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Orthostatic intolerance (and its subtype postural orthostatic tachycardia syndrome [POTS]) is an increasingly common complaint among adolescents associated with significant decrease in quality of life and frequent visits to primary care offices. As orthostatic intolerance becomes increasingly discussed online and through social media, we have observed that family angst and anxiety only heighten, often leading to requests for specialist referral to manage the symptoms. This often leads to delay in diagnosis, which further exacerbates the situation. In truth, however, a pragmatic approach applied by the primary care provider, including a ready explanation for the experienced symptoms, not only provides the bedrock for patient improvement, but also eases the anxiety of having a seemingly nebulous diagnosis. As physicians caring for these patients, we have seen success with treatment and seek to share this blueprint. Key points that will be covered include how to make an accurate diagnosis (using the “dizziness rule”), how to counsel about treatment, and clinic pitfalls to avoid. The description of care that follows is not based on systematic review and instead is exactly what is used in our office and what we hope will be successful in yours as well.

Edsel B Ing,1 Neil R Miller,2 Angeline Nguyen,2 Wanhua Su,3 Lulu LCD Bursztyn,4 Meredith Poole,5 Vinay Kansal,6 Andrew Toren,7 Dana Albreki,8 Jack G Mouhanna,9 Alla Muladzanov,10 Mikaël Bernier,11 Mark Gans,10 Dongho Lee,12 Colten Wendel,13 Claire Sheldon,13 Marc Shields,14 Lorne Bellan,15 Matthew Lee-Wing,15 Yasaman Mohadjer,16 Navdeep Nijhawan,1 Felix Tyndel,17 Arun NE Sundaram,17 Martin W ten Hove,18 John J Chen,19 Amadeo R Rodriguez,20 Angela Hu,21 Nader Khalidi,21 Royce Ing,22 Samuel WK Wong,23 Nurhan Torun24 1Ophthalmology, University of Toronto, Toronto, ON, Canada; 2Ophthalmology, Johns Hopkins University, Baltimore, MD, USA; 3Statistics, MacEwan University, Edmonton, AB, Canada; 4Ophthalmology, Western University, London, ON, Canada; 5Queens University, Kingston, ON, Canada; 6Ophthalmology, University of Saskatchewan, Saskatoon, SK, Canada; 7Laval University, Quebec, QC, Canada; 8Ophthalmology, University of Ottawa, Ottawa, ON, Canada; 9University of Ottawa, Ottawa, ON, Canada; 10Ophthalmology, McGill University, Montreal, QC, Canada; 11University of Sherbrooke, QC, Canada; 12University of British Columbia, Vancouver, BC, Canada; 13Ophthalmology, University of British Columbia, Vancouver, BC, Canada; 14Ophthalmology, University of Virginia, Fisherville, VA, USA; 15Ophthalmology, University of Manitoba, Winnipeg, MB, Canada; 16Ophthalmology, Eye Institute of West Florida, Tampa, FL, USA; 17Neurology, University of Toronto, Toronto, ON, Canada; 18Ophthalmology, Queens University, Toronto, ON, Canada; 19Ophthalmology & Neurology, Mayo Clinic, Rochester, MN, USA; 20Ophthalmology, McMaster University, Hamilton, ON, Canada; 21Rheumatology, McMaster University, Hamilton, ON, Canada; 22Undergraduate Science, Ryerson University, Toronto, ON, Canada; 23Statistics, University of Waterloo, Waterloo, ON, Canada; 24Ophthalmology, Harvard University, Boston, MA, USA Purpose: To develop and validate neural network (NN) vs logistic regression (LR) diagnostic prediction models in patients with suspected giant cell arteritis (GCA). Design: Multicenter retrospective chart review.Methods: An audit of consecutive patients undergoing temporal artery biopsy (TABx) for suspected GCA was conducted at 14 international medical centers. The outcome variable was biopsy-proven GCA. The predictor variables were age, gender, headache, clinical temporal artery abnormality, jaw claudication, vision loss, diplopia, erythrocyte sedimentation rate, C-reactive protein, and platelet level. The data were divided into three groups to train, validate, and test the models. The NN model with the lowest false-negative rate was chosen. Internal and external validations were performed.Results: Of 1,833 patients who underwent TABx, there was complete information on 1,201 patients, 300 (25%) of whom had a positive TABx. On multivariable LR age, platelets, jaw claudication, vision loss, log C-reactive protein, log erythrocyte sedimentation rate, headache, and clinical temporal artery abnormality were statistically significant predictors of a positive TABx (P≤0.05). The area under the receiver operating characteristic curve/Hosmer–Lemeshow P for LR was 0.867 (95% CI, 0.794, 0.917)/0.119 vs NN 0.860 (95% CI, 0.786, 0.911)/0.805, with no statistically significant difference of the area under the curves (P=0.316). The misclassification rate/false-negative rate of LR was 20.6%/47.5% vs 18.1%/30.5% for NN. Missing data analysis did not change the results.Conclusion: Statistical models can aid in the triage of patients with suspected GCA. Misclassification remains a concern, but cutoff values for 95% and 99% sensitivities are provided (https://goo.gl/THCnuU). Keywords: giant cell arteritis, temporal artery biopsy, neural network, logistic regression, prediction models, ophthalmology, rheumatology

The present study examined both mothers' reports and adolescents' perceptions of parents' educational involvement and their effects on the adolescents' functioning in school. The sample was drawn from 5 urban schools in Israel. Participants were 449 eighth grade students/adolescents (Female = 47%) and 126 mothers. Adolescents and their mothers completed parallel parents' educational involvement questionnaires, and adolescents completed questionnaires on learning strategies and self-evaluation. Multiple-group confirmatory factor analyses, based on the mothers' reports and adolescents' perceptions of parents' educational involvement revealed three factors: home-based, school-based, and communication-based knowledge of adolescents' activities in school. The analysis showed no relation between mothers' reports and adolescents' perceptions. However, adolescents' perceptions of their parents' educational involvement were significant predictors of the adolescents' learning strategies, self-evaluation, and academic achievement. Findings underline the congruence and incongruence between mothers and their adolescents, and the significant role parents play in their adolescents' schooling according to the adolescents' perceptions.

Edsel B Ing,1 Gabriela Lahaie Luna,2 Andrew Toren,3 Royce Ing,4 John J Chen,5 Nitika Arora,6 Nurhan Torun,7 Otana A Jakpor,8 J Alexander Fraser,9 Felix J Tyndel,10 Arun NE Sundaram,10 Xinyang Liu,11 Cindy TY Lam,1 Vivek Patel,12 Ezekiel Weis,13 David Jordan,14 Steven Gilberg,14 Christian Pagnoux,15 Martin ten Hove21Department of Ophthalmology and Vision Sciences, University of Toronto Medical School, Toronto, 2Department of Ophthalmology, Queen’s University, Kingston, ON, 3Department of Ophthalmology, University of Laval, Quebec, QC, 4Toronto Eyelid, Strabismus and Orbit Surgery Clinic, Toronto, ON, Canada; 5Mayo Clinic, Department of Ophthalmology and Neurology, 6Mayo Clinic, Department of Ophthalmology, Rochester, MN, 7Department of Surgery, Division of Ophthalmology, Harvard Medical School, Boston, MA, 8Harvard Medical School, Boston, MA, USA; 9Department of Clinical Neurological Sciences and Ophthalmology, Western University, London, 10Department of Medicine, University of Toronto Medical School, Toronto, ON, Canada; 11Department of Medicine, Fudan University Shanghai Medical College, Shanghai, People’s Republic of China; 12Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; 13Departments of Ophthalmology, Universities of Alberta and Calgary, Edmonton and Calgary, AB, 14Department of Ophthalmology, University of Ottawa, Ottawa, ON, 15Vasculitis Clinic, Mount Sinai Hospital, Toronto, ON, CanadaPurpose: To develop and validate a diagnostic prediction model for patients with suspected giant cell arteritis (GCA).Methods: A retrospective review of records of consecutive adult patients undergoing temporal artery biopsy (TABx) for suspected GCA was conducted at seven university centers. The pathologic diagnosis was considered the final diagnosis. The predictor variables were age, gender, new onset headache, clinical temporal artery abnormality, jaw claudication, ischemic vision loss (VL), diplopia, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelet level. Multiple imputation was performed for missing data. Logistic regression was used to compare our models with the non-histologic American College of Rheumatology (ACR) GCA classification criteria. Internal validation was performed with 10-fold cross validation and bootstrap techniques. External validation was performed by geographic site.Results: There were 530 complete TABx records: 397 were negative and 133 positive for GCA. Age, jaw claudication, VL, platelets, and log CRP were statistically significant predictors of positive TABx, whereas ESR, gender, headache, and temporal artery abnormality were not. The parsimonious model had a cross-validated bootstrap area under the receiver operating characteristic curve (AUROC) of 0.810 (95% CI =0.766–0.854), geographic external validation AUROC’s in the range of 0.75–0.85, calibration pH–L of 0.812, sensitivity of 43.6%, and specificity of 95.2%, which outperformed the ACR criteria.Conclusion: Our prediction rule with calculator and nomogram aids in the triage of patients with suspected GCA and may decrease the need for TABx in select low-score at-risk subjects. However, misclassification remains a concern.Keywords: temporal artery biopsy, diagnosis, prediction rule, nomogram, giant cell arteritis, validation

Active hepatitis C virus (HCV) prevalence (i.e., HCV PCR positivity) in Israel is estimated to range from 0.1% to >5.5%, depending on risk group affiliation; seroprevalence (i.e., HCV antibody positivity) [...]

Non-neovascular or dry age-related macular degeneration (AMD) is a multi-factorial disease with degeneration of the aging retinal-pigmented epithelium (RPE). Lysosomes play a crucial role in RPE health via phagocytosis and autophagy, which are regulated by transcription factor EB/E3 (TFEB/E3). Here, we find that increased AKT2 inhibits PGC-1α to downregulate SIRT5, which we identify as an AKT2 binding partner. Crosstalk between SIRT5 and AKT2 facilitates TFEB-dependent lysosomal function in the RPE. AKT2/SIRT5/TFEB pathway inhibition in the RPE induced lysosome/autophagy signaling abnormalities, disrupted mitochondrial function and induced release of debris contributing to drusen. Accordingly, AKT2 overexpression in the RPE caused a dry AMD-like phenotype in aging Akt2 KI mice, as evident from decline in retinal function. Importantly, we show that induced pluripotent stem cell-derived RPE encoding the major risk variant associated with AMD (complement factor H; CFH Y402H) express increased AKT2, impairing TFEB/TFE3-dependent lysosomal function. Collectively, these findings suggest that targeting the AKT2/SIRT5/TFEB pathway may be an effective therapy to delay the progression of dry AMD.

Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8+ T cells. The cardiac-specific protein α-myosin, which is absent from the thymus3,4, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8+ T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.

Tuberculosis (TB) and COVID-19 were leading infectious causes of illness and death globally in 2020. In the United States, >17 million COVID-19 cases and [approximately equal to] 7,000 TB cases [...]

Multiple roles of reactive oxygen species (ROS) and their consequences for health and disease are emerging throughout biological sciences. This development has led researchers unfamiliar with the complexities of ROS and their reactions to employ commercial kits and probes to measure ROS and oxidative damage inappropriately, treating ROS (a generic abbreviation) as if it were a discrete molecular entity. Unfortunately, the application and interpretation of these measurements are fraught with challenges and limitations. This can lead to misleading claims entering the literature and impeding progress, despite a well-established body of knowledge on how best to assess individual ROS, their reactions, role as signalling molecules and the oxidative damage that they can cause. In this consensus statement we illuminate problems that can arise with many commonly used approaches for measurement of ROS and oxidative damage, and propose guidelines for best practice. We hope that these strategies will be useful to those who find their research requiring assessment of ROS, oxidative damage and redox signalling in cells and in vivo.

Background: Girls with a mild intellectual disability generally receive less sexuality education than their non-disabled peers, while their needs for sexual knowledge are possibly greater. This study aimed to evaluate the effect and process of a new sexuality education programme (Girls' Talk+), focused on sexual health among girls with a mild intellectual disability in the Netherlands. Methods: A mixed methods approach was applied, using participant questionnaires (n = 249), logs written by trainers (n = 17) and interviews with trainers (n = 10). Descriptive statistics and linear regression models were used to analyse the quantitative data. Several coding phases were used to analyse the interviews. Results and conclusions: This study provides some indication that Girls' Talk+ has positive results on improving knowledge, attitude, and self-efficacy in relation to sexual health as well as trainer and participant satisfaction with the programme.

Introduction Prostate cancer (PCa) is the most common cancer for men in 112 countries (1). This disease is highly dependent on the androgen receptor (AR), a transcription factor that modulates [...], Just like the androgen receptor (AR), the estrogen receptor [alpha] (ER[alpha]) is expressed in the prostate and is thought to influence prostate cancer (PCa) biology. Yet the incomplete understanding of ER[alpha] functions in PCa hinders our ability to fully comprehend its clinical relevance and restricts the repurposing of estrogen- targeted therapies for the treatment of this disease. Using 2 human PCa tissue microarray cohorts, we first demonstrate that nuclear ER[alpha] expression was heterogeneous among patients, being detected in only half of the tumors. Positive nuclear ER[alpha] levels were correlated with disease recurrence, progression to metastatic PCa, and patient survival. Using in vitro and in vivo models of the normal prostate and PCa, bulk and single-cell RNA-Seq analyses revealed that estrogens partially mimicked the androgen transcriptional response and activated specific biological pathways linked to proliferation and metabolism. Bioenergetic flux assays and metabolomics confirmed the regulation of cancer metabolism by estrogens, supporting proliferation. Using cancer cell lines and patient- derived organoids, selective estrogen receptor modulators, a pure anti-estrogen, and genetic approaches impaired cancer cell proliferation and growth in an ER[alpha]-dependent manner. Overall, our study revealed that, when expressed, ER[alpha] functionally reprogrammed PCa metabolism, was associated with disease progression, and could be targeted for therapeutic purposes.