Reflex strategy to ensure accurate total testosterone results from consumer initiated, self-collected capillary samples.

BACKGROUND: Self-collected capillary samples are convenient for direct access testing (DAT), but exogenous testosterone use may cause falsely elevated total testosterone (TT) results. We designed a quality assurance workflow to differentiate between accurate or erroneous supraphysiological TT concentrations. METHODS: Clinical samples with TT > 1500 ng/dL were reflexed to luteinizing hormone (LH) and follicle stimulating hormone (FSH) and screened for exogenous testosterone use. Samples (n = 120) with normal TT were reflexed to LH/FSH as a control. RESULTS: A total of 8572 TT samples were evaluated, of which 533 (6.2 %) had TT > 1500 ng/dL and were reflexed. Of these, 441 (82.7 %) had significantly decreased LH/FSH (<0.85/<0.7mIU/mL, respectively), 72 (13.5 %) had normal or borderline normal LH/FSH, and 20 (3.8 %) had insufficient plasma volume. In patients with TT > 1500 ng/dL, injectable exogenous testosterone use was most commonly accompanied by significantly decreased LH/FSH, while topical testosterone use was most commonly accompanied by detectable LH/FSH. Control samples were almost all (99.2 %) within or above the LH/FSH reference intervals. Unique patients ordered 351 TT tests where at least one TT result was > 1500 ng/dL. Based on TT and LH/FSH results, we hypothesized that patients were intermittently or consistently overusing exogenous testosterone, resolved elevated TT with recollection, or repeatedly contaminated their sample. CONCLUSION: Self-collected capillary specimens are acceptable for TT testing. A quality assurance reflex to LH/FSH can determine the validity of supraphysiological TT results in a consumer initiated/DAT population.

Strengthening oropharyngeal muscles as an approach to treat post-stroke obstructive sleep apnea: A feasibility randomised controlled trial.

This study aimed to determine the feasibility of a randomised controlled trial (RCT) evaluating oropharyngeal exercise (OPE) intervention as an alternative therapy for obstructive sleep apnea (OSA) in patients with stroke or transient ischaemic attack (TIA). Despite the high prevalence of OSA in this population, the standard therapy, continuous positive airway pressure (CPAP), is often poorly tolerated. Thirty stroke/TIA patients with OSA unable to tolerate CPAP were randomly assigned to an oropharyngeal exercise or sham exercise protocol. They performed exercises for 6 weeks, 5 days per week, 30 minutes twice per day. Feasibility was ascertained by the proportion of enrolled patients who completed more than 80% of the OPE regimen. Isometric tongue pressures, apnea-hypopnea index (AHI), oxygen desaturation index (ODI), daytime sleepiness, and quality of life (QOL) outcomes were collected at baseline, post-training (6-week follow-up), and retention (10-week follow-up) to document preliminary efficacy. Adherence to study exercises was excellent, with 83% of participants completing more than 80% of the exercises. The isometric tongue pressures were observed to improve in the oropharyngeal exercise group (compared with the sham group), along with a decrease in OSA severity (measured by the AHI and ODI), reduced daytime sleepiness, and enhanced quality of life outcomes following the exercise programme. Only the effects on posterior isometric tongue pressure and daytime sleepiness remained significantly different between groups at the retention session. In conclusion, an RCT evaluating the efficacy of oropharyngeal exercises on post-stroke/TIA OSA is feasible and our preliminary results suggest a clinically meaningful effect.

Development and validation of a model gene therapy biodistribution assay for AVGN7 using digital droplet polymerase chain reaction.

Biodistribution assays are integral to gene therapy commercialization and have traditionally used real-time qPCR. Droplet digital PCR (ddPCR), however, has distinct advantages including higher sensitivity and absolute quantification but is underused because of lacking regulatory guidance and meaningful examples in the literature. We report a fit-for-purpose model process to validate a good laboratory practice (GLP)-compliant ddPCR assay for AVGN7, a Smad7 gene therapeutic for muscle wasting. Duplexed primer/probe sets for Smad7 and mouse TATA-box binding protein were optimized using gBlock DNA over a dynamic range of 10-80,000 copies/reaction in 250 ng mouse gDNA. Linearized plasmid and mouse gDNA were used for validation, which determined precision, accuracy, ruggedness/robustness, selectivity, recovery, specificity, dilution linearity, and stability. Inter-run precision and accuracy met previously established criteria with bias between -5% and 15%, coefficient of variation (CV) less than 19%, and total error within 8%-35%. The limit of detection was 2.5 copies/reaction, linearity was confirmed at 40-80,000 copies/reaction, specificity was demonstrated by single droplet populations and assay stability was demonstrated for benchtop, refrigerated storage, and repeated freeze-thaw cycles. The procedural road map provided exceeds recently established standards. It is also relevant to many IND-enabling processes, as validated ddPCR assays can be used in biodistribution studies and with vector titering and manufacturing quality control.

Role of Race and Insurance Status in Prostate Cancer Diagnosis-to-Treatment Interval.

INTRODUCTION: Numerous studies have shown that both race and insurance status may affect prostate cancer (PCa) workup and treatment. Preliminary investigations have shown that these factors may be associated with treatment delays, which may indicate inequitable care and increase risk of tumor progression. This investigation aimed to assess whether race and insurance impacted the interval between multiparametric MRI (mpMRI)-to-biopsy, and biopsy-to-prostatectomy. MATERIALS AND METHODS: A single-institution analysis of 261 patients with recorded race and insurance data was performed using an Institutional Review Board-compliant database with information spanning from 2016 to 2022. Race was self-reported during intake, and insurance status was retrieved from the electronic medical record. Insurance was sub-divided into private, Medicare, and Medicaid. Diagnostic or treatment latency was defined as time between mpMRI-to-biopsy, or biopsy-to-surgery. RESULTS: Stratified by race, there was no difference in either latency period when comparing African American (AA) and white patients. Stratified by insurance status, there was no difference in time from mpMRI-to-biopsy (P = .50), but there was a significantly longer interval from biopsy-to-prostatectomy for patients with Medicaid insurance (P = .02). Patients with Medicaid waited on average 168 days to receive surgery, in contrast to 92 days for private and 87 for Medicare. Notably, 82% of Medicaid patients were AA. CONCLUSION: Insurance status, which is inherently linked to race and social determinants of health, portended a significantly increased interval between biopsy and surgery. Physicians should be aware of the relationship between insurance status and treatment delay, as well as its potential downstream consequences.

Psychometric Properties of a New Measure of Upper Limb Performance in Post-Stroke Individuals: Trunk-Based Index of Performance.

BACKGROUND: Several measures of upper limb (UL) motor tasks have been developed to characterize recovery. However, UL performance and movement quality measures in isolation may not provide a true profile of functional recovery. OBJECTIVE: To investigate the measurement properties of a new trunk-based Index of Performance (IPt) of the UL combining endpoint performance (accuracy and speed) and movement quality (trunk displacement) in stroke. METHODS: Participants with stroke (n = 25, mean time since stroke: 18.7 ± 17.2 months) performed a reaching task over 3 evaluation sessions. The IPt was computed based on Fitts' Law that incorporated endpoint accuracy and speed corrected by the amount of trunk displacement. Test-retest reliability was analyzed using intraclass correlation coefficient (ICC) and Bland-Altman plots. Standard error of measurement (SEM) and Minimal Detectable Change (MDC) were determined. Validity was investigated through the relationship between IPt, Fugl-Meyer Assessment (FMA-UE), and Action Research Arm Test (ARAT), as well as the ability of IPt to distinguish between levels of UL motor impairment severity. RESULTS: Test-retest reliability was excellent (ICC = .908, 95% CI: 0.807-0.96). Bland-Altman did not show systematic differences. SEM and MDC95 were 14% and 39%, respectively. Construct validity was satisfactory. The IPt showed low-to-moderate relationships with FMA-UE (R2 ranged from .236 to .428) and ARAT (R2 ranged from .277 to .306). IPt scores distinguished between different levels of UL severity. CONCLUSIONS: The IPt showed evidence of good reliability, and initial validity. The IPt may be a promising tool for research and clinical settings. Further research is warranted to investigate its validity with additional comparator instruments.

Functional Neuroplasticity and Motor Skill Change Following Gross Motor Interventions for Children With Diplegic Cerebral Palsy.

BACKGROUND: Gross motor intervention designs for children with diplegic cerebral palsy (DCP) require an improved understanding of the children's potential for neuroplasticity. OBJECTIVE: To identify relations between functional neuroplasticity and motor skill changes following gross motor interventions for children with DCP. METHODS: There were 17 participants with DCP (ages 8-16 years; 6 females; Gross Motor Function Classification System Level I [n = 9] and II [n = 8]). Each completed a 6-week gross motor intervention program that was directed toward achievement of individualized motor/physical activity goals. Outcomes were assessed pre/post and 4 to 6 months post-intervention (follow-up). An active ankle dorsiflexion task was completed during functional magnetic resonance imaging. The ratio of motor cortical activation volume in each hemisphere was calculated using a laterality index. The Challenge was the primary gross motor skill measure. Change over time and relations among outcomes were evaluated. RESULTS: Challenge scores improved post-intervention (4.57% points [SD 4.45], P = .004) and were maintained at follow-up (0.75% [SD 6.57], P = 1.000). The laterality index for dominant ankle dorsiflexion increased (P = .033), while non-dominant change was variable (P = .534). Contralateral activation (laterality index ≥+0.75) was most common for both ankles. Challenge improvements correlated with increased ipsilateral activity (negative laterality index) during non-dominant dorsiflexion (r = -.56, P = .045). Smaller activation volume during non-dominant dorsiflexion predicted continued gross motor gains at follow-up (R2 = .30, P = .040). CONCLUSIONS: Motor cortical activation during non-dominant ankle dorsiflexion is a modest indicator of the potential for gross motor skill change. Further investigation of patterns of neuroplastic change will improve our understanding of effects. CLINICALTRIALS.GOV REGISTRY: NCT02584491 and NCT02754128.

The role of oral and pharyngeal motor exercises in post-stroke recovery: A scoping review.

OBJECTIVE: To analyze intervention goals, protocols, and outcome measures used for oral and pharyngeal motor exercises in post-stroke recovery. DATA SOURCES: MEDLINE, EMBASE, CINAHL, PsychINFO, and Cochrane databases were searched in September 2022. METHODS: Studies were included if they (1) recruited post-stroke adult patients, (2) administered exercises for the oral and/ or pharyngeal muscles, and (3) reported results at baseline and post-exercise. The extracted data included intervention goals, protocols, and outcomes. All outcomes were classified according to the International Classification of Functioning, Disability and Health (ICF). RESULTS: A total of 26 studies were identified. Their intervention goals aimed to rehabilitate a broad spectrum of muscle groups within the oral cavity and pharynx and to improve the functions of swallowing, speech, facial expressions, or sleep breathing. Protocol duration ranged from 1 to 13 weeks, with various exercise repetitions (times per day) and frequency (days per week). Half of the studies reported using feedback to support the training, and these studies varied in the feedback strategy and technology tool. A total of 37 unique outcome measures were identified. Most measures represented the body functions and body structure component of the ICF, and several of these measures showed large treatment effects. CONCLUSIONS: This review demonstrated inconsistency across published studies in intervention goals and exercise protocols. It has also identified current limitations and provided recommendations for the selection of outcome measures while advancing a multidisciplinary view of oral and pharyngeal exercises in post-stroke recovery across relevant functions.

Characteristics and Perspectives of Human Trafficking Education: A Survey of U.S. Medical School Administrators and Students.

Objective: To assess the timing, duration, methodology, and content of human trafficking (HT) curricula in U.S. medical schools. Methods: An anonymous, cross-sectional survey was sent through email and phone to administrators of 199 U.S. allopathic and osteopathic medical schools. A supplementary survey was sent to students and faculty through email listservs and social media links. Data collection occurred from April to October 2020 and findings were analyzed through SAS software. All study measures were approved by the institutional review board. Results: Administrators were from 22 states and 34 schools (n = 51/199 schools; response rate: 25.6%) and n = 41 responded to all questions. Of these, 32% (13/41) self-identified as deans, 34.1% (14/41) as faculty, and 29.3% (12/41) as other administrators. Less than half (41.5%, n = 17/41) reported an HT curriculum. There was a wide range in length (average = 3 hours) and when present was almost always mandatory (n = 51, 88.2%). Few curricula mentioned labor (23.5%) or organ (5.9%) trafficking, or at-risk populations such as lesbian, gay, bisexual, trans, queer, and intersex (LGBTQI) members (13.7%), foreign nationals (7.8%), victims of political conflict (3.9%), and indigenous peoples (2.0%). Students and staff (n = 242) were from 34 states and 83 schools, and n = 36 (27.5%) reported a curriculum. Less than half (44.4%) felt the length (average 4.1 hours) was sufficient. Conclusions: Less than half of respondents reported an HT curriculum. It is unclear how well this curriculum prepares students to treat victim-survivors of HT. Future work is necessary to incorporate effective education on HT for trainees and evaluate patient outcomes after curricular implementation.

Transcranial direct current stimulation leads to faster acquisition of motor skills, but effects are not maintained at retention.

Practice is required to improve one's shooting technique in basketball or to play a musical instrument well. Learning these motor skills may be further enhanced by transcranial direct current stimulation (tDCS). We aimed to investigate whether tDCS leads to faster attainment of a motor skill, and to confirm prior work showing it improves skill acquisition and retention performance. Fifty-two participants were tested; half received tDCS with the anode on primary motor cortex and cathode on the contralateral forehead while concurrently practicing a sequential visuomotor isometric pinch force task on Day 1, while the other half received sham tDCS during practice. On Day 2, retention of the skill was tested. Results from a Kaplan-Meier survival analysis showed that participants in the anodal group attained a pre-defined target level of skill faster than participants in the sham group (χ2 = 9.117, p = 0.003). Results from a nonparametric rank-based regression analysis showed that the rate of improvement was greater in the anodal versus sham group during skill acquisition (F(1,249) = 5.90, p = 0.016), but there was no main effect of group or time. There was no main effect of group or time, or group by time interaction when comparing performance at the end of acquisition to retention. These findings suggest anodal tDCS improves performance more quickly during skill acquisition but does not have additional benefits on motor learning after a period of rest.

Reevaluating Corticosteroid Classification Models in Patient Patch Testing.

Importance: Individuals with allergic contact dermatitis to one topical corticosteroid may also react to other corticosteroids. Corticosteroid classification models have been proposed to predict such copositivity, recommend representative screening corticosteroids, and guide allergen avoidance. Objective: To use patient data to determine copositivity patterns between corticosteroids and evaluate against previous corticosteroid classification models. Design, Setting, and Participants: This qualitative study included a retrospective analysis of the Mayo Clinic Contact Dermatitis Group corticosteroid patch test data from 2010 to 2019. Among patients undergoing patch testing with the Mayo Clinic's standard or steroid series who consented to research participation, 5637 patients were included in the analysis. Copositivity rates were determined between corticosteroids and analyzed by hierarchical clustering for comparison to previous classification models. Main Outcomes and Measures: The frequency of patch test positivity to each of the analyzed corticosteroids was noted and compared with previously published patch test positivity rates. Copositivity rates between each pair of corticosteroids were determined, and overall copositivity patterns were analyzed and evaluated against known steroid classes. Results: A total of 49 472 individual patches were applied to 5637 patients, testing 18 corticosteroids. Patch test positivity rates ranged between 0.3% and 4.7%. The fluocinonide positivity rate corresponded to the highest copositivity rate with other corticosteroids (mean [SD], 50.7% [26.1%]). Tixocortol-21-pivalate, 0.1%, and tixocortol-21-pivalate, 1%, positivity rates corresponded to the lowest copositivity rates (mean [SD], 4.1% [1.7%] and 3.6% [1.4%], respectively). Hierarchical clustering elucidated patterns that did not support previous corticosteroid classification models. Conclusions and Relevance: In this qualitative study, copositivity rates were variable between corticosteroids, and overall patch test positivity for allergy to topical corticosteroids was rare. Previously published corticosteroid classifications are not supported by real patient-derived data and may not be accurate in predicting corticosteroid copositivity.

Decreasing the Lower Limit of Quantitation for Urine Albumin Improves Clinical Utility.

BACKGROUND: Urine albumin-to-creatinine ratio (uACR) is a screening assay for chronic kidney disease (CKD). A value of >30 mg/g is flagged abnormal, but lower ratios have prognostic implications. Thus, to maximize diagnostic utility, urine albumin (uAlb) should be measurable to 3 mg/L to match the lowest creatinine concentration generally utilized (10 mg/dL). Most uAlb assays have lower limits of quantitation (LLOQs) 2- to 4-fold higher. We sought to determine the performance characteristics of a commonly used uAlb assay at 3 mg/L and to evaluate the clinical screening impact of reducing the LLOQ. METHODS: Urine was serially diluted to assess uAlb linearity and precision for concentrations near the claimed LLOQ (12 mg/L). Samples (n = 30) with uAlb <12 mg/L were compared between laboratories. Sequential samples (n = 1239) were evaluated for clinical impact of reducing the measuring range to 3 mg/L. RESULTS: The assay was linear to 1.6 mg/L. Interday precision at 3.7 mg/L and 4.3 mg/L was 7.7% and 8.6%, respectively. Minimal bias was observed between labs (y = 1.091x - 0.75; average bias = -0.13 mg/L). Clinical validation demonstrated 501 of 1239 samples (40.4%) had uAlb <12 mg/L. Using 11.9 mg/L as the numerator for samples with uAlb <12 mg/dL and urine creatinine >10 mg/L, 107 of 499 (21.4%) would have a ratio flagged abnormal at >30 mg/g. Using the numeric value for these samples to 3 mg/L reduced alarm to <1%. CONCLUSIONS: A uAlb LLOQ of 3 mg/L improves screening utility of uACR by simplifying reporting and clinical interpretation when uAlb is low and provides clinical information for prognostic tools developed for people at risk of CKD.

Changes in Companion Diagnostic Labelling: Implementation of FDA's April 2020 Guidance for Industry for In Vitro CDx Labeling for Specific Oncology Therapeutic Groups.

Advanced understanding of the molecular pathways of oncologic diseases has shifted therapeutic treatment development to focus on mechanism of actions targeting specific genomic alterations. These precision medicines are indicated for patient subsets defined by these specific mutations as determined by diagnostic devices approved by the Food and Drug Administration (FDA). The Intended Use section within the companion diagnostic (CDx) labeling has historically specified the therapeutic products for which they have been clinically validated. In April 2020, the FDA reiterated their position that therapeutic class labeling may be used, if appropriate, instead of named products. Labels for FDA approved in vitro CDxs were reviewed to evaluate the implementation of therapeutic class labeling. A total of 47 devices have been approved as of 2 January 2022, of which 3 labels were found to contain therapeutic class labeling: two devices targeting EGFR mutations for the treatment of non-small cell lung cancer (NSCLC), and one targeting BRAF V600E and BRAF/MEK inhibitor combinations for melanoma. Two devices received therapeutic class labeling upon initial approval, while the third implemented the language though a label revision. A total of 25 different indications were identified across the 47 CDx devices, of which 9 (34.6%) were associated with more than 1 CDx device. Implementation of therapeutic class labeling has been slow following the release of the FDA's April 2020 guidance; however, the potential to incorporate such language into existing and newly approved CDx labels exists. Precedence and manufacturer experience are expected to drive an increase in therapeutic class labeling.

Atypical Functional Connectivity During Unfamiliar Music Listening in Children With Autism.

Background: Atypical processing of unfamiliar, but less so familiar, stimuli has been described in Autism Spectrum Disorder (ASD), in particular in relation to face processing. We examined the construct of familiarity in ASD using familiar and unfamiliar songs, to investigate the link between familiarity and autism symptoms, such as repetitive behavior. Methods: Forty-eight children, 24 with ASD (21 males, mean age = 9.96 years ± 1.54) and 24 typically developing (TD) controls (21 males, mean age = 10.17 ± 1.90) completed a music familiarity task using individually identified familiar compared to unfamiliar songs, while magnetoencephalography (MEG) was recorded. Each song was presented for 30 s. We used both amplitude envelope correlation (AEC) and the weighted phase lag index (wPLI) to assess functional connectivity between specific regions of interest (ROI) and non-ROI parcels, as well as at the whole brain level, to understand what is preserved and what is impaired in familiar music listening in this population. Results: Increased wPLI synchronization for familiar vs. unfamiliar music was found for typically developing children in the gamma frequency. There were no significant differences within the ASD group for this comparison. During the processing of unfamiliar music, we demonstrated left lateralized increased theta and beta band connectivity in children with ASD compared to controls. An interaction effect found greater alpha band connectivity in the TD group compared to ASD to unfamiliar music only, anchored in the left insula. Conclusion: Our results revealed atypical processing of unfamiliar songs in children with ASD, consistent with previous studies in other modalities reporting that processing novelty is a challenge for ASD. Relatively typical processing of familiar stimuli may represent a strength and may be of interest to strength-based intervention planning.

Differential Effects of Speech and Language Therapy and rTMS in Chronic Versus Subacute Post-stroke Aphasia: Results of the NORTHSTAR-CA Trial.

BACKGROUND & OBJECTIVE: Contralesional 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the right pars triangularis combined with speech-language therapy (SLT) has shown positive results on the recovery of naming in subacute (5-45 days) post-stroke aphasia. NORTHSTAR-CA is an extension of the previously reported NORTHSTAR trial to chronic aphasia (>6 months post-stroke) designed to compare the effectiveness of the same rTMS protocol in both phases. METHODS: Sixty-seven patients with left middle cerebral artery infarcts (28 chronic, 39 subacute) were recruited (01-2014 to 07-2019) and randomized to receive rTMS (N = 34) or sham stimulation (N = 33) with SLT for 10 days. Primary outcome variables were Z-score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment. Chronic and subacute results were compared. RESULTS: Adverse events were rare, mild, and did not differ between groups. Language outcomes improved significantly in all groups irrespective of treatment and recovery phase. At 30-day follow-up, there was a significant interaction of stimulation and recovery phase on naming recovery (P <.001). Naming recovery with rTMS was larger in subacute (Mdn = 1.91/IQR = .77) than chronic patients (Mdn = .15/IQR = 1.68/P = .015). There was no significant rTMS effect in the chronic aphasia group. CONCLUSIONS: The addition of rTMS to SLT led to significant supplemental gains in naming recovery in the subacute phase only. While this needs confirmation in larger studies, our results clarify neuromodulatory vs training-induced effects and indicate a possible window of opportunity for contralesional inhibitory stimulation interventions in post-stroke aphasia. NORTHSTAR TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02020421.

Comparison of sports skills movement training to lower limb strength training for independently ambulatory children with cerebral palsy: a randomised feasibility trial.

PURPOSE: The best approach to delivering advanced gross motor skills interventions for children with cerebral palsy (CP) is unknown. This study's aim was to assess trial feasibility and compare effectiveness of sports skills movement training (Brain change after Fun, Athletic Sports skills Training [BeFAST]) to conventional lower limb strength training (Brain change after Strength Training focusing ON Gait [BeSTRONG]) for improving advanced gross motor skills of children with CP. METHODS: Twenty independently ambulatory children with CP (mean age 12 ± 2.6 years) were randomly assigned to a 6-week programme of BeFAST or BeSTRONG, individualised to participant goals. Primary scientific outcome measures were the Challenge and Canadian Occupational Performance Measure (COPM) assessed pre/post and 4-month post-intervention. Process, resource, and management indicators assessed trial feasibility. RESULTS: There was no between group difference for the Challenge (p = 0.325), however significant post-intervention Challenge improvements were observed in BeFAST (p = 0.031) but not BeSTRONG (p = 0.055). Between group post-intervention scores were higher in BeFAST for COPM Performance (p = 0.001), and relative gains were maintained 4-month post-intervention. Pre-set criteria were met for 84% of feasibility indicators. CONCLUSIONS: Sports skills movement training may be an effective option to support advanced gross motor skill gains and target goals of independently ambulatory children with CP. Trial feasibility, including early evidence of effectiveness, indicates readiness for a full-scale randomised trial.Implications for rehabilitationChildren with cerebral palsy have potential to improve advanced gross motor skills.Strength training is a commonly used approach in gross motor therapy programmes.Sports skill training may be an effective option that better targets children's goals.