Exploring the complexity of systemic sclerosis etiology by trio whole genome sequencing.

Systemic sclerosis (SSc) is a heterogeneous rare autoimmune fibrosing disorder affecting connective tissue. The etiology of systemic sclerosis is largely unknown and many genes have been suggested as susceptibility loci of modest impact by genome-wide association study (GWAS). Multiple factors can contribute to the pathological process of the disease, which makes it more difficult to identify possible disease-causing genetic alterations. In this study, we have applied whole genome sequencing (WGS) in 101 indexed family trios, supplemented with transcriptome sequencing on cultured fibroblast cells of four patients and five family controls where available. Single nucleotide variants (SNVs) and copy number variants (CNVs) were examined, with emphasis on de novo variants. We also performed enrichment test for rare variants in candidate genes previously proposed in association with systemic sclerosis. We identified 42 exonic and 34 ncRNA de novo SNV changes in 101 trios, from a total of over 6000 de novo variants genome wide. We observed higher than expected de novo variants in PRKXP1 gene. We also observed such phenomenon along with increased expression in patient group in NEK7 gene. Additionally, we also observed significant enrichment of rare variants in candidate genes in the patient cohort, further supporting the complexity/multi-factorial etiology of systemic sclerosis. Our findings identify new candidate genes including PRKXP1 and NEK7 for future studies in SSc. We observed rare variant enrichment in candidate genes previously proposed in association with SSc, which suggest more efforts should be pursued to further investigate possible pathogenetic mechanisms associated with those candidate genes.

Racial variability in immune responses only partially explains differential systemic sclerosis disease severity.

OBJECTIVE: To understand if autoantibodies account for racial variation in disease severity, we compared autoantibody distribution and associated phenotype between self-identified black and white systemic sclerosis (SSc) patients. METHODS: 803 black and 2178 white SSc patients had systematic testing for autoantibodies using Euroimmun (centromere (ACA), RNA-polymerase III (POLR3), Scl70, PM/Scl, NOR90, Th/To, Ku, U3RNP and Ro52) and commercial ELISA (U1RNP). In this observational study, logistic regression was performed to assess the association between self-identified race and outcomes, adjusting for autoantibodies. To estimate whether the effect of race was mediated by autoantibody status, race coefficients from multivariate models including and excluding autoantibodies were compared. RESULTS: Anti-Scl70, anti-U1RNP, anti-U3RNP, anti-Th/To, anti-Ku and anti-NOR90 were more common in the black cohort than in the white cohort, which was enriched for ACA, anti-POLR3 and anti-PM/Scl. Black individuals had a higher prevalence of severe Raynaud's, skin, lung, gastrointestinal and renal disease whereas white individuals had a higher prevalence of severe heart and muscle disease. Adjusting for autoantibodies decreased the effect of race on outcome for telangiectasias, forced vital capacity <70%, pulmonary hypertension and severe lung, heart, muscle and gastrointestinal disease by 11%-44% and increased the association between race and renal crisis and severe kidney disease by 37%-52%. CONCLUSIONS: This study is the largest systematic analysis of autoantibody responses in a geographically diverse population of black SSc patients. Black and white individuals with SSc have distinct autoantibody profiles. Autoantibodies explain only a fraction of the effect of race on clinical outcomes, suggesting other factors contribute to disparate outcomes between these groups.

Minimal Detectable Changes of the HAQ-DI, PROMIS-29v2.0 Domains, and PHQ-8 in Systemic Sclerosis: A SPIN Cohort Cross-Sectional Study.

OBJECTIVE: Systemic sclerosis (SSc) is a rare, chronic, autoimmune disorder associated with disability, diminished physical function, fatigue, pain, and mental health concerns. We assessed minimal detectable changes (MDCs) of the Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient Reported Outcomes Measurement Information System-29 Profile version 2.0 (PROMIS-29v2.0) domains, and Patient Health Questionnaire-8 (PHQ-8) in SSc. METHODS: Scleroderma Patient-centered Intervention Network Cohort participants completed the HAQ-DI, PROMIS-29v2.0 domains, and PHQ-8 at baseline assessments from April 2014 until August 2023. We estimated MDC95 and MDC90 with 95% confidence intervals (CI) generated via the percentile bootstrapping method resampling 1000 times. We compared MDC estimates by age, sex and SSc subtype. RESULTS: A total of 2,571 participants were included. Most were female (N = 2,241; 87%), and 38% (N = 976) had diffuse SSc. Mean (SD) age was 54.9 (12.7) years and duration since onset of first non-Raynaud phenomenon symptom 10.8 (8.7) years. MDC95 estimate was 0.41 points (95% CI: 0.40 to 0.42) for the HAQ-DI, between 4.88 points (95% CI: 4.72 to 5.05) and 9.02 points (95% CI: 8.80 to 9.23) for the 7 PROMIS-29v2.0 domains, and 5.16 points (95% CI: 5.06 to 5.26) for the PHQ-8. MDC95 estimates were not materially different across subgroups. CONCLUSION: MDC95 and MDC90 estimates were precise and similar across age, sex and SSc subtype groups. HAQ-DI MDC95 and MDC90 were substantially larger than previous estimates of HAQ-DI minimal important difference from several small studies. Minimally important differences of all measures should be evaluated in large studies using anchor-based methods.

Perioperative Management of Antithrombotic Therapy.

This JAMA Clinical Guidelines Synopsis summarizes the American College of Chest Physicians' 2022 guideline on perioperative management of patients taking oral anticoagulation or antiplatelet therapy who are undergoing an elective surgery or procedure.

Vitamin D Insufficiency and Epistemic Humility: An Endocrine Society Guideline Communication.

A long-held precept is that vitamin D supplementation primarily, if not exclusively, benefits individuals with low circulating 25-hydroxyvitamin D (25[OH]D) concentrations at baseline. However, the most appropriate 25(OH)D threshold to distinguish unacceptably low vs reliably adequate concentrations remains controversial. Such threshold proposals have largely been based on observational studies, which provide less robust evidence compared to randomized clinical trials (RCTs). Since the Endocrine Society's first vitamin D-related guideline was published in 2011, several large vitamin D-related RCTs have been published, and a newly commissioned guideline development panel (GDP) prioritized 4 clinical questions related to the benefits and harms of vitamin D supplementation in generally healthy individuals with 25(OH)D levels below a threshold. The GDP determined that available clinical trial evidence does not permit the establishment of 25(OH)D thresholds that specifically predict meaningful benefit with vitamin D supplementation. The panel noted important limitations in the available evidence, and the panel's overall certainty in the available evidence was very low. Nonetheless, based on the GDP's analyses and judgments, the Endocrine Society no longer endorses its previously proposed definition of vitamin D "sufficiency" (ie, at least 30 ng/mL [75 nmol/L]) or its previously proposed definition of vitamin D "insufficiency" (ie, greater than 20 ng/mL [50 nmol/L] but lower than 30 ng/mL [75 nmol/L]). The Endocrine Society's rationale for such is the subject of this Guideline Communication.

Navigating Complexities: Vitamin D, Skin Pigmentation, and Race.

Vitamin D plays a critical role in many physiological functions, including calcium metabolism and musculoskeletal health. This commentary aims to explore the intricate relationships among skin complexion, race, and 25-hydroxyvitamin D (25[OH]D) levels, focusing on challenges the Endocrine Society encountered during clinical practice guideline development. Given that increased melanin content reduces 25(OH)D production in the skin in response to UV light, the guideline development panel addressed the potential role for 25(OH)D screening in individuals with dark skin complexion. The panel discovered that no randomized clinical trials have directly assessed vitamin D related patient-important outcomes based on participants' skin pigmentation, although race and ethnicity often served as presumed proxies for skin pigmentation in the literature. In their deliberations, guideline panel members and selected Endocrine Society leaders underscored the critical need to distinguish between skin pigmentation as a biological variable and race and ethnicity as socially determined constructs. This differentiation is vital to maximize scientific rigor and, thus, the validity of resulting recommendations. Lessons learned from the guideline development process emphasize the necessity of clarity when incorporating race and ethnicity into clinical guidelines. Such clarity is an essential step toward improving health outcomes and ensuring equitable healthcare practices.

The role of membrane transporters in the absorption of atrazine following nasal exposure.

OBJECTIVE: The purpose of these studies was to investigate the uptake of atrazine across the nasal mucosa to determine whether direct transport to the brain through the olfactory epithelium is likely to occur. These studies were undertaken to provide important new information about the potential for the enhanced neurotoxicity of herbicides following nasal inhalation. MATERIALS AND METHODS: Transport of atrazine from aqueous solution and from commercial atrazine-containing herbicide products was assessed using excised nasal mucosal tissues. The permeation rate and the role of membrane transporters in the uptake of atrazine across the nasal mucosa were also investigated. Histological examination of the nasal tissues was conducted to assess the effects of commercial atrazine-containing products on nasal tissue morphology. RESULTS: Atrazine showed high flux across both nasal respiratory and olfactory tissues, and efflux transporters were found to play an essential role in limiting its uptake at low exposure concentrations. Commercial atrazine-containing herbicide products showed remarkably high transfer across the nasal tissues, and histological evaluation showed significant changes in the morphology of the nasal epithelium following exposure to the herbicide products. DISCUSSION: Lipophilic herbicides such as atrazine can freely permeate across the nasal mucosa despite the activity of efflux transporters. The adjuvant compounds in commercial herbicide products disrupt the nasal mucosa's epithelial barrier, resulting in even greater atrazine permeation across the tissues. The properties of the herbicide itself and those of the formulated products play crucial roles in the potential for the enhanced neurotoxicity of herbicides following nasal inhalation.

Factors associated with physical function among people with systemic sclerosis: a SPIN cohort cross-sectional study.

OBJECTIVES: To compare physical function in systemic sclerosis (SSc, scleroderma) to general population normative data and identify associated factors. METHODS: Scleroderma Patient-centered Intervention Network Cohort participants completed the Physical Function domain of the Patient-Reported Outcomes Measurement Information System Version 2 upon enrolment. Multivariable linear regression was used to assess associations of sociodemographic, lifestyle, and disease-related variables. RESULTS: Among 2,385 participants, mean physical function T-score (43.7, SD = 8.9) was ∼2/3 of a standard deviation (SD) below the US general population (mean = 50, SD = 10). Factors associated in multivariable analysis included older age (-0.74 points per SD years, 95% CI -0.78 to -1.08), female sex (-1.35, -2.37 to -0.34), fewer years of education (-0.41 points per SD in years, -0.75 to -0.07), being single, divorced, or widowed (-0.76, -1.48 to -0.03), smoking (-3.14, -4.42 to -1.85), alcohol consumption (0.79 points per SD drinks per week, 0.45-1.14), BMI (-1.41 points per SD, -1.75 to -1.07), diffuse subtype (-1.43, -2.23 to -0.62), gastrointestinal involvement (-2.58, -3.53 to -1.62), digital ulcers (-1.96, -2.94 to -0.98), moderate (-1.94, -2.94 to -0.93) and severe (-1.76, -3.24 to -0.28) small joint contractures, moderate (-2.10, -3.44 to -0.76) and severe (-2.54, -4.64 to -0.44) large joint contractures, interstitial lung disease (-1.52, -2.27 to -0.77), pulmonary arterial hypertension (-3.72, -4.91 to -2.52), rheumatoid arthritis (-2.10, -3.64 to -0.56) and idiopathic inflammatory myositis (-2.10, -3.63 to -0.56). CONCLUSION: Physical function is impaired for many individuals with SSc and associated with multiple disease factors.

Myeloablation Followed by Hematopoietic Stem Cell Transplantation and Long-Term Normalization of Systemic Sclerosis Molecular Signatures.

OBJECTIVE: In the randomized Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablation, followed by hematopoietic stem cell transplantation (HSCT), led to the normalization of systemic sclerosis (SSc) peripheral blood cell (PBC) gene expression signature at the 26-month visit. Herein, we examined long-term molecular changes ensuing 54 months after randomization for individuals receiving an HSCT or 12 months of intravenous cyclophosphamide (CYC). METHODS: Global PBC transcript studies were performed in study participants at pretreatment baseline and at 38 months and 54 months after randomization, as well as in healthy controls using Illumina HT-12 arrays. RESULTS: Thirty (HSCT = 19 and CYC = 11) participants had 38-month samples available, and 26 (HSCT = 16 and CYC = 11) had 54-month samples available. In the paired comparison to baseline, a significant down-regulation of interferon modules and an up-regulation of cytotoxic/natural killer module were observed at the 38-month and 54-month visits in the HSCT arm, indicating a long-term normalization of baseline SSc gene expression signature. No differentially expressed modules were detected in the CYC arm. In comparison to samples from healthy controls, 38-month visit samples in the HSCT arm showed an up-regulation of B cell and plasmablast modules and a down-regulation of myeloid and inflammation modules. Importantly, 54-month HSCT samples did not show any differentially expressed modules compared to healthy control samples, suggesting completion of immune reconstitution. Participants in the CYC arm continued to show an SSc transcript signature in comparison to controls at both time points. CONCLUSION: Paralleling the observed clinical benefit, HSCT leads to durable long-term normalization of the molecular signature in SSc, with completion of immune resetting to 54 months after HSCT.

The association of resilience and positive mental health in systemic sclerosis: A Scleroderma Patient-centered Intervention Network (SPIN) cohort cross-sectional study.

OBJECTIVE: A previous study using Scleroderma Patient-centered Intervention Network (SPIN) Cohort data identified five classes of people with systemic sclerosis (also known as scleroderma) based on patient-reported somatic (fatigue, pain, sleep) and mental health (anxiety, depression) symptoms and compared indicators of disease severity between classes. Across four classes ("low", "normal", "high", "very high"), there were progressively worse somatic and mental health outcomes and greater disease severity. The fifth ("high/low") class, however, was characterized by high disease severity, fatigue, pain, and sleep but low mental health symptoms. We evaluated resilience across classes and compared resilience between classes. METHODS: Cross-sectional study. SPIN Cohort participants completed the 10-item Connor-Davidson-Resilience Scale (CD-RISC) and PROMIS v2.0 domains between August 2022 and January 2023. We used latent profile modeling to identify five classes as in the previous study and multiple linear regression to compare resilience levels across classes, controlling for sociodemographic and disease variables. RESULTS: Mean CD-RISC score (N = 1054 participants) was 27.7 (standard deviation = 7.3). Resilience decreased progressively across "low" to "normal" to "high" to "very high" classes (mean 4.7 points per step). Based on multiple regression, the "high/low" class exhibited higher resilience scores than the "high" class (6.0 points, 95% confidence interval [CI] 4.9 to 7.1 points; standardized mean difference = 0.83, 95% CI 0.67 to 0.98). CONCLUSIONS: People with worse disease severity and patient-reported outcomes reported substantially lower resilience, except a class of people with high disease severity, fatigue, pain, and sleep disturbance but positive mental health and high resilience.

A Prospective Observational Study of Disease Severity and Mortality in Hispanic American Patients With Systemic Sclerosis.

OBJECTIVE: To characterize disease manifestations in Hispanic American patients with systemic sclerosis (SSc) in comparison with non-Hispanic White and Black patients. METHODS: Longitudinal clinical characteristics were collected prospectively in the Genetics versus Environment in Scleroderma Outcome Study cohort. All patients fulfilled the classification criteria for SSc and had a disease duration less than five years at enrollment. RESULTS: A cohort of 427 patients, consisting of 124 Hispanic, 220 non-Hispanic White, and 83 non-Hispanic Black participants were examined. At enrollment, Hispanic patients were significantly younger but had longer disease duration, higher frequency of U1-RNP positivity as well as concurrent systemic lupus erythematosus (SLE) diagnosis, and lower income and educational levels in comparison to non-Hispanic White patients. Compared with non-Hispanic Black patients, Hispanic patients had more frequently limited cutaneous involvement and anticentromere antibodies. In the longitudinal analysis, Hispanic patients had significantly lower forced vital capacity percents predicted (point estimate, -9.3%; P < 0.001) than non-Hispanic White but not Black patients. Hispanic patients had similar longitudinal modified Rodnan Skin Scores like non-Hispanic White patients but lower measurements than non-Hispanic Black patients (point estimate, -3.2; P = 0.029). Hispanic patients had significantly higher serially obtained perceived functional disability scores than White patients (point estimate, 0.29; P < 0.001). Hispanic patients also had higher mortality rates than White Americans even after adjustment for age, gender, and socioeconomic statuses. CONCLUSION: Hispanic patients have higher likelihood of having U1-RNP positivity and SLE overlap, more severe restrictive lung disease, as well as higher rate of mortality than non-Hispanic White patients.

Moderators of Loneliness Trajectories in People with Systemic Sclerosis During the COVID-19 Pandemic: A SPIN COVID-19 Cohort Longitudinal Study.

BACKGROUND: Many individuals with systemic sclerosis (SSc) are at heightened risk for COVID-19 related morbidity and isolation due to interstitial lung disease, frailty, and immunosuppressant use. Minimal research has explored loneliness predictors in individuals with chronic illnesses during COVID-19. This study evaluated moderators of loneliness trajectories in individuals with SSc during COVID-19. METHODS: Longitudinal data were analyzed across 30 timepoints from April 2020 to May 2022 from 775 adults in the Scleroderma Patient-centered Intervention Network (SPIN) COVID-19 Cohort. Hierarchical linear modeling evaluated cross-level moderators of loneliness trajectories, including marital status, baseline number of household members, number of virtual or telephone one-on-one or virtual group conversations, number of hours spent enjoying in-person household conversations or activities, and satisfaction with quality of in-person household conversations (all in the past week). Level-1 moderation analyses assessed effects of conversation, activity, and satisfaction means and slopes over time. RESULTS: Baseline values were not statistically significant moderators of loneliness trajectories. Higher mean (averaged over time) virtual or telephone one-on-one and in-person household conversations, in-person household activity, and in-person household conversation satisfaction were associated with lower loneliness trajectories (ps < .05). The relationship between in-person household conversation satisfaction and loneliness trajectory was statistically significantly but minimally attenuated over time (p < .001). CONCLUSIONS: For people with SSc, higher mean conversation, activity, and satisfaction variables were associated with lower levels of loneliness during the pandemic, but changes in these social variables were generally not predictive of changes in loneliness.

What do infectious disease specialists think about managing long COVID?

This survey of infectious disease providers on long COVID care revealed a lack of familiarity with existing resources, a sentiment of missing guidelines, and scarcity of dedicated care centers. The low response rate suggests that infectious disease specialists do not consider themselves as the primary providers of long COVID care.

Refining Clinical Quantification of Depth of Suppression in Amblyopia through Synoptophore Measurement.

BACKGROUND: Amblyopia is associated with unbalanced suppression between the two eyes. Existing clinical measures of suppression, such as the Worth 4 Dot test, provide qualitative information about suppression but cannot precisely quantify it. The Synoptophore, a well-established instrument in binocular vision clinics, has historically been used to gauge suppression qualitatively as well but has the capability to quantify suppression. We extended the capability of the Synoptophore through the development of a systematic protocol of illumination manipulation to quantify suppression in amblyopia. METHODS: Twenty-six previously treated adult amblyopes underwent our protocol on the Synoptophore to measure the illumination balance needed to obtain fusion responses. Separately, these same amblyopes were tested with Worth 4 Dot as it is classically performed in the United States, utilizing different test distances and room illuminations to qualify the suppression response. RESULTS: Smaller, more central targets revealed larger magnitudes of suppression for both the Synoptophore and Worth 4 Dot tests (Synoptophore: χ25,26 = 25.538, p < 0.001; Worth 4 Dot: χ23,26 = 39.020, p < 0.001). There was a significant correlation between the two tests for depth of suppression measurements (rΤ > 0.345, p < 0.036), with more sensitivity measured by the Synoptophore, as suppression could be graded on a quantitative scale. Strabismic amblyopes demonstrated more suppression than non-strabismic amblyopes (z > 2.410, p < 0.016). Additionally, depth of suppression was correlated with interocular difference in both visual acuity (rΤ = 0.604, p < 0.001) and stereoacuity (rΤ = 0.488, p = 0.001). CONCLUSIONS: We extended the utility of the Synoptophore by measuring its illuminance outputs and developing a suppression testing protocol that compared favorably with Worth 4 Dot (clinic standard) while improving upon the latter through more sensitive quantification of suppression.

Developing rights-based standards for children having tests, treatments, examinations and interventions: using a collaborative, multi-phased, multi-method and multi-stakeholder approach to build consensus.

Children continue to experience harm when undergoing clinical procedures despite increased evidence of the need to improve the provision of child-centred care. The international ISupport collaboration aimed to develop standards to outline and explain good procedural practice and the rights of children within the context of a clinical procedure. The rights-based standards for children undergoing tests, treatments, investigations, examinations and interventions were developed using an iterative, multi-phased, multi-method and multi-stakeholder consensus building approach. This consensus approach used a range of online and face to face methods across three phases to ensure ongoing engagement with multiple stakeholders. The views and perspectives of 203 children and young people, 78 parents and 418 multi-disciplinary professionals gathered over a two year period (2020-2022) informed the development of international rights-based standards for the care of children having tests, treatments, examinations and interventions. The standards are the first to reach international multi-stakeholder consensus on definitions of supportive and restraining holds.    Conclusion: This is the first study of its kind which outlines international rights-based procedural care standards from multi-stakeholder perspectives. The standards offer health professionals and educators clear evidence-based tools to support discussions and practice changes to challenge prevailing assumptions about holding or restraining children and instead encourage a focus on the interests and rights of the child. What is Known: • Children continue to experience short and long-term harm when undergoing clinical procedures despite increased evidence of the need to improve the provision of child-centred care. • Professionals report uncertainty and tensions in applying evidence-based practice to children's procedural care. What is New: • This is the first study of its kind which has developed international rights-based procedural care standards from multi-stakeholder perspectives. • The standards are the first to reach international multi-stakeholder consensus on definitions of supportive and restraining holds.

Evaluation of bioadhesive gels for local action in the esophagus.

Direct drug administration to the esophagus faces several obstacles, including continuous salivary dilution and removal of the dosage form from the tissue surface due to esophageal peristalsis. These actions often result in short exposure times and reduced concentrations of drug at the esophageal surface, providing limited opportunities for drug absorption into or across the esophageal mucosa. A variety of bioadhesive polymers were investigated for their ability to resist removal by salivary washings using an ex vivo porcine esophageal tissue model. Hydroxypropylmethylcellulose and carboxymethylcellulose both have reported bioadhesive properties, but neither was able to withstand repeated exposure to saliva, and the gels formulated with these polymers were quickly removed from the esophageal surface. Two polyacrylic polymers, carbomer and polycarbophil, also showed limited esophageal surface retention when exposed to salivary washing, likely due to the ionic composition of saliva affecting the inter-polymer interactions necessary for these polymers to maintain their increased viscosities. In situ gel forming polysaccharide gels (ion-triggered), including xanthan gum, gellan gum, and sodium alginate, showed superior tissue surface retention, and formulations containing these bioadhesive polymers along with ciclesonide, an anti-inflammatory soft prodrug, were investigated as potential, locally-acting esophageal delivery systems. Exposure of a segment of esophagus to the ciclesonide-containing gels resulted in therapeutic concentrations of des-ciclesonide, the active drug metabolite, in the tissues within 30 min. Increasing des-CIC concentrations were also observed over a 3-hour exposure interval suggesting continued release and absorption of ciclesonide into the esophageal tissues. These results demonstrate the ability to achieve therapeutic drug concentrations in the esophageal tissues using in situ gel-forming bioadhesive polymer delivery systems, and these systems provide promising opportunities for the local treatment of esophageal disease.

Validity, Reliability, and Differential Item Functioning of English and French Versions of the 10-Item Connor-Davidson Resilience Scale in Systemic Sclerosis: A Scleroderma Patient-Centered Intervention Network Cohort Study.

OBJECTIVE: Some individuals with systemic sclerosis (SSc) report positive mental health, despite severe disease manifestations, which may be associated with resilience, but no resilience measure has been validated in SSc. This study was undertaken to assess the validity, reliability, and differential item functioning (DIF) between English- and French-language versions of the 10-item Connor-Davidson Resilience Scale (CD-RISC-10) in SSc. METHODS: Eligible participants were enrolled in the Scleroderma Patient-centered Intervention Network Cohort and completed the CD-RISC-10 between August 2022 and January 2023. We used confirmatory factor analysis (CFA) to evaluate the CD-RISC-10 factor structure and conducted DIF analysis across languages with Multiple Indicators Multiple Causes models. We tested convergent validity with another measure of resilience and measures of self-esteem and depression and anxiety symptoms. We assessed internal consistency and test-retest reliability using Cronbach's alpha and intraclass correlation coefficient (ICC). RESULTS: A total of 962 participants were included in this analysis. CFA supported a single-factor structure (Tucker-Lewis index = 0.99, comparative fit index = 0.99, root mean square error of approximation = 0.08 [90% confidence interval (90% CI) 0.07, 0.09]). We found no meaningful DIF. Internal consistency was high (α = 0.93 [95% CI 0.92, 0.94]), and we found that correlations with other measures of psychological functioning were moderate to large (|r| = 0.57-0.78) and confirmed study hypotheses. The scale showed good 1-2-week test-retest reliability (ICC 0.80 [95% CI 0.75, 0.85]) in a subsample of 230 participants. CONCLUSION: The CD-RISC-10 is a valid and reliable measure of resilience in SSc, with score comparability across English and French versions.

Adequacy of using a single nasal swab for rapid influenza diagnostic testing, PCR, and whole genome sequencing.

Rapid influenza diagnostic tests (RIDT) demonstrate varying sensitivities, often necessitating reverse transcriptase polymerase chain reaction (RT-PCR) to confirm results. The two methods generally require separate specimens. Using the same anterior nasal swab for both RIDT and molecular confirmation would reduce cost and waste and increase patient comfort. The aim of this study was to determine if RIDT residual nasal swab (rNS) specimens are adequate for RT-PCR and whole genome sequencing (WGS). We performed RT-PCR and WGS on paired rNS and nasopharyngeal or oropharyngeal (NP/OP) swab specimens that were collected from primary care patients across all ages. We randomly selected 199 and 40 paired specimens for RT-PCR and WGS, respectively, from the 962 paired surveillance specimens collected during the 2014-2015 influenza season. Sensitivity and specificity for rNS specimens were 81.3% and 96.7%, respectively, as compared to NP/OP specimens. The mean cycle threshold (Ct) value for the NP/OP specimen was significantly lower when the paired specimens were both positive than when the NP/OP swab was positive and the nasal swab was negative (25.5 vs 29.5; p<0.001). Genomic information was extracted from all 40 rNS specimens and 37 of the 40 NP/OP specimens. Complete WGS reads were available for 67.5% (14 influenza A; 13 influenza B) of the rNS specimens and 59.5% (14 influenza A; 8 influenza B) of the NP/OP specimens. It is feasible to use a single anterior nasal swab for RIDT followed by RT-PCR and/or WGS. This approach may be appropriate in situations where training and supplies are limited. Additional studies are needed to determine if residual nasal swabs from other rapid diagnostic tests produce similar results.

Dioptric differences between clinically determined and metric-optimised refractions for adults with Down syndrome.

PURPOSE: Refractions based on the optimisation of single-value wavefront-derived metrics may help determine appropriate corrections for individuals with Down syndrome where clinical techniques fall short. This study compared dioptric differences between refractions obtained using standard clinical techniques and two metric-optimised methods: visual Strehl ratio (VSX) and pupil fraction tessellated (PFSt), and investigated characteristics that may contribute to the differences between refraction types. METHODS: Thirty adults with Down syndrome (age = 29 ± 10 years) participated. Three refractive corrections (VSX, PFSt and clinical) were determined and converted to vector notation (M, J0 , J45 ) to calculate the dioptric difference between pairings of each type using a mixed model repeated measures approach. Linear correlations and multivariable regression were performed to examine the relationship between dioptric differences and the following participant characteristics: higher order root mean square (RMS) for a 4 mm pupil diameter, spherical equivalent refractive error and Vineland Adaptive Behavior Scales (a measure of developmental ability). RESULTS: The least squares mean estimates (standard error) of the dioptric differences for each pairing were as follows: VSX versus PFSt = 0.51 D (0.11); VSX versus clinical = 1.19 D (0.11) and PFSt versus clinical = 1.04 D (0.11). There was a statistically significant difference in the dioptric differences between the clinical refraction and each of the metric-optimised refractions (p < 0.001). Increased dioptric differences in refraction were correlated with increased higher order RMS (R = 0.64, p < 0.001 [VSX vs. clinical] and R = 0.47, p < 0.001 [PFSt vs. clinical]) as well as increased myopic spherical equivalent refractive error (R = 0.37, p = 0.004 [VSX vs. clinical] and R = 0.51, p < 0.001 [PFSt vs. clinical]). CONCLUSIONS: The observed differences in refraction demonstrate that a significant portion of the refractive uncertainty is related to increased higher order aberrations and myopic refractive error. Methodology surrounding clinical techniques and metric-optimisation based on wavefront aberrometry may explain the difference in refractive endpoints.