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To analyze the effects of type 2 diabetes mellitus (T2DM), need for dental care, personal health practices and use of services on oral health-related quality of life (OHRQoL) in US adults.The sample included 2,945 participants (aged ≥ 20) selected from the National Health and Nutrition Examination Survey (NHANES) 2003-2004 stratified probability sample that represented 124,525,899 individuals in the weighted sample. Two-stage structural equation modelling (SEM) assessed interrelationships between T2DM regressions on factors associated with OHRQoL in a simplified three-factor Andersen Behavioral Model (ABM).SEM supported the hypotheses that T2DM directly predicted need (perceived need, evaluated need, general health condition) with a significant path coefficient of 0.49 (β=0.49, p⟨0.05). Need had direct (77%) and indirect (23%) effects on OHRQoL (βdirect=0.30, βindirect=0.09, p⟨ 0.001). Need predicted personal health practices including use of services (reason for dental visit, frequency of dental visits, smoking status) (β=0.46, p⟨0.001). Need, in turn, predicted OHRQoL (β=0.19, p⟨0.001). In the model, 23.8%, 59.7%, and 18.1% of the variance was explained by need, personal health practices including use of services, and OHRQoL, respectively.The results confirmed T2DM predicted need, which in sequence had direct and indirect effects on OHRQoL.

Human balance control is a critical prerequisite to nearly all activities, and human falls are a major health concern. The most robust way to assess reactive balance is to apply external perturbations. Perturbations are typically delivered with destabilizing motorized surfaces, external forces, visual motion, or neural stimulation. However, most devices that perturb walking in research settings are not likely to see wide clinical use due to cost, space, and time constraints. In contrast, there are low-cost destabilizing clinical tests that might require similar neural control mechanisms as walking. The present study examines and compares frontal plane balance responses with a research-based surface perturbation walking device to balance responses in a clinical standing balance assessment. We found that correlations between these walking and standing tests varied widely depending on the conditions compared. Correlations between standing and walking balance were highest when 1) a perturbation was present in walking tests, 2) subjects walked slowly, and 3) the standing tests were on foam as opposed to firm surface.Clinical Relevance- This study helps to clarify the relationship between standing and walking balance. We use the clinical test of sensory integration in standing balance and a perturbation treadmill device to measure walking balance.

The primary cilium has recently become the focus of intensive investigations into understanding the physical structure and processes of eukaryotic cells. This paper describes two tilt-series image datasets, acquired by transmission electron microscopy, of in situ chick-embryo sternal-cartilage primary cilia. These data have been released under an open-access licence, and are well suited to tomographic reconstruction and modelling of the cilium.

Recessive mutations in DNAJC3, an endoplasmic reticulum (ER)-resident BiP co-chaperone, have been identified in patients with multisystemic neurodegeneration and diabetes mellitus. To further unravel these pathomechanisms, we employed a non-biased proteomic approach and identified dysregulation of several key cellular pathways, suggesting a pathophysiological interplay of perturbed lipid metabolism, mitochondrial bioenergetics, ER-Golgi function, and amyloid-beta processing. Further functional investigations in fibroblasts of patients with DNAJC3 mutations detected cellular accumulation of lipids and an increased sensitivity to cholesterol stress, which led to activation of the unfolded protein response (UPR), alterations of the ER-Golgi machinery, and a defect of amyloid precursor protein. In line with the results of previous studies, we describe here alterations in mitochondrial morphology and function, as a major contributor to the DNAJC3 pathophysiology. Hence, we propose that the loss of DNAJC3 affects lipid/cholesterol homeostasis, leading to UPR activation, β-amyloid accumulation, and impairment of mitochondrial oxidative phosphorylation.

Introduction/Objective The aims of our study were to optimize the workflow of non-small cell carcinoma (NSCC) endobronchial ultrasound-guided bronchoscopy with transbronchial needle aspiration (EBUS-TBNA) samples to maximize tissue available for next-generation sequencing (NGS), preserve formalin-fixed paraffin-embedded (FFPE) cell blocks (CBs) for future testing, and shorten turnaround time (TAT) of NGS results. We evaluated the performance of supernatant fluid (SNF) processed from a dedicated aspirate for NGS testing. Methods/Case Report 20 EBUS-TBNA samples positive for NSCC on rapid on-site evaluation were collected and processed using a new workflow (Figure 1). Five aspirates were collected in formalin. One additional dedicated pass was collected fresh and centrifuged. The resulting cell pellet was added to the passes in formalin for FFPE CB processing. The SNF was recentrifuged. DNA and RNA were extracted from concentrated SNF for targeted testing using the Oncomine™ Precision Assay (Thermo Scientific™, Waltham, MA). NGS results from the corresponding FFPE CBs were used as “controls” for comparison. Results (if a Case Study enter NA) A total of 31 mutations were detected in SNF (Table 1). The most frequently mutated genes were TP53 (35%), EGFR (23%), KRAS (13%), CTNNB1 (6%), and ERBB2 (6%). EGFR and KRAS amplification, CDKN2A deletion, and SQSTM1-NTRK3 fusion alteration were also detected. There was 100% concordance between the mutations detected in SNF and corresponding FFPE CBs with comparable variant allele frequencies. TAT of NGS results was 1 day for SNF compared to 4 – 10 days for FFPE CB. Conclusion In our study, we were able to demonstrate the usefulness of NGS on SNF to provide reliable, rapid molecular results. This testing strategy was successfully incorporated into the workflow for tissue handling and processing between our clinical, cytopathology, and molecular teams. Molecular results were available at the same time as the cytologic diagnosis, allowing for timely reporting of a comprehensive diagnosis. This approach is particularly useful in patients with advanced disease requiring urgent management.

As a result of the COVID-19 pandemic, face coverings were introduced as a safety measure in certain environments in England and some research suggests that they can affect emotion recognition. Factors such as own-ethnicity bias (e.g. whether people perceiving and expressing emotions are of the same ethnicity) and social biases are also known to influence emotion recognition. However, it is unclear whether these factors interact with face coverings to affect emotion recognition. Therefore, this study examined the effects of face coverings, own-ethnicity biases, and attitudes on emotion recognition accuracy. In this study, 131 participants viewed masked and unmasked emotional faces varying in ethnicity and completed a questionnaire on their attitudes towards face masks. We found that emotion recognition was associated with masks and attitudes: accuracy was lower in masked than unmasked conditions and attitudes towards masks Inside and Outside were associated with emotion recognition. However, a match between perceiver and stimulus ethnicity did not have a significant effect on emotion recognition. Ultimately, our results suggest that masks, and negative attitudes towards them, were associated with poorer emotion recognition. Future research should explore different mask-wearing behaviours and possible in-group/out-group biases and their interaction with other social cues (e.g. in-group biases). Funding: This project was partially funded by internal funding awarded to RB by Brunel University London (BRIEF award 1086).

Objectives To determine maternal vs fetal origin for blood in placental intervillous thrombi (IVTs). Methods We used comparative analysis of microsatellites (short tandem repeats [STRs]), sex chromosome fluorescence in situ hybridization (FISH), and immunohistochemistry (IHC) for fetal (ɑ-fetoprotein [AFP]) and maternal (immunoglobulin M [IgM]) serum proteins to distinguish the origin of IVTs. Using an informatics approach, we tested the association between IVTs and fetomaternal hemorrhage (FMH). Results In 9 of 10 cases, the preponderance of evidence showed that the thrombus was mostly or entirely maternal in origin. In 1 case, the thrombus was of mixed origins. STR testing was prone to contamination by entrapped fetal villi. FISH was useful but limited only to cases with male fetuses. IgM showed stronger staining than AFP in 9 cases, supporting maternal origin. By informatics, we found no association between IVTs and FMH. Conclusions Evidence supports a maternal origin for blood in IVTs. IHC for IgM and AFP may be clinically useful in determining maternal vs fetal contribution to IVTs.

The decision to engage in escalated fighting involves an interplay between the individual’s estimate of the value of the resource under dispute, and the ability of the combatants to invest sufficient time and energy in the contest. Although fallow deer (Dama dama) contests usually take place between pairs of individuals, they are sometimes terminated by the intervention of dominant third-party individuals. Theory argues that these interventions prevent subordinates from gaining a competitive boost via a winner-effect; thus, interveners benefit by removing this threat to their status. Prior to intervention, third-party individuals often approach and closely follow the competing dyad before either abandoning their interest in the contest, or physically targeting one of the contestants. This study investigates the possibility that third-party following is an assessment process whereby individuals monitor the quality of fighting rivals during the annual rut. We tested three hypotheses: (i) that third-party followers are socially dominant individuals, that (ii) follow contests in order to assess the current quality of high-ranking rivals (iii) when resource abundance (i.e. the number of oestrus females) is high. Our results show that socially dominant individuals are most likely to follow contests; however, contrary to expectation, third-party males tended to follow dyads consisting of low-ranking rivals. We also show that as resource abundance increased in the population there was an increased tendency for males to follow contests, and a reduction in the probability of engaging in a third-party intervention of the contest. As expected by theory, dominance and resource abundance were important correlates of third-party following. Our results support the idea that socially dominant males monitor subordinate males who possess sufficient resources to expend in fighting, and who thus may be a threat to their status.

A deliberative democracy is reliant on an informed electorate discussing issues and presenting persuasive arguments. Individuals acquire information from exposure to political messages. Par...

The ATP-binding cassette (ABC) proteins play critical roles in maintaining lipid and sterol homeostasis in higher eukaryotes. In humans, several subfamily-A and -G members function as cholesterol transporters across the cellular membranes. Deficiencies of these ABC proteins can cause dyslipidemia that is associated with health conditions such as atherosclerosis, diabetes, fatty liver disease, and neurodegeneration. The physiological roles of ABC cholesterol transporters have been implicated in mediating cholesterol efflux for reverse cholesterol transport and in maintaining membrane integrity for cell survival. The precise role of these ABC transporters in cells remains elusive, and little is known about the sterol-transport mechanism. The membrane constituents of ABC transporters have been postulated to play a key role in determining the transport substrates and the translocation mechanisms via the transmembrane domains. Recent breakthroughs in determining high-resolution structures of the human sterol transporter ABCG5/G8 and its functional homologs have shed light on new structural features of ABC transporters, providing a more relevant framework for mechanistic analysis of cholesterol-transport ABC proteins. This minireview outlines what is known about ABCG cholesterol transporters, addresses key structural features in the putative sterol translocation pathway on the transmembrane domains, and concludes by proposing a mechanistic model of ABC cholesterol transporters.

Sinonasal glomangiopericytoma (SNGP) is a neoplasm arising in the nasal cavity and paranasal sinuses that shows perivascular myoid differentiation. The diagnosis of SNGP may be diagnostically challenging due to a large number of potential mimics. In the present study, we sought to characterize the histological and molecular features of six cases of SNGP found in prior surgical pathology records over a 15-year period. The average age at diagnosis was 48.5 years (range: 31-78 years), and the male-to-female ratio was 1:1. Imaging studies in all six cases demonstrated avidly enhancing, lobulated soft tissue masses in the nasal cavity, extending into the sinuses and nasopharynx. Histologically, the tumors were unencapsulated and composed of a proliferation of closely packed, bland, and uniform spindle cells growing deep to an intact surface respiratory epithelium. The cells were separated by a distinctive vascular network ranging from capillaries to large vascular spaces. All cases demonstrated strong positivity for smooth muscle actin, cyclin D1, CD99, and β-catenin (100%). Targeted sequencing revealed recurrent CTNNB1 missense mutations in all cases tested. Additionally, TLE1 was positive in all cases which has not been previously reported. No tested cases harbored SS18 translocations. We found that while no single marker resolves immunohistochemical overlap between SNGP and its histologic mimics, an extended immunohistochemical panel that includes β-catenin, cyclin D1, STAT6, smooth muscle actin, pan-cytokeratin cocktails, S100, and SOX10 helps to support the diagnosis of SNGP in diagnostically challenging cases without the need for molecular studies.

The present studies prove that conjugation of meningococcal lipooligosaccharides through their non-reducing terminus conserves their inner epitopes resulting in conjugates potent to induce a protective immune response. Four different oligosaccharides were obtained by specific degradations of the same L7 lipooligosaccharide (L7-LOS), and each was linked to tetanus toxoid by direct reductive amination. Two were truncated oligosaccharides with incomplete inner epitopes and were obtained by mild acid hydrolysis of lipooligosaccharide. The terminal galactose of one oligosaccharide was additionally enzymatically oxidized. These oligosaccharides were conjugated through a newly exposed terminal Kdo in reducing end or through oxidized galactose localized at non-reducing end of the core, respectively. The third was a full-length oligosaccharide obtained by O-deacylation of the L7-LOS and subsequent enzymatic removal of phosphate substituents from its lipid A moiety. The fourth one was also a full-length O-deacylated lipooligosaccharide, but treated with galactose oxidase. This allowed direct conjugation to tetanus toxoid through terminal 2-N-acyl-2-deoxy-d-glucopyranose or through oxidized galactose, respectively. Comparison of the immune performance of four conjugates in mice revealed, that while each was able to induce significant level of L7-LOS-specific IgG antibody, the conjugates made with the full-length saccharides were able to induce antibodies with increased bactericidal activity against homologous meningococci. Only full-length oligosaccharides were good inhibitors of the binding of L7-LOS to the bactericidal antiserum. Moreover, induction of the significant level of the L7-LOS-specific antibody by full-length lipooligosaccharide conjugated from non-reducing end, provided also the direct evidence that internal core epitopes are fully responsible for the immunorecognition and immunoreactivity.

Objective 1.) Describe demographic and clinical characteristics of pediatric nasal septal perforations (NSP), 2.) Analyze efficacy of treatment modalities in symptom management and resolution of pediatric NSP, 3.) Describe the surgical technique of external rhinoplasty with vascularized nasal septal flaps in the treatment of nasal septal perforations. Methods IRB-approved retrospective chart review of pediatric patients ages 0–18 years with nasal septal perforations treated at a tertiary care pediatric otolaryngology practice. Demographic and clinical characteristics including gender, age, race, and presenting symptoms, and location, size, and etiology of perforation were collected. Outcomes including persistence of perforation and symptoms at 1 year and most recent visit were recorded. A total of 20 patients were included. Statistical analysis used Fisher's t-test for categorical variables and Wilcoxon rank-sum for continuous variables. Results Median age was 167.5 months (1.5–221.0). The most common etiology was iatrogenic (40%), followed by button battery (20%). Thirty percent of patients underwent surgical repair. Fifty percent of patients who underwent surgical repair achieved closure of their perforation at most recent follow up. Conclusion Pediatric NSP is a challenging issue with limited literature to date. Iatrogenic causes (40%) and button batteries (20%) were the most common etiologies of nasal septal perforation in our study. We introduce an advancement in our center's surgical technique with a case illustration with repair via external rhinoplasty and bilateral vascularized nasal septal flaps. Future larger studies may further elucidate characteristics and treatment modalities associated with successful closure.

The breakdown of a Mil-spec coating system at fasteners in aluminum alloys after fatigue and environmental exposure was studied using electrochemical impedance spectroscopy. In addition, a statisti...

Congenital Central Hypoventilation Syndrome (CCHS) is a rare disease characterized by autonomic nervous system dysregulation. Central hypoventilation is the most prominent and clinically important presentation. CCHS is caused by mutations in paired-like homeobox 2b (PHOX2B) and is inherited in an autosomal dominant pattern. A co-occurrence of two asymptomatic PHOX2B variants with a classical CCHS presentation highlights the importance of clinical PHOX2B testing in parents and family members of all CCHS probands. Despite being an autosomal dominant disease, once a polyalanine repeat expansion mutation has been identified, sequencing of the other allele should also be considered.

Facebook and other social media are often utilized by political campaigns to communicate with the electorate and provide vital information about a candidate. However, in doing so, political campaig...

Background: Ripretinib, a broad-spectrum KIT and platelet-derived growth factor receptor A switch-control tyrosine kinase inhibitor, is approved for the treatment of adult patients with advanced gastrointestinal stromal tumor as ≥ fourth-line therapy. We present the efficacy and safety of ripretinib in patients with KIT-altered metastatic melanoma enrolled in the expansion phase of the ripretinib phase I study. Patients and methods: Patients with KIT-altered metastatic melanoma were enrolled and treated with ripretinib at the recommended phase II dose of 150 mg once daily in 28-day cycles. Investigator-assessed responses according to Response Evaluation Criteria In Solid Tumors version 1.1 were carried out on day 1 of cycles 3, 5, 7, every three cycles thereafter, and at a final study visit. Results: A total of 26 patients with KIT-altered metastatic melanoma (25 with KIT mutations, 1 with KIT-amplification) were enrolled. Patients had received prior immunotherapy (n = 23, 88%) and KIT inhibitor therapy (n = 9, 35%). Confirmed objective response rate (ORR) was 23% [95% confidence interval (CI) 9%-44%; one complete and five partial responses] with a median duration of response of 9.1 months (range, 6.9-31.3 months). Median progression-free survival (mPFS) was 7.3 months (95% CI 1.9-13.6 months). Patients without prior KIT inhibitor therapy had a higher ORR and longer mPFS (n = 17, ORR 29%, mPFS 10.2 months) than those who had received prior KIT inhibitor treatment (n = 9, ORR 11%, mPFS 2.9 months). The most common treatment-related treatment-emergent adverse events (TEAEs) of any grade in ≥15% of patients were increased lipase, alopecia, actinic keratosis, myalgia, arthralgia, decreased appetite, fatigue, hyperkeratosis, nausea, and palmar-plantar erythrodysesthesia syndrome. There were no grade ≥4 treatment-related TEAEs. Conclusions: In this phase I study, ripretinib demonstrated encouraging efficacy and a well-tolerated safety profile in patients with KIT-altered metastatic melanoma, suggesting ripretinib may have a clinically meaningful role in treating these patients. CA extern

Published risk stratification models of solitary fibrous tumor (SFT) have been associated with distant metastases outside the central nervous system (CNS), but have not been studied for tumors occurring in the CNS. In a retrospective review, we identified 72 cases of solitary fibrous tumor or hemangiopericytoma (HPC) diagnosed between January 2011 and December 2020 at our institution. The tumors involved the central nervous system (N = 17), thoracic cavity (N = 28), and extrathoracic sites (N = 27). The risk of local recurrence, distant metastasis, or death at 5 years was 57% (95% CI 23%, 76%) in the CNS, 24% (95% CI 2%, 41%) in the thoracic cavity, and 13% (95% CI 0%, 25%) in extrathoracic sites. By contrast, the risk of distant metastasis or death at 5 years was 13% (95% CI 0%, 29%) in CNS primaries, 5% (95% CI 0%, 14%) in thoracic primaries, and 14% (95% CI 0%, 27%) in extrathoracic primaries. Using the published 3- and 4-variable risk stratification models by Demicco et al., we retrospectively assessed our cases for risk of local recurrence, distant metastasis, and death. For tumors outside the CNS, we show that three- and four-variable risk stratification models were associated with recurrence-free survival in addition to the previously known association with distant metastasis (all P 0.05). In contrast, inside the CNS, we show that neither risk model is a significantly associated with clinical behavior, and that WHO grade is likely the best available prognostic tool, though none of the differences were significant. The lack of significant differences can be likely explained by the younger median age (47 years vs 61 years) and smaller median tumor size (3.5 cm vs 5.6 cm), downgrading the risk stratification scores in CNS compared to non-CNS primaries. In conclusion, existing risk stratification models of SFT are not associated with clinical behavior for tumors arising inside the CNS, but are associated with local recurrence in addition to distant metastasis outside the CNS.

The hydrogen-bond-accepting abilities for more than 100 organic molecules are quantified using 19F and 31P NMR spectroscopy with pentafluorobenzoic acid (PFBA) and phenylphosphinic acid (PPA) as commercially available, inexpensive probes. Analysis of pyridines and anilines with a variety of electronic modifications demonstrates that changes in NMR shifts can predict the secondary effects that contribute to H-bond-accepting ability, establishing the ability of PFBA and PPA binding to predict electronic trends. The H-bond-accepting abilities of various metal-chelating ligands and organocatalysts are also quantified. The measured Δδ(31P) and Δδp(19F) values correlate strongly with Hammett parameters, pKa of the protonated HBA, and proton-transfer basicity (pKBH+).

Rare diseases are individually rare but globally affect around 6% of the population, and in over 70% of cases are genetically determined. Their rarity translates into a delayed diagnosis, with 25% of patients waiting 5 to 30 years for one. It is essential to raise awareness of patients and clinicians of existing gene and variant-specific therapeutics at the time of diagnosis to avoid that treatment delays add up to the diagnostic odyssey of rare diseases' patients and their families.This paper aims to provide guidance and give detailed instructions on how to write homogeneous systematic reviews of rare diseases' treatments in a manner that allows the capture of the results in a computer-accessible form. The published results need to comply with the FAIR guiding principles for scientific data management and stewardship to facilitate the extraction of datasets that are easily transposable into machine-actionable information. The ultimate purpose is the creation of a database of rare disease treatments ("Treatabolome") at gene and variant levels as part of the H2020 research project Solve-RD.Each systematic review follows a written protocol to address one or more rare diseases in which the authors are experts. The bibliographic search strategy requires detailed documentation to allow its replication. Data capture forms should be built to facilitate the filling of a data capture spreadsheet and to record the application of the inclusion and exclusion criteria to each search result. A PRISMA flowchart is required to provide an overview of the processes of search and selection of papers. A separate table condenses the data collected during the Systematic Review, appraised according to their level of evidence.This paper provides a template that includes the instructions for writing FAIR-compliant systematic reviews of rare diseases' treatments that enables the assembly of a Treatabolome database that complement existing diagnostic and management support tools with treatment awareness data.

In 1960, Portugal celebrated the five-hundredth anniversary of the death of Prince Henry, a heroic figure acclaimed for his role in the early maritime dis- coveries. The celebrations lasted several months and were sponsored by the Portuguese state. They included a wide variety of diplomatic, academic and cultural initiatives. These festivities were used as an opportunity to unite the Portuguese populous in the face of various potential threats to the Estado Novo which surfaced during this time. Although they were dismissed by the British foreign office, the Royal Navy and Royal Air Force took the opportunity to participate in a heavily publicized naval review as their ‘oldest ally.’ A variety of Anglo-Portuguese exchanges occurred in the academic world through a series of state-sponsored history anthologies, an international con- ference and reciprocal exhibitions on the topic of the Portuguese discoveries. This paper looks at some key individuals that facilitated these exchanges in Britain using the correspondence that they left behind. It shows internatio- nal outreach in the Estado Novo’s official program of celebrations and the pragmatic management of the Anglo-Portuguese alliance., Práticas da História. Journal on Theory, Historiography and Uses of the Past, No. 8 (2019)

We search NANOGrav's 12.5-year data set for evidence of a gravitational wave background (GWB) with all the spatial correlations allowed by general metric theories of gravity. We find no substantial evidence in favor of the existence of such correlations in our data. We find that scalar-transverse (ST) correlations yield signal-to-noise ratios and Bayes factors that are higher than quadrupolar (tensor transverse, TT) correlations. Specifically, we find ST correlations with a signal-to-noise ratio of 2.8 that are preferred over TT correlations (Hellings and Downs correlations) with Bayesian odds of about 20:1. However, the significance of ST correlations is reduced dramatically when we include modeling of the Solar System ephemeris systematics and/or remove pulsar J0030$+$0451 entirely from consideration. Even taking the nominal signal-to-noise ratios at face value, analyses of simulated data sets show that such values are not extremely unlikely to be observed in cases where only the usual TT modes are present in the GWB. In the absence of a detection of any polarization mode of gravity, we place upper limits on their amplitudes for a spectral index of $\gamma = 5$ and a reference frequency of $f_\text{yr} = 1 \text{yr}^{-1}$. Among the upper limits for eight general families of metric theories of gravity, we find the values of $A^{95\%}_{TT} = (9.7 \pm 0.4)\times 10^{-16}$ and $A^{95\%}_{ST} = (1.4 \pm 0.03)\times 10^{-15}$ for the family of metric spacetime theories that contain both TT and ST modes., Comment: 24 pages, 18 figures, 3 appendices. Please send any comments/questions to Nima Laal (laaln@oregonstate.edu)

We report results from continued timing observations of PSR J0740+6620, a high-mass, 2.8-ms radio pulsar in orbit with a likely ultra-cool white dwarf companion. Our data set consists of combined pulse arrival-time measurements made with the 100-m Green Bank Telescope and the Canadian Hydrogen Intensity Mapping Experiment telescope. We explore the significance of timing-based phenomena arising from general-relativistic dynamics and variations in pulse dispersion. When using various statistical methods, we find that combining $\sim 1.5$ years of additional, high-cadence timing data with previous measurements confirms and improves upon previous estimates of relativistic effects within the PSR J0740+6620 system, with the pulsar mass $m_{\rm p} = 2.08^{+0.07}_{-0.07}$ M$_\odot$ (68.3\% credibility) determined by the relativistic Shapiro time delay. For the first time, we measure secular variation in the orbital period and argue that this effect arises from apparent acceleration due to significant transverse motion. After incorporating contributions from Galactic differential rotation and off-plane acceleration in the Galactic potential, we obtain a model-dependent distance of $d = 1.14^{+0.17}_{-0.15}$ kpc (68.3\% credibility). This improved distance confirms the ultra-cool nature of the white dwarf companion determined from recent optical observations. We discuss the prospects for future observations with next-generation facilities, which will likely improve the precision on $m_{\rm p}$ for J0740+6620 by an order of magnitude within the next few years., Final version after minor corrections during referee process. Published in the Astrophysical Journal Letters on 1 July 2021

The NANOGrav Collaboration reported strong Bayesian evidence for a common-spectrum stochastic process in its 12.5-yr pulsar timing array dataset, with median characteristic strain amplitude at periods of a year of $A_{\rm yr} = 1.92^{+0.75}_{-0.55} \times 10^{-15}$. However, evidence for the quadrupolar Hellings \& Downs interpulsar correlations, which are characteristic of gravitational wave signals, was not yet significant. We emulate and extend the NANOGrav dataset, injecting a wide range of stochastic gravitational wave background (GWB) signals that encompass a variety of amplitudes and spectral shapes, and quantify three key milestones: (I) Given the amplitude measured in the 12.5 yr analysis and assuming this signal is a GWB, we expect to accumulate robust evidence of an interpulsar-correlated GWB signal with 15--17 yrs of data, i.e., an additional 2--5 yrs from the 12.5 yr dataset; (II) At the initial detection, we expect a fractional uncertainty of $40\%$ on the power-law strain spectrum slope, which is sufficient to distinguish a GWB of supermassive black-hole binary origin from some models predicting more exotic origins;(III) Similarly, the measured GWB amplitude will have an uncertainty of $44\%$ upon initial detection, allowing us to arbitrate between some population models of supermassive black-hole binaries. In addition, power-law models are distinguishable from those having low-frequency spectral turnovers once 20~yrs of data are reached. Even though our study is based on the NANOGrav data, we also derive relations that allow for a generalization to other pulsar-timing array datasets. Most notably, by combining the data of individual arrays into the International Pulsar Timing Array, all of these milestones can be reached significantly earlier., 15 pages, 7 figures

Sleep is crucial for optimal well-being, and sex differences in sleep quality have significant implications for women’s health. We review the current literature on sex differences in sleep, such as differences in objective and subjective sleep measures and their relationship with aging. We then discuss the convincing evidence for the role of ovarian hormones in regulating female sleep, and survey how these hormones act on a multitude of brain regions and neurochemicals to impact sleep. Lastly, we identify several important areas in need of future research to narrow the knowledge gap and improve the health of women and other understudied populations.

Background We present a yet to be described association of SARS-CoV-2 infection with Kikuchi-Fujimoto disease. Case presentation A 32-year-old physician with history of SARS-CoV-2 infection presented to the emergency department with 2 weeks of fever, chills, and right sided cervical lymphadenopathy. He was treated empirically for presumed folliculitis with worsening of symptoms leading to repeat presentation to the emergency department. Extensive workup was unrevealing of an infectious cause and needle biopsy of the lesion was unrevealing. An excisional lymph node biopsy revealed follicular hyperplasia with necrotic foci showing abundance of histiocytes at the edge of necrosis with CD8 predominance of T-cells. Final diagnosis was deemed to be Kikuchi-Fujimoto disease. Antibiotic therapy was discontinued, and the patient’s symptoms resolved with steroid therapy and expectant management. Conclusions This is the first report of a patient developing Kikuchi-Fujimoto disease following SARS-CoV-2 infection. Clinicians should be aware of Kikuchi-Fujimoto disease as a possibility when approaching patients with hyper-inflammatory states who present with cervical lymphadenopathy.

BACKGROUND: The rapid spread of SARS-CoV-2, the causative agent of Coronavirus disease 2019 (COVID-19), has been accompanied by the emergence of distinct viral clades, though their clinical significance remains unclear. Here, we aimed to investigate the phylogenetic characteristics of SARS-CoV-2 infections in Chicago, Illinois, and assess their relationship to clinical parameters. METHODS: We performed whole-genome sequencing of SARS-CoV-2 isolates collected from COVID-19 patients in Chicago in mid-March, 2020. Using these and other publicly available sequences, we performed phylogenetic, phylogeographic, and phylodynamic analyses. Patient data was assessed for correlations between demographic or clinical characteristics and virologic features. FINDINGS: The 88 SARS-CoV-2 genome sequences in our study separated into three distinct phylogenetic clades. Clades 1 and 3 were most closely related to viral sequences from New York and Washington state, respectively, with relatively broad distributions across the US. Clade 2 was primarily found in the Chicago area with limited distribution elsewhere. At the time of diagnosis, patients infected with Clade 1 viruses had significantly higher average viral loads in their upper airways relative to patients infected with Clade 2 viruses, independent of disease severity. INTERPRETATION: These results show that multiple variants of SARS-CoV-2 were circulating in the Chicago area in mid-March 2020 that differed in their relative viral loads in patient upper airways. These data suggest that differences in virus genotype can impact viral load and may influence viral spread. FUNDING: Dixon Family Translational Research Award, Northwestern University Clinical and Translational Sciences Institute (NUCATS), National Institute of Allergy and Infectious Diseases (NIAID), Lurie Comprehensive Cancer Center, Northwestern University Emerging and Re-emerging Pathogens Program.

Background Good reading skills are important for appropriate functioning in everyday life, scholastic performance, and acquiring a higher socioeconomic status. We conducted the first systematic review and meta-analysis to quantify possible deficits in specific reading skills in people with a variety of mental illnesses, including personality disorders (PDs). Methods We performed a systematic search of multiple databases from inception until February 2020 and conducted random-effects meta-analyses. Results The search yielded 34 studies with standardized assessments of reading skills in people with one or more mental illnesses. Of these, 19 studies provided data for the meta-analysis. Most studies (k = 27; meta-analysis, k = 17) were in people with schizophrenia and revealed large deficits in phonological processing (Hedge’s g = −0.88, p g = −0.96, p g = −1.22, p = 0.002), relative to healthy controls; the single-word reading was less affected (Hedge’s g = −0.70, p g g = −0.85, p g = −0.95, p = 0.0003). Conclusions People with schizophrenia, and possibly forensic PD populations, demonstrate a range of reading skills deficits. Future studies are needed to establish how these deficits directly compare to those seen in developmental or acquired dyslexia and to explore the potential of dyslexia interventions to improve reading skills in these populations.

Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6‐months of age. RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt‐tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease., Heterozygous mutations in nuclear genes interacting with mt‐tRNAGlu induce the integrated stress response and metabolic rearrangements, reducing penetrance and promoting spontaneous recovery in a rare mitochondrial myopathy.

CCHS is an extremely rare congenital disorder requiring artificial ventilation as life support. Typically caused by heterozygous polyalanine repeat expansion mutations (PARMs) in the PHOX2B gene, identification of a relationship between PARM length and phenotype severity has enabled anticipatory management. However, for patients with non-PARMs in PHOX2B (NPARMs, ~10% of CCHS patients), a genotype-phenotype correlation has not been established. This comprehensive report of PHOX2B NPARMs and associated phenotypes, aims at elucidating potential genotype-phenotype correlations that will guide anticipatory management.An international collaboration (clinical, commercial, and research laboratories) was established to collect/share information on novel and previously published PHOX2B NPARM cases. Variants were categorized by type and gene location. Categorical data were analyzed with chi-square and Fisher's exact test; further pairwise comparisons were made on significant results.Three hundred two individuals with PHOX2B NPARMs were identified, including 139 previously unreported cases. Findings demonstrate significant associations between key phenotypic manifestations of CCHS and variant type, location, and predicted effect on protein function.This study presents the largest cohort of PHOX2B NPARMs and associated phenotype data to date, enabling genotype-phenotype studies that will advance personalized, anticipatory management and help elucidate pathological mechanisms. Further characterization of PHOX2B NPARMs demands longitudinal clinical follow-up through international registries.

When galaxies merge, the supermassive black holes in their centers may form binaries and emit low-frequency gravitational radiation in the process. In this paper, we consider the galaxy 3C 66B, which was used as the target of the first multimessenger search for gravitational waves. Due to the observed periodicities present in the photometric and astrometric data of the source, it has been theorized to contain a supermassive black hole binary. Its apparent 1.05-year orbital period would place the gravitational-wave emission directly in the pulsar timing band. Since the first pulsar timing array study of 3C 66B, revised models of the source have been published, and timing array sensitivities and techniques have improved dramatically. With these advances, we further constrain the chirp mass of the potential supermassive black hole binary in 3C 66B to less than (1.65 ± 0.02) × 109 M ⊙ using data from the NANOGrav 11-year data set. This upper limit provides a factor of 1.6 improvement over previous limits and a factor of 4.3 over the first search done. Nevertheless, the most recent orbital model for the source is still consistent with our limit from pulsar timing array data. In addition, we are able to quantify the improvement made by the inclusion of source properties gleaned from electromagnetic data over “blind” pulsar timing array searches. With these methods, it is apparent that it is not necessary to obtain exact a priori knowledge of the period of a binary to gain meaningful astrophysical inferences.

International audience; Background: Hereditary peripheral neuropathies are inherited disorders affecting the peripheral nervous system, including Charcot-Marie-Tooth disease, familial amyloid polyneuropathy and hereditary sensory and motor neuropathies. While the molecular basis of hereditary peripheral neuropathies has been extensively researched, interventional trials of pharmacological therapies are lacking. Objective: We collated evidence for the effectiveness of pharmacological and gene-based treatments for hereditary peripheral neuropathies. Methods: We searched several databases for randomised controlled trials (RCT), observational studies and case reports of therapies in hereditary peripheral neuropathies. Two investigators extracted and analysed the data independently, assessing study quality using the Oxford Centre for Evidence Based Medicine 2011 Levels of Evidence in conjunction with the Jadad scale. Results: Of the 2046 studies initially identified, 119 trials met our inclusion criteria, of which only 36 were carried over into our final analysis. Ascorbic acid was shown to have no therapeutic benefit in CMT1A, while a combination of baclofen, naltrexone and sorbitol (PXT3003) demonstrated some efficacy, but phase III data are incomplete. In TTR-related amyloid polyneuropathy tafamidis, patisiran, inotersen and revusiran showed significant benefit in high quality RCTs. Smaller studies showed the efficacy of L-serine for SPTLC1-related hereditary sensory neuropathy, riboflavin for Brown-Vialetto-Van Laere syndrome (SLC52A2/3) and phytanic acid-poor diet in Refsum disease (PHYH). Conclusions: The 'treatable' variants highlighted in this project will be flagged in the treatabolome database to alert clinicians at the time of the diagnosis and enable timely treatment of patients with hereditary peripheral neuropathies.