Safety and effectiveness of abatacept in juvenile idiopathic arthritis: results from the PRINTO/PRCSG registry.

OBJECTIVE: To report the interim 5-year safety and effectiveness of abatacept in patients with juvenile idiopathic arthritis (JIA) in the PRINTO/PRCSG registry. METHODS: The Abatacept JIA Registry (NCT01357668) is an ongoing observational study of children with JIA receiving abatacept; enrolment started in January 2013. Clinical sites enrolled patients with JIA starting or currently receiving abatacept. Eligible patients were assessed for safety (primary end point) and effectiveness over 10 years. Effectiveness was measured by clinical 10-joint Juvenile Arthritis Disease Activity Score (cJADAS10) in patients with JIA over 5 years. As-observed analysis is presented according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. RESULTS: As of 31 March 2020, 587 patients were enrolled; 569 are included in this analysis (including 134 new users) with 1214.6 patient-years of safety data available. Over 5 years, the incidence rate (IR) per 100 patient-years of follow-up of serious adverse events was 5.52 (95% confidence interval [CI]: 4.27, 7.01) and of events of special interest was 3.62 (95% CI: 2.63, 4.86), with 18 serious infections (IR 1.48 [95% CI: 0.88, 2.34]). As early as month 3, 55.9% of patients achieved cJADAS10 low disease activity and inactive disease (20.3%, 72/354 and 35.6%, 126/354, respectively), sustained over 5 years. Disease activity measures improved over 5 years across JIA categories. CONCLUSION: Abatacept was well tolerated in patients with JIA, with no new safety signals identified and with well-controlled disease activity, including some patients achieving inactive disease or remission. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01357668.

The effects of generating examples on comprehension and metacomprehension.

Teachers and students often report using examples to support learning. Research has shown benefits of viewing provided examples and generating examples during declarative concept learning; however, there is less work showing clear benefits when learners generate their own examples on comprehension measures while students are attempting to learn from expository science texts. The present study tested whether generating examples would be useful for improving comprehension and comprehension monitoring in the context of an undergraduate science course. In a pre-post design, students completed an initial reading activity, followed by taking practice tests on each topic. Some students were assigned to complete an additional example generation activity after taking the practice tests. Some students also evaluated the quality of generated examples and received explanatory feedback. While there was an overall improvement in comprehension for all students, those who generated examples without the opportunity to evaluate the quality had the smallest overall learning gains. Students who evaluated the quality of examples showed the greatest learning gains on application-based test questions. And, although overall overconfidence decreased, there were no differences between conditions. These results suggest that example generation may not always be as helpful for improving learning as many students and teachers assume. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Conceptual overlap among texts impedes comprehension monitoring.

For decades, research on metacomprehension has demonstrated that many learners struggle to accurately discriminate their comprehension of texts. However, while reviews of experimental studies on relative metacomprehension accuracy have found average intra-individual correlations between predictions and performance of around .27 for adult readers, in some contexts even lower near-zero accuracy levels have been reported. One possible explanation for those strikingly low levels of accuracy is the high conceptual overlap between topics of the texts. To test this hypothesis, in the present work participants were randomly assigned to read one of two text sets that differed in their degree of conceptual overlap. Participants judged their understanding and completed an inference test for each topic. Across two studies, mean relative accuracy was found to match typical baseline levels for the low-overlap text sets and was significantly lower for the high-overlap text sets. Results suggest text similarity is an important factor impacting comprehension monitoring accuracy that may have contributed to the variable and sometimes inconsistent results reported in the metacomprehension literature.

Psychiatric disorders during pregnancy in asymptomatic and mildly symptomatic SARS-CoV-2 positive women: Prevalence and effect on outcome.

The effect of psychiatric comorbidity on pregnancy outcome among SARS-CoV-2 positive women with asymptomatic and mildly symptomatic infections remains largely unknown. We reviewed the electronic medical records of all pregnant women who received care at Mayo Health System and tested positive for SARS-CoV-2 (RT-PCR) from March 2020 through October 2021. Among 789 patients, 34.2% (n = 270) had psychiatric comorbidity. Of those with psychiatric comrobidity, 62.2% (n = 168) had depression prior to pregnancy, and 5.2% (n = 14) reported new-onset depression during pregnancy. Before pregnancy, 65.6% (n = 177) had anxiety, and 4.4% (n = 12) developed anxiety during pregnancy Thirteen percent of SARS-CoV-2 positive pregnant women (n = 108) received psychotropic medication during pregnancy. In addition, 6.7% (n = 18) and 10.7% (n = 29) of pregnant women with psychiatric comorbidity had documented nicotine, cannabis and/ or illicit substance use during and prior to pregnancy, respectively. We depicted a significantly higher risk for cesarean delivery [35.6% vs. 24.9%) in asymptomatic and mildly symptomatic SARS-CoV-2 positive pregnant women with psychiatric comorbidity. In conclusion, the prevalence rates of depression, anxiety, and prescribed antidepressant medications during pregnancy among asymptomatic and mildly symptomatic SARS-CoV-2 infected women were substantially higher than average, which negatively impacted pregnancy and neonatal outcomes.

Interdisciplinary Care Provided in a Rural Setting to Patient with Below-Knee Amputation.

As a result of severe injury, limb amputation remains a pivotal procedure to preserve residual function of an injured extremity. Complications following amputation can impact successful rehabilitation. This case report aims to highlight the clinical importance of interdisciplinary care demonstrated by a 65-year-old Caucasian male below-knee amputee (BKA) who presented to an amputee clinic with complaints of right distal tibia pain. He reported that he was seen at a small rural clinic and was told he had "deterioration of his tibia". Physical exam revealed a well-healed below-knee amputation stump with tenderness to palpation of the right lateral distal residual fibula. Upon prosthetic modifications managed by our prosthetist, the patient's symptoms persisted. Further work up by Physical Medicine and Rehabilitation (PM&R) revealed a sharp edge to the distal fibula and the need for surgical revision by plastic surgery. Conditions resulting from the initial operation left this patient with factors that significantly impacted the process of restoring function to this BKA. Management of care for amputees commonly involves a variety of healthcare provider consisting of, but not limited to, primary care, physiatrists, prosthetists, plastic surgeons, and physical and occupational therapists. The aim of this case report is to illustrate how the fundamental collaboration rooted in interdisciplinary care is paramount to ensure that comprehensive care is delivered to this complex patient population that reside in rural areas.

Multiple lineages of monkeypox virus detected in the United States, 2021-2022.

Monkeypox is a viral zoonotic disease endemic in Central and West Africa. In May 2022, dozens of non-endemic countries reported hundreds of monkeypox cases, most with no epidemiological link to Africa. We identified two lineages of monkeypox virus (MPXV) among two 2021 and seven 2022 US monkeypox cases: the major 2022 outbreak variant called B.1 and a minor contemporaneously sampled variant called A.2. Analyses of mutations among these two variants revealed an extreme preference for GA-to-AA mutations indicative of human APOBEC3 cytosine deaminase activity among Clade IIb MPXV (previously West African, Nigeria) sampled since 2017. Such mutations were not enriched within other MPXV clades. These findings suggest that APOBEC3 editing may be a recurrent and a dominant driver of MPXV evolution within the current outbreak.

Downregulation of Src-family tyrosine kinases by Srcasm and c-Cbl: A comparative analysis.

AIM: Elevated Src-Family tyrosine kinase (SFK) activity drives carcinogenesis in vivo and elevated SFK activity is found ubiquitously in human cancers. Although human squamous cell carcinomas (SCCs) demonstrate increased SFK activity, in silico analysis of SCCs demonstrates that only 0.4% of lesions contain mutations that could potentially increase SFK activity; similarly, a low frequency of activating SFK mutations is found in other major cancers. These findings indicate that SFK activation in cancers likely is not due to activating mutations but alternative mechanisms. To evaluate potential alternative mechanisms, we evaluated the selectivity of c-Cbl and Srcasm in downregulating native and activated mutant forms of SFKs. MATERIALS AND METHODS: We co-transfected native and activated forms of Src and Fyn with c-Cbl and Srcasm into HaCaT cells and monitored the ability of Srcasm and c-Cbl to downregulate native and activated forms of SFKs by Western blotting. The mechanism of downregulation was probed using mutant forms of Srcasm and c-Cbl and using proteosomal and lysosomal inhibition. RESULTS: The data indicate that Srcasm downregulates native Fyn and Src more effectively than c-Cbl, whereas c-Cbl preferentially downregulates activated SFK mutants, including Fyn Y528F, more effectively than Srcasm. Srcasm downregulates SFKs through a lysosomal-dependent mechanism while c-Cbl utilizes a proteosomal-dependent mechanism. CONCLUSION: Given the rarity of activating SFK mutations in human cancer, these data indicate that decreasing Srcasm level/function may represent a mechanism for increasing SFK activity in SCC and other human tumors.

Secretomics: a biochemical footprinting tool for developing microalgal cultivation strategies.

Microalgae offer a promising source of biofuel and a wide array of high-value biomolecules. Large-scale cultivation of microalgae at low density poses a significant challenge in terms of water management. High-density microalgae cultivation, however, can be challenging due to biochemical changes associated with growth dynamics. Therefore, there is a need for a biomarker that can predict the optimum density for high biomass cultivation. A locally isolated microalga Cyanobacterium aponinum CCC734 was grown with optimized nitrogen and phosphorus in the ratio of 12:1 for sustained high biomass productivity. To understand density-associated bottlenecks secretome dynamics were monitored at biomass densities from 0.6 ± 0.1 to 7 ± 0.1 g/L (2 to 22 OD) in batch mode. Liquid chromatography coupled with mass spectrometry identified 880 exometabolites in the supernatant of C. aponinum CCC734. The PCA analysis showed similarity between exometabolite profiles at low (4 and 8 OD) and mid (12 and 16 OD), whereas distinctly separate at high biomass concentrations (20 and 22 OD). Ten exometabolites were selected based on their role in influencing growth and are specifically present at low, mid, and high biomass concentrations. Taking cues from secretome dynamics, 5.0 ± 0.5 g/L biomass concentration (16 OD) was optimal for C. aponinum CCC734 cultivation. Further validation was performed with a semi-turbidostat mode of cultivation for 29 days with a volumetric productivity of 1.0 ± 0.2 g/L/day. The secretomes-based footprinting tool is the first comprehensive growth study of exometabolite at the molecular level at variable biomass densities. This tool may be utilized in analyzing and directing microalgal cultivation strategies and reduction in overall operating costs.

Hypergranulotic Dyskeratotic Acanthoma: Another Histologically Distinctive Acanthoma.

ABSTRACT: Various acanthomas have been named based on their distinctive histopathologic patterns. Hypergranulotic dyskeratotic acanthoma represents another acanthoma with a distinctive histopathologic pattern that has been rarely reported. In this article, clinical and histological features of hypergranulotic dyskeratotic acanthoma are delineated. A retrospective analysis was performed of cases with diagnosis or suggested diagnosis of hypergranulotic dyskeratotic acanthoma between 2012 and 2017 from 2 dermatopathology laboratories. Forty-eight potentials were identified, of which 18 cases met the inclusion histologic criteria. Most cases came from women (78%) with a mean age of 53 years, and the thigh was the most common site involved. All cases had the following histopathological findings: (1) verrucous or digitated epidermal hyperplasia, (2) hyperkeratosis dominated by basketweave or compact orthokeratosis, (3) hypergranulosis involving the breadth of the lesion, and (4) presence of enlarged, often indistinctly bordered, keratinocytes with cytoplasm characterized by a blue-gray granular peripheral zone sometimes showing outstretched desmosomes and central perinuclear eosinophilic zones, a combination of findings representing slowly evolving dyskeratosis. Retrospective nature and a small sample size are the major limitations of the study. In sum, hypergranulotic dyskeratotic acanthoma can be easily distinguished from other acanthomas based on their repeatable histopathological findings.

Partnering to Increase Colorectal Cancer Screening: Perspectives of Community Advisory Board Members.

The Patient-Centered Outcomes Research Institute (PCORI) defines engagement in research as the meaningful involvement of patients, caregivers, clinicians, insurers, and others throughout the entire research process-from planning to conducting the study to disseminating study results. The purposes of this paper are to (a) describe methods used to engage community members across the various phases of a PCORI-funded comparative effectiveness trial to increase colorectal cancer screening; and (b) report results of qualitative and quantitative evaluations of community advisory board members' experiences on this project. Decisions to join and stay engaged with the study included feeling valued and appreciated, being compensated, the opportunity to contribute to research based on their skills and expertise, and being committed to colon cancer prevention efforts. Challenges identified by advisory board members included the significant time commitment, transportation, and meeting location. Lessons learned and guidance for researchers committed to patient and community engagement are described.

Predicting Design-Induced Error on the Flight Deck : An Aircraft Engine Oil Leak Scenario.

OBJECTIVE: To explore the types of errors that commercial pilots may make when trying to resolve a suspected engine oil leak using the interfaces currently available. BACKGROUND: The decisions that pilots make often have to be made quickly and under time pressure, with the emphasis on avoiding critical situations from arising. To make the correct decisions, it is vital that pilots have accurate and up-to-date information available. However, interaction with flight deck interfaces may lead to error if they are not effectively designed. METHOD: A hierarchical task analysis was conducted using evidence from pilot interview data to understand the pilots' typical response to a suspected engine oil leak scenario. This was used as the primary input into the Systematic Human Error Reduction and Prediction Approach (SHERPA). RESULTS: A total of 108 possible errors were identified. The most common error type was a retrieval error, in which flight crews may retrieve the wrong information about the engine. A number of remedial measures are proposed to try and overcome such issues. CONCLUSION: This analysis provides an initial starting point for identifying potential future design ideas that can assist the pilots in dealing with oil leaks. APPLICATION: This work has identified the value of applying human error identification methodologies to the assessment of current flight deck processes surrounding engine oil leaks. The method presented permits the operational analysis of possible errors on the flight deck and facilitates the proposition of remedial measures to implement technological innovations that can mitigate error.

Fractional Ablative Laser-Assisted Photodynamic Therapy as Field Treatment for Actinic Keratoses: Our Anecdotal Experience.

Actinic keratoses (AKs) are common skin lesions that are often considered to be precancerous markers for the future development of skin cancers. There are various treatment options, including cryotherapy, imiquimod, 5-fluorouracil, curettage, lasers, and photodynamic therapy (PDT). Laser-assisted drug delivery, using the combination of a fractional ablative laser with PDT, is an effective therapy. Our clinical experience with six patients demonstrates that the combination of fractional ablative 2,940nm erbium:yttrium-aluminum-garnet laser with blue light PDT is safe and effective for the field treatment of AKs. (SKINmed. 2020;18:214-216).

Enhanced Algal Photosynthetic Photon Efficiency by Pulsed Light.

We present experimental results demonstrating that, relative to continuous illumination, an increase of a factor of 3-10 in the photon efficiency of algal photosynthesis is attainable via the judicious application of pulsed light for light intensities of practical interest (e.g., average-to-peak solar irradiance). We also propose a simple model that can account for all the measurements. The model (1) reflects the essential rate-limiting elements in bioproductivity, (2) incorporates the impact of photon arrival-time statistics, and (3) accounts for how the enhancement in photon efficiency depends on the timescales of light pulsing and photon flux density. The key is avoiding "clogging" of the photosynthetic pathway by properly timing the light-dark cycles experienced by algal cells. We show how this can be realized with pulsed light sources, or by producing pulsed-light effects from continuous illumination via turbulent mixing in dense algal cultures in thin photobioreactors.

Scleromyxedema in a patient with thyroid disease: an atypical case or a case for revised criteria?

Lichen myxedematosus (LM), commonly referred to as papular mucinosis, is a rare papular eruption defined by mucin deposition in the dermis. Scleromyxedema (SM) is a generalized papular and sclerodermoid form of LM. It is a progressive disease of unknown etiology with systemic manifestations that cause serious morbidity and mortality. Current criteria list thyroid dysfunction as an exclusion for the diagnosis of SM. Cases of LM associated with thyroid dysfunction have been defined as atypical. We describe a patient with uncontrolled hypothyroidism due to Hashimoto thyroiditis who subsequently developed a diffuse papular eruption with systemic signs and symptoms attributable to SM. Diagnostic workup, including laboratory studies and histologic specimens from the skin and muscle, were consistent with SM. Furthermore, our patient responded clinically to intravenous immunoglobulin (IVIg) and lenalidomide. We discuss the diagnostic criteria, differential diagnoses, and diagnostic challenges associated with LM in association with thyroid dysfunction. We propose that the presence of thyroid disease should not preclude the diagnosis of SM. Finally, we add to the case reports and series of successful treatments of SM with IVIg and lenalidomide.

In vitro characterization and preclinical immunogenicity of Typhax, a typhoid fever protein capsular matrix vaccine candidate.

Typhax is an investigational typhoid fever vaccine candidate that was GMP manufactured applying Protein Capsular Matrix Vaccine (PCMV) technology. It consists of Vi polysaccharide antigen, derived from S. Typhi, non-covalently entrapped in a glutaraldehyde catalyzed cross-linked α-poly-L-lysine and CRM197 protein matrix. Analysis of Typhax determined the average molecular weight of the vaccine particles was approximately 6 x 106 Daltons, corresponding to particles containing 1-2 molecules of Vi polysaccharide and 10-20 molecules of CRM197 protein. The ratio of the concentration of Vi to CRM197 protein in Typhax is 2.4:1. Preclinical immunogenicity studies in mice demonstrated that Typhax was immunogenic and elicited a significant increase in anti-Vi IgG antibody titers following each immunization. The anti-Vi IgG antibody response elicited by Typhax in rabbits increased as the dose increased from 0.1 µg to 2.5 µg. Further, at the 2.5 and 10 µg dose levels, the anti-Vi IgG antibody titers increased after the second and third immunizations. At the 10 µg dose level, 100% of rabbits seroconverted. In the non-human primate (NHP) study, 100% seroconversion was observed at both 2.5 µg and 10 µg dose levels after the first immunization. A murine in vivo immunopotency study demonstrated that Typhax stored at 4°C was stable for at least 30 months. Collectively, the Typhax in vitro profile, preclinical immunogenicity studies, and rabbit toxicology study indicate that Typhax is a viable typhoid fever vaccine candidate for Phase 1 clinical trial evaluation.

Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy.

OBJECTIVE: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA). METHODS: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal. RESULTS: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36). CONCLUSION: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.

Distributed cognition in aviation operations: a gate-to-gate study with implications for distributed crewing.

The network analysis method, Event Analysis of Systemic Teamwork (EAST), was used to examine routine aviation operations from multiple perspectives from six key areas (i.e. Dispatch, ATC, ATM, Maintenance, Loading, and the Cockpit). Data was collected over a five-day observational field trial at an international air cargo operator. Researchers recorded the activities of agents operating within the six key areas over three outbound and two inbound flights. Three networks (i.e. social, information and task) were created for four key phases of flight: (i) pre-flight checks and engines start (ii) taxi, take-off and assent, (iii) descent, landing and taxi, and (iv) park and shut down. The networks represent a 'work audit' of short-haul cargo operations, which enabled a detailed understanding of the interactions and connections within the current system. Implications for the future of distributed crewing concepts are discussed. Practitioner Summary: An analysis of the aviation system was undertaken using the amalgamated data from three outbound and two inbound flights. These analyses show the social, information and task interactions for cargo operations. This has been used to specify requirements for future distributed crewing options.

The effects of comprehension-test expectancies on metacomprehension accuracy.

A set of four experiments assessed the effects of establishing a comprehension-test expectancy (in contrast to a memory-test expectancy) on relative metacomprehension accuracy. Typically readers show poor relative metacomprehension accuracy while learning from text (i.e., they are unable to discriminate topics they have understood well from topics they have understood poorly). In the first experiment, both readers who were given no test expectancy and those who were given a memory-test expectancy made judgments that were more predictive of performance on memory tests than inference tests. However, readers who were given a comprehension-test expectancy made judgments that were more predictive of inference-test performance. This effect was replicated and extended in two additional experiments that showed an effect of comprehension-test expectancy even when no example test items were provided, and when the expectancy was established only after reading. A fourth experiment showed that establishing a comprehension-test expectancy still had an effect on accuracy even when metacomprehension accuracy was already being improved via a self-explanation activity. The results show robust and reliable benefits to metacomprehension accuracy from a comprehension-test expectancy that serves as portable knowledge that learners can apply to monitoring future learning from text. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Cadaveric simulation for improving surgical training in dermatology.

Simulation models are rapidly changing medical education, especially the training of dermatology residents. Various models are available, including cadaveric simulations. Our study evaluates the impact of a cadaveric simulation on the training of dermatology residents. Over a period of three years, cadaveric simulation was shown to increase the surgical knowledge of residents. Residents were more confident in their knowledge of surgical anatomy and also surgical skills. Cadaveric simulation may offer a positive impact on resident training in dermatology.