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The basal ganglia are thought to be important in the selection of wanted and the suppression of unwanted motor patterns according to explicit rules (i.e. response inhibition). The subthalamic nucleus has been hypothesized to play a particularly critical role in this function. Deep brain stimulation of the subthalamic nucleus in individuals with Parkinson's disease has been used to test this hypothesis, but results have been variable. Based on current knowledge of the anatomical organization of the subthalamic nucleus, we propose that the location of the contacts used in deep brain stimulation could explain variability in the effects of deep brain stimulation of the subthalamic nucleus on response inhibition tasks. We hypothesized that stimulation affecting the dorsal subthalamic nucleus (connected to the motor cortex) would be more likely to affect motor symptoms of Parkinson's disease, and stimulation affecting the ventral subthalamic nucleus (connected to higher order cortical regions) would be more likely to affect performance on a response inhibition task. We recruited 10 individuals with Parkinson's disease and bilateral deep brain stimulation of the subthalamic nucleus with one contact in the dorsal and another in the ventral subthalamic region on one side of the brain. Patients were tested with a Go-No-Go task and a motor rating scale in three conditions: stimulation off, unilateral dorsal stimulation and unilateral ventral stimulation. Both dorsal and ventral stimulation improved motor symptoms, but only ventral subthalamic stimulation affected Go-No-Go performance, decreasing hits and increasing false alarms, but not altering reaction times. These results suggest that the ventral subthalamic nucleus is involved in the balance between appropriate selection and inhibition of prepotent responses in cognitive paradigms, but that a wide area of the subthalamic nucleus region is involved in the motor symptoms of Parkinson's disease. This finding has implications for resolving inconsistencies in previous research, highlights the role of the ventral subthalamic nucleus region in response inhibition and suggests an approach for the clinical optimization of deep brain stimulation of the subthalamic nucleus for both motor and cognitive functions. [ABSTRACT FROM AUTHOR]

Summary: Admixture is a fundamental process that has shaped levels and patterns of genetic variation in human populations. RFMIX version 2 (RFMIX2) utilizes a robust modeling approach to identify the genetic ancestries in admixed populations. However, this software does not have a built-in method to visually summarize the results of analyses. Here, we introduce the AncestryGrapher toolkit, which converts the numerical output of RFMIX2 into graphical representations of global and local ancestry (i.e., the per-individual ancestry components and the genetic ancestry along chromosomes, respectively)., Results: To demonstrate the utility of our methods, we applied the AncestryGrapher toolkit to visualize the global and local ancestry of individuals in the North African Mozabite Berber population from the Human Genome Diversity Panel (HGDP). Our results showed that the Mozabite Berbers derived their ancestry from the Middle East, Europe, and sub-Saharan Africa (global ancestry). We also found that the population origin of ancestry varied considerably along chromosomes (local ancestry). For example, we observed variance in local ancestry in the genomic region on chromosome 2 containing the regulatory sequence in the MCM6 gene associated with lactase persistence (LP), a human adaptive trait tied to the cultural development of adult milk consumption. Overall, the AncestryGrapher toolkit facilitates the exploration, interpretation, and reporting of ancestry patterns in human populations., Availability and Implementation: The AncestryGrapher toolkit is free and open source on https://github.com/alisi1989/RFmix2-Pipeline-to-plot., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2024. Published by Oxford University Press.)

(1) Background: Pulmonary hypertension (PH) increases pulmonary vascular resistance and right ventricular (RV) afterload. Assessment of RV systolic function in PH using RV fractional area change (RV FAC) as a marker directly correlates with mortality and the need for extracorporeal membrane oxygenation (ECMO). However, few studies have assessed neurodevelopmental outcomes. We hypothesize that cardiac RV systolic dysfunction with lower RV FAC is associated with worse neurodevelopmental impairment (NI). (2) Methods: Retrospective study of 42 subjects with PH to evaluate neurodevelopmental outcomes in the first two years of life based on (i) subjective assessment of RV systolic function and (ii) RV FAC, a specific echocardiographic marker for RV function. (3) Results: Subjects from the initial study cohort ( n = 135) with PH who had long-term follow-up were divided into RV dysfunction (study, n = 20) and non-RV dysfunction (control, n = 22) groups. RV FAC in the study vs. control group (0.18 vs. 0.25) was lower ( p = 0.00017). There was no statistically significant difference in NI either with RV dysfunction or lower RV FAC. Although not significant, RV dysfunction was associated with longer mean duration of mechanical ventilation, time on ECMO, and length of stay. In the initial cohort (135), mortality was 16.3% and the percentage of NI was 62%. (4) Conclusions: Neonatal pulmonary hypertension is associated with a high degree of neurodevelopment impairment. Early RV systolic dysfunction, as identified by RV FAC, was not an optimal predictive biomarker for infants with PH and neurodevelopmental impairment.

Pentaerythritol tetranitrate (PETN) has been used extensively in commercial detonators and other explosive applications for many decades. Here, we show the results of a comprehensive 1.5 year aging study of PETN in commercial detonators, addressing batch-to-batch variations, surface area changes, and comparisons of aged loose powders side-by-side with identically aged detonators. Function time analysis of the aged detonators has also been provided and discussed in the context of powder aging. This large-scale, statistically relevant study addresses long-standing questions on PETN aging without the complications from making comparisons between multiple batches of material. We have evaluated the aging time required to reach the maximum measured amount of PETN coarsening and estimated an activation barrier of ∼123 kJ mol -1 , which is higher than literature values reported by Gee et al. It is possible that this discrepancy is due to the fact that that this study cannot quantify the relative contributions of surface diffusion versus sublimation processes. At the lower temperatures of 50 and 60 °C, we assume that surface diffusion dominates over sublimation processes, even at longer aging times. At the higher temperature of 75 °C, we assume that both surface diffusion and sublimation contribute at the early time points, which are included in the Arrhenius analysis for coarsening., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Molecular imaging of brain vesicular acetylcholine transporter provides a biomarker to explore cholinergic systems in humans. We aimed to characterize the distribution of, and optimize methods to quantify, the vesicular acetylcholine transporter-specific tracer (-)-(1-(8-(2-[ 18 F]fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-piperidin-4-yl)(4-fluorophenyl)methanone ([ 18 F]VAT) in the brain using PET. Methods: Fifty-two healthy participants aged 21-97 y had brain PET with [ 18 F]VAT. [ 3 H]VAT autoradiography identified brain areas devoid of specific binding in cortical white matter. PET image-based white matter reference region size, model start time, and duration were optimized for calculations of Logan nondisplaceable binding potential (BP ND ). Ten participants had 2 scans to determine test-retest variability. Finally, we analyzed age-dependent differences in participants. Results: [ 18 F]VAT was widely distributed in the brain, with high striatal, thalamic, amygdala, hippocampal, cerebellar vermis, and regionally specific uptake in the cerebral cortex. [ 3 H]VAT autoradiography-specific binding and PET [ 18 F]VAT uptake were low in white matter. [ 18 F]VAT SUVs in the white matter reference region correlated with age, requiring stringent erosion parameters. Logan BP ND estimates stabilized using at least 40 min of data starting 25 min after injection. Test-retest variability had excellent reproducibility and reliability in repeat BP ND calculations for 10 participants (putamen, 6.8%; r > 0.93). We observed age-dependent decreases in the caudate and putamen (multiple comparisons corrected) and in numerous cortical regions. Finally, we provide power tables to indicate potential mean differences that can be detected between 2 groups of participants. Conclusion: These results validate a reference region for BP ND calculations and demonstrate the viability, reproducibility, and utility of using the [ 18 F]VAT tracer in humans to quantify cholinergic pathways., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Among patients with triple-negative breast cancer (TNBC), several studies have suggested that deregulated microRNA (miRNA) expression may be associated with a more aggressive phenotype. Although tumor molecular signatures may be race- and/or ethnicity-specific, there is limited information on the molecular profiles in women with TNBC of Hispanic and Latin American ancestry. We simultaneously profiled TNBC biopsies for the genome-wide copy number and miRNA global expression from 28 Latina women and identified a panel of 28 miRNAs associated with copy number alterations (CNAs). Four selected miRNAs (miR-141-3p, miR-150-5p, miR-182-5p, and miR-661) were validated in a subset of tumor and adjacent non-tumor tissue samples, with miR-182-5p being the most discriminatory among tissue groups (AUC value > 0.8). MiR-141-3p up-regulation was associated with increased cancer recurrence; miR-661 down-regulation with larger tumor size; and down-regulation of miR-150-5p with larger tumor size, high p53 expression, increased cancer recurrence, presence of distant metastasis, and deceased status. This study reinforces the importance of integration analysis of CNAs and miRNAs in TNBC, allowing for the identification of interactions among molecular mechanisms. Additionally, this study emphasizes the significance of considering the patients ancestral background when examining TNBC, as it can influence the relationship between intrinsic tumor molecular characteristics and clinical manifestations of the disease.

Activated leukocyte cell adhesion molecule (ALCAM) is a cell adhesion molecule that supports T cell activation, leukocyte migration, and (lymph)angiogenesis and has been shown to contribute to the pathology of various immune-mediated disorders, including asthma and corneal graft rejection. In contrast to monoclonal antibodies (mAbs) targeting ALCAM's T cell expressed binding partner CD6, no ALCAM-targeting mAbs have thus far entered clinical development. This is likely linked with the broad expression of ALCAM on many different cell types, which increases the risk of eliciting unwanted treatment-induced side effects upon systemic mAb application. Targeting ALCAM in surface-exposed tissues, such as the lungs or the cornea, by a topical application could circumvent this issue. Here, we report the development of various stability- and affinity-improved anti-ALCAM mAb fragments with cross-species reactivity towards mouse, rat, monkey, and human ALCAM. Fragments generated in either mono- or bivalent formats potently blocked ALCAM-CD6 interactions in a competition ELISA, but only bivalent fragments efficiently inhibited ALCAM-ALCAM interactions in a leukocyte transmigration assay. The different fragments displayed a clear size-dependence in their ability to penetrate the human corneal epithelium. Furthermore, intranasal delivery of anti-ALCAM fragments reduced leukocyte infiltration in a mouse model of asthma, confirming ALCAM as a target for topical application in the lungs., Competing Interests: Noria Segueni is a study director at Artimmune (https://www.artimmune.com/, accessed on 20 June 2023), the contract research company that performed the mouse asthma study. Yulia Kaluzhny is a principal scientist at MatTek (https://www.mattek.com/, accessed on 20 June 2023), a company providing 3D corneal tissue models. The authors have no additional relevant affiliations or conflicting financial interests. All other co-authors declare no conflict of interests.

Background: Individuals released from carceral facilities have high rates of hospitalization and death, especially in the weeks immediately after their return to community settings. During this transitional process, individuals leaving incarceration are expected to engage with multiple providers working in separate, complex systems, including health care clinics, social service agencies, community-based organizations, and probation and parole services. This navigation is often complicated by individuals' physical and mental health, literacy and fluency, and socioeconomic status. Personal health information technology, which can help people access and organize their health information, could improve the transition from carceral systems to the community and mitigate health risks upon release. Yet, personal health information technologies have not been designed to meet the needs and preferences of this population nor tested for acceptability or use., Objective: The objective of our study is to develop a mobile app to create personal health libraries for individuals returning from incarceration to help bridge the transition from carceral settings to community living., Methods: Participants were recruited through Transitions Clinic Network clinic encounters and professional networking with justice-involved organizations. We used qualitative research methods to assess the facilitators and barriers to developing and using personal health information technology for individuals returning from incarceration. We conducted individual interviews with people just released from carceral facilities (n=~20) and providers (n=~10) from the local community and carceral facilities involved with the transition for returning community members. We used rigorous rapid qualitative analysis to generate thematic output characterizing the unique circumstances impacting the development and use of personal health information technology for individuals returning from incarceration and to identify content and features for the mobile app based on the preferences and needs of our participants., Results: As of February 2023, we have completed 27 qualitative interviews with individuals recently released from carceral systems (n=20) and stakeholders (n=7) who support justice-involved individuals from various organizations in the community., Conclusions: We anticipate that the study will characterize the experiences of people transitioning from prison and jails to community settings; describe the information, technology resources, and needs upon reentry to the community; and create potential pathways for fostering engagement with personal health information technology., International Registered Report Identifier (irrid): DERR1-10.2196/44748., (©Marisol Foumakoye, Meredith Campbell Britton, Emile Ansari, Monya Saunders, Terika McCall, Emily A Wang, Lisa B Puglisi, T Elizabeth Workman, Qing Zeng-Treitler, Yin Ying, Shira Shavit, Cynthia A Brandt, Karen H Wang. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 03.05.2023.)

Background: Twice weekly lateral flow tests (LFTs) for secondary school children was UK Government policy from 8 March 2021. We evaluate use of LFTs (both supervised at test centres, and home test kits) in school-aged children in Cheshire and Merseyside., Methods: We report (i) number of LFT positives (ii) proportion of LFT positive with confirmatory reverse transcription polymerase chain reaction (PCR) test within 2 days, and (iii) agreement between LFT-positive and confirmatory PCR, and dependence of (i-iii) on COVID-19 prevalence., Findings: 1 248 468 LFTs were taken by 211 255 12-18 years old, and 163 914 by 52 116 5-11 years old between 6 November 2020 and 31 July 2021. Five thousand three hundred and fourteen (2.5%) 12-18 years old and 1996 (3.8%) 5-11 years old returned LFT positives, with 3829 (72.1%) and 1535 (76.9%) confirmatory PCRs, and 3357 (87.7%) and 1383 (90.1%) confirmatory PCR-positives, respectively.Monthly proportions of LFT positive with PCR negative varied between 4.7% and 35.3% in 12-18 years old (corresponding proportion of all tests positive: 9.7% and 0.3%).Deprivation and non-White ethnicity were associated with reduced uptake of confirmatory PCR., Interpretation: Substantial inequalities in confirmatory testing need more attention to avoid further disadvantage through education loss. When prevalence is low additional measures, including confirmatory testing, are needed. Local Directors of Public Health taking more control over schools testing may be needed., Funding: DHSC, MRC, NIHR, EPSRC., (© The Author(s) 2022. Published by Oxford University Press on behalf of Faculty of Public Health.)

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Studies have reported elevated rates of dissociative symptoms and comorbid dissociative disorders in functional neurological disorder (FND); however, a comprehensive review is lacking., Aims: To systematically review the severity of dissociative symptoms and prevalence of comorbid dissociative disorders in FND and summarise their biological and clinical associations., Method: We searched Embase, PsycInfo and MEDLINE up to June 2021, combining terms for FND and dissociation. Studies were eligible if reporting dissociative symptom scores or rates of comorbid dissociative disorder in FND samples. Risk of bias was appraised using modified Newcastle-Ottawa criteria. The findings were synthesised qualitatively and dissociative symptom scores were included in a meta-analysis (PROSPERO CRD42020173263)., Results: Seventy-five studies were eligible (FND n = 3940; control n = 3073), most commonly prospective case-control studies ( k = 54). Dissociative disorders were frequently comorbid in FND. Psychoform dissociation was elevated in FND compared with healthy ( g = 0.90, 95% CI 0.66-1.14, I 2 = 70%) and neurological controls ( g = 0.56, 95% CI 0.19-0.92, I 2 = 67%). Greater psychoform dissociation was observed in FND samples with seizure symptoms versus healthy controls ( g = 0.94, 95% CI 0.65-1.22, I 2 = 42%) and FND samples with motor symptoms ( g = 0.40, 95% CI -0.18 to 1.00, I 2 = 54%). Somatoform dissociation was elevated in FND versus healthy controls ( g = 1.80, 95% CI 1.25-2.34, I 2 = 75%). Dissociation in FND was associated with more severe functional symptoms, worse quality of life and brain alterations., Conclusions: Our findings highlight the potential clinical utility of assessing patients with FND for dissociative symptomatology. However, fewer studies investigated FND samples with motor symptoms and heterogeneity between studies and risk of bias were high. Rigorous investigation of the prevalence, features and mechanistic relevance of dissociation in FND is needed.

Elevated circulating lactate has been associated with obesity and insulin resistance. The aim of the current study was to determine if lactate-induced lysine lactylation (kla), a post-translational modification, was present in human skeletal muscle and related to insulin resistance. Fifteen lean (Body Mass Index: 22.1 ± 0.5 kg/m 2 ) and fourteen obese (40.6 ± 1.4 kg/m 2 ) adults underwent a muscle biopsy and 2-h oral glucose tolerance test. Skeletal muscle lactylation was increased in obese compared to lean females (19%, p < 0.05) and associated with insulin resistance (r = 0.37, p < 0.05) in the whole group. Skeletal muscle lactylation levels were significantly associated with markers of anaerobic metabolism (plasma lactate and skeletal muscle lactate dehydrogenase [LDH], p < 0.05) and negatively associated with markers of oxidative metabolism (skeletal muscle cytochrome c oxidase subunit 4 and Complex I [pyruvate] OXPHOS capacity, p < 0.05). Treatment of primary human skeletal muscle cells (HSkMC) with sodium lactate for 24 h increased protein lactylation and IRS-1 serine 636 phosphorylation in a similar dose-dependent manner ( p < 0.05). Inhibition of glycolysis (with 2-deoxy-d-glucose) or LDH-A (with sodium oxamate or LDH-A siRNA) for 24 h reduced HSkMC lactylation which paralleled reductions in culture media lactate accumulation. This study identified the existence of a lactate-derived post-translational modification in human skeletal muscle and suggests skeletal muscle lactylation could provide additional insight into the regulation of skeletal muscle metabolism, including insulin resistance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Maschari, Saxena, Law, Walsh, Campbell and Consitt.)

Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.

Objective: Parkinson disease (PD) is defined by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid β (Aβ) and tau accumulation, occur in some LBD cases. We sought to quantify α-syn, Aβ, and tau accumulation in neocortical, limbic, and basal ganglia regions., Methods: We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 LBD, seven Alzheimer disease (AD), and six control cases. We measured insoluble α-syn, Aβ, and tau with recently developed sandwich ELISAs., Results: We detected a wide range of insoluble α-syn accumulation in LBD cases. The majority had substantial α-syn accumulation in most regions, and dementia severity correlated with neocortical α-syn. However, three cases had low neocortical levels that were indistinguishable from controls. Eight LBD cases had substantial Aβ accumulation, although the mean Aβ level in LBD was lower than in AD. The presence of Aβ was associated with greater α-syn accumulation. Tau accumulation accompanied Aβ in only one LBD case., Interpretation: LBD is associated with insoluble α-syn accumulation in neocortical regions, but the relatively low neocortical levels in some cases suggest that other changes contribute to impaired function, such as loss of neocortical innervation from subcortical regions. The correlation between Aβ and α-syn accumulation suggests a pathophysiologic relationship between these two processes., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Study Design: Cross-sectional study design., Objective: There are multiple accepted treatment options for internal fixation of mandibular angle fractures. The purpose of this study was to determine if there is a safe zone for lateral border fixation of mandibular angle fractures., Methods: One hundred coronal images of facial computed tomography (CT) scans were reviewed on patients between the ages of 18 to 48. Measurements were taken in the area of the second and third molar region related to the inferior border to the superior extent of the inferior alveolar canal and apex of the second molar root, along with buccal cortical measurements to the inferior alveolar canal and apical third of the second molar root., Results: The average measurement of the inferior border in the second molar area to the inferior alveolar canal and apex of the root was 1.12 cm (0.70-1.77) and 1.39 cm (0.91-2.30), respectively. The average measurement of the inferior border of the third molar to the inferior alveolar canal was 1.26 cm (0.78-1.83). The average measurement of the buccal cortex of the second molar to the inferior alveolar canal and apical one-third of the root was 0.64 cm (0.34-1.25) and 0.59 cm (0.33-0.98), respectively. The average measurement of the third molar buccal cortex to the inferior alveolar canal was 0.45 cm (0.18-0.98)., Conclusion: In the area of the second molar region, there is no ubiquitous safe zone for screw placement, cortical bone thickness is more critical than vertical placement of the fixation plate and screws. In the third molar region, cortical bone thickness and vertical orientation may provide a safe zone for screw placement., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Redondoviridae is a newly established family of circular Rep-encoding single-stranded (CRESS) DNA viruses found in the human ororespiratory tract. Redondoviruses were previously found in ∼15% of respiratory specimens from U.S. urban subjects; levels were elevated in individuals with periodontitis or critical illness. Here, we report higher redondovirus prevalence in saliva samples: four rural African populations showed 61 to 82% prevalence, and an urban U.S. population showed 32% prevalence. Longitudinal, limiting-dilution single-genome sequencing revealed diverse strains of both redondovirus species ( Brisavirus and Vientovirus ) in single individuals, persistence over time, and evidence of intergenomic recombination. Computational analysis of viral genomes identified a recombination hot spot associated with a conserved potential DNA stem-loop structure. To assess the possible role of this site in recombination, we carried out in vitro studies which showed that this potential stem-loop was cleaved by the virus-encoded Rep protein. In addition, in reconstructed reactions, a Rep-DNA covalent intermediate was shown to mediate DNA strand transfer at this site. Thus, redondoviruses are highly prevalent in humans, found in individuals on multiple continents, heterogeneous even within individuals and encode a Rep protein implicated in facilitating recombination. IMPORTANCE Redondoviridae is a recently established family of DNA viruses predominantly found in the human respiratory tract and associated with multiple clinical conditions. In this study, we found high redondovirus prevalence in saliva from urban North American individuals and nonindustrialized African populations in Botswana, Cameroon, Ethiopia, and Tanzania. Individuals on both continents harbored both known redondovirus species. Global prevalence of both species suggests that redondoviruses have long been associated with humans but have remained undetected until recently due to their divergent genomes. By sequencing single redondovirus genomes in longitudinally sampled humans, we found that redondoviruses persisted over time within subjects and likely evolve by recombination. The Rep protein encoded by redondoviruses catalyzes multiple reactions in vitro , consistent with a role in mediating DNA replication and recombination. In summary, we identify high redondovirus prevalence in humans across multiple continents, longitudinal heterogeneity and persistence, and potential mechanisms of redondovirus evolution by recombination.

Thirty-nine years ago, scrub typhus (ST), a disease, was not among the China's notifiable diseases. However, ST has reemerged to become a growing public health issue in the southwest part of China. The major factors contributing to an increased incidence and prevalence of this disease include rapid globalization, urbanization, expansion of humans into previously uninhabited areas, and climate change. The clinical manifestation of ST also consists of high fever, headache, weakness, myalgia, rash, and an eschar. In severe cases, complications (e.g. multi-organ failure, jaundice, acute renal failure, pneumonitis, myocarditis, and even death) can occur. The diagnosis of ST is mainly based on serological identification by indirect immunofluorescence assay and other molecular methods. Furthermore, several groups of antibiotics (e.g. tetracycline, chloramphenicol, macrolides, and rifampicin) are currently effective in treating this disease. This fact suggests the need for robust early diagnostic techniques, increased surveillance, and prompt treatment, and develop future vaccine.

Objective: To examine specific symptom progression patterns and possible disease staging in Parkinson disease clinical subtypes., Methods: We recently identified Parkinson disease clinical subtypes based on comprehensive behavioral evaluations, "Motor Only," "Psychiatric & Motor," and "Cognitive & Motor," which differed in dementia and mortality rates. Parkinson disease participants ("Motor Only": n = 61, "Psychiatric & Motor": n = 17, "Cognitive & Motor": n = 70) and controls (n = 55) completed longitudinal, comprehensive motor, cognitive, and psychiatric evaluations (average follow-up = 4.6 years). Hierarchical linear modeling examined group differences in symptom progression. A three-way interaction among time, group, and symptom duration (or baseline age, separately) was incorporated to examine disease stages., Results: All three subtypes increased in motor dysfunction compared to controls. The "Motor Only" subtype did not show significant cognitive or psychiatric changes compared to the other two subtypes. The "Cognitive & Motor" subtype's cognitive dysfunction at baseline further declined compared to the other two subtypes, while also increasing in psychiatric symptoms. The "Psychiatric & Motor" subtype's elevated psychiatric symptoms at baseline remained steady or improved over time, with mild, steady decline in cognition. The pattern of behavioral changes and analyses for disease staging yielded no evidence for sequential disease stages., Interpretation: Parkinson disease clinical subtypes progress in clear, temporally distinct patterns from one another, particularly in cognitive and psychiatric features. This highlights the importance of comprehensive clinical examinations as the order of symptom presentation impacts clinical prognosis., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: To investigate the global expression profile of miRNAs, their impact on cellular signaling pathways, and their association with poor prognostic parameters in African-American (AA) patients with triple negative breast cancer (TNBC)., Methods: Twenty-five samples of AA TNBC patients were profiled for global miRNA expression and stratified considering three clinical-pathological parameters: tumor size, lymph node (LN), and recurrence (REC) status. Differential miRNA expression analysis was performed for each parameter, and their discriminatory power was determined by Receiver Operating Characteristic (ROC) curve analysis. KMplotter was assessed to determine the association of the miRNAs with survival, and functional enrichment analysis to determine the main affected pathways and miRNA/mRNA target interactions., Results: A panel of eight, 23 and 27 miRNAs were associated with tumor size, LN, and REC status, respectively. Combined ROC analysis of two (miR-2117, and miR-378c), seven (let-7f-5p, miR-1255b-5p, miR-1268b, miR-200c-3p, miR-520d, miR-527, and miR-518a-5p), and three (miR-1200, miR-1249-3p, and miR-1271-3p) miRNAs showed a robust discriminatory power based on tumor size (AUC = 0.917), LN (AUC = 0.945) and REC (AUC = 0.981) status, respectively. Enrichment pathway analysis revealed their involvement in proteoglycans and glycan and cancer-associated pathways. Eight miRNAs with deregulated expressions in patients with large tumor size, positive LN metastasis, and recurrence were significantly associated with lower survival rates. Finally, the construction of miRNA/mRNA networks based in experimentally validated mRNA targets, revealed nodes of critical cancer genes, such as AKT1, BCL2, CDKN1A, EZR and PTEN., Conclusions: Altogether, our data indicate that miRNA deregulated expression is a relevant biological factor that can be associated with the poor prognosis in TNBC of AA patients, by conferring to their TNBC cells aggressive phenotypes that are reflected in the clinical characteristics evaluated in this study., (© 2021. The Author(s).)

Dendritic cell (DC) migration to draining lymph nodes (dLNs) is a slow process that is believed to begin with DCs approaching and entering into afferent lymphatic capillaries. From capillaries, DCs slowly crawl into lymphatic collectors, where lymph flow induced by collector contraction supports DC detachment and thereafter rapid, passive transport to dLNs. Performing a transcriptomics analysis of dermal endothelial cells, we found that inflammation induces the degradation of the basement membrane (BM) surrounding lymphatic collectors and preferential up-regulation of the DC trafficking molecule VCAM-1 in collectors. In crawl-in experiments performed in ear skin explants, DCs entered collectors in a CCR7- and β1 integrin-dependent manner. In vivo, loss of β1-integrins in DCs or of VCAM-1 in lymphatic collectors had the greatest impact on DC migration to dLNs at early time points when migration kinetics favor the accumulation of rapidly migrating collector DCs rather than slower capillary DCs. Taken together, our findings identify collector entry as a critical mechanism enabling rapid DC migration to dLNs in inflammation., Competing Interests: Disclosures: The authors declare no competing interests exist., (© 2021 Arasa et al.)

Nuclear envelope proteins play an important role in regulating nuclear size and structure in cancer. Altered expression of nuclear lamins are found in many cancers and its expression is correlated with better clinical outcomes. The nucleus is the largest organelle in the cell with a diameter between 10 and 20 μm. Nuclear size significantly impacts cell migration. Nuclear structural changes are predicted to impact cancer metastasis by regulating cancer cell migration. Here we show emerin regulates nuclear structure in invasive breast cancer cells to impact cancer metastasis. Invasive breast cancer cells had 40% to 50% less emerin than control cells, which resulted in decreased nuclear size. Overexpression of GFP-emerin in invasive breast cancer cells rescued nuclear size and inhibited migration through 3.0 and 8.0 μm pores. Mutational analysis showed emerin binding to nucleoskeletal proteins was important for its regulation of nuclear structure, migration, and invasion. Importantly, emerin expression inhibited lung metastasis by 91% in orthotopic mouse models of breast cancer. Emerin nucleoskeleton-binding mutants failed to inhibit metastasis. These results support a model whereby emerin binding to the nucleoskeleton regulates nuclear structure to impact metastasis. In this model, emerin plays a central role in metastatic transformation, because decreased emerin expression during transformation causes the nuclear structural defects required for increased cell migration, intravasation, and extravasation. IMPLICATIONS: Modulating emerin expression and function represents new targets for therapeutic interventions of metastasis, because increased emerin expression rescued cancer metastasis., (©2021 American Association for Cancer Research.)

Lactase persistence (LP) is a genetically-determined trait that is prevalent in African, European and Arab populations with a tradition of animal herding and milk consumption. To date, genetic analyses have identified several common variants that are associated with LP. Furthermore, data have indicated that these functional alleles likely have been maintained in pastoralist populations due to the action of recent selection, exemplifying the ongoing evolution of anatomically modern humans. Additionally, demographic history has also played a role in the geographic distribution of LP and associated alleles in Africa. In particular, the migration of ancestral herders and their subsequent admixture with local populations were integral to the spread of LP alleles and the culture of pastoralism across the continent. The timing of these demographic events was often correlated with known major environmental changes and/or the ability of domesticated cattle to resist/avoid infectious diseases. This review summarizes recent advances in our understanding of the genetic basis and evolutionary history of LP, as well as the factors that influenced the origin and spread of pastoralism in Africa., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Junctional adhesion proteins play important roles in controlling angiogenesis, vascular permeability and leukocyte trafficking. CD112 (nectin-2) belongs to the immunoglobulin superfamily and was shown to engage in homophilic and heterophilic interactions with a variety of binding partners expressed on endothelial cells and on leukocytes. Recent in vitro studies suggested that CD112 regulates human endothelial cell migration and proliferation as well as transendothelial migration of leukocytes. However, so far, the role of CD112 in endothelial cell biology and in leukocyte trafficking has not been elucidated in vivo. We found CD112 to be expressed by lymphatic and blood endothelial cells in different murine tissues. In CD112-deficient mice, the blood vessel coverage in the retina and spleen was significantly enhanced. In functional in vitro studies, a blockade of CD112 modulated endothelial cell migration and significantly enhanced endothelial tube formation. An antibody-based blockade of CD112 also significantly reduced T cell transmigration across endothelial monolayers in vitro. Moreover, T cell homing to the spleen was significantly reduced in CD112-deficient mice. Overall, our results identify CD112 as a regulator of angiogenic processes in vivo and demonstrate a novel role for CD112 in T cell entry into the spleen.

To date, SARS-CoV-2 (the virus that causes COVID-19) has spread to almost every region of the world, infecting millions and resulting in the deaths of hundreds of thousands of people. Although it was predicted that Africa would suffer a massive loss of life due to this pandemic, the number of COVID-19 cases has been relatively low across the continent. Researchers have speculated that several factors may be responsible for this outcome in Africa, including the extensive experience that countries have with infectious diseases and the young median age of their populations. However, it is still important for African countries to adopt aggressive and bold approaches against COVID-19, in case the nature of the pandemic changes. This short review will summarize the status of the outbreak in Africa and propose possible reasons for current trends, as well as discuss interventions aimed at preventing a rapid increase in the number of COVID-19 cases in the future., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain unknown. The use of CSF levels of amyloid beta 1-42 , total tau, and phosphorylated tau 181 as quantitative traits in genetic studies have provided novel insights into Alzheimer's disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson's disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson's disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta 1-42 levels (effect = - 0.5, p = 9.2 × 10 -19 ). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau 181 levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson's disease risk meta-analysis were associated with Parkinson's disease status (p = 0.035) and the genomic architecture of CSF amyloid beta 1-42 (R 2  = 2.29%; p = 2.5 × 10 -11 ). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta 1-42 levels (p = 7.3 × 10 -04 ). Two-sample Mendelian Randomization revealed that CSF amyloid beta 1-42 plays a role in Parkinson's disease (p = 1.4 × 10 -05 ) and age at onset (p = 7.6 × 10 -06 ), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta 1-42 (p = 3.8 × 10 -06 ), higher mean cortical binding potentials (p = 5.8 × 10 -08 ), and higher Braak amyloid beta score (p = 4.4 × 10 -04 ). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson's disease, CSF amyloid beta 1-42 , and APOE.

Denoising fMRI data requires assessment of frame-to-frame head motion and removal of the biases motion introduces. This is usually done through analysis of the parameters calculated during retrospective head motion correction (i.e., 'motion' parameters). However, it is increasingly recognized that respiration introduces factitious head motion via perturbations of the main (B0) field. This effect appears as higher-frequency fluctuations in the motion parameters (>0.1 ​Hz, here referred to as 'HF-motion'), primarily in the phase-encoding direction. This periodicity can sometimes be obscured in standard single-band fMRI (TR 2.0-2.5 ​s) due to aliasing. Here we examined (1) how prevalent HF-motion effects are in seven single-band datasets with TR from 2.0 to 2.5 ​s and (2) how HF-motion affects functional connectivity. We demonstrate that HF-motion is more common in older adults, those with higher body mass index, and those with lower cardiorespiratory fitness. We propose a low-pass filtering approach to remove the contamination of high frequency effects from motion summary measures, such as framewise displacement (FD). We demonstrate that in most datasets this filtering approach saves a substantial amount of data from FD-based frame censoring, while at the same time reducing motion biases in functional connectivity measures. These findings suggest that filtering motion parameters is an effective way to improve the fidelity of head motion estimates, even in single band datasets. Particularly large data savings may accrue in datasets acquired in older and less fit participants., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Based on multi-domain classification of Parkinson disease (PD) subtypes, we sought to determine the key features that best differentiate subtypes and the utility of PD subtypes to predict clinical milestones., Methods: Prospective cohort of 162 PD participants with ongoing, longitudinal follow-up. Latent class analysis (LCA) delineated subtypes based on score patterns across baseline motor, cognitive, and psychiatric measures. Discriminant analyses identified key features that distinguish subtypes at baseline. Cox regression models tested PD subtype differences in longitudinal conversion to clinical milestones, including deep brain stimulation (DBS), dementia, and mortality., Results: LCA identified distinct subtypes: "motor only" (N = 63) characterized by primary motor deficits; "psychiatric & motor" (N = 17) characterized by prominent psychiatric symptoms and moderate motor deficits; "cognitive & motor" (N = 82) characterized by impaired cognition and moderate motor deficits. Depression, executive function, and apathy best discriminated subtypes. Since enrollment, 22 had DBS, 48 developed dementia, and 46 have died. Although there were no subtype differences in rate of DBS, dementia occurred at a higher rate in the "cognitive & motor" subtype. Surprisingly, mortality risk was similarly elevated for both "cognitive & motor" and "psychiatric & motor" subtypes compared to the "motor only" subtype (relative risk = 3.15, 2.60)., Interpretation: Psychiatric and cognitive features, rather than motor deficits, distinguish clinical PD subtypes and predict greater risk of subsequent dementia and mortality. These results emphasize the value of multi-domain assessments to better characterize clinical variability in PD. Further, differences in dementia and mortality rates demonstrate the prognostic utility of PD subtypes., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.

Background and Aim: Hypoglossal nerve stimulation (HNS) decreases obstructive sleep apnoea (OSA) severity via genioglossus muscle activation and decreased upper airway collapsibility. This study assessed the safety and effectiveness at 6 months post-implantation of a novel device delivering bilateral HNS via a small implanted electrode activated by a unit worn externally, to treat OSA: the Genio™ system., Methods: This prospective, open-label, non-randomised, single-arm treatment study was conducted at eight centres in three countries (Australia, France and the UK). Primary outcomes were incidence of device-related serious adverse events and change in the apnoea-hypopnoea index (AHI). The secondary outcome was the change in the 4% oxygen desaturation index (ODI). Additional outcomes included measures of sleepiness, quality of life, snoring and device use. This trial was registered with ClinicalTrials.gov, number NCT03048604., Results: 22 out of 27 implanted participants (63% male, aged 55.9±12.0 years, body mass index (BMI) 27.4±3.0 kg·m -2 ) completed the protocol. At 6 months BMI was unchanged (p=0.85); AHI decreased from 23.7±12.2 to 12.9±10.1 events·h -1 , a mean change of 10.8 events·h -1 (p<0.001); and ODI decreased from 19.1±11.2 to 9.8±6.9 events·h -1 , a mean change of 9.3 events·h -1 (p<0.001). Daytime sleepiness (Epworth Sleepiness Scale; p=0.01) and sleep-related quality of life (Functional Outcomes of Sleep Questionnaire-10; p=0.02) both improved significantly. The number of bed partners reporting loud, very intense snoring, or leaving the bedroom due to participant snoring decreased from 96% to 35%. 91% of participants reported device use >5 days per week, and 77% reported use for >5 h per night. No device-related serious adverse events occurred during the 6-month post-implantation period., Conclusions: Bilateral HNS using the Genio™ system reduces OSA severity and improves quality of life without device-related complications. The results are comparable with previously published HNS systems despite minimal implanted components and a simple stimulation algorithm., Competing Interests: Conflict of interest: P.R. Eastwood reports support for undertaking trials from Nyxoah SA, during the conduct of the study; support for undertaking trials from Oventus Pty Ltd and Zelda Therapeutics, outside the submitted work. Conflict of interest: M. Barnes has nothing to disclose. Conflict of interest: S.G. MacKay reports grants from NHMRC and Garnett-Passe RWF (conjoint grant), outside the submitted work. Conflict of interest: J.R. Wheatley reports grants from Nyxoah, during the conduct of the study. Conflict of interest: D.R. Hillman reports support for undertaking trials from Nyxoah SA, during the conduct of the study; support for undertaking trials from Oventus Pty Ltd and Zelda Therapeutics, outside the submitted work. Conflict of interest: X-L. Nguyên reports grants from Serenity Medical Services, during the conduct of the study. Conflict of interest: R. Lewis reports personal fees from Nyxoah SA, during the conduct of the study. Conflict of interest: M.C. Campbell reports personal fees from Nyxoah, outside the submitted work. Conflict of interest: B. Pételle reports consultancy fees from Bluesom, support for meeting attendance from Nyxoah, outside the submitted work. Conflict of interest: J.H. Walsh reports support for undertaking trials from Nyxoah SA, during the conduct of the study; support for undertaking trials from Oventus Pty Ltd and Zelda Therapeutics, outside the submitted work. Conflict of interest: A.C. Jones reports personal fees from Nyxoah, during the conduct of the study. Conflict of interest: C.E. Palme reports personal fees from Nyoxah, during the conduct of the study. Conflict of interest: A. Bizon has nothing to disclose. Conflict of interest: N. Meslier has nothing to disclose. Conflict of interest: C. Bertolus has nothing to disclose. Conflict of interest: K.J. Maddison has undertaken sponsored research projects for Nyxoah Pty Ltd, during the conduct of the study; has undertaken sponsored research projects for Nyxoah Pty Ltd, Oventus Pty Ltd and Zelda Pty Ltd, and reports grants from Sir Charles Gairdner Hospital and Australian and New Zealand College of Anaesthetists, outside the submitted work. Conflict of interest: L. Laccourreye reports non-financial support from Medtronic France and Integra LifeSciences Services, outside the submitted work. Conflict of interest: G. Raux has nothing to disclose. Conflict of interest: K. Denoncin has nothing to disclose. Conflict of interest: V. Attali reports personal fees for consultancy from Nyxoah, during the conduct of the study; personal fees for lectures from Resmed, institutional fees for research from Imthera, outside the submitted work. Conflict of interest: F. Gagnadoux has nothing to disclose. Conflict of interest: S.H. Launois is an employee of Serenity Medical Services/Bioserenity, reports personal fees for lectures from Cidelec, travel and/or meeting expenses from Vitalaire, S2A Santé Asten La Poste and UCB Pharma, grants from Resmed, outside the submitted work., (Copyright ©ERS 2020.)

Background: Lymphotoxin-α (LTα), located in the Major Histocompatibility Complex (MHC) class III region on chromosome 6, encodes a cytotoxic protein that mediates a variety of antiviral responses among other biological functions. Furthermore, several genotypes at this gene have been implicated in the onset of a number of complex diseases, including myocardial infarction, autoimmunity, and various types of cancer. However, little is known about levels of nucleotide variation and linkage disequilibrium (LD) in and near LTα, which could also influence phenotypic variance. To address this gap in knowledge, we examined sequence variation across ~ 10 kilobases (kbs), encompassing LTα and the upstream region, in 2039 individuals from the 1000 Genomes Project originating from 21 global populations., Results: Here, we observed striking patterns of diversity, including an excess of intermediate-frequency alleles, the maintenance of multiple common haplotypes and a deep coalescence time for variation (dating > 1.0 million years ago), in global populations. While these results are generally consistent with a model of balancing selection, we also uncovered a signature of positive selection in the form of long-range LD on chromosomes with derived alleles primarily in Eurasian populations. To reconcile these findings, which appear to support different models of selection, we argue that selective sweeps (particularly, soft sweeps) of multiple derived alleles in and/or near LTα occurred in non-Africans after their ancestors left Africa. Furthermore, these targets of selection were predicted to alter transcription factor binding site affinity and protein stability, suggesting they play a role in gene function. Additionally, our data also showed that a subset of these functional adaptive variants are present in archaic hominin genomes., Conclusions: Overall, this study identified candidate functional alleles in a biologically-relevant genomic region, and offers new insights into the evolutionary origins of these loci in modern human populations.

Objectives: This report describes the surgical implantation of a novel bilateral hypoglossal nerve stimulator (Genio system®, Nyxoah S.A., Belgium) and the successful treatment of a patient with moderate obstructive sleep apnea (OSA)., Study Design: Surgical technique description and case study report., Methods: The bilateral implantable stimulator (IS) simultaneously stimulates both genioglossus (GG) muscles to reduce airway obstruction. At night, patients wear an activation chip under their chin that wirelessly transmits energy to the implant and enables the nerve stimulation. Surgical implantation of the IS is performed under general anesthesia by making a small incision above the hyoid bone and dissecting through the platysma, mylohyoid, and geniohyoid muscles to the GG muscle. The hypoglossal nerve branches are then identified, followed by suturing the IS in place. The system was evaluated in an otherwise healthy, 60-year-old woman with moderate OSA (apnea hypopnea index (AHI): 25/hr, nadir O 2 saturation: 78%). Appropriate stimulation settings were determined at 2-, 3-, and 6-months post implantation during polysomnography (PSG) and changes in apnea and hypopnea events and oxygen desaturation recorded., Results: The surgery was well tolerated by the patient with an uneventful recovery. The PSG at 6 months showed that AHI per hour, obstructive apnea events per hour, hypopnea events per hour, and oxygen desaturation index have been reduced by 88%, 92%, 88%, and 97%, respectively, and nadir O 2 saturation improved to 91%., Conclusions: The absence of complications and considerable reduction of apnea and hypopnea events in this case study help demonstrate the potential safety and efficacy of the bilateral hypoglossal nerve stimulator., Level of Evidence: 4., (© 2019 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals, Inc. on behalf of The Triological Society.)

Blood culture acquisition is integral in the assessment of patients with sepsis, though there exists a lack of clarity relating to clinical states that warrant acquisition. We investigated the clinical status of critically ill children in the timeframe proximate to acquisition of blood cultures. The associated rates of systemic inflammatory response syndrome (72%) and sepsis (57%) with blood culture acquisition were relatively low suggesting a potential overutilization of blood cultures. Efforts are needed to improve decision making at the time that acquisition of blood cultures is under consideration and promote percutaneous blood draws over indwelling lines.

The hallmark pathology underlying Parkinson disease (PD) is progressive synucleinopathy, beginning in caudal brainstem that later spreads rostrally. However, the primarily subcortical pathology fails to account for the wide spectrum of clinical manifestations in PD. To reconcile these observations, resting-state functional connectivity (FC) can be used to examine dysfunction across distributed brain networks. We measured FC in a large, single-site study of nondemented PD (N = 107; OFF medications) and healthy controls (N = 46) incorporating rigorous quality control measures and comprehensive sampling of cortical, subcortical and cerebellar regions. We employed novel statistical approaches to determine group differences across the entire connectome, at the network-level, and for select brain regions. Group differences respected well-characterized network delineations producing a striking "block-wise" pattern of network-to-network effects. Surprisingly, these results demonstrate that the greatest FC differences involve sensorimotor, thalamic, and cerebellar networks, with notably smaller striatal effects. Split-half replication demonstrates the robustness of these results. Finally, block-wise FC correlations with behavior suggest that FC disruptions may contribute to clinical manifestations in PD. Overall, these results indicate a concerted breakdown of functional network interactions, remote from primary pathophysiology, and suggest that FC deficits in PD are related to emergent network-level phenomena rather than focal pathology., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Activated leukocyte cell adhesion molecule (ALCAM, CD166) is a cell adhesion molecule of the immunoglobulin superfamily and has been implicated in diverse pathophysiological processes including T cell activation, leukocyte trafficking, and (lymph)angiogenesis. However, exploring the therapeutic potential of ALCAM blockade in immune-mediated inflammatory disorders has been difficult due to the lack of antibodies with blocking activity toward murine ALCAM. In this study, we identified and characterized a monoclonal antibody with high affinity and specificity for murine ALCAM. This antibody reduced in vitro T cell activation induced by antigen-presenting dendritic cells (DCs) as well as (trans)migration of murine DCs across lymphatic endothelial monolayers. Moreover, it reduced emigration of DCs from in vitro -cultured human skin biopsies. Similarly, antibody-based blockade of ALCAM reduced (lymph)angiogenic processes in vitro and decreased developmental lymphangiogenesis in vivo to levels observed in ALCAM-deficient mice. Since corneal allograft rejection is an important medical condition that also involves (lymph)angiogenesis, DC migration and T cell activation, we investigated the therapeutic potential of ALCAM blockade in murine corneal disease. Blocking ALCAM lead to DC retention in corneas and effectively prevented corneal allograft rejection. Considering that we also detected ALCAM expression in human corneal DCs and lymphatics, our findings identify ALCAM as a potential novel therapeutic target in human corneal allograft rejection.

Afferent lymphatic vessels contribute to immunity by transporting antigen and leukocytes to draining lymph nodes (LNs) and are emerging as new players in the regulation of peripheral tolerance. Performing intravital microscopy in inflamed murine ear skin we found that migrating dendritic cells (DCs) and antigen-experienced effector T cells spend considerable time arresting or clustering within afferent lymphatic capillaries. We also observed that intralymphatic T cells frequently interacted with DCs. When imaging polyclonal T cells during an ongoing contact-hypersensitivity response, most intralymphatic DC-T cell interactions were short-lived. Conversely, during a delayed-type-hypersensitivity response, cognate antigen-bearing DCs engaged in long-lived MHCII-(I-A/I-E)-dependent interactions with antigen-specific T cells. Long-lived intralymphatic DC-T cell interactions reduced the speed of DC crawling but did not delay overall DC migration to draining LNs. While further consequences of these intralymphatic interactions still need to be explored, our findings suggest that lymphatic capillaries represent a unique compartment in which adaptive immune interaction and modulation occur.

Despite its critical role in the defense against microbial infection and tumor development, little is known about the range of nucleotide and haplotype variation at IFN-γ, or the evolutionary forces that have shaped patterns of diversity at this locus. To address this gap in knowledge, we examined sequence data from the IFN-γ gene in 1461 individuals from 15 worldwide populations. Our analyses uncovered novel patterns of variation in distinct African populations, including an excess of high frequency-derived alleles, unusually long haplotype structure surrounding the IFN-γ gene, and a "star-like" genealogy of African-specific haplotypes carrying variants previously associated with infectious disease. We also inferred a deep time to coalescence of variation at IFN-γ (~ 0.8 million years ago) and ancient ages for common polymorphisms predating the evolution of modern humans. Taken together, these results are congruent with a model of positive selection on standing variation in African populations. Furthermore, we inferred that common variants in intron 3 of IFN-γ are the likely targets of selection. In addition, we observed a paucity of non-synonymous substitutions relative to synonymous changes in the exons of IFN-γ in African and non-African populations, suggestive of strong purifying selection. Therefore, we contend that positive and purifying selection have influenced levels of diversity in different regions of IFN-γ, implying that these distinct genic regions are, or have been, functionally important. Overall, this study provides additional insights into the evolutionary events that have contributed to the frequency and distribution of alleles having a role in human health and disease.

Background: Gut microbiota from individuals in rural, non-industrialized societies differ from those in individuals from industrialized societies. Here, we use 16S rRNA sequencing to survey the gut bacteria of seven non-industrialized populations from Tanzania and Botswana. These include populations practicing traditional hunter-gatherer, pastoralist, and agropastoralist subsistence lifestyles and a comparative urban cohort from the greater Philadelphia region., Results: We find that bacterial diversity per individual and within-population phylogenetic dissimilarity differs between Botswanan and Tanzanian populations, with Tanzania generally having higher diversity per individual and lower dissimilarity between individuals. Among subsistence groups, the gut bacteria of hunter-gatherers are phylogenetically distinct from both agropastoralists and pastoralists, but that of agropastoralists and pastoralists were not significantly different from each other. Nearly half of the Bantu-speaking agropastoralists from Botswana have gut bacteria that are very similar to the Philadelphian cohort. Based on imputed metagenomic content, US samples have a relative enrichment of genes found in pathways for degradation of several common industrial pollutants. Within two African populations, we find evidence that bacterial composition correlates with the genetic relatedness between individuals., Conclusions: Across the cohort, similarity in bacterial presence/absence compositions between people increases with both geographic proximity and genetic relatedness, while abundance weighted bacterial composition varies more significantly with geographic proximity than with genetic relatedness.

Fibronectin (FN) plays a major role in the stability and organization of the extracellular matrix (ECM). We have previously demonstrated that FN interacts directly with Hsp90, as well as showing that the Hsp90 inhibitor novobiocin results in FN turnover via a receptor mediated process. However, the receptor involved has not been previously identified. LRP1 is a ubiquitous receptor responsible for the internalisation of numerous ligands that binds both Hsp90 and FN, and therefore we investigated whether LRP1 was involved in novobiocin-mediated FN turnover. FN, LRP1 and Hsp90 could be isolated in a common complex, and inhibition of Hsp90 by novobiocin increased the colocalisation of FN and LRP1. Novobiocin induced an increase (at low concentrations) followed by a loss of FN that was primarily derived from extracellular matrix-associated FN and led to a concomitant increase in intracellular FN. The effect of novobiocin was specific to LRP1-expressing cells and could be recapitulated by an LRP1 blocking antibody and the allosteric C-terminal Hsp90 inhibitor SM253, but not the N-terminal inhibitor geldanamycin. Together these data suggest that LRP1 is required for FN turnover in response to Hsp90 inhibition by novobiocin, which may have unintended physiological consequences in contexts where C-terminal Hsp90 inhibition is to be used therapeutically.

The anatomical connections of the subthalamic nucleus (STN) have driven hypotheses about its functional anatomy, including the hypothesis that the precise anatomical location of STN deep brain stimulation (DBS) contributes to the variability of motor and non-motor responses across patients with Parkinson's disease (PD). We previously tested the hypothesis using a three-dimensional (3D) statistical method to interpret the acute effects of unilateral DBS at each patient's clinically optimized DBS settings and active contact. Here, we report a similar analysis from a new study in which DBS parameters were standardized and DBS locations were chosen blind to clinical response. In 74 individuals with PD and STN DBS, STN contacts were selected near the dorsal and ventral borders of the STN contralateral to the more affected side of the body. Participants were tested off PD medications in each of three unilateral DBS conditions (ventral STN DBS, dorsal STN DBS and DBS off) for acute effects on mood, apathy, working memory, response inhibition and motor function. Voltage, frequency and pulse width were standardized, and participants and raters were blind to condition. In a categorical analysis, both dorsal and ventral STN DBS improved mean motor function without affecting cognitive measures. Ventral STN DBS induced greater improvement in rigidity and anxiety than dorsal STN DBS. In the 3D analysis, contact location was significant for body hypokinesia, rigidity and resting tremor, with the greatest improvement occurring with DBS in dorsal STN and zona incerta. The 3D results provide new, direct functional evidence for the anatomically derived model of STN, in which motor function is best represented in dorsal STN. However, our data suggest that functional segregation between motor and non-motor areas of the STN is limited, because locations that induced improvements in motor function and mood overlapped substantially., Competing Interests: The authors declare no competing interests.

Breast cancers (BCas) that lack expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are referred to as triple negative breast cancers (TNBCs) and have the poorest clinical outcome. Once these aggressive tumors progress to distant organs, the median survival decreases to 12 months. With endocrine therapies being ineffective in this BCa subtype, highly toxic chemo- and radiation therapies are the only options. A better understanding of the functional role(s) of molecular targets contributing to TNBC progression could help in the design and development of new treatments that are more targeted with less toxicity. CAPER (Co-activator of AP-1 and ER) is a nuclear transcriptional co-activator that was recently involved in ER-positive BCa progression, however its role in hormone-independent cancers remains unknown. Our current report demonstrates that CAPER expression is upregulated in human TNBC specimens compared to normal breast tissue and that its selective downregulation through a lentiviral-mediated shRNA knockdown approach resulted in decreased cell numbers in MDA-MB-231 and BT549 TNBC cell lines without affecting the growth of non-tumorigenic cell line MCF-10A. Concordant with these observations, CAPER knockdown was also associated with a decrease in DNA repair proteins leading to a marked increase in apoptosis, through caspase-3/7 activation without any changes in cell cycle. Collectively, we propose CAPER as an important signaling molecule in the development of TNBC linked to DNA repair mechanisms, which could lead to new therapeutic modalities for the treatment of this aggressive cancer., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Context: The number of patients discharged from acute care hospitals to skilled nursing facilities (SNFs) is rising. These patients have increasingly complex needs and many experience poor outcomes while under SNF care, including hospital readmissions. Patients' goals of care (GoC) are viewed as a factor contributing to unplanned hospital readmissions from SNFs. However, clinicians' perspectives of GoC for hospitalized patients discharged to SNFs are not well-described., Objectives: To explore how clinicians view GoC for hospitalized patients discharged to SNFs., Methods: Qualitative study using semi-structured interviews and thematic analysis., Results: Forty-one clinicians from one acute care hospital and two SNFs completed interviews ranging in length from 14 to 52 minutes (mean = 32 minutes). Of the sample, 22% were nurses, 20% physicians, 15% were from care management, and 15% were from social services. Respondents viewed patients' GoC for continuing treatment at the SNF as important, but acknowledged that they were infrequently discussed during hospitalization. Many respondents felt that patients and families had unrealistic GoC for SNF care. Factors that contributed to unrealistic GoC included patients' limited knowledge of disease processes, prognosis, and treatment options; and inconsistent or insufficient communication of GoC among hospital and SNF clinicians, the patient, and family members. Respondents associated a lack of GoC or unrealistic GoC with patients' dissatisfaction with SNF care, unplanned transitions to hospice, and hospital readmissions., Conclusions: Respondents reported that GoC conversations infrequently occurred during hospitalization, contributing to unrealistic patient and family expectations for SNF care and poor patient outcomes. Interventions are needed that facilitate timely, accurate, and consistent GoC discussions across care continuums., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)