Presynaptic GABA A receptors control integration of nicotinic input onto dopaminergic axons in the striatum.

Axons of dopaminergic neurons express gamma-aminobutyric acid type-A receptors (GABA A Rs) and nicotinic acetylcholine receptors (nAChRs) which are both independently positioned to shape striatal dopamine release. Using electrophysiology and calcium imaging, we investigated how interactions between GABA A Rs and nAChRs influence dopaminergic axon excitability. Direct axonal recordings showed that benzodiazepine application suppresses subthreshold axonal input from cholinergic interneurons (CINs). In imaging experiments, we used the first temporal derivative of presynaptic calcium signals to distinguish between direct- and nAChR-evoked activity in dopaminergic axons. We found that GABA A R antagonism with gabazine selectively enhanced nAChR-evoked axonal signals. Acetylcholine release was unchanged in gabazine suggesting that GABA A Rs located on dopaminergic axons, but not CINs, mediated this enhancement. Unexpectedly, we found that a widely used GABA A R antagonist, picrotoxin, inhibits axonal nAChRs and should be used cautiously for striatal circuit analysis. Overall, we demonstrate that GABA A Rs on dopaminergic axons regulate integration of nicotinic input to shape presynaptic excitability.

Invasive cancer and spontaneous regression two weeks after papillomavirus infection.

Development of invasive cancer in mammals is thought to require months or years after initial events such as mutation or viral infection. Rarely, invasive cancers regress spontaneously. We show that cancers can develop and regress on a timescale of weeks, not months or years. Invasive squamous cell carcinomas developed in normal adult, immune-competent mice as soon as 2 weeks after infection with mouse papillomavirus MmuPV1. Tumor development, regression or persistence was tissue- and strain-dependent. Cancers in infected mice developed rapidly at sites also prone to papillomavirus-induced tumors and cancers in humans - the throat, anus, and skin - and their frequency was increased in mice constitutively expressing the papillomavirus E5 oncogene, which MmuPV1 lacks. Cancers and dysplasia in the throat and anus regressed completely within 4-8 weeks of infection; however, skin lesions in the ear persisted. T-cell depletion in the mouse showed that regression of throat and anal tumors requires T cells. We conclude that papillomavirus infection suffices for rapid onset of invasive cancer, and persistence of lesions depends on factors including tissue type and host immunity. The speed of these events should promote rapid progress in the study of viral cancer development, persistence, and regression.

Associations between 6-minute walk distance and physiologic measures and clinical outcomes in myositis-associated interstitial lung disease.

OBJECTIVE: The 6-min walk test (6MWT) is a simple test widely used to assess sub-maximal exercise capacity in chronic respiratory diseases. We explored the relationship of 6-min walk distance (6MWD) with measurements of physiological, clinical, radiographic measures in patients with myositis-associated interstitial lung disease (MA-ILD). METHOD: We analyzed data from the Abatacept in Myositis Associated Interstitial lung disease (Attack My-ILD) study, a 48-week multicentre randomized trial of patients with anti-synthetase antibodies and active MA-ILD. 6MWD, forced vital capacity (FVC), diffusing capacity (DLCO), high resolution CT, and various physician/patient reported outcome measures were obtained during the trial. Spearman's correlations and repeated-measures analysis with linear mixed-effects models were used to estimate the associations between 6MWD and various physiologic, clinical and radiographic parameters both cross-sectionally and longitudinally. RESULTS: Twenty participants with a median age of 57, 55% male and 85% white were analyzed. Baseline 6MWD did not associate with baseline PFTs. Repeated-measures analysis showed 6MWD over time associated with FVC over time, but not with DLCO. 6MWD over time also correlated with UCSD dyspnea score, Borg scores, as well as global disease activity and muscle strength over time. Emotional role functioning, vitality, general health and physical functioning scores by short form 36 also correlated with 6MWD over time. CONCLUSIONS: : Exploratory work in a small cohort of MA-ILD demonstrated 6MWD over time associated with parallel changes in FVC and patient reported outcomes of dyspnea, but not with DLCO. Larger studies are needed to validate the reliability, responsiveness and utility of the 6MWT in MA-ILD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT03215927.

Assessing the global prevalence of wild birds in trade.

Trade represents a significant threat to many wild species and is often clandestine and poorly monitored. Information on which species are most prevalent in trade and potentially threatened by it therefore remains fragmentary. We used 7 global data sets on birds in trade to identify species or groups of species at particular risk and assessed the extent to which they were congruent in terms of the species recorded in trade. We used the frequency with which species were recorded in the data sets as the basis for a trade prevalence score that was applied to all bird species globally. Literature searches and questionnaire surveys were used to develop a list of species known to be heavily traded to validate the trade prevalence score. The score was modeled to identify significant predictors of trade. Although the data sets sampled different parts of the broad trade spectrum, congruence among them was statistically strong in all comparisons. Furthermore, the frequency with which species were recorded within data sets was positively correlated with their occurrence across data sets, indicating that the trade prevalence score captured information on trade volume. The trade prevalence score discriminated well between species identified from semi-independent assessments as heavily or unsustainably traded and all other species. Globally, 45.1% of all bird species and 36.7% of globally threatened bird species had trade prevalence scores ≥1. Species listed in Appendices I or II of CITES, species with large geographical distributions, and nonpasserines tended to have high trade prevalence scores. Speciose orders with high mean trade prevalence scores included Falconiformes, Psittaciformes, Accipitriformes, Anseriformes, Bucerotiformes, and Strigiformes. Despite their low mean prevalence score, Passeriformes accounted for the highest overall number of traded species of any order but had low representation in CITES appendices. Geographical hotspots where large numbers of traded species co-occur differed among passerines (Southeast Asia and Eurasia) and nonpasserines (central South America, sub-Saharan Africa, and India). This first attempt to quantify and map the relative prevalence in trade of all bird species globally can be used to identify species and groups of species that may be at particular risk of harm from trade and can inform conservation and policy interventions to reduce its adverse impacts.

Análisis de la prevalencia mundial de aves silvestres en el mercado Resumen El mercado representa una amenaza importante para muchas especies silvestres y a menudo es clandestino y mal vigilado. Por ello, la información sobre las especies más presentes en el mercado y bajo amenaza potencial todavía está fragmentada. Utilizamos siete conjuntos de datos mundiales sobre aves comercializadas para identificar especies o grupos de especies bajo riesgo especial y evaluamos hasta qué punto eran congruentes en cuanto a las especies registradas en el comercio. Utilizamos la frecuencia con la que las especies se registraban en los conjuntos de datos como base para una puntuación de prevalencia del comercio que se aplicó a todas las especies de aves a nivel mundial. Para validar la puntuación de prevalencia del comercio, realizamos búsquedas bibliográficas y cuestionarios para elaborar una lista de especies que se sabe son objeto de comercio intenso. Modelamos la puntuación para identificar los predictores significativos del mercado. Aunque los conjuntos de datos muestrearon partes distintas del amplio espectro del mercado, la congruencia entre ellos fue estadísticamente robusta en todas las comparaciones. Además, la frecuencia con la que se registraron las especies dentro de los conjuntos de datos se correlacionó positivamente con su presencia en todos los conjuntos de datos, lo que indica que la puntuación de prevalencia del mercado captó información sobre el volumen de este. La puntuación de prevalencia del mercado distinguió entre las especies identificadas a partir de evaluaciones semiindependientes como objeto de comercio intenso o insostenible y todas las demás especies. A nivel mundial, el 45.1% de todas las especies de aves y el 36.7% de las especies de aves amenazadas mundialmente tenían puntuaciones de prevalencia del mercado ≥1. Las especies incluidas en los Apéndices I o II de CITES, las especies con una amplia distribución geográfica y los no paseriformes tendieron a tener puntuaciones elevadas de prevalencia del mercado. Los órdenes de especies con puntuaciones medias de prevalencia del mercado elevadas fueron Falconiformes, Psittaciformes, Accipitriformes, Anseriformes, Bucerotiformes y Strigiformes. A pesar de su baja puntuación media de prevalencia, los Passeriformes representaron el mayor número total de especies comercializadas de todos los órdenes, pero tuvieron una baja representación en los apéndices de CITES. Los puntos calientes geográficos en los que coexisten un gran número de especies comercializadas difieren entre los paseriformes (Sudeste Asiático y Eurasia) y los no paseriformes (centro de Sudamérica, África subsahariana e India). Este primer intento de cuantificar y cartografiar la prevalencia relativa en el comercio de todas las especies de aves a escala mundial puede utilizarse para identificar especies y grupos de especies que pueden correr un riesgo especial de sufrir daños a causa del comercio y puede servir de base para intervenciones políticas y de conservación destinadas a reducir sus efectos adversos.

Rapid differentiation of MOGAD and MS after a single optic neuritis.

BACKGROUND: Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein IgG-associated disease (MOGAD). This study evaluated the applicability of optical coherence tomography (OCT) for differentiating between both diseases in two independent cohorts. METHODS: One hundred sixty two patients from seven sites underwent standard OCT and high-contrast visual acuity (HCVA) testing at least 6 months after first ON. Of these, 100 patients (32 MOGAD, 68 MS) comprised the primary investigational cohort, while 62 patients (31 MOGAD, 31 MS) formed a validation cohort. A composite score distinguishing between MOGAD and MS was developed using multivariate logistic regression. RESULTS: Bilateral simultaneous ON occurred more frequently in MOGAD compared to MS (46.9 vs. 11.8%, p < 0.001). OCT revealed more peripapillary retinal nerve fiber layer (pRNFL) atrophy in all segments in MOGAD compared to predominantly temporal pRNFL atrophy in MS (p < 0.001). HCVA was better preserved in MS (p = 0.007). pRNFL thickness in all except for temporal segments was suitable for differentiating MOGAD and MS. Simultaneous bilateral ON and critical atrophy in nasal (< 58.5 µm) and temporal superior (< 105.5 µm) segments were included into the composite score as three independent predictors for MOGAD. The composite score distinguished MOGAD from MS with 75% sensitivity and 90% specificity in the investigational cohort, and 68% sensitivity and 87% specificity in the validation cohort. CONCLUSION: Following a single ON-episode, MOGAD exhibits more pronounced global pRNFL atrophy and lower visual acuity after ON compared to MS. The introduced OCT-based composite score enabled differentiation between the two entities across both cohorts.

Microbiological quality and native lactic acid bacteria diversity of artisanal Mexican cheeses: A review.

This review aims to provide an overview of artisanal Mexican cheeses microbiota focused on microbiological quality and safety, as well as native Lactic acid Bacteria (LAB) diversity. For the search, key words of artisanal Mexican cheeses varieties was carried out through several online databases and original articles were screened and data about populations of indicator microorganisms, presence of pathogens, and native LAB identified were extracted. Several artisanal Mexican cheeses exceeded the permissible limit established in Mexican regulation (NOM-243-SSA1-2010) for indicator microorganisms, as well as in some types of cheese, the presence of pathogens was confirmed. However, other varieties of artisanal Mexican cheeses possess unique physicochemical characteristics, and during their manufacturing particular steps are used that contribute to ensuring their quality and safety. Additionally, strains able to control the growth of pathogenic and spoilage bacteria are part of the microbiota of some artisanal Mexican cheeses. About native LAB diversity, it is composed by species of Lactobacillus, Enterococcus, Streptococcus, Leuconostoc, Weisella, Lactococcus, Pediococus, Aerococus, Carnobacterium, Tetragenococus, among others genera. Otherwise, artisanal Mexican cheeses represent an important source of specific LAB with several approaches within human health because they showed potential for the development of functional foods, nutraceutical, and bioprotective cultures.

Increased Susceptibility of WHIM Mice to Papillomavirus-induced Disease is Dependent upon Immune Cell Dysfunction.

Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome is a rare primary immunodeficiency disease in humans caused by a gain of function in CXCR4, mostly due to inherited heterozygous mutations in CXCR4. One major clinical symptom of WHIM patients is their high susceptibility to human papillomavirus (HPV) induced disease, such as warts. Persistent high risk HPV infections cause 5% of all human cancers, including cervical, anogenital, head and neck and some skin cancers. WHIM mice bearing the same mutation identified in WHIM patients were created to study the underlying causes for the symptoms manifest in patients suffering from the WHIM syndrome. Using murine papillomavirus (MmuPV1) as an infection model in mice for HPV-induced disease, we demonstrate that WHIM mice are more susceptible to MmuPV1-induced warts (papillomas) compared to wild type mice. Namely, the incidence of papillomas is higher in WHIM mice compared to wild type mice when mice are exposed to low doses of MmuPV1. MmuPV1 infection facilitated both myeloid and lymphoid cell mobilization in the blood of wild type mice but not in WHIM mice. Higher incidence and larger size of papillomas in WHIM mice correlated with lower abundance of infiltrating T cells within the papillomas. Finally, we demonstrate that transplantation of bone marrow from wild type mice into WHIM mice normalized the incidence and size of papillomas, consistent with the WHIM mutation in hematopoietic cells contributing to higher susceptibility of WHIM mice to MmuPV1-induced disease. Our results provide evidence that MmuPV1 infection in WHIM mice is a powerful preclinical infectious model to investigate treatment options for alleviating papillomavirus infections in WHIM syndrome.

Pervasive heteroplasmy in an invasive ambrosia beetle (Scolytinae) in southern California.

Heteroplasmy, the presence of multiple mitochondrial genotypes (mitotypes) within an individual, has long been thought to be a rare aberrance that is quickly removed by selection or drift. However, heteroplasmy is being reported in natural populations of eukaryotes with increasing frequency, in part due to improved diagnostic methods. Here, we report a seemingly stable heteroplasmic state in California populations of the polyphagous shothole borer (PSHB), Euwallacea fornicatus; an invasive ambrosia beetle that is causing significant tree dieback. We develop and validate a qPCR assay utilizing locked nucleic acid probes to detect different mitotypes, and qualitatively assess heteroplasmy in individual PSHB. We prove the utility of this assay by: (1) mitotyping field-collected PSHB, documenting the prevalence of heteroplasmy across its range in California; and, (2) measuring relative titers of each mitotype across multiple generations of heteroplasmic laboratory colonies to assess the stability of transmission through the maternal germline. We show that our findings are unlikely to be explained by the existence of NUMTs by next generation sequencing of contiguous sections of mitochondrial DNA, where each of the observed heteroplasmic sites are found within fully functional coding regions of mtDNA. Subsequently, we find heteroplasmic individuals are common in Californian field populations, and that heteroplasmy persists for at least 10 generations in experimental colonies. We also looked for evidence of the common occurrence of paternal leakage, but found none. In light of our results, we discuss competing hypotheses as to how heteroplasmy may have arisen, and continues to perpetuate, in Californian PSHB populations.

Current State, Needs, and Opportunities for Wearable Robots in Military Medical Rehabilitation and Force Protection.

Despite advances in wearable robots across various fields, there is no consensus definition or design framework for the application of this technology in rehabilitation or musculoskeletal (MSK) injury prevention. This paper aims to define wearable robots and explore their applications and challenges for military rehabilitation and force protection for MSK injury prevention. We conducted a modified Delphi method, including a steering group and 14 panelists with 10+ years of expertise in wearable robots. Panelists presented current wearable robots currently in use or in development for rehabilitation or assistance use in the military workforce and healthcare. The steering group and panelists met to obtain a consensus on the wearable robot definition applicable for rehabilitation or primary injury prevention. Panelists unanimously agreed that wearable robots can be grouped into three main applications, as follows: (1) primary and secondary MSK injury prevention, (2) enhancement of military activities and tasks, and (3) rehabilitation and reintegration. Each application was presented within the context of its target population and state-of-the-art technology currently in use or under development. Capturing expert opinions, this study defines wearable robots for military rehabilitation and MSK injury prevention, identifies health outcomes and assessment tools, and outlines design requirements for future advancements.

Does Knee Arthroplasty Have a Beneficial Effect on Return to Work in Patients with Knee Osteoarthritis who Receive Long-Term Disability Benefits in the Netherlands?

PURPOSE: Optimal timing of knee arthroplasty (KA) is complex: operating at a younger age increases life time risk of revision, while delay results in an increased risk of job loss. This study evaluates whether disability benefits recipients due to knee osteoarthritis have an increased odds of returning to work (RTW) following KA. METHODS: A retrospective cohort study was performed among long-term disability benefits recipients due to knee osteoarthritis using data of the Dutch Employee Insurance Agency. Logistic regression assessed whether recipients with KA had a higher odds of RTW in 10 years following start of disability benefits, compared to those without KA. RESULTS: A total of 159 participants were included. During 10-year follow up, 42% had received KA and 37% had returned to work. No association was observed between KA and RTW (OR 1.39, 95% CI 0.62-3.12). Prognostic factors for RTW were being the main breadwinner (OR 7.93, 95% CI 2.95-21.32) and classification as 100% work disability (OR 0.20, 95% CI 0.09-0.45). CONCLUSIONS: KA has no beneficial effect on RTW among patients with knee osteoarthritis granted long-term disability in the Netherlands. For RTW, KA is probably best performed within the two years of paid sick leave before long-term disability is assessed in the Netherlands.

GDF10 is a negative regulator of vascular calcification.

Cardiovascular mortality is particularly high and increasing in patients with chronic kidney disease, with vascular calcification (VC) a major pathophysiologic feature. VC is a highly regulated biological process similar to bone formation involving osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). We have previously demonstrated that loss of T-cell death associated gene 51 (TDAG51) expression leads to an attenuation of medial VC. We now show a significant induction of circulating levels of growth differentiation factor 10 (GDF10) in TDAG51-/- mice, which was of interest due to its established role as an inhibitor of osteoblast differentiation. The objective of this study was to examine the role of GDF10 in the osteogenic transdifferentiation of VSMCs. Using primary mouse and human VSMCs, as well as ex vivo aortic ring cultures, we demonstrated that treatment with recombinant human (rh) GDF10 mitigated phosphate-mediated hydroxyapatite (HA) mineral deposition. Furthermore, ex vivo aortic rings from GDF10-/- mice exhibited increased HA deposition compared to C57BL/6J controls. To explain our observations, we identified that rhGDF10 treatment reduced protein expression of runt-related transcription factor 2, a key driver of osteogenic transdifferentiation of VSMCs and VC. In support of these findings, in vivo treatment with rhGDF10 attenuated VD3-induced VC. Furthermore, we demonstrated an increase in circulating GDF10 in patients with chronic kidney disease with clinically defined severe VC, as assessed by coronary artery calcium score. Thus, our studies identify GDF10 as a novel inhibitor of mineral deposition and as such, may represent a potential novel biomarker and therapeutic target for the detection and management of VC.

Localized estimation of event-related neural source activity from simultaneous MEG-EEG with a recurrent neural network.

Estimating intracranial current sources underlying the electromagnetic signals observed from extracranial sensors is a perennial challenge in non-invasive neuroimaging. Established solutions to this inverse problem treat time samples independently without considering the temporal dynamics of event-related brain processes. This paper describes current source estimation from simultaneously recorded magneto- and electro-encephalography (MEEG) using a recurrent neural network (RNN) that learns sequential relationships from neural data. The RNN was trained in two phases: (1) pre-training and (2) transfer learning with L1 regularization applied to the source estimation layer. Performance of using scaled labels derived from MEEG, magnetoencephalography (MEG), or electroencephalography (EEG) were compared, as were results from volumetric source space with free dipole orientation and surface source space with fixed dipole orientation. Exact low-resolution electromagnetic tomography (eLORETA) and mixed-norm L1/L2 (MxNE) source estimation methods were also applied to these data for comparison with the RNN method. The RNN approach outperformed other methods in terms of output signal-to-noise ratio, correlation and mean-squared error metrics evaluated against reference event-related field (ERF) and event-related potential (ERP) waveforms. Using MEEG labels with fixed-orientation surface sources produced the most consistent estimates. To estimate sources of ERF and ERP waveforms, the RNN generates temporal dynamics within its internal computational units, driven by sequential structure in neural data used as training labels. It thus provides a data-driven model of computational transformations from psychophysiological events into corresponding event-related neural signals, which is unique among MEEG source reconstruction solutions.

Targeted inhibition of BET proteins in HPV16-positive head and neck squamous cell carcinoma reveals heterogeneous transcriptional responses.

Human papillomaviruses (HPV), most commonly HPV16, are associated with a subset of head and neck squamous cell carcinoma (HNSCC) tumors, primarily oropharyngeal carcinomas, with integration of viral genomes into host chromosomes associated with worse survival outcomes. We analyzed TCGA data and found that HPV+ HNSCC expressed higher transcript levels of the bromodomain and extra terminal domain (BET) family of transcriptional coregulators. The role of BET protein-mediated transcription of viral-cellular genes in the viral-HNSCC genomes needs to be better understood. Using a combination of TAME-Seq, qRT-PCR, and immunoblot analyses, we show that BET inhibition downregulates E6 and E7 significantly, with heterogeneity in the downregulation of viral transcription across different HPV+ HNSCC cell lines. Chemical BET inhibition was phenocopied with the knockdown of BRD4, mirroring the downregulation of viral E6 and E7 expression. We found that BET inhibition directly downregulated c-Myc and E2F expression and induced CDKN1A (p21) expression, leading to a G1-cell cycle arrest with apoptotic activity. Overall, our studies demonstrate that BET inhibition regulates both E6 and E7 viral and key cellular cell cycle regulator E2F gene expression and cellular gene expression in HPV-associated HNSCC and highlight the potential of BET inhibitors as a therapeutic strategy for this disease while also underscoring the importance of considering the heterogeneity in cellular responses to BET inhibition.

Increasing power in screening trials by testing control-arm specimens: application to multicancer detection screening.

BACKGROUND: Cancer screening trials have required large sample sizes and long time-horizons to demonstrate cancer mortality reductions, the primary goal of cancer screening. We examine assumptions and potential power gains from exploiting information from testing control-arm specimens, which we call the "intended effect" (IE) analysis that we explain in detail herein. The IE analysis is particularly suited to tests that can be conducted on stored specimens in the control arm, such as stored blood for multicancer detection (MCD) tests. METHODS: We simulated hypothetical MCD screening trials to compare power and sample size for the standard vs IE analysis. Under two assumptions that we detail herein, we projected the IE analysis for 3 existing screening trials (National Lung Screening Trial [NLST], Minnesota Colon Cancer Control Study [MINN-FOBT-A], and Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial-colorectal component [PLCO-CRC]). RESULTS: Compared with the standard analysis for the 3 existing trials, the IE design could have reduced cancer-specific mortality P values 6-fold (NLST), 33-fold (MINN-FOBT-A), or 260 000-fold (PLCO-CRC) or, alternately, reduced sample size (90% power) by 25% (NLST), 47% (MINN-FOBT-A), or 63% (PLCO-CRC). For potential MCD trial designs requiring 100 000 subjects per arm to achieve 90% power for multicancer mortality for the standard analysis, the IE analysis achieves 90% power for only 37 500-50 000 per arm, depending on assumptions concerning control-arm test-positives. CONCLUSIONS: Testing stored specimens in the control arm of screening trials to conduct the IE analysis could substantially increase power to reduce sample size or accelerate trials and could provide particularly strong power gains for MCD tests.

Biochemical and biophysical approaches to characterization of the aromatic amino acid hydroxylases.

The aromatic amino acid hydroxylases phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase utilize a non-heme iron to catalyze the hydroxylation of the aromatic rings of their amino acid substrates, with a tetrahydropterin serving as the source of the electrons necessary for the monooxygenation reaction. These enzymes have been subjected to a variety of biochemical and biophysical approaches, resulting in a detailed understanding of their structures and mechanism. We summarize here the experimental approaches that have led to this understanding.

Loss of normal facial asymmetry in schizophrenia and bipolar disorder: Implications for development of brain asymmetry in psychotic illness.

Development of the craniofacies occurs in embryological intimacy with development of the brain and both show normal left-right asymmetries. While facial dysmorphology occurs to excess in psychotic illness, facial asymmetry has yet to be investigated as a putative index of brain asymmetry. Ninety-three subjects (49 controls, 22 schizophrenia, 22 bipolar disorder) received 3D laser surface imaging of the face. On geometric morphometric analysis with (x, y, z) visualisations of statistical models for facial asymmetries, in controls the upper face and periorbital region, which share embryological intimacy with the forebrain, showed marked asymmetries. Their geometry included: along the x-axis, rightward asymmetry in its dorsal-medial aspects and leftward asymmetry in its ventral-lateral aspects; along the z-axis, anterior protrusion in its right ventral-lateral aspect. In both schizophrenia and bipolar disorder these normal facial asymmetries were diminished, with residual retention of asymmetries in bipolar disorder. This geometry of normal facial asymmetries shows commonalities with that of normal frontal lobe asymmetries. These findings indicate a trans-diagnostic process that involves loss of facial asymmetries in both schizophrenia and bipolar disorder. Embryologically, they implicate loss of face-brain asymmetries across gestational weeks 7-14 in processes that involve genes previously associated with risk for schizophrenia.

Sacubitril/Valsartan in Pediatric Heart Failure (PANORAMA-HF): A Randomized, Multicenter, Double-Blind Trial.

BACKGROUND: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), is an established treatment for heart failure (HF) with reduced left ventricular ejection fraction. It has not been rigorously compared with angiotensin-converting enzyme inhibitors in children. PANORAMA-HF (Prospective Trial to Assess the Angiotensin Receptor Blocker Neprilysin Inhibitor LCZ696 Versus Angiotensin-Converting Enzyme Inhibitor for the Medical Treatment of Pediatric HF) is a randomized, double-blind trial that evaluated the pharmacokinetics and pharmacodynamics (PK/PD), safety, and efficacy of sacubitril/valsartan versus enalapril in children 1 month to <18 years of age with HF attributable to systemic left ventricular systolic dysfunction (LVSD). METHODS: Children with HF attributable to LVSD were randomized to sacubitril/valsartan versus enalapril to assess the efficacy and safety of sacubitril/valsartan at 52 weeks of follow-up. The primary end point of the study was to determine whether sacubitril/valsartan was superior to enalapril for the treatment of pediatric patients with HF attributable to systemic LVSD, assessed using a primary global rank end point consisting of ranking patients from worst to best on the basis of clinical events such as death, listing for urgent heart transplant, mechanical life support requirement, worsening HF, New York Heart Association (NYHA)/Ross class, Patient Global Impression of Severity (PGIS), and Pediatric Quality of Life Inventory physical functioning domain. The change from baseline to 52 weeks in NT-proBNP (N-terminal pro-B-type natriuretic peptide) was an exploratory end point. RESULTS: A total of 375 children (mean age, 8.1±5.6 years; 52% female) were randomized to sacubitril/valsartan (n=187) or enalapril (n=188). At week 52, no significant difference was observed between the 2 treatment arms in the global rank end point (Mann-Whitney probability, 0.52 [95% CI, 0.47-0.58]; Mann-Whitney odds, 0.91 [95% CI, 0.72-1.14]; P=0.42). At week 52, clinically meaningful reductions were observed in both treatment arms in NYHA/Ross, PGIS, Patient Global Impression of Change, and NT-proBNP, without significant differences between groups. Adverse events were similar between treatment arms (incidence: sacubitril/valsartan, 88.8%; enalapril, 87.8%), and the safety profile of sacubitril/valsartan was acceptable in children. CONCLUSIONS: In this study, sacubitril/valsartan did not show superiority over enalapril in the treatment of children with HF attributable to systemic LVSD using the prespecified global rank end point. However, both treatment arms showed clinically meaningful improvements over 52 weeks. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02678312.

Impact of sex, serostatus, and smoking on risk for rheumatoid arthritis-associated interstitial lung disease subtypes.

OBJECTIVES: RA-associated interstitial lung disease (RA-ILD) includes multiple subtypes with varying histopathology, prognosis, and potential treatments. Limited research has investigated risk factors for different RA-ILD subtypes. Therefore, we examined demographic, serologic, and lifestyle associations with RA-ILD subtypes. METHODS: We systematically identified RA-ILD cases and RA-noILD controls in the Brigham RA Sequential Study and Mass General Brigham Biobank RA cohort. We determined RA-ILD subtype (usual interstitial pneumonia [UIP], nonspecific interstitial pneumonia [NSIP], and other/indeterminate) through chest high-resolution computed tomography imaging pattern. We investigated associations between demographic, lifestyle, and serologic factors and major RA-ILD subtypes using multivariable logistic regression. RESULTS: Among 3328 RA patients, we identified 208 RA-ILD cases and 547 RA-noILD controls. RA-UIP was associated with older age (OR 1.03 per year, 95%CI 1.01 to 1.05), male sex (OR 2.15, 95%CI 1.33 to 3.48), and seropositivity (OR 2.08 95%CI 1.24 to 3.48) while RA-NSIP was significantly associated only with seropositive status (OR 3.21, 95%CI 1.36 to 7.56). Non-fibrotic ILDs were significantly associated with smoking (OR 2.81, 95%CI 1.52 to 5.21). Having three RA-ILD risk factors (male, seropositive, smoking) had an OR of 6.89 (96%CI 2.41 to 19.7) for RA-UIP compared to having no RA-ILD risk factors. CONCLUSIONS: Older age, seropositivity, and male sex were strongly associated with RA-UIP while RA-related autoantibodies were associated with RA-NSIP. These findings suggest RA-ILD sex differences may be driven by RA-UIP and emphasizes the importance of further studies to clarify RA-ILD heterogeneity and optimize screening and treatment approaches.