The effects of endurance trainability phenotype, sex, and interval running training on bone collagen synthesis in adult rats.

Bone is influenced by many factors such as genetics and mechanical loading, but the short-term physiological effects of these factors on bone (re)modelling are not well characterised. This study investigated the effects of endurance trainability phenotype, sex, and interval running training (7-week intervention) on bone collagen formation in rats using a deuterium oxide stable isotope tracer method. Bone samples of the femur diaphysis, proximal tibia, mid-shaft tibia, and distal tibia were collected after necropsy from forty-six 9 ±â€¯3-month male and female rats selectively bred for yielding low (LRT) or high (HRT) responses to endurance training. Bone collagen proteins were isolated and hydrolysed, and fractional synthetic rates (FSRs) were determined by the incorporation of deuterium into protein-bound alanine via GC-pyrolysis-IRMS. There was a significant large main effect of phenotype at the femur site (p < 0.001; η2g = 0.473) with HRT rats showing greater bone collagen FSRs than LRT rats. There was a significant large main effect of phenotype (p = 0.008; η2g = 0.178) and a significant large main effect of sex (p = 0.005; η2g = 0.196) at the proximal site of the tibia with HRT rats showing greater bone collagen FSRs than LRT rats, and male rats showing greater bone collagen FSRs compared to female rats. There was a significant large main effect of training at the mid-shaft site of the tibia (p = 0.012; η2g = 0.159), with rats that underwent interval running training having greater bone collagen FSRs than control rats. Similarly, there was a significant large main effect of training at the distal site of the tibia (p = 0.050; η2g = 0.156), with rats in the interval running training group having greater bone collagen FSRs compared to rats in the control group. Collectively, this evidence highlights that bone responses to physiological effects are site-specific, indicating that interval running training has positive effects on bone collagen synthesis at the tibial mid-shaft and distal sites, whilst genetic factors affect bone collagen synthesis at the femur diaphysis (phenotype) and proximal tibia (phenotype and sex) in rats.

Is there a role for [18F]-FMISO PET to guide dose adaptive radiotherapy in head and neck cancer? A review of the literature.

Purpose: Hypoxia is a major cause of radioresistance in head and neck cancer (HNC), resulting in treatment failure and disease recurrence. 18F-fluoromisonidazole [18F]FMISO PET has been proposed as a means of localising intratumoural hypoxia in HNC so that radiotherapy can be specifically escalated in hypoxic regions. This concept may not be deliverable in routine clinical practice, however, given that [18F]FMISO PET is costly, time consuming and difficult to access. The aim of this review was to summarise clinical studies involving [18F]FMISO PET to ascertain whether it can be used to guide radiotherapy treatment in HNC. Methods: A comprehensive literature search was conducted on PubMed and Web of Science databases. Studies investigating [18F]FMISO PET in newly diagnosed HNC patients were considered eligible for review. Results: We found the following important results from our literature review: 1)Studies have focussed on comparing [18F]FMISO PET to other hypoxia biomarkers, but currently there is no evidence of a strong correlation between [18F]FMISO and these biomarkers.2)The results of [18F]FMISO PET imaging are not necessarily repeatable, and the location of uptake may vary during treatment.3)Tumour recurrences do not always occur within the pretreatment hypoxic volume on [18F]FMISO PET.4)Dose modification studies using [18F]FMISO PET are in a pilot phase and so far, none have demonstrated the efficacy of radiotherapy dose painting according to [18F]FMISO uptake on PET. Conclusions: Our results suggest it is unlikely [18F]FMISO PET will be suitable for radiotherapy dose adaptation in HNC in a routine clinical setting. Part of the problem is that hypoxia is a dynamic phenomenon, and thus difficult to delineate on a single scan. Currently, it is anticipated that [18F]FMISO PET will remain useful within the research setting only.

The dexamethasone suppression test as a biomarker for suicidal behavior: A systematic review and meta-analysis.

BACKGROUND: The dexamethasone suppression test (DST), which measures HPA-axis functioning, is a potential biomarker for suicidal behavior. The current study aimed (a) to synthesize available knowledge on the association between DST non-suppression and suicidal behavior, and (b) to study potential moderators. METHODS: A total of 4236 studies were screened, 43 were included. Suicide attempts and suicide completion were studied separately. The meta-analysis included 37 effect sizes for suicide attempts (n = 3733) and 11 effect sizes for suicide completion (n = 1626). RESULTS: DST non-suppression was associated with completed suicide (odds ratio (OR) = 2.10, (95 % CI [1.37, 3.23]). For suicide attempts, we found no evidence that DST status was associated in the overall meta-analysis including all patient samples. However, moderator analysis indicated that the DST status was associated with suicide attempts in patient samples that included psychopathology other than just mood disorders, such as psychotic, substance use and personality disorders (OR = 2.34, 95 % CI [1.39-3.93], k = 11). LIMITATIONS: The potential influence of publication bias and exclusion of some relevant published studies (since effect sizes could not be calculated, authors could not supply data or authors could not be reached) are limitations. Furthermore, missing moderator data decreased our ability to explain heterogeneity between studies. CONCLUSIONS: The results of this meta-analysis support the hypothesis that DST non-suppression is predictive of suicidal behavior. More research is needed to investigate optimal cut-off values, confounding factors and the potential usefulness of the DST in clinical practice in terms of personalized medicine.

People who die by suicide without having attended hospital-based psychiatric care: Who are the ones that do not seek help?

BACKGROUND: Little is known regarding those who die by suicide without having received help. The aim of this study was to compare those who died by suicide without having attended psychiatric care with controls (a) with a psychiatric diagnosis and (b) from the general population. METHODS: Cases were all individuals 15+ who lived in Denmark during 2010-2021 and had died by suicide without having attended hospital-based psychiatric care. Cases were matched to controls from the two comparison-groups using a 1:10 ratio and compared using age-and sex-adjusted logistic regression analyses. Geographical variations in psychiatric care utilization were examined. RESULTS: Among 7119 individuals who died by suicide, 3474 (48.8 %) had not attended psychiatric care. Compared to controls with a psychiatric diagnosis, cases were more likely to be male (OR, 3.9, 95 % CI, 3.6-4.2), older (80+ years: OR, 10.7, 95 % CI, 9.2-12.5), have lost a close relative (OR, 1.8, 95 % CI, 1.3-2.6) or recently retired (OR, 1.4, 95 % CI, 1.0-1.1.8). Compared to controls from the general population, cases were associated with male sex (OR, 4.6, 95 % CI, 4.2-5.0), living alone (OR, 2.3, 95 % CI, 2.2-2.5), unemployment (OR, 2.1, 95 % CI, 1.8-2.5), and having lost a close relative (OR, 5.0, 95 % CI, 3.5-7.2) or divorced (OR, 3.6, 95 % CI, 2.7-4.9). LIMITATIONS: Characteristics and preceding events were limited to available register data. CONCLUSIONS: About half of all who died by suicide had not attended psychiatric care. Being older, male, or exposed to recent stressors were some of the major markers when compared to controls.

Dynamics of magnetization growth and relaxation in ferrofluids.

The dynamics of the growth and relaxation of the magnetization in ferrofluids are determined using theory based on the Fokker-Planck-Brown equation, and Brownian-dynamics simulations. Magnetization growth starting from an equilibrium nonmagnetized state in zero field, and following an instantaneous application of a uniform field of arbitrary strength, is studied with and without interparticle interactions. Similarly, magnetization relaxation is studied starting from an equilibrium magnetized state in a field of arbitrary strength, and following instantaneous removal of the field. In all cases, the dynamics are studied in terms of the time-dependent magnetization m(t). The field strength is described by the Langevin parameter α, the strength of the interparticle interactions is described by the Langevin susceptibility χ_{L}, and the individual particles undergo Brownian rotation with time τ_{B}. For noninteracting particles, the average growth time decreases with increasing α due to the torque exerted by the field, while the average relaxation time stays constant at τ_{B}; with vanishingly weak fields, the timescales coincide. The same basic picture emerges for interacting particles, but the weak-field timescales are larger due to collective particle motions, and the average relaxation time exhibits a weak, nonmonotonic field dependence. A comparison between theoretical and simulation results is excellent for noninteracting particles. For interacting particles with χ_{L}=1 and 2, theory and simulations are in qualitative agreement, but there are quantitative deviations, particularly in the weak-field regime, for reasons that are connected with the description of interactions using effective fields.

Initiation of noninvasive ventilation in patients with amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Noninvasive ventilation (NIV) has been shown to improve survival and symptom burden in patients with amyotrophic lateral sclerosis (ALS). However, limited data exist regarding the clinical and physiological parameters at the time of NIV initiation. This study aimed to describe the clinical characteristics and respiratory physiological markers in a cohort of ALS patients with chronic respiratory failure. METHODS: This is a single-center retrospective cohort study of patients with ALS assessed for NIV initiation between February 2012 and January 2021. NIV was initiated based on insurance eligibility criteria: daytime hypercapnia, defined by partial pressure of carbon dioxide (PaCO2) >45 mm Hg using diurnal transcutaneous CO2 (TcCO2) as a surrogate, a maximal inspiratory pressure (MIP) <60 cmH2O or forced vital capacity (FVC) <50% predicted normal. RESULTS: We identified 335 patients with ALS and chronic respiratory failure referred to an outpatient home ventilation clinic for NIV initiation. The mean age was 64 years ±11; 151 (45%) were female, 326 (97%) were white, and 100 (29%) had bulbar-onset ALS. At the time of NIV initiation, the mean FVC was 64% ± 19%, the mean MIP; 41 cmH2O ± 17, and diurnal TcCO2; 40 ± 6 mmHg. The most common reasons for NIV initiation were MIP <60 cmH2O (58%) and multiple concomitant indications (28%). Within 1 year of NIV initiation, 126 (37%) patients were deceased. DISCUSSION: We found that impairment in inspiratory force was the most common reason for NIV initiation and often preceded significant declines in FVC.

Planetary health learning objectives: foundational knowledge for global health education in an era of climate change.

Planetary health is an emerging field that emphasises that humans depend on a healthy Earth for survival and, conversely, that the sustainability of Earth systems is dependent on human behaviours. In response to member demands for resources to support teaching and learning related to planetary health, the Consortium of Universities for Global Health (CUGH) convened a working group to develop a set of planetary health learning objectives (PHLOs) that would complement the existing ten CUGH global health learning objectives. The eight PHLOs feature Earth system changes, planetary boundaries, and climate change science; ecological systems and One Health; human health outcomes; risk assessment, vulnerability, and resilience; policy, governance, and laws (including the UN Framework Convention on Climate Change and the Paris Agreement); roles and responsibilities of governments, businesses, civil society organisations, other institutions, communities, and individuals for mitigation, adaptation, conservation, restoration, and sustainability; environmental ethics, human rights, and climate justice; and environmental literacy and communication. Educators who use the PHLOs as a foundation for teaching, curriculum design, and programme development related to the health-environment nexus will equip learners with a knowledge of planetary health science, interventions, and communication that is essential for future global health professionals.

Caveolin-1 knockout mitigates breast cancer metastasis to the lungs via integrin α3 dysregulation in 4T1-induced syngeneic breast cancer model.

Caveolin-1 (Cav-1) is a critical lipid raft protein playing dual roles as both a tumor suppressor and promoter. While its role in tumorigenesis, progression, and metastasis has been recognized, the explicit contribution of Cav-1 to the onset of lung metastasis from primary breast malignancies remains unclear. Here, we present the first evidence that Cav-1 knockout in mammary epithelial cells significantly reduces lung metastasis in syngeneic breast cancer mouse models. In vitro, Cav-1 knockout in 4T1 cells suppressed extracellular vesicle secretion, cellular motility, and MMP secretion compared to controls. Complementing this, in vivo analyses demonstrated a marked reduction in lung metastatic foci in mice injected with Cav-1 knockout 4T1 cells as compared to wild-type cells, which was further corroborated by mRNA profiling of the primary tumor. We identified 21 epithelial cell migration genes exhibiting varied expression in tumors derived from Cav-1 knockout and wild-type 4T1 cells. Correlation analysis and immunoblotting further revealed that Cav-1 might regulate metastasis via integrin α3 (ITGα3). In silico protein docking predicted an interaction between Cav-1 and ITGα3, which was confirmed by co-immunoprecipitation. Furthermore, Cav-1 and ITGα3 knockdown corroborated its role in metastasis in the cell migration assay.

Exploring student preferences for implementing a digital mental health intervention in a university setting: Qualitative study within a randomised controlled trial.

Objective: Digital interventions can be effective in preventing and treating common mental health conditions among university students. Incorporating student experiences and perspectives in the design and implementation of these programmes may improve uptake and engagement. This qualitative study explored university students' perspectives of a low-intensity video-based mental health intervention, their recommendations for implementing the programme in university settings, and their views and recommendations to address barriers to engagement. Methods: Participants (N = 115) were students (mean = 20.63 years, SD = 2.10) with elevated distress from 31 Australian universities drawn from a randomised controlled trial of the Uni Virtual Clinic-Lite (UVC-Lite). Data from students randomised to the intervention condition were collected via semi-structured interviews (n = 12) and open-ended questions during post-intervention surveys (n = 103). Data were analysed using content analysis. Results: Participants generally reported positive views of the intervention, and most felt it should be offered to students as a universal intervention. Multiple methods of disseminating the intervention were suggested, including through university counselling, official platforms (e.g. student support services) and informal channels (e.g. word-of-mouth promotion). Difficulty integrating the programme into everyday life, pre-existing beliefs about mental health and technology-related factors were highlighted as barriers to engagement. Conclusion: A low-intensity video-based mental health intervention was generally considered to be acceptable and appropriate for students with mild to moderate distress. Participants provided several suggestions to encourage uptake of the intervention and possible pathways to disseminate the intervention to students. The effectiveness of these should be examined in future trials.

The psychosocial impacts of the 15 March terrorist attack on the Christchurch Muslim community: A descriptive, cross-sectional assessment.

OBJECTIVE: On 15 March 2019, a white supremacist terrorist carried out sequential attacks on two mosques in Christchurch, New Zealand during Friday prayers. This resulted in the loss of 51 lives, 40 others sustained gunshot injuries, and there were approximately 250 survivors. This study aimed to evaluate the impacts on community members, assess clinical needs, facilitate access to appropriate interventions and provide insights into working with a traumatised and diverse population. METHODS: This cross-sectional study used semi-structured clinical interviews and self-report measures to assess social and demographic factors, mental health disorders and well-being for adult Muslims 11-32 months post-attack. RESULTS: A total of 189 participants completed assessments. The sample was diverse, representing 34 different ethnicities and participant proximity to the attack was complex, with personal and familial exposures. Elevated levels of psychological distress and psychopathology were found with 38% of participants reporting moderate/severe psychological distress on the Kessler-10, 39% reporting post-traumatic stress disorder on the post-traumatic stress disorder checklist-5, and 40% reporting poor well-being or possible depression on the World Health Organization-5 Well Being Index. Secondary stressors were also documented, as well as high scores for post-traumatic growth and the importance of faith. CONCLUSION: This study provides valuable insights into the repercussions of the Christchurch mosque attack on the affected community, describing the complexity of exposure and the substantial burden of morbidity experienced. It also highlights the high levels of social connectedness and the role of faith in promoting positive outcomes in the recovery process for this population.

Arachnoid Cysts in Athletes with Sports-Related Concussion: A Case Series and Literature Review.

BACKGROUND: Arachnoid cysts (AC) are associated with a risk of rupture or haemorrhage following head impact and pose a potential predisposing factor for significant complications of sport-related concussion. Despite a recognised association between ACs and intracranial haemorrhage/cyst rupture, the risk profile of participating in contact sports with AC is not well defined. We report a retrospective case series of players presenting to the Birmingham Sports Concussion Clinic between 2017 and 2023 and underwent MRI head, with a comprehensive review of the prior literature. RESULTS: 432 athletes underwent MRI of which 11 were identified to have AC (middle fossa n = 8; posterior fossa n = 2, intraventricular n = 1). Average maximal diameter was 4.1 ± 1.2 cm. 64% had a protracted recovery (≥ 3 months). 9% experienced an AC specific complication (cyst rupture, complete neurological recovery, maximal diameter 6.5 cm, Galassi II, 4 previous concussions). 91% of patients (mean maximal diameter 3.9 ± 1.0 cm) experienced no complications despite multiple previous accumulated sports-related concussions (mean 3.3, range 1-9). Case studies from the literature are summarised (n = 63), with 98% reporting complications, none of which resulted in adverse or unfavourable neurological outcomes. Across prospective and retrospective cohort studies, 1.5% had a structural injury, and (where outcome was reported) all had a favourable outcome. CONCLUSIONS: AC is an incidental finding in athletes, with the majority in our cohort having sustained serial concussions without AC complication. The single complication within this cohort occurred in the largest AC, and AC size is proposed as a tentative factor associated with increased risk of contact sports participation. Complications of AC appear to be a rare occurrence. This case series and review has not identified evidence to suggest that participation in sports with AC is of significant risk, though individualised assessment and discussion of the potential risks of contact sports participation should be offered.

Micro-nanoplastics and cardiovascular diseases: evidence and perspectives.

Emerging evidence indicates that chemical exposures in the environment are overlooked drivers of cardiovascular diseases (CVD). Recent evidence suggests that micro- and nanoplastic (MNP) particles derived largely from the chemical or mechanical degradation of plastics might represent a novel CVD risk factor. Experimental data in preclinical models suggest that MNPs can foster oxidative stress, platelet aggregation, cell senescence, and inflammatory responses in endothelial and immune cells while promoting a range of cardiovascular and metabolic alterations that can lead to disease and premature death. In humans, MNPs derived from various plastics, including polyethylene and polyvinylchloride, have been detected in atherosclerotic plaques and other cardiovascular tissues, including pericardia, epicardial adipose tissues, pericardial adipose tissues, myocardia, and left atrial appendages. MNPs have measurable levels within thrombi and seem to accumulate preferentially within areas of vascular lesions. Their presence within carotid plaques is associated with subsequent increased incidence of cardiovascular events. To further investigate the possible causal role of MNPs in CVD, future studies should focus on large, prospective cohorts assessing the exposure of individuals to plastic-related pollution, the possible routes of absorption, the existence of a putative safety limit, the correspondence between exposure and accumulation in tissues, the timing between accumulation and CVD development, and the pathophysiological mechanisms instigated by pertinent concentrations of MNPs. Data from such studies would allow the design of preventive, or even therapeutic, strategies. Meanwhile, existing evidence suggests that reducing plastic production and use will produce benefits for the environment and for human health. This goal could be achieved through the UN Global Plastics Treaty that is currently in negotiation.

Disseminated pleomorphic rhabdomyosarcoma in a horse.

An 8-y-old National Show Horse mare was presented for evaluation of pneumonia and laminitis. Harsh bronchovesicular sounds were auscultated throughout both lung fields, and the mare had signs of moderately painful laminitis. Thoracic ultrasonography revealed lung consolidation throughout the dorsal aspect of both lungs, and radiography revealed an extensive diffuse-to-patchy bronchointerstitial lung pattern. The mare's clinical condition rapidly deteriorated, and euthanasia was elected. On postmortem examination, the lungs, omentum, spleen, liver, adrenal glands, kidneys, and femur contained 0.5-2.5-cm, firm, tan nodules. Histologically, the lungs, spleen, liver, kidneys, adrenal glands, omentum, left eye, and femur were infiltrated by bundles and nests of pleomorphic polygonal-to-spindloid cells intermixed with frequent multinucleate cells. Lymphatic vessels in the affected tissues were frequently distended with tumor emboli. Neoplastic cells were diffusely positive for vimentin, desmin, sarcomeric actin, myoblastic differentiation protein 1, and myogenin, supportive of the diagnosis of rhabdomyosarcoma (RMS), which is a rare neoplasm in horses. Cross-striations were not evident with H&E or phosphotungstic acid-hematoxylin stains. Markedly pleomorphic neoplastic cells, multinucleate cells, and lack of cross-striations suggested the subclassification of pleomorphic RMS.

Assessing muscle protein synthesis rates in vivo in humans: the deuterated water (2H2O) method.

Skeletal muscle tissue is in a constant state of turnover, with muscle tissue protein synthesis and breakdown rates ranging between 1-2 % across the day in vivo in humans. Muscle tissue remodeling is largely controlled by the up- and down-regulation of muscle tissue protein synthesis rates. Research studies generally apply stable isotope labeled amino acids to assess muscle protein synthesis rates in vivo in humans. Following labeled amino acid administration in a laboratory setting, muscle tissue samples are collected over several hours to assess the incorporation rate of these labeled amino acids in muscle tissue protein. To allow quantification of bulk muscle protein synthesis rates over more prolonged periods, the use of deuterated water methodology has regained much interest. Ingestion of daily boluses of deuterium oxide (2H2O) results in 2H-enrichment of the body water pool. The available 2H-atoms become incorporated into endogenously synthesized alanine primarily through transamination of pyruvate in the liver. With 2H-alanine widely available to all tissues, it becomes incorporated into de novo synthesized tissue proteins. Assessing the increase in tissue protein-bound 2H-alanine enrichment in muscle biopsy samples over time allows for calculation of muscle protein synthesis rates over several days or even weeks. As the deuterated water method allows for assessment of muscle tissue protein synthesis rates under free living conditions in non-laboratory settings, there is an increasing interest in its application. This manuscript describes the theoretical background of the deuterated water method and offers a comprehensive tutorial to correctly apply the method to determine bulk muscle protein synthesis rates in vivo in humans.

Improving Individualized Rhabdomyosarcoma Prognosis Predictions Using Somatic Molecular Biomarkers.

Purpose: Molecular markers, such as FOXO1 fusion genes and TP53 and MYOD1 mutations, increasingly influence risk-stratified treatment selection for pediatric rhabdomyosarcoma (RMS). This study aims to integrate molecular and clinical data to produce individualized prognosis predictions that can further improve treatment selection. Patients and Methods: Clinical variables and somatic mutation data for 20 genes from 641 RMS patients in the United Kingdom and the United States were used to develop three Cox proportional hazard models for predicting event-free survival (EFS). The 'Baseline Clinical' (BC) model included treatment location, age, fusion status, and risk group. The 'Gene Enhanced 2' (GE2) model added TP53 and MYOD1 mutations to the BC predictors. The 'Gene Enhanced 6' (GE6) model further included NF1, MET, CDKN2A, and MYCN mutations, selected through LASSO regression. Model performance was assessed using likelihood ratio (LR) tests and optimism-adjusted, bootstrapped validation and calibration metrics. Results: The GE6 model demonstrated superior predictive performance, offering 39% more predictive information than the BC model (LR p<0.001) and 15% more than the GE2 model (LR p<0.001). The GE6 model achieved the highest discrimination with a C-index of 0.7087, a Nagalkerke R2 of 0.205, and appropriate calibration. Mutations in TP53, MYOD1, CDKN2A, MET, and MYCN were associated with higher hazards, while NF1 mutation correlated with lower hazard. Individual prognosis predictions varied between models in ways that may suggest different treatments for the same patient. For example, the 5-year EFS for a 10-year-old patient with high-risk, fusion-negative, NF1-positive disease was 50.0% (95% confidence interval: 39-64%) from BC but 76% (64-90%) from GE6. Conclusion: Incorporating molecular markers into RMS prognosis models improves prognosis predictions. Individualized prognosis predictions may suggest alternative treatment regimens compared to traditional risk-classification schemas. Improved clinical variables and external validation are required prior to implementing these models into clinical practice.

Isolated external jugular thrombophlebitis secondary to acute pharyngitis: a case report and a review of the literature.

BACKGROUND: External Jugular Thrombophlebitis (EJT) is a rare clinical phenomenon with few reports in the literature, especially in the pediatric population. This is a report of an unusual case of right-sided EJT in a pediatric patient secondary to acute pharyngitis with sinusitis most prominent on the left side. CASE PRESENTATION: A 13-year-old presented to the emergency department with worsening upper respiratory infectious (URI) symptoms and facial swelling, cough, throat pain, and emesis. The patient had traveled to Switzerland and received amoxicillin for strep throat 6 weeks before this hospitalization. Physical examination revealed nasal purulence, allodynia over the right side of the face without overlying erythema, and oropharyngeal exudate. CT scan revealed left-sided predominate sinusitis and right external jugular vein thrombosis. Blood cultures confirmed the presence of group A streptococcus infection. Treatment included IV antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs), IV steroids, and anticoagulation. Follow-up imaging demonstrated improvement in thrombosis, cellulitis, and sinus disease. The patient was discharged on antibiotics for 6 weeks and anticoagulation for 10 weeks. Follow-up imaging at 6 months revealed no EJT, and medications were discontinued. CONCLUSIONS: EJT is a rare condition, and to our knowledge, no reports of EJT with sinusitis most pronounced on the contralateral side have been published. Physicians will benefit from noting clinical signs of EJT such as facial edema, headache, erythema, and palpable neck mass, especially if these symptoms occur with URI symptoms refractory to treatment. The use of anticoagulation is controversial for internal jugular vein thrombosis, and while no guidelines for EJT exist, anticoagulation is likely not necessary save for severe complications.

Gestational SARS-CoV-2 Infection in a Ugandan Birth Cohort: High Incidence, Mild Maternal Disease, and Evidence of Association with Transient Infant Stunting.

Many questions remain about the prevalence and effects of SARS-CoV-2 infection in malaria-endemic African countries like Uganda, particularly in vulnerable groups such as pregnant women. We describe SARS-CoV-2 immunoglobulin (Ig)G and IgM antibody responses and clinical outcomes in mother-infant dyads enrolled in malaria chemoprevention trials in Uganda. From December 2020-February 2022, among 400 unvaccinated pregnant women enrolled at 12-20 weeks gestation and followed through delivery, 128 (32%) were seronegative for anti-SARS-CoV-2 IgG and IgM at enrollment and delivery, 80 (20%) were infected prior to or early in pregnancy, and 192 (48%) were infected or re-infected with SARS-CoV-2 during pregnancy. We observed preferential binding of plasma IgG to Wuhan-Hu-1-like antigens in individuals seroconverting up to early 2021, and to Delta variant antigens in a subset of individuals in mid-2021. Breadth of IgG binding to all variants improved over time, consistent with affinity maturation of the antibody response in the cohort. No women experienced severe respiratory illness during the study. SARS-CoV-2 infection in early pregnancy was associated with lower median length-for-age Z-score at age 3 months compared with no infection or late pregnancy infect (-1.54 versus -0.37 and -0.51, P = 0.009). These findings suggest that pregnant Ugandan women experienced high levels of SARS-CoV-2 infection without severe respiratory illness. Variant-specific serology testing demonstrated evidence of antibody affinity maturation at the population level. Early gestational SARS-CoV-2 infection was associated with transient shorter stature in early infancy. Further research should explore the significance of this finding and define targeted measures to prevent infection in pregnancy.

Impact of Disease Factors of Patients with Psoriasis and Psoriatic Arthritis on Biologic Therapy Switching: Real-World Evidence from the CorEvitas Psoriasis Registry.

INTRODUCTION: Patients with psoriasis (PSO) and psoriatic arthritis (PsA) may frequently switch biologic therapies over the course of treatment because of symptom variability and individual responses. Real-world studies analyzing patient characteristics and clinical factors associated with biologic switching are limited. METHODS: This longitudinal cohort study used real-world data from the CorEvitas Psoriasis Registry to evaluate the relationship between associated disease factors and biologic switching among patients with PSO and PsA in the United States (US) and Canada following initiation of a biologic. Patients were evaluated between April 2015-August 2022. Combinations of disease severity (as measured by Psoriasis Area Severity Index [PASI]) and Dermatology Life Quality Index (DLQI) as a measure of health-related quality of life (HRQoL) were assessed, and the association with time to switching was calculated using Cox proportional hazards regression modeling. RESULTS: Among 2580 patient-initiations (instances of patients initiating a biologic), 504 (19.5%) switched biologics within 30 months of initiation. Switching was more frequent when either PASI > 10 or DLQI > 5 compared with PASI ≤ 10 or DLQI ≤ 5 at follow-up. Patients with higher skin involvement (PASI > 10) and impact on HRQoL (DLQI > 5) were 14 times more likely to switch (hazard ratio = 14.2, 95% confidence interval: 10.7, 18.9) than those with lower skin involvement (PASI ≤ 10) and HRQoL (DLQI ≤ 5). CONCLUSIONS: Patients with PSO and PsA treated in a real-world dermatology setting with substantial disease factors following biologic initiation were more likely to switch therapies. Those with PASI > 10 and DLQI > 5 switched more frequently than those with PASI ≤ 10 and DLQI ≤ 5.

Many patients with psoriasis may also have a related condition called psoriatic arthritis. Biologic medications work by helping to reduce inflammation and are commonly used to treat the symptoms of psoriasis and psoriatic arthritis. Patients might not all respond the same way to treatment and may need to change their medications over time. It is important we understand the reasons for switching medications to help patients better manage their symptoms.This study used information from a database on patients with both psoriasis and psoriatic arthritis. The database includes information on patients' medical history, including when they start and change their medication. We looked at data from patients who switched medications and patients who did not switch medications and examined differences in both how serious a doctor found their disease and the patients' own opinions of their overall health.We found that patients were more likely to change their biologic medication if they had more difficult psoriasis and psoriatic arthritis symptoms that caused worse skin problems, joint pain, and effects on their overall health compared with patients who had not changed their medication. These results suggest that it is important to consider both how serious a doctor finds their disease and patients' opinions of how much their symptoms affect their overall health. Understanding the reasons why patients switch medications will help to develop better ways of managing psoriasis and psoriatic arthritis.

Silica Nanoparticles Decorated with Ceria Quantum Dots Modulate Intra- and Extracellular Reactive Oxygen Species Formation and Selectively Reduce Human A375 Melanoma Cell Proliferation.

Nanomaterials show great promise for cancer treatment. Nonetheless, most nanomaterials lack selectivity for cancer cells, damaging healthy ones. Cerium dioxide (ceria, CeO2) nanoparticles have been shown to exert selective toxicity toward cancer cells due to the redox modulating properties they display as their size decreases. However, these particles suffer from poor suspension stability. The efficacy of CeO2 nanoparticles for cancer treatment is hampered by their innate high surface energy, which leads to particle agglomeration and, consequently, reactivity loss. This effect increases as particle size decreases; as such, quantum dots (QDs) suffer most from this phenomenon. In this study, it is proposed that silicon dioxide (silica, SiO2) nanoparticles can provide an inert platform for surface encrusted CeO2 QDs and that the resulting nanocomposite (hereafter QDCeO2/SiO2) not only will exhibit negligible agglomeration compared with CeO2 alone but also will improve the modulation of reactive oxygen species (ROS) leading to selective reduction of human A375 melanoma cell proliferation. The SiO2 nanoparticles had a bimodal size distribution with median particle size of 66 and 168 nm, while the CeO2 quantum dots encrusted on their surface had a size of 3.2 nm. An elevated Ce3+/Ce4+ ratio led to the QDCeO2/SiO2 nanocomposite displaying synergistic superoxide dismutase- and catalase-like activity, favoring the accumulation of ROS at pH 6.5 which translated into QDCeO2/SiO2 exerting selective oxidative stress in, and toward, the melanoma cells. Treatment with 50 µg mL-1 QDCeO2/SiO2 significantly reduced cell proliferation by 27% compared to untreated control cells in the colony formation assay. Treatment with either SiO2 or CeO2 alone did not affect the cell proliferation. These results highlight the benefit of dispersing CeO2 QDs on the surface of core nanoparticles and the resulting enhancement of selective redox reactivity and proliferation arrest when compared to CeO2 nanoparticles alone. Furthermore, the method employed here to encrust CeO2 QDs could lead to the facile synthesis of new nanocomposites with enhanced control of ROS activity, not only for in vitro studies using other cancer cell lines of interest but also in animal models and perhaps leading to clinical trials in melanoma patients.

Systematic prioritization of functional variants and effector genes underlying colorectal cancer risk.

Genome-wide association studies of colorectal cancer (CRC) have identified 170 autosomal risk loci. However, for most of these, the functional variants and their target genes are unknown. Here, we perform statistical fine-mapping incorporating tissue-specific epigenetic annotations and massively parallel reporter assays to systematically prioritize functional variants for each CRC risk locus. We identify plausible causal variants for the 170 risk loci, with a single variant for 40. We link these variants to 208 target genes by analyzing colon-specific quantitative trait loci and implementing the activity-by-contact model, which integrates epigenomic features and Micro-C data, to predict enhancer-gene connections. By deciphering CRC risk loci, we identify direct links between risk variants and target genes, providing further insight into the molecular basis of CRC susceptibility and highlighting potential pharmaceutical targets for prevention and treatment.