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Caregivers of adolescents with autism spectrum disorder commonly experience stigma. However, how stigma influences social interactions of adolescents with autism spectrum disorder is unclear. We aimed to explore the impact of caregiver stigma on real-life social experiences of Taiwanese adolescents with autism spectrum disorder. In the context of everyday activities, 76 adolescents with autism spectrum disorder who were not intellectually disabled (69 males, aged 10–16 years) carried a mobile device that prompted them 7 times, randomly, each day for 7 days to record with whom they were interacting, what they perceived, and how they felt about the interactions. Caregivers completed the Affiliate Stigma Scale to measure caregiver stigma. Multilevel analyses revealed that participants whose caregivers perceived high levels of stigma were more likely than those whose caregivers experienced less stigma to interact with family members and less likely to be interested in interacting with people at school. However, those participants also experienced more anxiety while interacting with family members. The findings shed light on ways that caregiver stigma impacted the social experiences of adolescents with autism spectrum disorder and suggest that, in promoting social participation for adolescents with autism spectrum disorder, researchers and service providers must support caregivers to manage stigma. Lay abstract Caregivers of people with autism spectrum disorder commonly experience stigma. As a result, they may avoid contact with others, in turn, influencing their child’s social participation. This study aimed to explore the impact of stigma perceived by the caregivers on the everyday social experience of Taiwanese adolescents with autism spectrum disorder. We asked 76 adolescents with autism spectrum disorder who did not have intellectual disability (69 males, aged 10–16 years) to carry a mobile device for 7 days. The device prompted them 7 times each day to record who they were interacting with, what they perceived, and how they felt about their social interactions. In addition, we asked their caregivers to complete the Affiliate Stigma Scale to measure their experience of stigma. We found that participants whose caregivers perceived high levels of stigma were more likely to spend time with family members and less likely to be interested in interacting with people at school. Those participants also were more likely to experience anxiety while interacting with family. Our study suggests that it is important for clinicians to implement support services for adolescents with autism spectrum disorder and help caregivers in managing stigma to promote their child’s social participation.

Some immune system cells express type A and/or type B &gamma, aminobutyric acid receptors (GABAA-Rs and/or GABAB-Rs). Treatment with GABA, which activates both GABAA-Rs and GABAB-Rs), and/or a GABAA-R-specific agonist inhibits disease progression in mouse models of type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, and COVID-19. Little is known about the clinical potential of specifically modulating GABAB-Rs. Here, we tested lesogaberan, a peripherally restricted GABAB-R agonist, as an interventive therapy in diabetic NOD mice. Lesogaberan treatment temporarily restored normoglycemia in most newly diabetic NOD mice. Combined treatment with a suboptimal dose of lesogaberan and proinsulin/alum immunization in newly diabetic NOD mice or a low-dose anti-CD3 in severely hyperglycemic NOD mice greatly increased T1D remission rates relative to each monotherapy. Mice receiving combined lesogaberan and anti-CD3 displayed improved glucose tolerance and, unlike mice that received anti-CD3 alone, had some islets with many insulin+ cells, suggesting that lesogaberan helped to rapidly inhibit &beta, cell destruction. Hence, GABAB-R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABAB-Rs and GABAA-Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.

Malaria is an infectious disease caused by Plasmodium parasites, transmitted through mosquito bites. Symptoms include fever, headache, and vomiting, and in severe cases, seizures and coma. The World Health Organization reports that there were 228 million cases and 405,000 deaths in 2018, with Africa representing 93% of total cases and 94% of total deaths. Rapid diagnosis and subsequent treatment are the most effective means to mitigate the progression into serious symptoms. However, many fatal cases have been attributed to poor access to healthcare resources for malaria screenings. In these low-resource settings, the use of light microscopy on a thin blood smear with Giemsa stain is used to examine the severity of infection, requiring tedious and manual counting by a trained technician. To address the malaria endemic in Africa and its coexisting socioeconomic constraints, we propose an automated, mobile phone-based screening process that takes advantage of already existing resources. Through the use of convolutional neural networks (CNNs), we utilize a SSD multibox object detection architecture that rapidly processes thin blood smears acquired via light microscopy to isolate images of individual red blood cells with 90.4% average precision. Then we implement a FSRCNN model that upscales 32 × 32 low-resolution images to 128 × 128 high-resolution images with a PSNR of 30.2, compared to a baseline PSNR of 24.2 through traditional bicubic interpolation. Lastly, we utilize a modified VGG16 CNN that classifies red blood cells as either infected or uninfected with an accuracy of 96.5% in a balanced class dataset. These sequential models create a streamlined screening platform, giving the healthcare provider the number of malaria-infected red blood cells in a given sample. Our deep learning platform is efficient enough to operate exclusively on low-tier smartphone hardware, eliminating the need for high-speed internet connection.

Objective Weakness of the hand is a major impairment which limits independent living. Neuromuscular electrical stimulation (NMES) is a common approach to help restore muscle strength. Traditional NMES directly over the muscle often leads to a rapid onset of muscle fatigue. In this study, we investigated the force sustainability of finger flexor muscles using a transcutaneous nerve stimulation approach. Approach Finger flexion forces and high-density electromyogram (HD EMG) signals were obtained while electrical stimulation was applied to the ulnar and median nerve bundles through a stimulation grid on the proximal arm segment. Stimulation was also applied to the finger flexor muscle belly targeting the motor point, serving as a control condition. The force produced from the two stimulation approaches were initially matched, and muscle fatigue was subsequently induced with 5 min of continuous stimulation. The rate of decay of the force and EMG amplitude were quantified, and the spatial distribution of the muscle activation during the sustained contraction was also evaluated. Main results The proximal nerve stimulation approach induced a slower decay in both force and EMG, compared with the stimulation at the motor point. The spatial distribution of the elicited muscle activation showed that the proximal nerve stimulation led to a distributed activation across the intrinsic and extrinsic finger flexor muscles and also activated a wider area within the extrinsic muscle. Significance Our findings demonstrated that the stimulation of the proximal nerve bundles can elicit sustained force output and delayed decrease in the rate of force decline. This is potentially due to a spatially distributed activation of the muscle fibers, compared with the traditional motor point stimulation. Future development of our nerve stimulation approach may enable prolonged usage during rehabilitation or assistance for better functional outcomes.

Real-world stressors are complex and multimodal, involving physical, psychological, and social dimensions. However, the brain networks that mediate stress responses to these stimuli need to be further studied. We used c-Fos mapping in mice to characterize brain circuits activated by exposure to a single episode of multimodal stress (MMS), and compared these to circuits activated by electric foot shocks (EFS). We focused on characterizing c-Fos activity in stress-relevant brain regions including the paraventricular nucleus (PVN) of the hypothalamus and the bed nucleus of the stria terminalis (BNST). We also assessed stress-induced activation of CRH-positive neurons in each of these structures. MMS and EFS activated an overlapping network of brain regions with a similar time course. c-Fos expression within the PVN and the BNST peaked 30–60 min after exposure to both MMS and EFS, and returned to baseline levels within 24 h. Quantification of c-Fos expression within BNST subregions revealed that while c-Fos expression peaked in all subregions 30–60 min after MMS and EFS exposure, the neuronal density of c-Fos expression was significantly higher in the dorsomedial and ventral BNST relative to the dorsolateral BNST. Our preliminary assessment indicated that a great majority of MMS or EFS-activated neurons in the PVN were CRH-positive (>87%); in contrast, about 6–35% of activated neurons in the BNST were CRH-positive. Our findings indicate that both MMS and EFS are effective at activating stress-relevant brain areas and support the use of MMS as an effective approach for studying multidimensional stress in animal models. The results also reveal that the PVN and BNST are part of a common neural circuit substrate involved in neural processing related to stress. Keywords: Multimodal stress, c-Fos, BNST, PVN, CRH

OBJECTIVE We reduced the computed tomography (CT)-reconstructed field of view (FOV), increasing pixel density across airway structures and reducing partial volume effects, to determine whether this would improve accuracy of airway wall thickness quantification. METHODS We performed CT imaging on a lung phantom and 29 participants. Images were reconstructed at 30-, 15-, and 10-cm FOV using a medium-smooth kernel. Cross-sectional airway dimensions were compared at each FOV with repeated-measures analysis of variance. RESULTS Phantom measurements were more accurate when FOV decreased from 30 to 15 cm (P < 0.05). Decreasing FOV further to 10 cm did not significantly improve accuracy. Human airway measurements similarly decreased by decreasing FOV (P < 0.001). Percent changes in all measurements when reducing FOV from 30 to 15 cm were less than 3%. CONCLUSIONS Airway measurements at 30-cm FOV are near the limits of CT resolution using a medium-smooth kernel. Reducing reconstructed FOV would minimally increase sensitivity to detect differences in airway dimensions.

Background As resident “index” procedures change in volume due to advances in technology or reliance on simulation, it may be difficult to ensure trainees meet case requirements. Training programs are in need of metrics to determine how many residents their institutional volume can support. Objective As a case study of how such metrics can be applied, we evaluated a case distribution simulation model to examine program-level mediastinoscopy and endobronchial ultrasound (EBUS) volumes needed to train thoracic surgery residents. Methods A computer model was created to simulate case distribution based on annual case volume, number of trainees, and rotation length. Single institutional case volume data (2011–2013) were applied, and 10 000 simulation years were run to predict the likelihood (95% confidence interval) of all residents (4 trainees) achieving board requirements for operative volume during a 2-year program. Results The mean annual mediastinoscopy volume was 43. In a simulation of pre-2012 board requirements (thoracic pathway, 25; cardiac pathway, 10), there was a 6% probability of all 4 residents meeting requirements. Under post-2012 requirements (thoracic, 15; cardiac, 10), however, the likelihood increased to 88%. When EBUS volume (mean 19 cases per year) was concurrently evaluated in the post-2012 era (thoracic, 10; cardiac, 0), the likelihood of all 4 residents meeting case requirements was only 23%. Conclusions This model provides a metric to predict the probability of residents meeting case requirements in an era of changing volume by accounting for unpredictable and inequitable case distribution. It could be applied across operations, procedures, or disease diagnoses and may be particularly useful in developing resident curricula and schedules.

This study describes the synthesis of deuterium-labelled fosamprenavir calcium. The stable isotopic-labelled compound was prepared starting from L-phenylalanine in 18 steps with a 9% overall yield. Copyright © 2010 John Wiley & Sons, Ltd.

Introduction Work-hour restrictions have decreased flexibility in scheduling and reduced exposure to certain operative cases. These restrictions may affect a resident's ability to meet certification requirements, particularly for rare, unscheduled cases (e.g., cardiothoracic transplants). We developed a computer-based simulation model using variables such as case volume and program size to demonstrate the influence of these factors on the likelihood of certifying a set of residents on rare cases. Methods We built a simulator to predict the probability of attaining certification for surgical residents, using cardiothoracic transplants as a test case. Inputs to the model included operating times, call schedules, and procurement travel times, as well as information on the distribution of times between transplants. Results We simulated 100 years of schedules using our current system parameters of an average of 33 heart and 31 lung transplants per year, and assuming an Accreditation Council for Graduate Medical Education–compliant daily-rotating call schedule. Despite having enough transplants to certify all residents for lungs if all opportunities were distributed equally among residents, the certification rate achieved when constrained by arrival time (and call schedules) and work restrictions was only 55%. Our calculations show that meeting minimum transplant-certification requirements for all residents would require at least 1.5 times the expected number of annual transplants. Conclusions Our model enables analysis of a given program's ability to certify its residents based on program size and volume. These results could be used to design alternative scheduling paradigms to improve certification rates, without requiring reductions in certification requirements or program size.

Background Certain operative cases occur unpredictably and/or have long operative times, creating a conflict between Accreditation Council for Graduate Medical Education (ACGME) rules and adequate training experience. Methods A ProModel-based simulation was developed based on historical data. Probabilistic distributions of operative time calculated and combined with an ACGME compliant call schedule. Results For the advanced surgical cases modeled (cardiothoracic transplants), 80-hour violations were 6.07% and the minimum number of days off was violated 22.50%. There was a 36% chance of failure to fulfill any (either heart or lung) minimum case requirement despite adequate volume. Conclusions The variable nature of emergency cases inevitably leads to work hour violations under ACGME regulations. Unpredictable cases mandate higher operative volume to ensure achievement of adequate caseloads. Publically available simulation technology provides a valuable avenue to identify adequacy of case volumes for trainees in both the elective and emergency setting.

Hematopoietic stem cells (HSCs) reside in the bone marrow in specific niches at the border between bone cells and the bone marrow (endosteal niche) or around blood vessels (perivascular niche). In the endosteal niche, HSCs are maintained at low oxygen levels in a quiescent (dormant) state by adhesion to niche cells. We have previously shown that Gfi1b restricts the expansion and proliferation of HSCs as well as their mobilization or re-localization into peripheral blood. We have proposed that Gfi1b exerts this function by regulating the expression of surface molecules such as integrins on HSCs that are required to maintain them in their bone marrow niche at a quiescent state. The objective of this study was to gain more insight into the precise molecular mechanisms by which Gfi1b regulates HSCs dormancy and mobilization and to obtain insights that may be exploited in the future to improve stem cell therapies or the expansion of human hematopoietic stem cells for clinical use. Immune precipitation and mass spectrometry identified a series of Gfi1b interacting proteins, most notably a group of regulators of the canonical Wnt/beta-catenin pathway. Independent protein IP validation of these findings suggested that Gfi1b can interact with several inhibitors of the canonical Wnt/beta catenin pathway namely with APC (Adenomatous polyposis coli) a tumor suppressor protein and important factor in the beta-catenin destruction complex, with the DNA helicase and chromatin remodeling factor CHD8, which silences beta catenin mediated transcription, with CtBP which antagonizes beta-catenin activity and is part of the LSD1/CoRest histone demethylase complex and with the direct beta-catenin inhibitors TLE1 and TLE3 (also called Groucho). Of particular interest was that the interactions between the Groucho proteins and Gfi1b were dependent on a previously unidentified Groucho binding domain (GBD) in Gfi1b. This is a well-conserved six-amino acid stretch that is found in the middle part of the Gfi1b protein. In addition, the binding of CtBP was dependent on the presence of the 20 amino acid N-terminal SNAG domain in Gfi1b that also mediates LSD1 binding. Using luciferase reporter gene assays (TOP/FOP reporter assay), we found that Gfi1b was able to significantly up-regulates TCF/beta-catenin-dependent transcription upon activation by LiCl or Wnt3A in HEK293 cells. This activity of Gfi1b was dependent on both the presence of the SNAG domain and the newly identified Groucho binding domain. Also, Gfi1b was able to reverse partially the inhibitory effect of CtBP and TLE3 on beta-catenin activity in the TOP/FOP reporter assays. To obtain further evidence that Gfi1b is indeed implicated in regulating the Wnt/beta catenin signaling pathway in hematopoietic stem cells, we FACS sorted Lin-Kit1+Sca+ hematopoietic progenitors (LSK cells) from wt and Gfi1b deficient mice and tested them for expression of Wnt effector genes using a Wnt signaling specific PCR array. We observed that the majority of Wnt target genes were significantly down regulated in Gfi1 deficient LSKs compared to wt LSKs. Among the genes affected the most were typical Wnt targets such as Axin2, Frz7, Tcf4, Klf5, Vegfa and Ccnd1. To show that Gfi1b is able to regulate Wnt pathway effectors in vivo in HSCs, we crossed Gfi1b flox/flox, Mx-Cre mice with animals that carry a NLS-lacZ reporter gene under the control of the endogenous Axin2 promoter/enhancer region. Treatment with pIpC, which deletes Gfi1b correlated with a significant decrease of Axin2 expression in HSCs and MPP1, which are high Gfi1b expressing cells. The Axin2 reporter was not affected by Gfi1b deletion in MPP2 or GMPs, which express low levels or no Gfi1b. The canonical Wnt/b-catenin signaling pathway is recognized as one of the elements that are critically important in the regulation of HSC function. Here we have identified Gfi1b as a potential new player in the Wnt-beta catenin signaling pathway. Our data suggest that Gfi1b acts on at least two inhibitory complexes of this pathway, on the TLE family of Groucho proteins and the CtBP/LSD1 complex and regulates effectors of the Wnt/beta-catenin signaling cascade. We propose therefore that Gfi1b may titer the level of activation of the Wnt/beta-catenin signaling pathway in HSCs, which offers an explanation of the hematopoietic stem cell phenotype seen in mice lacking Gfi1b. Disclosures: No relevant conflicts of interest to declare.