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Burnout is an occupational phenomenon with the potential to affect a person's physical and mental health, job satisfaction and quality of work. There is evidence of burnout occurring in the midwifery profession, but inadequate data on the prevalence of, and the factors associated with, burnout.Identify the prevalence of burnout in a population of midwives and explore what individual and workforce characteristics, and what occupational stressors, were associated with burnout.A cross-sectional survey of permanently employed midwives was conducted in a tertiary maternity service in Melbourne, Australia in 2017. Data collected included individual and workforce-related characteristics and occupational stressors. Burnout was explored using the Copenhagen Burnout Inventory. Univariate and multivariate analyses were conducted to ascertain associations between respondents' characteristics, stressors, and burnout levels.A total of 257/266 midwives (97%) responded. There were significant levels of exhaustion and fatigue among respondents; 68% of midwives were experiencing personal burnout, 51% work-related burnout, and 10% were experiencing client-related burnout. Being aged ≤ 35 years, and/or having inadequate support was associated with personal and work-related burnout. Having inadequate acknowledgement was associated with client-related burnout.Health services need to understand the risk factors for burnout among midwives, identify and support groups that are most vulnerable, and address areas that are amenable to intervention. In our context this means ensuring midwives receive adequate acknowledgement and support, particularly younger midwives. These findings need to be tested in other settings to help inform a broader understanding and ensure the sustainability of the midwifery profession.

SARS-CoV-2, the etiologic agent of the COVID-19 pandemic, has had an enduring impact on global public health. However, SARS-CoV-2 is only one of multiple pathogenic human coronaviruses (CoVs) to have emerged since the turn of the century. CoVs encode for several nonstructural proteins (NSPS) that are essential for viral replication and pathogenesis. Among them is nsp15, a uridine-specific viral endonuclease that is important in evading the host immune response and promoting viral replication. Despite the established function of nsp15 as a uridine-specific endonuclease, little is known about other determinants of its cleavage specificity. In this study we investigate the role of RNA secondary structure in SARS-CoV-2 nsp15 endonuclease activity.Using a series ofin vitroendonuclease assays, we observed that thermodynamically stable RNA structures were protected from nsp15 cleavage relative to RNAs lacking stable structure. We leveraged the s2m RNA from the SARS 3’UTR as a model for our structural studies as it adopts a well-defined structure with several uridines, two of which are unpaired and thus high probably targets for nsp15 cleavage. We found that SARS-CoV-2 nsp15 specifically cleaves s2m at the unpaired uridine within the GNRNA pentaloop of the RNA. Further investigation revealed that the position of uridine within the pentaloop also impacted nsp15 cleavage efficiency, suggesting that positioning within the pentaloop is necessary for optimal presentation of the scissile uridine and alignment within the nsp15 catalytic pocket. Our findings indicate that RNA secondary structure is an important determinant of nsp15 cleavage and provides insight into the molecular mechanisms of recognition of RNA by nsp15.

Norovirus infection is characterised by a rapid onset of disease and the development of debilitating symptoms including projectile vomiting and diffuse diarrhoea. Vaccines and antivirals are sorely lacking and developments in these areas are hampered by the lack of an adequate cell culture system to investigate human norovirus replication and pathogenesis. Herein, we describe how the model norovirus, Mouse norovirus (MNV), produces a viral protein, NS3, with the functional capacity to attenuate host protein translation which invokes the activation cell death via apoptosis. We show that this function of NS3 is conserved between human and mouse viruses and map the protein domain attributable to this function. Our study highlights a critical viral protein that mediates crucial activities during replication, potentially identifying NS3 as a worthy target for antiviral drug development.

Inhibition control is an essential executive function and the cornerstone of important skills during children’s development, like self-regulation and the development of social and language abilities. Better inhibition control is associated with higher academic achievement (e.g., reasoning skills, mathematics, and science). Music training requires inhibition control when learning new motor skills of an instrument, synchronized group training, monitoring performance, and auditory stream prioritization. This meta-analysis examined for the first time whether music-based training improves inhibition control in children. A rigorous search of the literature from 1980 to 2022 yielded 2182 records (N = 1528). Twenty studies had longitudinal designs, of which eight were randomized-clinical trials (RCTs) with an active control condition. Inhibition control measures included the flanker, go/no-go, and Stroop tests or similar preschool adaptations. A random-effects meta-analysis of these studies showed a moderate-to-large effect size for improvement in inhibition control after music training compared to control programs in the eight RCTs (SMD= 0.63,CI= 0.41 to 0.85,p< .0001). The full set of twenty longitudinal studies that included quasi-experimental designs and passive control groups showed a small-to-moderate effect size (SMD= 0.36,CI= 0.21 to 0.50,p< .0001). These findings highlight that music training, probably owing to its time-bound multisensory and multimodal demands fostering brain plasticity, plays a privileged role in improving executive functioning in children, especially inhibition control. We recommend further validation of music training to complement education and as a therapeutic tool for clinical populations with inhibition control difficulties (e.g., Autism, ADHD).Public Significance StatementThis meta-analysis is the first to show that music training in children specifically improves inhibition control, a critical executive function for self-regulation. Children generally enjoy music training, a complex multimodal activity that engages cognitive and speech abilities. Our results demonstrate that music training is an effective approach for strengthening cognition and highlight its potential to complement the rehabilitation of certain clinical disorders that involve inhibition control deficits. This review also identifies some limitations of current research and provides recommendations for future work.

Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CLpro) encoded by diverse coronaviruses, including SARS-CoV-2, cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CLpro, including 3CLpro-mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8’s ability to sense coronavirus 3CLpros, and instead enables sensing of 3C proteases (3Cpro) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intra-species variation in inflammasome-mediated viral sensing and immunopathology.

Background The first-in-class treatment PF-06480605 targets the tumor necrosis factor-like ligand 1A (TL1A) molecule in humans. Results from the phase 2a TUSCANY trial highlighted the safety and efficacy of PF-06480605 in ulcerative colitis. Preclinical and in vitro models have identified a role for TL1A in both innate and adaptive immune responses, but the mechanisms underlying the efficacy of anti-TL1A treatment in inflammatory bowel disease (IBD) are not known. Methods Here, we provide analysis of tissue transcriptomic, peripheral blood proteomic, and fecal metagenomic data from the recently completed phase 2a TUSCANY trial and demonstrate endoscopic improvement post-treatment with PF-06480605 in participants with ulcerative colitis. Results Our results revealed robust TL1A target engagement in colonic tissue and a distinct colonic transcriptional response reflecting a reduction in inflammatory T helper 17 cell, macrophage, and fibrosis pathways in patients with endoscopic improvement. Proteomic analysis of peripheral blood revealed a corresponding decrease in inflammatory T-cell cytokines. Finally, microbiome analysis showed significant changes in IBD-associated pathobionts, Streptococcus salivarius, S. parasanguinis, and Haemophilus parainfluenzae post-therapy. Conclusions The ability of PF-06480605 to engage and inhibit colonic TL1A, targeting inflammatory T cell and fibrosis pathways, provides the first-in-human mechanistic data to guide anti-TL1A therapy for the treatment of IBD.

BACKGROUND: The effectiveness of music-based interventions (MI) in autism has been attested for decades. Yet, there has been little empirical investigation of the active ingredients, or processes involved in music-based interventions that differentiate them from other approaches. OBJECTIVES: Here, we examined whether two processes, joint engagement and movement, which have previously been studied in isolation, contribute as important active ingredients for the efficacy of music-based interventions. METHODS: In two separate analyses, we investigated whether (1) joint engagement with the therapist, measured using a coding scheme verified for reliability, and (2) movement elicited by music-making, measured using a computer-vision technique for quantifying motion, may drive the benefits previously observed in response to MI (but not a controlled non-MI) in children with autism. RESULTS: Compared to a non-music control intervention, children and the therapist in MI spent more time in triadic engagement (between child, therapist, and activity) and produced greater movement, with amplitude of motion closely linked to the type of musical instrument. CONCLUSIONS: Taken together, these findings provide initial evidence of the active ingredients of music-based interventions in autism.

Early diagnosis of drug-induced liver injury (DILI) continues to be a major hurdle during drug development and postmarketing. The objective of this study was to evaluate the diagnostic performance of promising biomarkers of liver injury—glutamate dehydrogenase (GLDH), cytokeratin-18 (K18), caspase-cleaved K18 (ccK18), osteopontin (OPN), macrophage colony-stimulating factor (MCSF), MCSF receptor (MCSFR), and microRNA-122 (miR-122) in comparison to the traditional biomarker alanine aminotransferase (ALT). Biomarkers were evaluated individually and as a multivariate model in a cohort of acetaminophen overdose (n = 175) subjects and were further tested in cohorts of healthy adults (n = 135), patients with liver damage from various causes (n = 104), and patients with damage to the muscle (n = 74), kidney (n = 40), gastrointestinal tract (n = 37), and pancreas (n = 34). In the acetaminophen cohort, a multivariate model with GLDH, K18, and miR-122 was able to detect DILI more accurately than individual biomarkers alone. Furthermore, the three-biomarker model could accurately predict patients with liver injury compared with healthy volunteers or patients with damage to muscle, pancreas, gastrointestinal tract, and kidney. Expression of K18, GLDH, and miR-122 was evaluated using a database of transcriptomic profiles across multiple tissues/organs in humans and rats. K18 mRNA (Krt18) and MiR-122 were highly expressed in liver whereas GLDH mRNA (Glud1) was widely expressed. We performed a comprehensive, comparative performance assessment of 7 promising biomarkers and demonstrated that a 3-biomarker multivariate model can accurately detect liver injury.

Adults and children with typical development (TD) remember vocal melodies (without lyrics) better than instrumental melodies, which is attributed to the biological and social significance of human vocalizations. Here we asked whether children with autism spectrum disorder (ASD), who have persistent difficulties with communication and social interaction, and adolescents and adults with Williams syndrome (WS), who are highly sociable, even indiscriminately friendly, exhibit a memory advantage for vocal melodies like that observed in individuals with TD. We tested 26 children with ASD, 26 adolescents and adults with WS of similar mental age, and 26 children with TD on their memory for vocal and instrumental (piano, marimba) melodies. After exposing them to 12 unfamiliar folk melodies with different timbres, we required them to indicate whether each of 24 melodies (half heard previously) was old (heard before) or new (not heard before) during an unexpected recognition test. Although the groups successfully distinguished the old from the new melodies, they differed in overall memory. Nevertheless, they exhibited a comparable advantage for vocal melodies. In short, individuals with ASD and WS show enhanced processing of socially significant auditory signals in the context of music. LAY SUMMARY: Typically developing children and adults remember vocal melodies better than instrumental melodies. In this study, we found that children with Autistic Spectrum Disorder, who have severe social processing deficits, and children and adults with Williams syndrome, who are highly sociable, exhibit comparable memory advantages for vocal melodies. The results have implications for musical interventions with these populations.

This study presents a comprehensive systematic review and meta-analysis of temporal processing in autism spectrum disorder (ASD) and developmental dyslexia (DD), two neurodevelopmental disorders in which temporal processing deficits have been highly researched. The results provide strong evidence for impairments in temporal processing in both ASD (g = 0.48) and DD (g = 0.82), as measured by judgments of temporal order and simultaneity. In individual analyses, multisensory temporal processing was impaired for both ASD and DD, and unisensory auditory, visual and tactile processing were all impaired in DD. In ASD, speech stimuli showed moderate impairment effect sizes, whereas nonspeech stimuli showed small effects. Greater reading and spelling skills in DD were associated with greater temporal precision. Temporal deficits did not show changes with age in either disorder. In addition to more clearly defining temporal impairments in ASD and DD, the results highlight common and distinct patterns of temporal processing between these disorders. Deficits are discussed in relation to existing theoretical models, and recommendations are made for future research.

BACKGROUND & AIMS:The enhanced liver fibrosis (ELF) test has been proposed for the non-invasive assessment of advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). We performed a systematic review to estimate the accuracy of this test against biopsy. METHODS:In this systematic review, we searched MEDLINE, Embase, Web of Science and the Cochrane Library for studies that included patients with NAFLD and that used both liver biopsy (as the reference standard) and the ELF test. Two authors independently screened the references, extracted the data and assessed the quality of included studies. Due to the variation in reported thresholds, we used a multiple thresholds random effects model for meta-analysis (diagmeta R-package). RESULTS:The meta-analysis of 11 studies reporting advanced fibrosis and 5 studies reporting significant fibrosis showed that the ELF test had a sensitivity of >0.90 for excluding fibrosis at a threshold of 7.7. However, as a diagnostic test at high thresholds, the test only achieved specificity and positive predictive value >0.80 in very high prevalence settings (>50%). To achieve a specificity of 0.90 for advanced and significant fibrosis, thresholds of 10.18 (sensitivity: 0.57) and 9.86 (sensitivity: 0.55) were required, respectively. CONCLUSION:The ELF test showed high sensitivity but limited specificity to exclude advanced and significant fibrosis at low cut-offs. The diagnostic performance of the test at higher thresholds was found to be more limited in low-prevalence settings. We conclude that clinicians should carefully consider the likely disease prevalence in their practice setting and adopt suitable test thresholds to achieve the desired performance. LAY SUMMARY:The enhanced liver fibrosis test has been suggested as a non-invasive blood test to aid the diagnosis of severe liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Our study results showed that the test has a high negative predictive value, especially in populations with low disease prevalence (likely encountered in primary care); so, it can exclude advanced fibrosis in patients with NAFLD. However, when prevalence is low, the positive predictive value of the enhanced liver fibrosis test is low, suggesting that additional strategies may be needed to make a positive diagnosis in such settings.

Alphaviruses (family Togaviridae) are a diverse group of positive-sense RNA (+ssRNA) viruses that are transmitted by arthropods and are the causative agent of several significant human and veterinary diseases. Interferon (IFN)-induced proteins with tetratricopeptide repeats (IFITs) are a family of RNA-binding IFN stimulated genes (ISGs) that are highly upregulated following viral infection, and have been identified as potential restrictors of alphaviruses. The mechanism by which IFIT1 restricts RNA viruses is dependent on self and non-self-discrimination of RNA, and alphaviruses evade this recognition via their 5’UTR. However, the role of IFIT2 during alphavirus replication and the mechanism of viral replication inhibition is unclear. In this study, we identify IFIT2 as a restriction factor for Venezuelan equine encephalitis virus (VEEV) and show that IFIT2 binds the 3’ untranslated region (3’UTR) of the virus. We investigated the potential role of variability in the 3’UTR of the virus affecting IFIT2 antiviral activity by studying infection with VEEV. Comparison of recombinant VEEV clones containing 3’UTR sequences derived from epizootic and enzootic isolates exhibited differential sensitivity to IFIT2 restriction in vitro infection studies, suggesting that the alphavirus 3’UTR sequence may function in part to evade IFIT2 restriction. In vitro binding assays demonstrate that IFIT2 binds to the VEEV 3’UTR, however in contrast to previous studies VEEV restriction did not appear to be dependent on the ability of IFIT2 to inhibit translation of viral RNA, suggesting a novel mechanism of IFIT2 restriction. Our study demonstrates that IFIT2 is a restriction factor for alphaviruses and variability in the 3’UTR of VEEV can modulate viral restriction by IFIT2. Ongoing studies are exploring the biological consequences of IFIT2-VEEV RNA interaction in viral pathogenesis and defining sequence and structural features of RNAs that regulate IFIT2 recognition.

Aims The HERMES (HEart failure Molecular Epidemiology for Therapeutic targets) consortium aims to identify the genomic and molecular basis of heart failure.Methods and results The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of >1.10 for common variants (allele frequency > 0.05) and >1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 x 10(-8) under an additive genetic model.Conclusions HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction.

To date, the development of disease-modifying therapies for Alzheimer’s disease (AD) has largely focused on the removal of amyloid beta Aβ fragments from the CNS. Proteomic profiling of patient fluids may help identify novel therapeutic targets and biomarkers associated with AD pathology. Here, we applied the Olink™ ProSeek immunoassay to measure 270 CSF and plasma proteins across 415 Aβ- negative cognitively normal individuals (Aβ- CN), 142 Aβ-positive CN (Aβ+ CN), 50 Aβ- mild cognitive impairment (MCI) patients, 75 Aβ+ MCI patients, and 161 Aβ+ AD patients from the Swedish BioFINDER study. A validation cohort included 59 Aβ- CN, 23 Aβ- + CN, 44 Aβ- MCI and 53 Aβ+ MCI. To compare protein concentrations in patients versus controls, we applied multiple linear regressions adjusting for age, gender, medications, smoking and mean subject-level protein concentration, and corrected findings for false discovery rate (FDR, q d q d q q

Background Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by socio-communicative difficulties and restricted patterns of behavior. Despite these challenges, some individuals with ASD have preserved or even enhanced sensory skills, for example in the case of music. As such, music provides a key way to study sensory processing and individual differences in ASD. However, current studies of music perception in ASD have mixed results. Methods This study sought to examine music perception in terms of melodic pitch, rhythm, and memory in school-age children with ASD compared to typically-developing (TD) children. Music perception was investigated as a function of verbal and non-verbal IQ, age, and ASD social symptom severity. Results Children with ASD performed similar to TD children on melodic pitch perception, rhythm perception and melodic memory. Melodic pitch perception in particular was strongly associated with non-verbal cognitive abilities in the ASD group. Similar effects of age on performance were observed in ASD and TD; in particular, rhythm discrimination increased with age in both groups. Music perception in ASD was not associated with ASD social symptom severity. Discussion These findings provide further evidence for intact melodic and rhythmic perception in children with ASD. In addition, music perception abilities were related to non-verbal cognitive ability and age in ASD, and not with ASD social symptom severity. This research provides a better understanding of individual differences in auditory processing, helps to better define phenotypes in ASD, and can guide future studies on the effects of music therapy in ASD.

Many host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from cellular innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flaviviruses, picornaviruses, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform correlates with protection from severe COVID-19. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests that early control of SARS-CoV-2 replication through OAS1 p46 is an important determinant of COVID-19 severity.

This chapter covers total quality management (TQM) with respect to the Lean and Six Sigma methods used to improve the effectiveness and efficiency of hospitality operations. In the first section, TQM is discussed. In the second section, Lean and Six Sigma techniques are examined individually. Then, Lean and Six Sigma are connected with an example of a housekeeping case study that applies both methodologies. In the third section, business analytics are explored and statistical process control analysis is demonstrated using a hotel room cleanliness example. The fourth section summarizes the concepts of change management, which is critical for embracing the philosophies of TQM. Finally, project management is discussed in the fifth and last section.

SUMMARYMany host RNA sensors are positioned in the cytosol to detect viral RNA during infection. However, most positive-strand RNA viruses replicate within a modified organelle co-opted from intracellular membranes of the endomembrane system, which shields viral products from host cell innate immune sensors. Targeting innate RNA sensors to the endomembrane system may enhance their ability to sense viral RNA generated by viruses that use these compartments for replication. Here, we reveal that an isoform of oligoadenylate synthetase 1, OAS1 p46, is prenylated and targeted to the endomembrane system. Membrane localization of OAS1 p46 confers enhanced access to viral replication sites and results in increased antiviral activity against a subset of RNA viruses including flavivirus, picornavirus, and SARS-CoV-2. Finally, our human genetic analysis shows that the OAS1 splice-site SNP responsible for production of the OAS1 p46 isoform strongly associates with COVID-19 severity. This study highlights the importance of endomembrane targeting for the antiviral specificity of OAS1 and suggests early control of SARS-CoV-2 replication through OAS1-p46 is an important determinant of COVID-19 severity.

Robin Hyde considers some of the anxieties around advanced practice and reflects on how to allay these

SARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease (endoU) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU inhibitors in the 1-20 μM range in vitro. Furthermore, Exebryl-1, a β-amyloid anti-aggregation molecule for Alzheimer’s therapy, was shown to have antiviral activity between 10 to 66 μM, in VERO, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU inhibitor and as a SARS-CoV-2 antiviral.Author summaryDrugs to treat COVID-19 are urgently needed. To address this, we searched libraries of drugs and drug-like molecules for inhibitors of an essential enzyme of the virus that causes COVID-19, SARS-CoV-2 nonstructural protein (nsp)15. We found several molecules that inhibited the nsp15 enzyme function and one was shown to be active in inhibiting the SARS-CoV-2 virus. This demonstrates that searching for SARS-CoV-2 nsp15 inhibitors can lead inhibitors of SARS-CoV-2, and thus therapeutics for COVID-19. We are currently working to see if these inhibitors could be turned into a drug to treat COVID-19.

Metabolic pathways and inflammatory processes are under circadian regulation. While rhythmic immune cell recruitment is known to impact infection outcomes, whether the circadian clock modulates immunometabolism remains unclear. We find the molecular clock Bmal1 is induced by inflammatory stimulants, including Ifn-γ/lipopolysaccharide (M1) and tumor conditioned medium, to maintain mitochondrial metabolism under these metabolically stressed conditions in mouse macrophages. Upon M1 stimulation, myeloid-specificBmal1knockout (M-BKO) renders macrophages unable to sustain mitochondrial function, enhancing succinate dehydrogenase (SDH)-mediated mitochondrial ROS production and Hif-1α-dependent metabolic reprogramming and inflammatory damage. In tumor-associated macrophages, the aberrant Hif-1α activation and metabolic dysregulation by M-BKO contribute to an immunosuppressive tumor microenvironment. Consequently, M-BKO increases melanoma tumor burden, while administrating an SDH inhibitor dimethyl malonate suppresses tumor growth. Therefore, Bmal1 functions as a metabolic checkpoint integrating macrophage mitochondrial metabolism, redox homeostasis and effector functions. This Bmal1-Hif-1α regulatory loop may provide therapeutic opportunities for inflammatory diseases and immunotherapy.

It is computationally challenging to fit models to big data. For example, satellite imagery data often contain billions to trillions of pixels and it is not possible to use a pixel-level analysis to identify drivers of land-use change and create predictions using all the data. A common strategy to reduce sample size consists of drawing a random sample but this approach is not ideal when the outcome of interest is rare in the landscape because it leads to very few pixels with this outcome. Here we show that a case-control (CC) sampling approach, in which all (or a large fraction of) pixels with the outcome of interest and a subset of the pixels without this outcome are selected, can yield much better inference and prediction than random sampling (RS) if the estimated parameters and probabilities are adjusted with the equations that we provide. More specifically, we show that a CC approach can yield unbiased inference with much less uncertainty when CC data are analyzed with logistic regression models and its semiparametric variants (e.g., generalized additive models). We also show that a random forest model, when fitted to CC data, can generate much better predictions than when fitted to RS data. We illustrate this improved performance of the CC approach, when used together with the proposed bias-correction adjustments, with extensive simulations and a case study in the Amazon region focused on deforestation.

The environmental impacts of energy generation plants, especially those with large dams, have been widely discussed in the Amazon region, but little attention has been paid to the impacts of the associated transmission lines. These impacts are likely to be substantial given the wide geographic extent of the lines and the relatively high forest cover in the traversed areas. Publicly available information about the location and extent of the transmission line network in the Amazon is neither accurate nor current, and its environmental impacts on terrestrial ecosystems have not been assessed on a large scale. This study estimates the scale of the impact of the current and planned transmission and distribution line network using a hand-digitized dataset and the predicted impact area determined from Environmental Impact Assessments. The Legal Amazon region contains 39,625 km of verified transmission and distribution lines, estimated to directly impact 23,467 km2 of land. We find that the transmission line network directly impacts double the area flooded by hydroelectric reservoirs in the Legal Amazon. Of the direct impact area, 5.1% is within protected areas and 10.3% overlaps with intact forest. By 2026, the transmission line network is estimated to grow by 37% in the Legal Amazon, increasing the direct impact to forests by 70% and to protected lands by 29%. Transmission lines are impacting enough land to be considered a serious conservation threat and should be treated as such in research and environmental planning in the Amazon region.

Music has been identified as a strength in people with Autism Spectrum Disorder; however, there is currently no neuroscientific evidence supporting its benefits. Given its universal appeal, intrinsic reward value and ability to modify brain and behaviour, music may be a potential therapeutic aid in autism. Here we evaluated the neurobehavioural outcomes of a music intervention, compared to a non-music control intervention, on social communication and brain connectivity in school-age children (ISRCTN26821793). Fifty-one children aged 6–12 years with autism were randomized to receive 8–12 weeks of music (n = 26) or non-music intervention (n = 25). The music intervention involved use of improvisational approaches through song and rhythm to target social communication. The non-music control was a structurally matched behavioural intervention implemented in a non-musical context. Groups were assessed before and after intervention on social communication and resting-state functional connectivity of fronto-temporal brain networks. Communication scores were higher in the music group post-intervention (difference score = 4.84, P = .01). Associated post-intervention resting-state brain functional connectivity was greater in music vs. non-music groups between auditory and subcortical regions (z = 3.94, P z = 3.16, P z = 4.01, P z = 3.57, P

Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened\ud risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified\ud 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and\ud implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved\ud in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression\ud with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were\ud putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry\ud lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression\ud and imply that a continuous measure of risk underlies the clinical phenotype.

Purpose Musical training is often linked to enhanced auditory discrimination, but the relative roles of pitch and time in music and speech are unclear. Moreover, it is unclear whether pitch and time processing are correlated across individuals and how they may be affected by attention. This study aimed to examine pitch and time processing in speech and tone sequences, taking musical training and attention into account. Method Musicians (16) and nonmusicians (16) were asked to detect pitch or timing changes in speech and tone sequences and make a binary response. In some conditions, the participants were focused on 1 aspect of the stimulus (directed attention), and in others, they had to pay attention to all aspects at once (divided attention). Results As expected, musicians performed better overall. Performance scores on pitch and time tasks were correlated, as were performance scores for speech and tonal stimuli, but most markedly in musicians. All participants performed better on the directed versus divided attention task, but again, musicians performed better than nonmusicians. Conclusion In general, this experiment shows that individuals with a better sense of pitch discrimination also have a better sense of timing discrimination in the auditory domain. In addition, although musicians perform better overall, these results do not support the idea that musicians have an added advantage for divided attention tasks. These findings serve to better understand how musical training and attention affect pitch and time processing in the context of speech and tones and may have applications in special populations. Supplemental Material https://doi.org/10.23641/asha.5895997