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Perturbation of thyroid hormone (T4) synthesis is known to cause numerous developmental, metabolic, and cognitive disorders in humans. Due to species differences in sensitivity to chemical exposures, there is a need for human-based in vitro approaches that recapitulate thyroid cellular architecture and T4 production when screening. To address these limitations, primary human thyrocytes, isolated from healthy adult donor tissues and cryopreserved at passage one (p’1) were characterized for cellular composition, 3D follicular architecture, and thyroglobulin (TG)/T4 expression and inhibition by prototype thyroid disrupting chemicals (TDC). Flow analysis of the post-thaw cell suspension showed >80% EpCAM-positive cells with 10%–50% CD90-positive cells. When seeded onto 96-well Matrigel®-coated plates and treated with bovine thyroid stimulating hormone (TSH), thyrocytes formed 3D microtissues during the initial 4–5 days of culture. The microtissues exhibited a stable morphology and size over a 14-day culture period. TG and T4 production were highest in microtissues when the proportion of CD90-positive cells, seeding density and thyroid stimulating hormone concentrations were between 10%–30%, 6K–12K cells per well, and 0.03–1 mIU/mL, respectively. At maximal TG and T4 production levels, average microtissue diameters ranged between 50 and 200 µm. The T4 IC50 values for two prototype TPO inhibitors, 6-propyl-2-thiouracil and methimazole, were ∼0.7 µM and ∼0.5 µM, respectively, in microtissue cultures treated between days 9 and 14. Overall, p’1 cryopreserved primary human thyrocytes in 3D microtissue culture represent a promising new model system to prioritize potential TDC acting directly on the thyroid as part of a weight-of-evidence hazard characterization.

Background:. Our objective was to develop a clinical practice guideline (CPG) for the treatment of acute lower extremity fractures in persons with a chronic spinal cord injury (SCI). Methods:. Information from a previous systematic review that addressed lower extremity fracture care in persons with an SCI as well as information from interviews of physical and occupational therapists, searches of the literature, and expert opinion were used to develop this CPG. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to determine the quality of evidence and the strength of the recommendations. An overall GRADE quality rating was applied to the evidence. Conclusions:. Individuals with a chronic SCI who sustain an acute lower extremity fracture should be provided with education regarding the risks and benefits of operative and nonoperative management, and shared decision-making for acute fracture management should be used. Nonoperative management historically has been the default preference; however, with the advent of greater patient independence, improved surgical techniques, and advanced therapeutics and rehabilitation, increased use of surgical management should be considered. Physical therapists, kinesiotherapists, and/or occupational therapists should assess equipment needs, skills training, and caregiver assistance due to changes in mobility resulting from a lower extremity fracture. Therapists should be involved in fracture management as soon as possible following fracture identification. Pressure injuries, compartment syndrome, heterotopic ossification, nonunion, malunion, thromboembolism, pain, and autonomic dysreflexia are fracture-related complications that clinicians caring for patients who have an SCI and a lower extremity fracture may encounter. Strategies for their treatment are discussed. The underlying goal is to return the patient as closely as possible to their pre-fracture functional level with operative or nonoperative management.

Abstract The development of a limited area model (LAM) capability for the nonhydrostatic Finite‐Volume Cubed‐Sphere (FV3) dynamical core is described and compared with a globally nested approach featuring two‐way feedback. Comparisons of the computational performance of the LAM relative to the two‐way nest reveal that the LAM configuration exhibits considerable improvement in efficiency. High‐resolution (i.e., 3‐km) LAM and nest configuration forecasts covering a 1‐month period show statistically comparable results for most parameters. Forecast differences between the two configurations primarily arise in the upper air temperature and height fields, which show a statistically significant increase in the magnitude of negative biases in geopotential height and upper‐air temperature using the LAM configuration relative to the nest at forecast lead times >24‐h. Precipitation forecasts over the full 60‐h forecast period are also evaluated and depict no statistically significant differences between the two configurations, with the nest configuration exhibiting slightly improved scores. Overall results suggest that while the FV3 LAM approach can introduce degradations into the forecast relative to the two‐way interactive nest at lead times >24‐h, these errors are generally small in magnitude and are accompanied by considerable improvement in computational efficiency.

An estimated 8.7% to 9.8% of school-age children in the United States have attention deficit hyperactivity disorder (ADHD), affecting 4.3 to 4.9 million public school students. ADHD is a costly disorder that often goes untreated, especially among adolescents. Accessible computer- based programs have emerged to address the neurocognitive deficits of ADHD, but results to date have been disappointing. In this study, we tested the acceptability, playability, and user satisfaction of a novel planning/organization skills training game, called "ATHEMOS," based on an established psychosocial treatment package (i.e., Challenging Horizons Program). We conducted eight focus groups during a three-year development period, using feedback from 72 young adolescents with ADHD to iteratively improve the game. Then, during a pilot study in the fourth year, we collected data from 16 young adolescents who played the game as part of a 6- to 16-week school-based intervention. Our findings suggest that the serious game resulted in acceptability and playability ratings only moderately below that of recreational games ([delta]= -0.40). Critically, average perceptions remained positive when delivered within a school-based ADHD intervention over several weeks or months, with strong overall user satisfaction. Boys found the game more acceptable than girls, with ratings near that of recreational games ([delta] = -0.23). We conclude that computer-assisted behavior interventions appeal to adolescents with ADHD and offer a potentially promising treatment delivery method in schools.

There is a paucity of data regarding renal trauma. The majority of cases of renal trauma are amenable to conservative management. We sought to streamline the management of renal trauma in the west of Ireland. Patients presenting with a computerised tomogram–confirmed renal injury were assessed over 5 years. Patient demographics, injury details, initial emergency department management, definitive management, and follow-up were assessed. Renal trauma was graded in a blind fashion (I-V). Twenty-five patients were identified; male:female (23:2). The mean age was 26 years. The majority of renal traumas were managed conservatively (92%); 8% patients underwent nephrectomy. The common mechanisms of renal injuries were road traffic accidents (44%). The majority of cases of renal injuries occur as a result of blunt trauma and can be conservatively treated. Two nephrectomies (8%) were performed. We believe this study potentially can be beneficial as part of an all-Ireland trauma database to improve patient outcome.

We performed a left nephroureterectomy for a gentleman with transitional cell carcinoma of the upper ureter. Histological analysis revealed it to be a T1 lesion, but to be highly mitotically active. The gentleman defaulted on adjuvant therapy and defaulted on follow-up. He represented with symptoms of acute spinal cord compression and magnetic resonance imaging demonstrated a lesion at T6/7. Neurosurgical resection of the lesion showed it to be a metastatic deposit from the ureteric primary. Despite surgical debulking and subsequent radiotherapy to the lesion, the patient died secondary to metastatic complications. This case report is of interest to the surgeon as it demonstrates both the high metastatic potential of upper tract carcinomas and educates the surgeon on the presentation of acute spinal cord compression.

How can universities support their students in pursuing civil rights activism? In doing so, how can universities prioritize students from marginalized communities who are most affected by justice issues? This paper will explore lessons learned from the nation's first civil rights clinic at the undergraduate level. Responding to the urgency of our time, the University of Southern California, Dornsife College, launched "Agents of Change: Civil Rights Advocacy Initiative" in January 2021 to support students in addressing civil rights challenges in the Los Angeles community. This paper will discuss the importance of the civil rights activism clinical model at the college level. It will also cover challenges and best practices in creating a college-level civil rights program that incorporates hands-on field work, community partnerships, mentorship, and custom-tailored curricular classes and modules.

The concept of ‘learned disuse’ is thought to be a signifcant barrier to recovery of sensory-motor function following a stroke. Unimpaired individuals learn new skills though practice, with feedback in various forms, but the problem facing the stroke patient is that they are unable to practice because of impaired motor control. Functional electrical stimulation (FES) can provide the experience for the patient of moving and consequently may limit the problem of learnt disuse and has been used with some success to improve recovery of upper limb motor control. Recent studies have shown that when stimulation is associated with a voluntary attempt to move the limb, improvement is enhanced but these techniques do not allow feedback that could be used to adjust stimulation parameters and thus provide more precise stimulation. This paper describes the design and construction of an experimental test facility that has been designed as part of a current project whose aim is to investigate the use of iterative learning control (ILC) and related strategies to mediate the electrical stimulation applied to a number of muscles of the shoulder and upper limb of stroke patients.

Esophageal cancer (EC) is an aggressive malignancy with an increasing incidence and a poor prognosis. EC is histologically divided into two major categories: adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). EAC and ESCC are molecularly different and therefore treatments should reflect the respective histological subtype. Combined modality therapy is needed for localized EC. When EC is advanced (stage 4), systemic therapy is the mainstay treatment for palliation. For localized EC, several strategies are considered standard, and more trials are necessary to determine a unified and more effective approach. The management for advanced EC is slowly evolving as immunotherapy is showing some promise for ESCC, but more data from ongoing studies are anticipated. Treatment advances will be based on high-definition genomic investigation of individual tumors. Herein, we review the contemporary trends in diagnosing and treating EAC and ESCC.

Purpose: Few studies have examined how the absolute risk of thromboembolism with COVID-19 has evolved over time across different countries. Researchers from the European Medicines Agency, Health Canada, and the United States (US) Food and Drug Administration established a collaboration to evaluate the absolute risk of arterial (ATE) and venous thromboembolism (VTE) in the 90 days after diagnosis of COVID-19 in the ambulatory (eg, outpatient, emergency department, nursing facility) setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. Patients and Methods: We conducted cohort studies of patients initially diagnosed with COVID-19 in the ambulatory setting from the seven specified countries. Patients were followed for 90 days after COVID-19 diagnosis. The primary outcomes were ATE and VTE over 90 days from diagnosis date. We measured country-level estimates of 90-day absolute risk (with 95% confidence intervals) of ATE and VTE. Results: The seven cohorts included 1,061,565 patients initially diagnosed with COVID-19 in the ambulatory setting before COVID-19 vaccines were available (through November 2020). The 90-day absolute risk of ATE during this period ranged from 0.11% (0.09– 0.13%) in Canada to 1.01% (0.97– 1.05%) in the US, and the 90-day absolute risk of VTE ranged from 0.23% (0.21– 0.26%) in Canada to 0.84% (0.80– 0.89%) in England. The seven cohorts included 3,544,062 patients with COVID-19 during vaccine availability (beginning December 2020). The 90-day absolute risk of ATE during this period ranged from 0.06% (0.06– 0.07%) in England to 1.04% (1.01– 1.06%) in the US, and the 90-day absolute risk of VTE ranged from 0.25% (0.24– 0.26%) in England to 1.02% (0.99– 1.04%) in the US. Conclusion: There was heterogeneity by country in 90-day absolute risk of ATE and VTE after ambulatory COVID-19 diagnosis both before and during COVID-19 vaccine availability. Plain Language Summary: Cohort studies of patients diagnosed with COVID-19 in both the ambulatory and hospital settings have suggested that SARS-CoV-2 infection promotes hypercoagulability that could lead to arterial or venous thromboembolism. However, few studies have examined how the risk of thromboembolism with COVID-19 has evolved over time across different countries. A new collaboration was established among the regulatory authorities of Canada, Europe, and the US within the International Coalition of Medicines Regulatory Authorities to evaluate the 90-day risk of both arterial and venous thromboembolism after initial diagnosis of COVID-19 in the ambulatory or hospital setting from seven countries across North America (Canada, US) and Europe (England, Germany, Italy, Netherlands, and Spain) within periods before and during COVID-19 vaccine availability. The study found that there was variability in the risk of both arterial and venous thromboembolism by month across the countries among patients initially diagnosed with COVID-19 in the ambulatory or hospital setting. Differences in the healthcare systems, prevalence of comorbidities in the study cohorts, and approaches to the case definitions of thromboembolism likely contributed to the variability in estimates of thromboembolism risk across the countries. [ABSTRACT FROM AUTHOR]