Using the alimentary tract as well as recent developments in interoceptive neuroscience and predictive processing as a guide, the current review summarizes evidence of gastrointestinal interoceptive dysfunction in eating disorders. RECENT FINDINGS: Eating is a complex process that begins well before and ends well after food consumption. Abnormal prediction and prediction-error signals may occur at any stage, resulting in aberrant gastrointestinal interoception and dysregulated gut sensations in eating disorders. Several interoceptive technologies have recently become available that can be paired with computational modeling and clinical interventions to yield new insights into eating disorder pathophysiology. Illuminating the neurobiology of gastrointestinal interoception in eating disorders requires a new generation of studies combining experimental probes of gut physiology with computational modeling. The application of such techniques within clinical trials frameworks may yield new tools and treatments with transdiagnostic relevance.

Beyond Description and Deficits: How Computational Psychiatry Can Enhance an Understanding of Decision-Making in Anorexia Nervosa.

PURPOSE OF REVIEW: Despite decades of research, knowledge of the mechanisms maintaining anorexia nervosa (AN) remains incomplete and clearly effective treatments elusive. Novel theoretical frameworks are needed to advance mechanistic and treatment research for this disorder. Here, we argue the utility of engaging a novel lens that differs from existing perspectives in psychiatry. Specifically, we argue the necessity of expanding beyond two historically common perspectives: (1) the descriptive perspective: the tendency to define mechanisms on the basis of surface characteristics and (2) the deficit perspective: the tendency to search for mechanisms associated with under-functioning of decision-making abilities and related circuity, rather than problems of over-functioning, in psychiatric disorders. RECENT FINDINGS: Computational psychiatry can provide a novel framework for understanding AN because this approach emphasizes the role of computational misalignments (rather than absolute deficits or excesses) between decision-making strategies and environmental demands as the key factors promoting psychiatric illnesses. Informed by this approach, we argue that AN can be understood as a disorder of excess goal pursuit, maintained by over-engagement, rather than disengagement, of executive functioning strategies and circuits. Emerging evidence suggests that this same computational imbalance may constitute an under-investigated phenotype presenting transdiagnostically across psychiatric disorders. A variety of computational models can be used to further elucidate excess goal pursuit in AN. Most traditional psychiatric treatments do not target excess goal pursuit or associated neurocognitive mechanisms. Thus, targeting at the level of computational dysfunction may provide a new avenue for enhancing treatment for AN and related disorders.

Eating Disorder Examination-Questionnaire and Clinical Impairment Assessment norms for intersectional identities using an MTurk sample.

OBJECTIVE: There are limited data to guide the interpretation of scores on measures of eating-disorder psychopathology among underrepresented individuals. We aimed to provide norms for the Eating Disorder Examination-Questionnaire (EDE-Q) and Clinical Impairment Assessment (CIA) across racial/ethnic, gender, and sexual identities, and sexual orientations and their intersections by recruiting a diverse sample of Amazon MTurk workers (MTurkers; N = 1782). METHOD: We created a comprehensive, quantitative assessment of racial/ethnic identification, gender identification, sex assigned at birth, current sexual identification, and sexual orientation called the Demographic Assessment of Racial, Sexual, and Gender Identities (DARSGI). We calculated normative data for each demographic category response option. RESULTS: Our sample was comprised of 68% underrepresented racial/ethnic identities, 42% underrepresented gender identities, 13% underrepresented sexes, and 49% underrepresented sexual orientations. We reported means and standard deviations for each demographic category response option and, where possible, mean estimates by percentile across intersectional groups. EDE-Q Global Score for a subset of identities and intersections in the current study were higher than previously reported norms for those identities/intersections. DISCUSSION: This is the most thorough reporting of norms for the EDE-Q and CIA among racial/ethnic, sexual, and gender identities, and sexual orientations and the first reporting on multiple intersections, filling some of the gaps for commonly used measures of eating-disorder psychopathology. These norms may be used to contextualize eating-disorder psychopathology reported by underrepresented individuals. The data from the current study may help inform research on the prevention and treatment of eating-disorder psychopathology in underrepresented groups. PUBLIC SIGNIFICANCE: We provide the most thorough reporting on racial/ethnic, sexual, and gender identities, and sexual orientations for the Eating Disorder Examination - Questionnaire and Clinical Impairment Assessment, and the first reporting on intersections, which fills some of the gaps for commonly used measures of eating-disorder psychopathology. These norms help inform research on the prevention and treatment of eating-disorder psychopathology in underrepresented groups.

Potent and sustained huntingtin lowering via AAV5 encoding miRNA preserves striatal volume and cognitive function in a humanized mouse model of Huntington disease.

Huntington disease (HD) is a fatal neurodegenerative disease caused by a pathogenic expansion of a CAG repeat in the huntingtin (HTT) gene. There are no disease-modifying therapies for HD. Artificial microRNAs targeting HTT transcripts for degradation have shown preclinical promise and will soon enter human clinical trials. Here, we examine the tolerability and efficacy of non-selective HTT lowering with an AAV5 encoded miRNA targeting human HTT (AAV5-miHTT) in the humanized Hu128/21 mouse model of HD. We show that intrastriatal administration of AAV5-miHTT results in potent and sustained HTT suppression for at least 7 months post-injection. Importantly, non-selective suppression of huntingtin was generally tolerated, however high dose AAV5-miHTT did induce astrogliosis. We observed an improvement of select behavioural and modest neuropathological HD-like phenotypes in Hu128/21 mice, suggesting a potential therapeutic benefit of miRNA-mediated non-selective HTT lowering. Finally, we also observed that potent reduction of wild type HTT (wtHTT) in Hu21 control mice was tolerated up to 7 months post-injection but may induce impairment of motor coordination and striatal atrophy. Taken together, our data suggests that in the context of HD, the therapeutic benefits of mHTT reduction may outweigh the potentially detrimental effects of wtHTT loss following non-selective HTT lowering.

Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease.

White matter abnormalities are a nearly universal pathological feature of neurodegenerative disorders including Huntington disease (HD). A long-held assumption is that this white matter pathology is simply a secondary outcome of the progressive neuronal loss that manifests with advancing disease. Using a mouse model of HD, here we show that white matter and myelination abnormalities are an early disease feature appearing before the manifestation of any behavioral abnormalities or neuronal loss. We further show that selective inactivation of mutant huntingtin (mHTT) in the NG2+ oligodendrocyte progenitor cell population prevented myelin abnormalities and certain behavioral deficits in HD mice. Strikingly, the improvements in behavioral outcomes were seen despite the continued expression of mHTT in nonoligodendroglial cells including neurons, astrocytes, and microglia. Using RNA-seq and ChIP-seq analyses, we implicate a pathogenic mechanism that involves enhancement of polycomb repressive complex 2 (PRC2) activity by mHTT in the intrinsic oligodendroglial dysfunction and myelination deficits observed in HD. Our findings challenge the long-held dogma regarding the etiology of white matter pathology in HD and highlight the contribution of epigenetic mechanisms to the observed intrinsic oligodendroglial dysfunction. Our results further suggest that ameliorating white matter pathology and oligodendroglial dysfunction may be beneficial for HD.

Erythropoietin Reduces Auto- and Alloantibodies by Inhibiting T Follicular Helper Cell Differentiation.

BACKGROUND: Although high-affinity IgG auto- and alloantibodies are important drivers of kidney inflammation that can result in ESKD, therapeutic approaches that effectively reduce such pathogenic antibodies remain elusive. Erythropoietin (EPO) has immunomodulatory functions, but its effects on antibody production are unknown. METHODS: We assessed the effect and underlying mechanisms of EPO/EPO receptor (EPOR) signaling on primary and secondary, T cell-dependent and T-independent antibody formation using in vitro culture systems, murine models of organ transplantation and lupus nephritis, and mice conditionally deficient for the EPOR expressed on T cells or B cells. RESULTS: In wild-type mice, recombinant EPO inhibited primary, T cell-dependent humoral immunity to model antigens and strong, polyclonal stimuli, but did not alter T-independent humoral immune responses. EPO also significantly impaired secondary humoral immunity in a potent allogeneic organ transplant model system. The effects required T cell, but not B cell, expression of the EPOR and resulted in diminished frequencies of germinal center (GC) B cells and T follicular helper cells (TFH). In vitro and in vivo experiments showed that EPO directly prevented TFH differentiation and function via a STAT5-dependent mechanism that reduces CD4+ T cell expression of Bcl6. In lupus models, EPO reduced TFH, GC B cells, and autoantibody production, and abrogated autoimmune glomerulonephritis, demonstrating clinical relevance. In vitro studies verified that EPO prevents differentiation of human TFH cells. CONCLUSIONS: Our findings newly demonstrate that EPO inhibits TFH-dependent antibody formation, an observation with potential implications for treating antibody-mediated diseases, including those of the kidney.

The role of rumination and positive beliefs about rumination in eating pathology.

PURPOSE: General and eating disorder (ED)-specific ruminations have been identified as key factors that may contribute to eating pathology. Positive beliefs about rumination (e.g., "Ruminating helps me to prevent future mistakes") may impact this association. However, the effect of positive beliefs about rumination on the links between rumination and ED symptom severity has not been investigated. This study sought to clarify relations between rumination and ED symptom severity and to evaluate the potential moderating effect of positive beliefs about rumination on these associations. METHODS: During a laboratory visit, undergraduate participants (N = 473, MAge = 18.90 ± 2.27, MBMI = 23.45 kg/m2 ± 4.31, 54.8% female) completed an online battery of questionnaires assessing general and ED-specific ruminative processes (e.g., brooding, reflection), positive beliefs about rumination, and global ED symptoms. Hierarchical multiple regression analyses assessed the unique contributions of specific ruminative processes, and the moderating effect of positive beliefs on associations between ruminative processes and ED symptom severity. RESULTS: Hierarchical multiple regression results suggest that, after controlling for gender and BMI, ED-specific brooding, b = 1.32, SE = 0.13, ß = 0.46, p < 0.0001, and reflection, b = 1.44, SE = 0.33, ß = 0.19, p < 0.0001, accounted for unique variance in ED symptom severity. Moderation model results indicate that, at low levels of general reflection, b = - 0.06, SE = 0.02, ß = - 0.51, p = 0.003, and ED-specific reflection, b = - 0.15, SE = 0.03, ß = - 0.59, p < 0.0001, increased positive beliefs about rumination were associated with greater ED symptom severity. CONCLUSION: Findings suggest ED-specific rumination accounts for ED symptom severity above and beyond general rumination, and that rumination-related expectancies influence the association between reflection and ED symptom severity. LEVEL OF EVIDENCE: Level III, evidence obtained from a well-designed cohort study.

Exploring the contributions of affective constructs and interoceptive awareness to feeling fat.

PURPOSE: Feeling fat, a subjective feeling of being overweight that does not always correspond to actual body weight, is commonly reported in patients with an eating disorder. Research suggests that feeling fat relates to deficits in interoceptive awareness, the perception and integration of signals related to body states. Relatedly, recent work has linked feeling fat to affective constructs, such as depressive symptoms and guilt. The current study explores the unique relationships between feeling fat, self-reported, and objective IA, guilt, alexithymia, and depressive symptoms. METHOD: Female undergraduates (N = 128) completed the 11th item of the Eating Disorder Examination Questionnaire, the Toronto Alexithymia Scale, the Guilt subscale of the Positive and Negative Affect Schedule, and the Beck Depression Inventory-II. Participants also completed two IA measures: a heartbeat perception task and the Multidimensional Assessment of Interoceptive Awareness. RESULTS: All collected measures explained 56% of the variability in feeling fat. Depressive symptoms, self-reported IA, and BMI accounted for significant variability in feeling fat. Relative weights analyses revealed that depressive symptoms accounted for the most variability in feeling fat (19%). This finding remained significant after controlling for BMI, which also accounted for significant variability in feeling fat (25%). CONCLUSIONS: Our results replicate previous findings that depressive symptoms relate significantly to feeling fat and extend this work by incorporating the role of interoceptive awareness, guilt, and alexithymia. Endorsement of feeling fat during an intake assessment may alert clinicians to assess for depressive symptoms, and focusing on depressive symptoms in treatment may improve feeling fat. LEVEL OF EVIDENCE: Level I Evidence obtained from an experimental study.