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Abstract: Lymphatic muscle cell (LMC) contractility and coverage of collecting lymphatic vessels (CLVs) are integral to effective lymphatic drainage and tissue homeostasis. In fact, defects in lym-phatic contractility have been identified in various conditions, including rheumatoid arthritis, in-flammatory bowel disease, and obesity. However, the fundamental role of LMCs in these patholog-ic processes is limited, primarily due to the difficulty in directly investigating the enigmatic nature of this poorly characterized cell type. LMCs are a unique cell type that exhibit dual tonic and phasic contractility with hybrid structural features of both vascular smooth muscle cells (VSMCs) and car-diac myocytes. While advances have been made in recent years to better understand the biochemis-try and function of LMCs, central questions regarding their origins, investiture into CLVs, and ho-meostasis remain unanswered. To summarize these discoveries, unexplained experimental results, and critical future directions, here we provide a focused review of current knowledge and open questions related to LMC progenitor cells, recruitment, maintenance, and regeneration. We also highlight the high-priority research goal of identifying LMC-specific genes towards genetic condi-tional-inducible in vivo gain and loss of function studies. While our interest in LMCs has been fo-cused on understanding lymphatic dysfunction in an arthritic flare, these concepts are integral to the broader field of lymphatic biology, and have important potential for clinical translation through tar-geted therapeutics to control lymphatic contractility and drainage. Discussion: While our interest in LMCs has been focused on understanding lymphatic dysfunction in an arthritic flare, these concepts are integral to the broader field of lymphatic biology, and have important potential for clinical translation through targeted therapeutics to control lymphatic contractility and drainage.

Locally derived endothelial nitric oxide (NO) contributes to the full expression of cutaneous vasodilation responses. Acute ultraviolet radiation (UVR) exposure attenuates NO-mediated vasodilation of the cutaneous microvasculature. Our findings suggest that in constitutively lightly pigmented skin, variation in skin melanin due to seasonal exposure to UVR does not alter the NO contribution to cutaneous vasodilation. Seasonal UVR exposure does not impact the NO-mediated cutaneous microvascular function.

The report of a detection of an absorption profile centred at 78 MHz in the continuum radio background spectrum by the EDGES experiment and its interpretation as the redshifted 21 cm signal of cosmological origin has become one of the most debated results of observational cosmology in recent times. The cosmological 21 cm has long been proposed to be a powerful probe for observing the early Universe and tracing its evolution over cosmic time. Even though the science case is well established, measurement challenges posed on the technical ground are not fully understood to the level of claiming a successful detection. EDGES’s detection has naturally motivated a number of experimental attempts worldwide to corroborate the findings. In this paper, we present a precision cross-correlation spectrometer HYPEREION purpose-designed for a precision radio background measurement between 50–120 MHz to detect the absorption profile reported by the EDGES experiment. HYPEREION implements a pre-correlation signal processing technique that self-calibrates any spurious additive contamination from within the system and delivers a differential measurement of the sky spectrum and a reference thermal load internal to the system. This ensures an unambiguous “zero-point” of absolute calibration of the purported absorption profile. We present the system design, measurement equations of the ideal system, systematic effects in the real system, and finally, an assessment of the real system output for the detection of the absorption profile at 78 MHz in the continuum radio background spectrum.

BACKGROUND: College students with intellectual disability (ID) face many challenges while maintaining employment. These challenges encompass both social and behavioral tribulations. Increasing social skills at work is a significant goal for practitioners and educators of adults with ID. Coaching strategies such as Covert Audio Coaching (CAC) and Remote Audio Coaching (RAC) have proven effective in teaching students with ID various employment related skills. OBJECTIVE: The purpose of this study was to determine if RAC would increase on-topic workplace communication skills for college students with ID. METHODS: This study used a multiple probe design to test the effects of RAC on teaching communication skills in the workplace. In this study, college students logged onto a Zoom call to speak with a co-worker about an employment topic while the interventionist used RAC to coach the student through the conversation. RESULTS: The results of this study demonstrated that the RAC intervention was effective in increasing on-topic exchanges between college students with ID and their co-workers. CONCLUSION: The COVID-19 pandemic has shifted the workplace to virtual settings for training and work tasks. RAC can be used as an employment support for adults with ID while minimizing in person contact. Limitations and implications of this study were further described at the end of the article.

Our laboratory has recently published a series of papers establishing the upper ambient temperature-humidity thresholds for maintaining heat balance, termed critical environmental limits, in young adults. However, no studies have investigated the relative influence of individual characteristics, such as sex, body size, and aerobic fitness, on those environmental limits. Here, we demonstrate the contributions of sex, body mass, body surface area, and maximal aerobic capacity on critical wet-bulb globe temperature (WBGT) limits in young adults.

BACKGROUND: Screening for islet autoantibodies in children and adolescents identifies individuals who will later develop type 1 diabetes, allowing patient and family education to prevent diabetic ketoacidosis at onset and to enable consideration of preventive therapies. We aimed to assess whether islet autoantibody screening is effective for predicting type 1 diabetes in adolescents aged 10−18 years with an increased risk of developing type 1 diabetes. METHODS: Data were harmonised from prospective studies from Finland (the Diabetes Prediction and Prevention study), Germany (the BABYDIAB study), and the USA (Diabetes Autoimmunity Study in the Young and the Diabetes Evaluation in Washington study). Autoantibodies against insulin, glutamic acid decarboxylase, and insulinoma-associated protein 2 were measured at each follow-up visit. Children who were lost to follow-up or diagnosed with type 1 diabetes before 10 years of age were excluded. Inverse probability censoring weighting was used to include data from remaining participants. Sensitivity and the positive predictive value of these autoantibodies, tested at one or two ages, to predict type 1 diabetes by the age of 18 years were the main outcomes. FINDINGS: Of 20 303 children with an increased type 1 diabetes risk, 8682 were included for the analysis with inverse probability censoring weighting. 1890 were followed up to 18 years of age or developed type 1 diabetes between the ages of 10 years and 18 years, and their median follow-up was 18·3 years (IQR 14·5–20·3). 442 (23·4%) of 1890 adolescents were positive for at least one islet autoantibody, and 262 (13·9%) developed type 1 diabetes. Time from seroconversion to diabetes diagnosis increased by 0·64 years (95% CI 0·34–0·95) for each 1-year increment of diagnosis age (Pearson’s correlation coefficient 0·88, 95% CI 0·50–0·97, p=0·0020). The median interval between the last prediagnostic sample and diagnosis was 0·3 years (IQR 0·1–1·3) in the 227 participants who were autoantibody positive and 6·8 years (1·6–9·9) for the 35 who were autoantibody negative. Single screening at the age of 10 years was 90% (95% CI 86–95) sensitive, with a positive predictive value of 66% (60–72) for clinical diabetes. Screening at two ages (10 years and 14 years) increased sensitivity to 93% (95% CI 89–97) but lowered the positive predictive value to 55% (49–60). INTERPRETATION: Screening of adolescents at risk for type 1 diabetes only once at 10 years of age for islet autoantibodies was highly effective to detect type 1 diabetes by the age of 18 years, which in turn could enable prevention of diabetic ketoacidosis and participation in secondary prevention trials. FUNDING: JDRF International.

With global warming, much attention has been paid to the upper limits of human adaptability. However, the time to reach a generally accepted core temperature criterion (40.2°C) associated with heat-related illness above (uncompensable heat stress) and just below (compensable heat stress) the upper limits for heat balance remains unclear. Forty-eight (22 men/26 women; 23 ± 4 yr) subjects were exposed to progressive heat stress in an environmental chamber during minimal activity (MinAct, 159 ± 34 W) and light ambulation (LightAmb, 260 ± 55 W) in warm-humid (WH; ∼35°C,60% RH) and hot-dry (HD; 43°C-48°C,25% RH) environments until heat stress became uncompensable. For each condition, we compared heat storage (

Objective: Essential tremor (ET) is a common neurological disorder that has been associated with 60% increased risk of developing dementia. The goals of the present study were to: (a) learn whether individuals with advanced ET symptoms seeking deep brain stimulation (DBS) surgery would fall into distinct cognitive subgroups, and (b) learn how empirically derived subgroups map onto criteria for mild cognitive impairment (MCI). Method: Patients with ET (N = 201; mean age = 68.9 ± 8.9 years) undergoing pre-surgical evaluation for DBS completed a multi-domain neurocognitive assessment consisting of memory, executive function, visuospatial skill, language, and processing speed. Two cluster analytic approaches (K-means, hierarchical) were independently conducted to classify cognitive patterns using domain composites. Demographics, clinical characteristics, and proportion of cases meeting neuropsychologically defined criteria for MCI were examined among clusters. Results: A three-cluster solution reflected a Low Executive group (N = 64), Low Memory Multi-Domain group (N = 41), and Cognitively Normal group (N = 96). The Cognitively Normal group was older and more educated, with a higher Dementia Rating Scale-2 score. In total, 27.4% of participants met criteria for MCI. Of the MCI cases, most were in the Low Executive (41.8%) or Low Memory Multi-Domain groups (49.1%). In the latter, 65.9% of its members were classified as MCI versus 35.9% in the Low Executive group. Conclusions: Our study identified three cognitive subtypes of ET patients presenting for DBS. Future work should examine the subgroups for progression to dementia, particularly the Low Memory Multi-Domain subgroup which may be at highest risk.

Friction can occur between veterinarians and their clients when they are not aligned on the goals of care for a pet and what constitutes the best outcome of a case. Veterinarians frequently concentrate on providing the diagnostic and treatment protocol that is perceived to result in the best medical outcome for their patient. Pet owners frequently consider a myriad of factors relating to the pet as well as how different diagnostic and treatment recommendations will affect individual family members and the family as a whole in both concrete and subjective terms. This misalignment can lead to veterinarians experiencing moral distress and families feeling guilt and shame about their pet’s care decisions. In this paper we examine the interdependencies of families and their pets and the factors that pet owners may consider in making care decisions. These factors, adapted from the concept of Family Quality of Life as used in the human health field, can be divided into three domains including pet-centric factors, family-centric factors, and external factors. By better understanding that there are a multitude of considerations that influence owners’ care decisions and communicating with owners in a nonjudgmental manner, veterinarians can more holistically support families, decrease their own moral distress, and arrive at diagnostic and treatment plans that represent the overall best approach for the family and the patient.

Hepatitis E virus (HEV) is an emerging viral disease known to cause acute viral hepatitis globally. Various genotypes of HEV have been identified that produce genotype specific lesions depending on the HEV targeted population. Pregnant or immunosuppressed individuals develop significantly more severe hepatitis E in comparison to the general population. In the last 40 years, we discovered that the tropism of HEV is not restricted to the liver, and virus replication was demonstrated in multiple organs. Out of the 10 body systems described in humans, HEV produces lesions causing a broad range of extrahepatic clinical manifestations in each of them. Affected body systems include nervous and musculoskeletal, cardiovascular, digestive, endocrine, integumentary, renal, respiratory, immune, and reproductive systems producing systemic lesions. All extrahepatic signs are caused by either direct HEV replication in these tissues, or indirectly by various immune mediated mechanisms. Extrahepatic replication features of HEV allowed it to cross the placental barrier, blood–brain barrier (BBB), and blood–testis barrier (BTB) that do not typically grant entry to viruses in general. Thus, in this review, we summarized the extrahepatic replication sites of HEV, listed the body systems where HEV invaded, and described multiple animal models including immunocompetent and immunosuppressed that were used to study the extrahepatic replication sites of HEV.

Vaccines against SARS-CoV-2 that induce mucosal immunity capable of preventing infection and disease remain urgently needed. In this study, we demonstrate the efficacy of Bordetella colonization factor A (BcfA), a novel bacteria-derived protein adjuvant, in SARS-CoV-2 spike-based prime-pull immunizations. We show that i.m. priming of mice with an aluminum hydroxide– and BcfA-adjuvanted spike subunit vaccine, followed by a BcfA-adjuvanted mucosal booster, generated Th17-polarized CD4+ tissue-resident memory T cells and neutralizing Abs. Immunization with this heterologous vaccine prevented weight loss following challenge with mouse-adapted SARS-CoV-2 (MA10) and reduced viral replication in the respiratory tract. Histopathology showed a strong leukocyte and polymorphonuclear cell infiltrate without epithelial damage in mice immunized with BcfA-containing vaccines. Importantly, neutralizing Abs and tissue-resident memory T cells were maintained until 3 mo postbooster. Viral load in the nose of mice challenged with the MA10 virus at this time point was significantly reduced compared with naive challenged mice and mice immunized with an aluminum hydroxide–adjuvanted vaccine. We show that vaccines adjuvanted with alum and BcfA, delivered through a heterologous prime-pull regimen, provide sustained protection against SARS-CoV-2 infection.

Trabalho é fonte de prazer e sofrimento, repercutindo na saúde mental dos trabalhadores, como residentes em saúde. Portanto, objetivou-se analisar os impactos psicossociais da pandemia da covid-19 na saúde mental de residentes em saúde atuantes em ambiente hospitalar. Nesta pesquisa, qualitativa e de campo, realizaram-se entrevistas semiestruturadas on-line e, para interpretar os dados, utilizou-se o método de análise temática. Identificaram-se quatro categorias: inter-relação entre trabalho, aspectos psicossociais e saúde mental das residentes que evidenciou condições precárias de trabalho; pandemia da covid-19 e imposição a mudanças ilustraram sobrecarga de trabalho, perda da autonomia e, por outro lado, fortalecimento das relações; sentimentos e cuidado de si que apontaram prevalência de medo e estresse; e desenvolvimento de habilidades para lidar com sofrimento psíquico, incluindo autocuidado, organização e fortalecimento da rede de apoio. Concluiu-se que o contexto pandêmico desencadeou mais efeitos adversos que promotores à saúde mental de residentes em hospitais, realçando necessidade do cuidado de forma complexa.

Meeting the needs of persons with upper limb loss in Uganda requires an understanding of the needs and desires of the local population. The limitations of resources and accessibility for the individual gave rise to a focused design methodology for delivering a culturally acceptable solution using 3D Printing technology. A series of co-design activities were held in Uganda and provided direct feedback to drive the design of two prototypes based on acceptable aesthetics and priority Activities of Daily Living. Two terminal device prototypes were 3D printed in the UK. These can be directly attached to a standard proximal socket thread. The passive hand was printed in a flexible filament and the prehensor was printed in a durable impact resistant material. Local researchers in Uganda have similar 3D printers, filaments, and assembly hardware, which allowed for concurrent development and refinement of the prototypes. Local participation provides a rich user feedback environment to understand which elements of prosthetic device design are integral to delivering acceptable prosthetics solutions for fabrication in Uganda. 3D printing can provide a viable route to addressing the needs of the user. The proposed terminal devices are now in the process of being printed locally for field testing.

Mathematics teacher educators play a key role in supporting secondary mathematics teachers’ development of effective, research-based formative assessment (FA) practices. We used qualitative research synthesis as a tool to identify actionable recommendations for mathematics teacher educators as they work with teachers on FA practices in secondary classrooms. These recommendations can strengthen the research-based practices of mathematics teacher educators as they support teachers’ collections and uses of FA data to move student thinking forward in secondary mathematics. We share and discuss recommendations for mathematics teacher educators to connect pedagogical content knowledge of students, teaching, and curriculum to FA practices. We also highlight the usefulness of the qualitative synthesis method, meta-aggregation, for generating research-based connections between theory and practice in mathematics education.

Bacteria protect themselves from the toxicity of antimicrobial metabolites they produce through several strategies. In one resistance mechanism, bacteria assemble a non-toxic precursor on a N-acyl-d-asparagine prodrug motif in the cytoplasm, then export it to the periplasm where a dedicated d-amino peptidase hydrolyzes the prodrug motif. These prodrug-activating peptidases contain an N-terminal periplasmic S12 hydrolase domain and C-terminal transmembrane domains (TMDs) of varying lengths: type I peptidases contain three transmembrane helices, and type II peptidases have an additional C-terminal ABC half-transporter. We review studies which have addressed the role of the TMD in function, the substrate specificity, and the biological assembly of ClbP, the type I peptidase that activates colibactin. We use modeling and sequence analyses to extend those insights to other prodrug-activating peptidases and ClbP-like proteins which are not part of prodrug resistance gene clusters. These ClbP-like proteins may play roles in the biosynthesis or degradation of other natural products, including antibiotics, may adopt different TMD folds, and have different substrate specificity compared to prodrug-activating homologs. Finally, we review the data supporting the long-standing hypothesis that ClbP interacts with transporters in the cell and that this association is important for the export of other natural products. Future investigations of this hypothesis as well as of the structure and function of type II peptidases will provide a complete account of the role of prodrug-activating peptidases in the activation and secretion of bacterial toxins.

Positive-strand RNA viruses have been the cause of several recent outbreaks and epidemics, including the Zika virus epidemic in 2015, the SARS outbreak in 2003, and the ongoing SARS-CoV-2 pandemic. On June 18-22, 2022, researchers focusing on positive-strand RNA viruses met for the Keystone Symposium "Positive-Strand RNA Viruses" to share the latest research in molecular and cell biology, virology, immunology, vaccinology, and antiviral drug development. This report presents concise summaries of the scientific discussions at the symposium.

Managing Construction and demolition waste (CDW) is a severe and growing urban challenge, particularly in post-conflict countries. Though Kosovo has significantly rebuilt and developed after the Liberation War, these initiatives have accompanied suboptimal waste management. This research evaluates CDW management in Kosovo by assessing current practices and operations vis-a-vis the legal framework and EU requirements. It identifies instruments and policies capable of ameliorating gaps and proposes a more sustainable and circular CDW management system for Kosovo. Information was primarily collected during on-site visits to Pristina and the surroundings by a cohort of Urban Management Students from the Technische Universität Berlin, students from Kosovo, and the local office of the Gesellschaft für Internationale Zusammenarbeit, GIZ. The analysis identified gaps in Kosovo's CDW management and its observance and enforcement of existing CDW legislation, including an ambiguous licensing system impeding sustainable demolition, storage, and transport; the absence of approved CDW storage options leading to uncontrolled disposal; and an underdeveloped market for recycling and reuse, deterring stakeholders from further pursuit of circular practices. These gaps were compounded by poor recordkeeping, obscuring precise information on CDW streams. Possible instruments and incentives to support Kosovo's transition to a more sustainable CDW management system were then identified.

ObjectivesThis qualitative study examined how families share information and feelings about advanced pediatric cancer from the perspective of both parents and children, as well as how these perspectives vary by child developmental stage.MethodsParticipants (24 mothers, 20 fathers, 23 youth [children and adolescents]) were from a larger longitudinal study at an academic pediatric hospital. Eligible youth had advanced cancer (physician-estimated prognosis of 8 years old to participate independently), had an English-speaking parent, and lived within 140 miles of the hospital. Interviews were completed at enrollment and asked how families share information and emotions about the child’s cancer as a family.ResultsSaturation was reached at 20 interviews for mothers, fathers, and youth. Analyses revealed 4 major themes: (A) parents managing cancer-related information based on child age/developmental stage and processing styles of family members; (B) parents withholding poor prognosis information and emotions to maintain positivity; (C) lack of personal and familial emotion sharing; and (D) emotion sharing among their family and externally. Both parents and youth endorsed themes A, C, and D, but only parents endorsed theme B. Adolescents endorsed more themes than children. Parents of children (as opposed to adolescents) endorsed theme A more.Significance of resultsAlthough both parents and youth with advanced cancer were generally willing to talk about treatment, emotions were not consistently shared. Perspectives varied depending on the child’s developmental stage. Clinicians should assess parent and child information and emotion-sharing needs and provide individualized support to families regarding communication about advanced cancer.

Gabapentin (GBP) is a structural analog of gamma-aminobutyric acid (GABA) that is commonly used in palliative care for symptom management indications including neuropathic pain syndromes, hiccups, cough, and anxiety. An uncommon adverse effect of GBP is urinary incontinence (UI). We report the case of a 61-year-old male with metastatic non-small cell lung cancer who developed probable overflow UI while receiving 1200 mg/day of GBP for chemotherapy-induced peripheral neuropathy. The patient self-tapered GBP to 600 mg/day which resolved the overflow UI, but resulted in poorly controlled bilateral foot pain. The palliative care physician rotated the patient to pregabalin 150 mg/day and his bilateral foot pain improved after his regimen was titrated to 200 mg/day. The patient did not experience overflow UI while taking pregabalin despite the similar pharmacology and comparable doses to GBP. We believe this is the first case report to describe subsequent achievement of pain control by substituting pregabalin without recurrence of UI. Healthcare professionals should consider GBP as a potential cause when evaluating patients presenting with new onset overflow UI.

Mutations in the DYNC1H1 gene have been linked to multiple neurologic syndromes with a multitude of clinical manifestations, both ocular and non-ocular. Previous case reports have outlined various ocular phenotypes, including cataracts of congenital onset, infantile onset, and adult onset with lack of further ophthalmologic detail. Our case report outlines, in more detail, a 24-month-old male with a heterozygous mutation in the DYNC1H1 gene who developed a white, intumescent cataract in his left eye and a posterior subcapsular cataract in his right eye with evidence of progressive axial myopia. Based on the findings outlined in our case we suggest eye exams at regular intervals during early childhood in patients with DYNC1H1 mutations to screen for amblyogenic ocular pathology and potential rapidly developing cataracts.

Idosos possuem seus direitos garantidos em Constituição, principalmente no que se refere ao cuidado integral para que possam vivenciar um envelhecimento ativo e saudável. Portanto, objetivou-se discutir sobre as atividades de promoção de saúde realizadas junto a idosos por meio da facilitação de oficinas terapêuticas expressivas por estudantes do curso de Psicologia de uma universidade pública do norte do Paraná, pautando-se nos pressupostos de grupo operativo. Trata-se de um relato de experiência extensionista em um serviço de convivência e fortalecimento de vínculos. Participaram das oficinas de três a onze idosos por encontro, tendo ocorrido um total de doze encontros com rodas de conversas mediadas pela utilização de imagens - majoritariamente -, sons e movimentos. Foram trabalhados temas como história de vida, autoimagem, mudanças, adoecimento, autoconhecimento, autocuidado e redes de apoio. Para registrar os dados da intervenção foi utilizado o diário de campo como instrumento. Os resultados foram sistematizados e analisados a fim de discutir as aproximações entre lógica assistencial, ações em saúde e práticas psicológicas com viés terapêutico, apontando à importância da inserção de uma ação alinhada com a demanda e a comunicação de qualidade com o serviço. Essa construção coletiva buscou o envolvimento ativo dos participantes a partir de propostas que incentivaram a autonomia do indivíduo, a cooperação, a reflexão e o pensar criativo. Ademais, diante da alta demanda por um espaço de fala, percebeu-se que, apesar dos obstáculos ao desenvolvimento do grupo, a convivência grupal possibilitou vinculação, empatia e acolhimento entre os participantes, contando com a colaboração dos recursos na expressão de sentimentos, desejos e pensamentos. A partir disso, abordou-se a experiência do envelhecer, o que possibilitou reverberações afetivas, fortalecimento de vínculos interpessoais e aprendizagem. Assim, as oficinas terapêuticas funcionaram como estratégias promotoras de saúde em um espaço socioassistencial que preconiza o cuidado integralizado à terceira idade.

ObjectiveExamine the relationship between the National Institutes of Health Toolbox Emotion Battery (Emotion Toolbox) and traditional measures in Parkinson’s disease (PD).MethodPersons with PD (n = 30) and cognitively healthy older adults (OA; n = 40) completed the Emotion Toolbox consisting of Well-Being, Negative Affect, and Social Satisfaction scores along with traditional measures of depression (Beck Depression Inventory-II [BDI-II]), anxiety (State–Trait Anxiety Inventory [STAI]), and apathy (Apathy Scale [AS]); total raw scores).ResultsSeparate bootstrapped analyses of covariance indicated that the PD group scored higher on BDI-II and STAI-State compared to OA (ps ConclusionsThe Emotion Toolbox showed moderate-strong correlations with traditional measures in persons with PD. Even so, it did not capture the group differences between PD and OA and had a somewhat lower classification accuracy rate for persons with PD who had a formal psychiatric diagnosis than traditional measures. Together, findings question the utility of the Emotion Toolbox as a stand-alone emotion screener in PD.

Pitt Hopkins Syndrome (PTHS) is a rare syndromic form of autism spectrum disorder (ASD) caused by autosomal dominant mutations in the Transcription Factor 4 (TCF4) gene. TCF4 is a basic helix-loop-helix transcription factor that is critical for neurodevelopment and brain function through its binding to cis-regulatory elements of target genes. One potential therapeutic strategy for PTHS is to identify dysregulated target genes and normalize their dysfunction. Here, we propose that SCN10A is an important target gene of TCF4 that is an applicable therapeutic approach for PTHS. Scn10a encodes the voltage-gated sodium channel Nav1.8 and is consistently shown to be upregulated in PTHS mouse models. In this perspective, we review prior literature and present novel data that suggests inhibiting Nav1.8 in PTHS mouse models is effective at normalizing neuron function, brain circuit activity and behavioral abnormalities and posit this therapeutic approach as a treatment for PTHS.

Aims/hypothesis The aim of this study was to explore the utility of islet autoantibody (IAb) levels for the prediction of type 1 diabetes in autoantibody-positive children. Methods Prospective cohort studies in Finland, Germany, Sweden and the USA followed 24,662 children at increased genetic or familial risk of developing islet autoimmunity and diabetes. For the 1403 who developed IAbs (523 of whom developed diabetes), levels of autoantibodies against insulin (IAA), glutamic acid decarboxylase (GADA) and insulinoma-associated antigen-2 (IA-2A) were harmonised for analysis. Diabetes prediction models using multivariate logistic regression with inverse probability censored weighting (IPCW) were trained using 10-fold cross-validation. Discriminative power for disease was estimated using the IPCW concordance index (C index) with 95% CI estimated via bootstrap. Results A baseline model with covariates for data source, sex, diabetes family history, HLA risk group and age at seroconversion with a 10-year follow-up period yielded a C index of 0.61 (95% CI 0.58, 0.63). The performance improved after adding the IAb positivity status for IAA, GADA and IA-2A at seroconversion: C index 0.72 (95% CI 0.71, 0.74). Using the IAb levels instead of positivity indicators resulted in even better performance: C index 0.76 (95% CI 0.74, 0.77). The predictive power was maintained when using the IAb levels alone: C index 0.76 (95% CI 0.75, 0.76). The prediction was better for shorter follow-up periods, with a C index of 0.82 (95% CI 0.81, 0.83) at 2 years, and remained reasonable for longer follow-up periods, with a C index of 0.76 (95% CI 0.75, 0.76) at 11 years. Inclusion of the results of a third IAb test added to the predictive power, and a suitable interval between seroconversion and the third test was approximately 1.5 years, with a C index of 0.78 (95% CI 0.77, 0.78) at 10 years follow-up. Conclusions/interpretation Consideration of quantitative patterns of IAb levels improved the predictive power for type 1 diabetes in IAb-positive children beyond qualitative IAb positivity status. Graphical abstract

This study uses personalized chronic lymphoblastic leukemia (CLL) cybrid cells to test various drugs/agents designed to improve mitochondrial function and cell longevity. Age-matched control (NL) and CLL cybrids were created. The NL and CLL cybrids were treated with ibrutinib (Ibr-10 μM), mitochondrial-targeted nutraceuticals such as alpha lipoic acid (ALA-1 mM), amla (Aml-300 μg), melatonin (Mel-1 mM), resveratrol (Res-100 μM) alone, or a combination of ibrutinib with nutraceuticals (Ibr + ALA, Ibr + Aml, Ibr + Mel, or Ibr + Res) for 48 h. MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide), H2DCFDA(2′,7′ Dichlorodihydrofluorescein diacetate), and JC1 assays were used to measure the cellular metabolism, intracellular ROS levels, and mitochondrial membrane potential (∆ψm), respectively. The expression levels of genes associated with antioxidant enzymes (SOD2, GPX3, and NOX4), apoptosis (BAX and CASP3), and inflammation (IL6, IL-1β, TNFα, and TGFβ) were measured using quantitative real-time PCR (qRT-PCR). CLL cybrids treated with Ibr + ALA, Ibr + Aml, Ibr + Mel, and Ibr + Res had (a) reduced cell survivability, (b) increased ROS production, (c) increased ∆ψm levels, (d) decreased antioxidant gene expression levels, and (e) increased apoptotic and inflammatory genes in CLL cybrids when compared with ibrutinib-alone-treated CLL cybrids. Our findings show that the addition of nutraceuticals makes the CLL cybrids more pro-apoptotic with decreased cell survival compared with CLL cybrids exposed to ibrutinib alone.

BackgroundThe novel optic neuritis (ON) diagnostic criteria include intereye differences (IED) of optical coherence tomography (OCT) parameters. IED has proven valuable for ON diagnosis in multiple sclerosis but has not been evaluated in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4+NMOSD). We evaluated the diagnostic accuracy of intereye absolute (IEAD) and percentage difference (IEPD) in AQP4+NMOSD after unilateral ON >6 months before OCT as compared with healthy controls (HC).MethodsTwenty-eight AQP4+NMOSD after unilateral ON (NMOSD-ON), 62 HC and 45 AQP4+NMOSD without ON history (NMOSD-NON) were recruited by 13 centres as part of the international Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica study. Mean thickness of peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) were quantified by Spectralis spectral domain OCT. Threshold values of the ON diagnostic criteria (pRNFL: IEAD 5 µm, IEPD 5%; GCIPL: IEAD: 4 µm, IEPD: 4%) were evaluated using receiver operating characteristics and area under the curve (AUC) metrics.ResultsThe discriminative power was high for NMOSD-ON versus HC for IEAD (pRNFL: AUC 0.95, specificity 82%, sensitivity 86%; GCIPL: AUC 0.93, specificity 98%, sensitivity 75%) and IEPD (pRNFL: AUC 0.96, specificity 87%, sensitivity 89%; GCIPL: AUC 0.94, specificity 96%, sensitivity 82%). The discriminative power was high/moderate for NMOSD-ON versus NMOSD-NON for IEAD (pRNFL: AUC 0.92, specificity 77%, sensitivity 86%; GCIP: AUC 0.87, specificity 85%, sensitivity 75%) and for IEPD (pRNFL: AUC 0.94, specificity 82%, sensitivity 89%; GCIP: AUC 0.88, specificity 82%, sensitivity 82%).ConclusionsResults support the validation of the IED metrics as OCT parameters of the novel diagnostic ON criteria in AQP4+NMOSD.

We present the results from the HST WFC3 and ACS data on an archetypal galaxy undergoing ram pressure stripping (RPS), ESO 137-001, in the nearby cluster Abell 3627. ESO 137-001 is known to host a prominent stripped tail detected in many bands from X-rays, Halpha to CO. The HST data reveal significant features indicative of RPS such as asymmetric dust distribution and surface brightness as well as many blue young star complexes in the tail. We study the correlation between the blue young star complexes from HST, HII regions from Halpha (MUSE) and dense molecular clouds from CO (ALMA). The correlation between the HST blue star clusters and the HII regions is very good, while their correlation with the dense CO clumps are typically not good, presumably due in part to evolutionary effects. In comparison to the Starburst99+Cloudy model, many blue regions are found to be young (< 10 Myr) and the total star formation (SF) rate in the tail is 0.3 - 0.6 M_Sun/yr for sources measured with ages less than 100 Myr, about 40% of the SF rate in the galaxy. We trace SF over at least 100 Myr and give a full picture of the recent SF history in the tail. We also demonstrate the importance of including nebular emissions and a nebular to stellar extinction correction factor when comparing the model to the broadband data. Our work on ESO 137-001 demonstrates the importance of HST data for constraining the SF history in stripped tails., 22 pages, 20 figures, 4 tables, published in MNRAS 06/2023

Purpose This review aimed to identify effective physical performance tests (PPT) as clinical outcome indicators for detecting and monitoring degenerative cervical myelopathy (DCM). Methods A comprehensive literature search was performed on seven electronic databases on the effectiveness in detection and monitoring of DCM by PPT. All included studies were reviewed and undergone quality assessments on the risk-of-bias by Newcastle-Ottawa Scale and were pooled by random-effect analysis with level of significance at 0.05. Homogeneity among studies was assessed by I2-statistics and effect of PPT was confirmed by Cohen’s d effect size and confidence intervals. Results Totally, 3111 articles were retrieved, and 19 studies were included for review and meta-analysis. There were 13 studies investigating PPT regarding the upper limbs and 12 studies regarding the lower limbs. Performance in 10-second-Grip-and-Release Test (G&R) and 9-Hole-Peg Test (9HPT) was studied in 10 and 3 articles, respectively, while 10-second-Stepping Test (SST), 30-meter-Walking Test (30MWT) and Foot-Tapping Test (FTT) for lower limbs were studied in 5, 4, and 3 articles correspondingly. Only 1 study utilized the Triangle-Stepping Test. High-quality study with fair risk-of-bias was revealed from Newcastle-Ottawa scale. Large effect size facilitated detection and monitoring in DCM was unveiling for G&R, 9HPT, SST, and 30MWT. FTT, while also effective, was hindered by a high-degree heterogeneity in the meta-analysis. Conclusion Effective PPT including G&R, 9HPT, SST, 30MWT, and FTT was identified for disease detection and monitoring in DCM.