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Abstract Background Previous research has demonstrated heterogeneous adaptive outcomes across the autism spectrum; however, the current literature remains limited in elucidating turning points and associated factors for longitudinal variability (chronogeneity). To address these empirical gaps, we aimed to provide a finer‐grained characterization of trajectories of adaptive functioning from early childhood to adolescence in autism. Methods Our sample (N = 406) was drawn from an inception cohort of children diagnosed Autistic at ages 2–5. Adaptive functioning was assessed with Vineland Adaptive Behavior Scales (VABS, 2nd Edition) across 6 visits from the time of diagnosis by age 18. Parallel‐process latent growth curve modeling were used to estimate domain‐level VABS trajectories, followed by latent class growth analysis to identify trajectory subgroups. Child characteristics at diagnosis, family demographics, and participation outcomes at adolescence were compared across subgroups. Results Piecewise latent growth models best described VABS trajectories with two turning points identified at around ages 5‐6 and 9–10, respectively reflecting transitions into school age and early adolescence. We parsed four VABS trajectory subgroups that vary by level of functioning and change rate for certain domains and periods. Around 16% of the sample exhibited overall adequate functioning (standard score >85) with notable early growth and social adaptation during adolescence. About 21% showed low adaptive functioning (standard score ≤70), with decreasing slopes by age 6 followed by improvements in communication and daily‐living skills by age 10. The other two subgroups (63% in total) were characterized by adaptive functioning between low and adequate levels, with relatively stable trajectories entering school age. These subgroups differed most in their cognitive ability at diagnosis, household income, and social participation in adolescence. Conclusions We identified key individual and family characteristics and time windows associated with distinct adaptive functioning trajectories, which have important implications for providing timely and tailored supports to Autistic people across developmental stages.

Abstract Osteoarthritis (OA) of the knee is a common degenerative articular disorder and is one of the main causes of pain and functional disability. Cartilage damage is frequently linked to elevated osteoarthritis incidence. Supercritical carbon dioxide (scCO2) decellularized cartilage graft produced from the porcine cartilage is an ideal candidate for cartilage tissue engineering. In the present study, we derived collagen type II (Col II) solution from the scCO2 decellularized porcine cartilage graft (dPCG) and compared its efficacy with hyaluronic acid (HA) in the surgical medial meniscectomy (MNX) induced post-traumatic osteoarthritis (PTOA) model. Dose-dependent attenuation of the OA (12.3 ± 0.8) progression was observed in the intra‐articular administration of Col II solution (7.3 ± 1.2) which significantly decreased the MNX-induced OA symptoms similar to HA. The pain of the OA group (37.4 ± 2.7) was attenuated dose-dependently by Col II solution (45.9 ± 4.1) similar to HA (43.1 ± 3.5) as evaluated by a capacitance meter. Micro‐CT depicted a dose-dependent attenuation of articular cartilage damage by the Col II solution similar to HA treatment. A significant (p

IntroductionThis study examined the prevalence of functional difficulties and associated factors in Canadian children/youth aged 5 to 17 years diagnosed with autism spectrum disorder (ASD). MethodsWe analyzed data from the 2019 Canadian Health Survey on Children and Youth (CHSCY), a nationally representative survey of Canadian children/youth that used the Washington Group Short Set on Functioning (WG-SS) to evaluate functioning in six daily tasks. For each functional domain, binary outcomes were derived (no/some difficulty, a lot of difficulty/no ability). We used logistic regression to identify associations between demographic characteristics, educational experiences, and perceived mental and general health and the most common functional difficulties, namely those related to remembering/concentrating, communication and self-care. All estimates were weighted to be representative of the target population. The bootstrap method was used to calculate variance estimates. ResultsAnalysis of the records of 660 children/youth with ASD revealed that the most common functional difficulties were remembering/concentrating (22%; 95% CI: 18–27), communicating (19%; 95% CI: 15–23) and self-care (13%; 95% CI: 10–17). Lower perceived mental health was associated with increased functional difficulties with remembering/concentrating. ASD diagnosis at a lower age and lower perceived general health were associated with increased functional difficulty with communication. Parental expectations for postsecondary education were associated with decreased functional difficulty for self-care. ConclusionOne or more functional difficulties from the WG-SS was present in 39% of Canadian children/youth aged 5 to 17 years with ASD. Functional difficulties with remembering/concentrating, communication and self-care were most common.

IntroductionCette étude porte sur la prévalence des difficultés fonctionnelles et des facteurs connexes chez les enfants et les jeunes canadiens de 5 à 17 ans ayant reçu un diagnostic de trouble du spectre de l'autisme (TSA). MéthodologieNous avons analysé les données tirées de l’Enquête canadienne sur la santé des enfants et des jeunes (ECSEJ) de 2019, une enquête nationale représentative de la population canadienne d’enfants et de jeunes, qui utilisait l’ensemble abrégé de questions sur le fonctionnement du Groupe de Washington (Washington Group Short Set on Functioning, WG-SS) pour évaluer le fonctionnement dans le cadre de six tâches quotidiennes. Pour chaque domaine fonctionnel, des résultats binaires ont été générés (aucune difficulté/quelques difficultés, beaucoup de difficultés/n’y parvient pas du tout). Nous avons ensuite utilisé une régression logistique pour déterminer les associations entre, d’une part, les caractéristiques sociodémographiques, les expériences d’apprentissage et la santé générale et mentale perçue et, d’autre part, les difficultés fonctionnelles les plus courantes, celles liées à la mémoire/concentration, à la communication et aux soins personnels. Toutes les estimations ont été pondérées de façon à être représentatives de la population cible. Nous avons utilisé la méthode « bootstrap » pour établir les estimations de la variance. RésultatsL’analyse des données des 660 enfants et jeunes atteints d’un TSA a révélé que les difficultés fonctionnelles les plus courantes concernaient la mémoire/concentration (22 %; IC à 95 % : 18 à 27), la communication (19 %; IC à 95 % : 15 à 23) et les soins personnels (13 %; IC à 95 % : 10 à 17). Une moins bonne santé mentale perçue était associée à des difficultés fonctionnelles accrues liées à la mémoire/concentration. Un diagnostic de TSA à un plus jeune âge et une moins bonne santé générale perçue étaient associés à des difficultés fonctionnelles accrues liées à la communication. Le fait que les parents avaient des attentes en matière d’études postsecondaires était associé à des difficultés fonctionnelles réduites liées aux de soins personnels. ConclusionL’étude a révélé que 39 % des enfants et des jeunes canadiens de 5 à 17 ans ayant reçu un diagnostic de TSA présentaient au moins une difficulté fonctionnelle citée dans l’ensemble de questions WG-SS, les difficultés fonctionnelles liées à la mémoire/ concentration, à la communication et aux soins personnels étant les plus fréquentes.

Introduction The developmentally variable nature of autism poses challenges in providing timely services tailored to a child’s needs. Despite a recent focus on longitudinal research, priority-setting initiatives with stakeholders highlighted the importance of studying a child’s day-to-day functioning and social determinants of health to inform clinical care. To address this, we are conducting a pragmatic multi-site, patient-oriented longitudinal investigation: the Pediatric Autism Research Cohort (PARC) Study. In young children (

Background and Objectives: Our study compared the visual and anatomical outcomes of polypoidal choroidal vasculopathy (PCV) patients receiving intravitreal aflibercept (IVA) with or without photodynamic therapy (PDT) over 12 months. Materials and Methods: This retrospective study was performed for 60 eyes from 60 patients with treatment-naïve PCV. Thirty eyes were treated using IVA monotherapy (IVA group), and thirty eyes were treated using a combination of IVA with PDT (IVA/PDT group). The baseline characteristics, treatment outcomes, and retreatment rates were compared between the two groups over a one-year follow-up period. Results: The best-corrected visual acuity (BCVA) was found to have improved significantly in the IVA/PDT group at every 3-month visit. However, no significant BCVA improvement was observed in the IVA group. A significantly lower retreatment rate and higher dry macula rate were found in the IVA/PDT group than that in the IVA group. In the entire population of the study, a better baseline vision and younger age were associated with better final visual outcomes. Retreatment was associated with poor baseline BCVA and IVA monotherapy. Conclusions: The combination of IVA and PDT may offer superior visual improvement and a higher dry macula rate compared to IVA monotherapy in the treatment of PCV patients while requiring fewer retreatments over 12 months.

Abstract Low testosterone level is an independent predictor of osteoporotic fracture in elderly men as well as increased fracture risk in men undergoing androgen deprivation. Androgens and androgen receptor (AR) actions are essential for bone development and homeostasis but their linkage to fracture repair remains unclear. Here we found that AR is highly expressed in the periosteum cells and is co-localized with a mesenchymal progenitor cell marker, paired-related homeobox protein 1 (Prrx1), during bone fracture repair. Mice lacking the AR gene in the periosteum expressing Prrx1-cre (AR-/Y;Prrx1::Cre) but not in the chondrocytes (AR-/Y;Col-2::Cre) exhibits reduced callus size and new bone volume. Gene expression data analysis revealed that the expression of several collagens, integrins and cell adhesion molecules were downregulated in periosteum-derived progenitor cells (PDCs) from AR-/Y;Prrx1::Cre mice. Mechanistically, androgens-AR signaling activates the AR/ARA55/FAK complex and induces the collagen-integrin α2β1 gene expression that is required for promoting the AR-mediated PDCs migration. Using mouse cortical-defect and femoral graft transplantation models, we proved that elimination of AR in periosteum of host mice impairs fracture healing, regardless of AR existence of transplanted donor graft. While testosterone implanted scaffolds failed to complete callus bridging across the fracture gap in AR-/Y;Prrx1::Cre mice, cell-based transplantation using DPCs re-expressing AR could lead to rescue bone repair. In conclusion, targeting androgen/AR axis in the periosteum may provide a novel therapy approach to improve fracture healing.

As a continuing demand for booster shots against SARS-CoV-2, ocular adverse events following the coronavirus disease-2019 (COVID-19) vaccines can cause significant visual impairment, and they warrant a high awareness and detailed documentation of possible ocular inflammatory manifestations. We present a case series of 11 patients presenting with ocular manifestations relevant to vaccine-associated autoimmune response within 6 weeks after the vaccination of the Oxford–AstraZeneca, the Moderna, and Pfizer-BioNTech vaccines at the main tertiary referral center in the most populated and most vaccinated city in Taiwan. Their diagnosis included five acute anterior uveitis, two multiple evanescent white dot syndrome, one probable Vogt–Koyanagi–Harada disease, one anterior scleritis, one relapsed idiopathic panuveitis, and one autoantibody-related central retinal artery occlusion. This report presented a broad spectrum of the ocular inflammatory events following the vaccination of COVID-19. Early recognition of the clinical manifestations mentioned herein with prompt management is crucial in recovering the patients' vision.

Background: Dravet syndrome is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy and SCN1A gene mutations. In some cases, non-SCN1A gene mutations can present with a phenotype very similar to that of Dravet syndrome. The aim of this study was to compare phenotypes of patients with SCN1A and non-SCN1A gene mutation-related Dravet syndrome. Methods: Thirty-six patients with Dravet syndrome-like phenotypes were followed from July 2017 to December 2019. We retrospectively analyzed their clinical profiles and genetic surveys. Results: Of the 36 enrolled patients, 15 (41.7%) had SCN1A mutations, one (2.8%) had an SCN8A mutation, one (2.8%) had an STX1B mutation, and five females (13.9%) had PCDH 19 mutations. The median age at first seizure onset was 7 months in those with SCN1A mutations, 1.3 years in those with PCDH19 mutations, and 10 months for the remaining patients. The majority of the patients with SCN1A mutations had status epilepticus (80% vs. 20%) and fever-sensitive seizures (76% vs. 31%) compared to those with PCDH19 mutations. The patients with SCN1A-related seizures had a higher rate of focal seizures as first seizure type than those without SCN1A mutations. Three of five (60%) patients with PCDH19 mutations had brain magnetic resonance imaging abnormalities. The three most commonly used antiseizure medications were sodium valproate, levetiracetam, and clobazam. Seven of the 15 patients with SCN1A mutations used stiripentol. The median time from seizure onset to genetic diagnosis was 6.6 years (range 4 months–22.3 years). Conclusion: The patients with SCN1A mutations in this study had high rates of fever-sensitive seizures, status epilepticus, seizure onset with focal seizure type, and relatively young age at seizure onset. The patients with PCDH19 mutations had a relatively high rate of abnormal brain magnetic resonance imaging findings.

Preparing communities around mines to face the impacts of mine closures is crucial in order to reduce disruptions to their livelihoods. Building the adaptive capacity of these communities will alleviate the burden on governments or mining companies in the future. Unfortunately, adaptive capacity has not yet been integrated into post-mining planning policies. This research aims to develop an adaptive capacity framework for post-mining planning in local communities, focusing on a case study conducted in Indonesia. We developed this framework using the Importance Performance Analysis (IPA) method. The findings indicate that the adaptive capacity framework provides a comprehensive approach to building the capacity to adapt and thrive in post-mining situations. This highlights the importance of continuing to disseminate post-mining plan information, prioritizing access to capital and former mine sites, fostering collaboration, and creating job opportunities. Simultaneously, efforts to increase skills should be reduced, and reallocation of efforts towards community institution building, establishing information centers, and improving community bonds should be prioritized in more important fields and programs. By adopting this framework, communities around mines in Indonesia are expected to enhance their resilience and ability to effectively respond to changing circumstances.

Extracellular matrix (ECM) scaffolds are extensively used in tissue engineering studies and numerous clinical applications for tissue and organ reconstructions. Due to the global severe shortage of human tissues and organs, xenogeneic biomaterials are a common source for human tissue engineering and regenerative medicine applications. Traditional methods for decellularization often disrupt the 3D architecture and damage the structural integrity of the ECM scaffold. To efficiently obtain natural ECM scaffolds from animal tissues and organs with intact architecture, we have developed a platform decellularization process using supercritical CO2 and tested its potential application in tissue engineering. A combination of human mesenchymal stem cells with a decellularized dermal matrix scaffold allowed complete regeneration of skin structure in a porcine full-thickness wound model.

PURPOSE: The purpose of this study is to compare the efficacy of intravitreal ranibizumab (IVR) alone and concurrent IVR with posterior subtenon triamcinolone acetonide (PSTA) injection for patients with diabetic macular edema (DME) refractory to IVR monotherapy. MATERIALS AND METHODS: We enrolled 43 eyes of 43 patients with DME who received at least three times of IVR, which resulted in poor anatomical responses, with central foveal thickness (CFT) reduction 300 μm. All the eyes received initial 3 monthly then pro re nata (PRN) IVR 0.5-mg injections. Twenty eyes continued PRN injections and 23 eyes received combined IVR 0.5 mg and PSTA 40 mg with at least 1-year follow-up. Best-corrected visual acuity (BCVA) and CFT were recorded from 1-month to 1-year follow-up. RESULTS: Following switch to combined therapy, the mean BCVA significantly improved from 0.61 ± 0.32 logarithm of the minimum angle of resolution (logMAR) to 0.45±0.39 logMAR at 6 month (P = 0.003), 0.43±0.35 logMAR at 9 months (P < 0.001), and 0.48±0.45 logMAR at 1 year (P = 0.03). In eyes with IVR alone, no significant VA improvement was noted throughout the year. Significantly better BCVA was noted in the combined group at 6-month, 9-month, and 1-year follow-up compared to IVR-alone group. The timing of combined therapy showed a significant association with 1-year BCVA (t = 3.25, P = 0.018). CONCLUSION: Concurrent IVR and PSTA resulted in significantly better visual outcomes in 1-year follow-up for those refractory to preceding ranibizumab monotherapy for DME. Early addition of PSTA predicted a better visual outcome.

Background: The aim of this study was to examine the predictive value of amplitude-integrated electroencephalography (aEEG) on 12-month seizure outcomes of infants with neonatal hypoxic-ischemic encephalopathy (HIE) treated with therapeutic hypothermia. Methods: We conducted this retrospective cohort study in a tertiary neonatal intensive care unit between May 2012 and September 2017. Neonates with HIE who received both therapeutic hypothermia (TH) and aEEG were enrolled. Results: A total of 23 infants (14 boys, nine girls) with a mean gestational age of 38.9 weeks were enrolled. Fifteen (65%) infants had moderate HIE and eight (35%) had severe HIE according to modified Sarnat staging. The mean aEEG recording time was 107.5 h. Twenty (86.9%) infants had seizure activity during the first 24 h after cooling and 14 (60.8%) had seizure activity during the first 24 h after rewarming. At 12 months, five (21.7%) infants had poor seizure outcomes. Repetitive seizures or status epilepticus pattern during the first 24 h after rewarming, but not the first 24 h after cooling, were associated with the presence of epilepsy at 12 months (p = 0.037). Conclusions: We identified a high incidence of electrographic seizures in infants with neonatal HIE treated with therapeutic hypothermia, and post-neonatal epilepsy in the children who survived after HIE. Repetitive seizures or status epilepticus pattern during the first 24 h after rewarming, but not in the first 24 h after cooling, were associated with the presence of epilepsy at 12 months.

Recent advances in longitudinal methodologies for observational studies have contributed to a better understanding of Autism as a neurodevelopmental condition characterized by within-person and between-person variability over time across behavioral domains. However, this finer-grained approach to the study of developmental variability has yet to be applied to Autism intervention science. The widely adopted experimental designs in the field—randomized control trials and quasi-experimental designs—hold value for inferring treatment effects; at the same time, they are limited in elucidating what works for whom, why, and when, given the idiosyncrasies of neurodevelopmental disorders where predictors and outcomes are often dynamic in nature. This perspective paper aims to serve as a primer for Autism intervention scientists to rethink the way we approach predictors of treatment response and treatment-related change using a dynamic lens. We discuss several empirical gaps, and potential methodological challenges and opportunities pertaining to: (1) capturing finer-grained treatment effects in specific behavioral domains as indexed by micro-level within-person changes during and beyond intervention; and (2) examining and modeling dynamic prediction of treatment response. Addressing these issues can contribute to enhanced study designs and methodologies that generate evidence to inform the development of more personalized interventions and stepped care approaches for individuals on the heterogeneous spectrum of Autism with changing needs across development.

Background: Growth hormone (GH) supplements have been shown to improve pregnancy and live-birth rates, suggesting that GH has a beneficial effect on oocyte quality. However, the effects of GH on implantation and receptivity remain unknown. This study evaluated the efficacy of GH in women aged more than 40 years participating in assisted reproductive technology (ART) programs. Methods: Cycles of in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET) in women aged more than 40 years (range, 40–43 years) between January 2009 and March 2014 at a university-based reproductive center were reviewed. Women were divided into two groups, those with and without GH co-stimulation. ART outcomes were evaluated. Results: Supplement of GH significantly lowered cycle cancellation rate by increasing the per cycle rates of harvesting at least one oocyte and transferring at least one embryo (80.2% vs. 69.4%). GH increased the per cycle clinical pregnancy (15.9% vs. 6.8%) and favorable ultrasonic endometrial pattern (60.9% vs. 39.3%) rates. GH also increased the per transfer clinical pregnancy (19.9% vs. 9.9%) and implantation (11.2% vs. 5.2%) rates and the rate of a favorable ultrasonic endometrial pattern (65.1% vs. 45.0%). Conclusion: GH supplementation reduces the cycle cancellation rate in women aged more than 40 years, and increases the favorable ultrasonic endometrial pattern, pregnancy, and implantation rates by its beneficial actions on embryo quality and endometrial receptivity. Keywords: Growth hormone, In vitro fertilization, Endometrial pattern, Endometrial receptivity, Implantation

The proviral integration site for moloney murine leukemia virus 1 (Pim1) is a serine/threonine kinase and able to promote cell proliferation, survival and drug resistance. Overexpression of Pim1 has been observed in many cancer types and is associated with the poor prognosis of breast cancer. However, it remains unclear whether Pim1 kinase is a potential therapeutic target for breast cancer patients. In this study, we found that Pim1 expression was strongly associated with HER2 expression and that HER2-overexpressing breast cancer cells were more sensitive to Pim1 inhibitor-induced inhibitions of cell viability and metastatic ability. Mechanistically, Pim1 inhibitor suppressed the expression of HER2 at least in part through transcriptional level. More importantly, Pim1 inhibitor overcame the resistance of breast cancer cells to HER2 tyrosine kinase inhibitor lapatinib. In summary, downregulation of HER2 by targeting Pim1 may be a promising and effective therapeutic approach not only for anti-cancer growth but also for circumventing lapatinib resistance in HER2-positive breast cancer patients.

Background: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an anti-neuronal antibody-mediated inflammatory brain disease that causes severe psychiatric and neurological deficits in previously healthy patients. The aims of this study were to demonstrate the clinical characteristics of patients diagnosed with anti-NMDA receptor encephalitis and to compare the different treatment strategies among these patients. Methods: Patients presenting with newly acquired psychiatric and/or neurological deficits were studied retrospectively from 2009 to 2017. Patients with evidence of anti-NMDA receptor antibodies in serum and/or cerebrospinal fluid were enrolled. The modified Rankin scale was used to assess the initial status and outcomes of the enrolled patients. Details of the clinical presentations and results of investigations were analyzed. Results: All (n = 24) of the patients received first-line immunotherapy (steroids, and/or intravenous immunoglobulin, and/or plasma exchange), and 14 patients received second-line immunotherapy (rituximab and/or cyclophosphamide). The mean time between the first- and second-line treatment was 13 days. During the first 6 months, 20 patients (20/24, 83%) achieved a good outcome (modified Rankin Scale score ≤2) and 15 patients (15/24, 62.5%) completely recovered. Four patients (17.7%) relapsed, and three patients (12.5%) had associated tumors. Conclusion: Immunotherapy is an effective treatment for anti-NMDA receptor encephalitis. Rituximab and/or cyclophosphamide are treatment options for those who cannot tolerate or do not respond to first-line immunotherapy. Prospective studies are necessary to investigate the role of rituximab and cyclophosphamide in anti-NMDA receptor encephalitis. Key Words: cyclophosphamide, anti-NMDAR encephalitis, immunotherapy, intravenous immunoglobulin, rituximab

Abstract Background Myasthenia gravis is the most common disease affecting the neuromuscular junction. The most common etiology among patients with juvenile myasthenia gravis is the production of antibodies against the acetylcholine receptor. However, the clinical outcome in relation to serum levels of anti-acetylcholine receptor antibodies in juvenile myasthenia gravis has rarely been discussed. We aimed to analyze the correlation between the presence of anti-acetylcholine receptor antibodies and outcome in juvenile myasthenia gravis. Methods Patients diagnosed with juvenile myasthenia gravis younger than of 20 years of age were retrospectively recruited from January 1995 to February 2017 in a tertiary referral medical center. According to the Myasthenia Gravis Foundation of America outcome scale, the primary outcome was complete symptom remission and cessation of medications for at least 1 year measured 2 years after diagnosis. Secondary outcome was complete symptom remission at the last outpatient clinic. Results A total of 54 patients were followed up for over 2 years. Nine patients (9/54, 16.7%) achieved complete remission without medication use at 2 years after diagnosis. Thirteen (24.1%) patients achieved complete remission during longer follow-up periods. Those with negative anti-acetylcholine receptor antibodies were more likely to achieve complete remission at 2 years (6/15 [40%] vs. 3/39 [7.7%], 95% Confidence interval [CI] 1.670 to 38.323) and at the last outpatient clinic follow-up (8/15 [53.3%] vs. 5/39 [12.8%], 95% CI 2.367 to 20.704). Thirteen patients with comorbid autoimmune thyroid diseases were older than those without disease (11.8 ± 5.8 years old vs. 8.0 ± 6.3 years old, 95% CI 0.018 to 7.33). Moreover, patients negative for anti-acetylcholine receptor antibodies were less likely comorbid with autoimmune thyroid disease (1/35 [2.9%] vs. 12/71 [16.9%], 95% CI 0.018 to 1.161). Conclusions Juvenile myasthenia gravis patients without anti-acetylcholine antibodies exhibited significantly increased complete remission rates and a reduced likelihood of comorbid autoimmune thyroid diseases compared with those with anti-acetylcholine receptor antibodies among Chinese.

Purpose. This retrospective study aimed to compare the efficacy of intravitreal ranibizumab (IVR) and intravitreal dexamethasone implant (IDI) for pseudophakic vitrectomized eyes with diabetic macular edema (DME) in a single institution. Methods. Pseudophakic vitrectomized eyes with treatment-naïve center-involved DME were enrolled, with one eye in each patient. They were divided into two groups: one group receiving IDI every 3 to 4 months and another group receiving IVR using 3 monthly plus treat-and-extend injections, all with monthly follow-up for 6 months. Switch of intravitreal drugs or deferred macular laser was not allowed. Primary outcome measures included change in central foveal thickness (CFT) in 1 mm by spectral-domain optical coherence tomography and best-corrected visual acuity (BCVA) at Month 6. Results. Twenty-two eyes were included in the IDI group and 26 eyes in the IVR group. The baseline demographics, glycosylated hemoglobin level, intraocular pressure (IOP), BCVA, and CFT did not significantly differ (p>0.05). Compared to baseline data, CFT decreased and BCVA improved significantly after either IDI or IVR at Month 6 (p

Intrauterine adhesion (IUA) is caused by artificial endometrial damage during intrauterine cavity surgery. The typical phenotype involves loss of spontaneous endometrium recovery and angiogenesis. Undesirable symptoms include abnormal menstruation and infertility; therefore, prevention and early treatment of IUA remain crucial issues. Extracorporeal shockwave therapy (ESWT) major proposed therapeutic mechanisms include neovascularization, tissue regeneration, and fibrosis. We examined the effects of ESWT and/or platelet-rich plasma (PRP) during preventive and therapeutic stages of IUA by inducing intrauterine mechanical injury in rats. PRP alone, or combined with ESWT, were detected an increased number of endometrial glands, elevated vascular endothelial growth factor protein expression (hematoxylin-eosin staining and immunohistochemistry), and reduced fibrosis rate (Masson trichrome staining). mRNA expression levels of nuclear factor-kappa B, tumor necrosis factor-α, transforming growth factor-β, interleukin (IL)-6, collagen type I alpha 1, and fibronectin were reduced during two stages. However, PRP alone, or ESWT combined with PRP transplantation, not only increased the mRNA levels of vascular endothelial growth factor (VEGF) and progesterone receptor (PR) during the preventive stage but also increased PR, insulin-like growth factor 1 (IGF-1), and IL-4 during the therapeutic stage. These findings revealed that these two treatments inhibited endometrial fibrosis and inflammatory markers, thereby inhibiting the occurrence and development of intrauterine adhesions.

Plastic optical components are light in weight, easy to manufacture, and amenable to mass production. However, plastic injection molded parts are liable to shrinkage and warpage as a result of the pressure and temperature variations induced during the molding process. Consequently, controlling the process parameters in such a way as to minimize the geometric deformation of the molded part and improve the performance of the optical component as a result remains an important concern. The present study considered the problem of optimizing the injection molding parameters for the plastic lens barrel of a bilateral telecentric lens (BTL) containing four lens assemblies. The study commenced by using CODE V optical software to design the lens assemblies and determine their optimal positions within the barrel. Taguchi experiments based on Moldex3D simulations were then performed to determine the processing conditions (i.e., maximum injection pressure, maximum packing pressure, melt temperature, mold temperature, and cooling time) which minimize the coaxiality of the plastic barrel. Finally, CODE V and grayscale analyses were performed to confirm the optical performance of the optimized BTL. The Taguchi results show that the coaxiality of the plastic lens barrel is determined mainly by the maximum packing pressure and melt temperature. In addition, the CODE V and grayscale analysis results confirm that the optimized BTL yields a better modulus transfer function, spot diagram performance, and image quality than a BTL produced using the general injection molding parameters.

Abstract The authors performed a retrospective and comparative study to compare the efficacy of intravitreal aflibercept and bevacizumab for patients with myopic choroidal neovascularization (mCNV). The patients with treatment-naïve mCNV received 1 + PRN intravitreal bevacizumab from March 2008 to February 2013, while from March 2013 to July 2016 patients were treated by 1 + PRN intravitreal aflibercept, all with monthly follow-up for 12 months. Primary outcome measures included change in central foveal thickness (CFT) in 1 mm by spectral-domain optic coherence tomography, and best corrected visual acuity (BCVA) at month 12. Complications after injections were recorded. The intra-group changes in CFT and BCVA were compared with Wilcoxon signed rank test, the between-group difference compared with Wilcoxon rank sum test. Fisher’s exact test was used for categorical comparison between groups. Seventy-eight eyes of 78 patients were collected. There were 42 eyes in bevacizumab group, with mean age of 53.2 ± 5.4 years and 27 female patients of them. The mean BCVA significantly improved from baseline 0.56 ± 0.35 logMAR to 0.35 ± 0.35 logMAR at Month 12 after bevacizumab treatment (p 0.05). There was no significant difference between bevacizumab and aflibercept groups in BCVA and CFT from Month 1 to Month 12 (p > 0.05). Injection number of aflibercept was 2.11 ± 0.41, less than that of bevacizumab (3.23 ± 0.38) during 12-month period (p = 0.01). There were no systemic thromboembolic event, elevated intraocular pressure, retinal detachment, or infectious endophthalmitis following injections in both groups. We concluded that both aflibercept and bevacizumab can effectively treat choroidal neovascularization in high myopes. Intravitreal aflibercept had similar efficacy but less treatment number than bevacizumab for mCNV during 12-month period.

Cigarette smoking is one of the leading risks for lung cancer and is associated with the insensitivity of non‐small cell lung cancer (NSCLC) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, it remains undetermined whether and how cigarette smoke affects the therapeutic efficacy of EGFR TKIs. In this study, our data showed that chronic exposure to cigarette smoke extract (CSE) or tobacco smoke‐derived carcinogen benzo[α]pyrene, B[α]P, but not nicotine‐derived nitrosamine ketone (NNK), reduced the sensitivity of wild‐type EGFR‐expressing NSCLC cells to EGFR TKIs. Treatment with TKIs almost abolished EGFR tyrosine kinase activity but did not show an inhibitory effect on downstream Akt and ERK pathways in B[α]P‐treated NSCLC cells. CSE and B[α]P transcriptionally upregulate c‐MET and activate its downstream Akt pathway, which is not inhibited by EGFR TKIs. Silencing of c‐MET reduces B[α]P‐induced Akt activation. The CSE‐treated NSCLC cells are sensitive to the c‐MET inhibitor crizotinib. These findings suggest that cigarette smoke augments oncogene addiction to c‐MET in NSCLC cells and that MET inhibitors may show clinical benefits for lung cancer patients with a smoking history.

Researchers increasingly employ longitudinal trajectory methods to understand developmental pathways of people on the autism spectrum across the lifespan. By assessing developmental or health-related outcome domains at three or more timepoints, trajectory studies can characterize their shape and varying rates of change over time. The purpose of this scoping review was to identify and summarize the published breadth of research that uses a trajectory study design to examine development in children (to age 18 years) diagnosed with autism. Using a systematic search and screening procedure, 103 studies were included. This review summarizes methodological characteristics across studies including the varying statistical approaches used. A series of figures maps where published research is available across 10 outcome domains and the ages over which children have been followed. Evidence gaps, informed by the perspectives of the autistic and caregiver stakeholders that were engaged in this review, are discussed. We recommend that future trajectory research addresses the absence of studies from low- and middle-income countries, considers longitudinal assessment of outcome domains that caregivers and autistic people consider meaningful, and plans follow-up periods with assessment timepoints that cover the gaps in ages where more outcome-specific data are needed.

Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2‐positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase‐dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin‐dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK‐mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor‐induced Akt activation.

Abstract SMYD3 is a methyltransferase highly expressed in many types of cancer. It usually functions as an oncogenic protein to promote cell cycle, cell proliferation, and metastasis. Here, we show that SMYD3 modulates another hallmark of cancer, DNA repair, by stimulating transcription of genes involved in multiple steps of homologous recombination. Deficiency of SMYD3 induces DNA-damage hypersensitivity, decreases levels of repair foci, and leads to impairment of homologous recombination. Moreover, the regulation of homologous recombination-related genes is via the methylation of H3K4 at the target gene promoters. These data imply that, besides its reported oncogenic abilities, SMYD3 may maintain genome integrity by ensuring expression levels of HR proteins to cope with the high demand of restart of stalled replication forks in cancers.

Purpose: To compare the two-year visual and anatomical outcomes of combination therapy of photodynamic therapy (PDT) with intravitreal aflibercept (IVA) or intravitreal ranibizumab (IVR) for patients with polypoidal choroidal vasculopathy (PCV), and to investigate the clinical factors with final visual outcome and retreatment. Methods: A retrospective medical chart review was performed for 55 eyes from 55 patients with PCV treated by a combination therapy of prompt PDT with either IVA (n = 30) or IVR (n = 25). Baseline data and treatment outcomes during the 24-month follow-up were compared between the two groups. Primary outcomes were the changes in best-corrected visual acuity (BCVA) and the rate of complete polyp regression. Secondary outcomes were the changes in central retinal thickness (CRT) and the rate of dry macula. Retreatment was administered in cases with persistent or recurrent submacular or intramacular fluid. Results: The BCVA significantly improved in the IVA/PDT group at every 6-month visit compared to the baseline. In the IVR/PDT group, there was a significant improvement of BCVA only at 6-months and 12-months, but not at 18-months and 24-months compared to the baseline. There were no significant differences in the BCVA change or CRT change between the two groups at every 6-month visit. A complete polyp regression rate at 3-months was 53.3% in IVA/PDT, and 52.0% in IVR/PDT. Significantly higher dry macula rate in Month 6 and 18 in the IVA/PDT group than in IVR/PDT group. Retreatment was performed in 26.7% patients in IVA/PDT, and in 60.0% patients in the IVR/PDT group. There were significantly lower retreatment rates in the IVA/PDT group than those in the IVR/PDT group. Better final BCVA was associated with better baseline BCVA and a younger age. Retreatment was associated with complete polyp regression at 3-months. Conclusions: Significant visual improvement was demonstrated in the IVA/PDT group at every 6-month visit, but only at a 6-month and a 12-month follow-up in the IVR/PDT group. Although changes of the BCVA/CRT and complete polyp regression rate were comparable between two groups, the IVA/PDT group required less retreatment and attained more dry macula results. Better baseline BCVA and younger age were associated with a better visual outcome.

Infants at elevated likelihood of developing autism display differences in sensory reactivity, especially hyporeactivity, as early as 7 months of age, potentially contributing to a developmental cascade of autism symptoms. Caregiver responsiveness, which has been linked to positive social communication outcomes, has not been adequately examined with regard to infant sensory reactivity. This study examined the multiplicative impact of infant sensory hypo- and hyperreactivity on caregiver responsiveness to sensory reactivity and regulation cues in 43 infants at elevated likelihood of autism. Sensory hyperreactivity was found to moderate the association between sensory hyporeactivity and caregiver responsiveness, such that caregivers of infants with moderately high sensory hypo- and hyperreactivity demonstrated higher responsiveness.

Nu Shu GPS: 25 °21’00.5N, 111°27’17.7E – an interdisciplinary cooperation between dance, calligraphy, and the body in multimedia performance, began with a diary exchange between the artist and a friend, who shared their thoughts by writing in the same journal. During this ‘diary swapping’ period, they developed a semiotic system that only the two of them could understand. Later, the artist came across Nu Shu, the only written language in the world that exclusively women learned to write and read. The artist attempts to explore all the possible metaphors and meanings implied by Nu Shu. The performance Nu Shu GPS: 25 °21’00.5N, 111°27’17 attempts to bring this secret method of communication back to life among modern Chinese women.This interdisciplinary performance work employs a practical approach to art through a creative collaboration among experts from different fields: choreographers, dancers, lighting designers, programmers, etc. It attempts to apply the three stages of the art creation process (Praxis, Symbol, Presence) as the three different faces for a theory regarding this work.

Conducting electrophysiological measurements from human brain function provides a medium for sending commands and messages to the external world, as known as a brain–computer interface (BCI). In this study, we proposed a smart helmet which integrated the novel hygroscopic sponge electrodes and a combat helmet for BCI applications; with the smart helmet, soldiers can carry out extra tasks according to their intentions, i.e., through BCI techniques. There are several existing BCI methods which are distinct from each other; however, mutual issues exist regarding comfort and user acceptability when utilizing such BCI techniques in practical applications; one of the main challenges is the trade-off between using wet and dry electroencephalographic (EEG) electrodes. Recently, several dry EEG electrodes without the necessity of conductive gel have been developed for EEG data collection. Although the gel was claimed to be unnecessary, high contact impedance and low signal-to-noise ratio of dry EEG electrodes have turned out to be the main limitations. In this study, a smart helmet with novel hygroscopic sponge electrodes is developed and investigated for long-term usage of EEG data collection. The existing electrodes and EEG equipment regarding BCI applications were adopted to examine the proposed electrode. In the impedance test of a variety of electrodes, the sponge electrode showed performance averaging 118 kΩ, which was comparable with the best one among existing dry electrodes, which averaged 123 kΩ. The signals acquired from the sponge electrodes and the classic wet electrodes were analyzed with correlation analysis to study the effectiveness. The results indicated that the signals were similar to each other with an average correlation of 90.03% and 82.56% in two-second and ten-second temporal resolutions, respectively, and 97.18% in frequency responses. Furthermore, by applying the proposed differentiable power algorithm to the system, the average accuracy of 21 subjects can reach 91.11% in the steady-state visually evoked potential (SSVEP)-based BCI application regarding a simulated military mission. To sum up, the smart helmet is capable of assisting the soldiers to execute instructions with SSVEP-based BCI when their hands are not available and is a reliable piece of equipment for strategical applications.

Fifty-two eyes of 52 patients with treatment-naïve macular edema associated with perfused branch retinal vein occlusion were retrospectively reviewed. Twenty-seven cases received PRN intravitreal bevacizumab, and 25 cases were treated by PRN intravitreal aflibercept with monthly follow-ups for 12 months. Both aflibercept and bevacizumab were effective in reduction of macular thickness and improvement of visual acuity for the participants. Both antivascular endothelial growth factor agents had similar efficacy and duration of treatment for these eyes with macular edema secondary to branch retinal vein occlusion during a 12-month period. No serious systemic or ocular adverse events were reported.

BQ chewing may produce significant amounts of reactive oxygen species (ROS), resulting in oral mucosa damage, and ROS may be metabolized by CYP26 families. Because the CYP26 polymorphisms associated with malignant oral disorders are not well known, we conducted an association study on the associations between the single nucleotide polymorphisms (SNP) of CYP26 families and the risks of malignant oral disorders. BQ chewers with the CYP26A1 rs4411227 C/C+C/G genotype and C allele showed an increased risk of oral and pharyngeal cancer (adjusted odds ratio (aOR) = 2.30 and 1.93, respectively). The CYP26B1 rs3768647 G allele may be associated with oral and pharyngeal cancer (aOR = 3.12) and OPMDs (aOR = 2.23). Subjects with the rs9309462 CT genotype and C allele had an increased risk of oral and pharyngeal cancer (aOR = 9.24 and 8.86, respectively) and OPMDs (aOR = 8.17 and 7.87, respectively). The analysis of joint effects between the CYP26A1 rs4411227 and CYP26B1 rs3768647/rs9309462 polymorphisms revealed statistical significance (aOR = 29.91 and 10.03, respectively). Additionally, we observed a significant mRNA expression of CY26A1 and CYP26B1 in cancerous tissues compared with adjacent noncancerous tissues. Our findings suggest that novel CYP26 polymorphisms are associated with an increased risk of malignant oral disorders, particularly among BQ chewers.

The multikinase inhibitor, sorafenib (Nexavar®, BAY43-9006), which inhibits both the Raf/MEK/ERK pathway and several receptor tyrosine kinases (RTKs), has shown significantly therapeutic benefits in advanced hepatocellular carcinoma (HCC). However, not all HCC patients respond to sorafenib well and new therapeutic strategies to optimize the efficacy of sorafenib are urgently required. Overexpression of breast cancer resistance protein (BCRP/ABCG2) mediates the drug-efflux of several tyrosine kinase inhibitors (TKIs) to attenuate their efficacy. This study aimed to investigate the role of BCRP/ABCG2 in the sensitivity of HCC to sorafenib. Our data showed that BCRP/ABCG2 mediated the efflux of sorafenib. Co-treatment with a BCRP/ABCG2 inhibitor greatly augmented the cytotoxicity of sorafenib in HCC cells. Similar results were also achieved by the competitive inhibitor of BCRP/ABCG2, gefitinib, in combination with sorafenib. These results suggest not only that BCRP/ABCG2 is a potential predictor for the sorafenib sensitivity in HCC, but also that blockage of BCRP/ABCG2 may be a potential strategy to increase the response of HCC cells to sorafenib.

The intersectin 1 (ITSN1) scaffold stimulates Ras activation on endocytic vesicles without activating classic Ras effectors. The identification of Class II phosphatidylinositol 3-kinase beta, PI3KC2β, as an ITSN1 target on vesicles and the presence of a Ras binding domain (RBD) in PI3KC2β suggests a role for Ras in PI3KC2β activation. Here, we demonstrate that nucleotide-free Ras negatively regulates PI3KC2β activity. PI3KC2β preferentially interacts in vivo with dominant-negative (DN) Ras, which possesses a low affinity for nucleotides. PI3KC2β interaction with DN Ras is disrupted by switch 1 domain mutations in Ras as well as RBD mutations in PI3KC2β. Using purified proteins, we demonstrate that the PI3KC2β-RBD directly binds nucleotide-free Ras in vitro and that this interaction is not disrupted by nucleotide addition. Finally, nucleotide-free Ras but not GTP-loaded Ras inhibits PI3KC2β lipid kinase activity in vitro. Our findings indicate that PI3KC2β interacts with and is regulated by nucleotide-free Ras. These data suggest a novel role for nucleotide-free Ras in cell signaling in which PI3KC2β stabilizes nucleotide-free Ras and that interaction of Ras and PI3KC2β mutually inhibit one another.

The sensitivity of non-small cell lung cancer (NSCLC) patients to EGFR tyrosine kinase inhibitors (TKIs) is strongly associated with activating EGFR mutations. Although not as sensitive as patients harboring these mutations, some patients with wild-type EGFR (wtEGFR) remain responsive to EGFR TKIs, suggesting that the existence of unexplored mechanisms renders most of wtEGFR-expressing cancer cells insensitive.Here, we show that acquired resistance of wtEGFR-expressing cancer cells to an EGFR TKI, gefitinib, is associated with elevated expression of breast cancer resistance protein (BCRP/ABCG2), which in turn leads to gefitinib efflux from cells. In addition, BCRP/ABCG2 expression correlates with poor response to gefitinib in both cancer cell lines and lung cancer patients with wtEGFR. Co-treatment with BCRP/ABCG2 inhibitors enhanced the anti-tumor activity of gefitinib.Thus, BCRP/ABCG2 expression may be a predictor for poor efficacy of gefitinib treatment, and targeting BCRP/ABCG2 may broaden the use of gefitinib in patients with wtEGFR.

The goal of sustainable water quality management is to keep total pollutant discharges from exceeding the assimilation capacity of a water body. Climate change may influence streamflows, and further alter assimilation capacity and degrade river sustainability. The purposes of this study are to evaluate the effect of climate change on sustainable water quality management and design an early warning indicator to issue warnings on river sustainability. A systematic assessment procedure is proposed here, including a weather generation model, the streamflow component of GWLF, QUAL2E, and an optimization model. The Touchen creek in Taiwan is selected as the study area. Future climate scenarios derived from projections of four global climate models (GCMs) and two pollutant discharge scenarios, as usual and proportional to population, are considered in this study. The results indicate that streamflows may very likely increase in humid seasons and decrease in arid seasons, respectively. The reduction of streamflow in arid seasons may further degrade water quality and assimilation capacity. In order to provide warnings to trigger necessary adaptation strategies, an early warning indicator is designed and its 30-year moving average is calculated. Finally, environmental monitoring systems and methods to prioritize adaptation strategies are discussed for further studies in the future.

This report focuses on the occupational health risks associated with the use of artificial stones containing high levels of crystalline silica in the production of kitchen countertops. It presents the case of a 43-yr-old man who developed severe silicosis due to his occupation involving cutting and polishing quartz stone raw materials. A retrospective analysis of the patient's medical records and occupational history was conducted. The diagnosis of severe silicosis, moderate restrictive lung disease, and bilateral pneumothorax was based on clinical manifestations, pulmonary function test, radiological findings, and histological reports. The patient underwent lung transplantation, and his pulmonary function improved post-surgery. The study highlights the significant health risks associated with procedures involving artificial stones and emphasizes the importance of awareness and protective measures for employees and workers. Clinicians should be cautious when diagnosing respiratory symptoms in patients with a history of occupational exposure to artificial stones containing high levels of crystalline silica. [ABSTRACT FROM AUTHOR]

Introduction: This study examined the prevalence of functional difficulties and associated factors in Canadian children/youth aged 5 to 17 years diagnosed with autism spectrum disorder (ASD). Methods: We analyzed data from the 2019 Canadian Health Survey on Children and Youth (CHSCY), a nationally representative survey of Canadian children/youth that used the Washington Group Short Set on Functioning (WG-SS) to evaluate functioning in six daily tasks. For each functional domain, binary outcomes were derived (no/some difficulty, a lot of difficulty/no ability). We used logistic regression to identify associations between demographic characteristics, educational experiences, and perceived mental and general health and the most common functional difficulties, namely those related to remembering/concentrating, communication and self-care. All estimates were weighted to be representative of the target population. The bootstrap method was used to calculate variance estimates. Results: Analysis of the records of 660 children/youth with ASD revealed that the most common functional difficulties were remembering/concentrating (22%; 95% CI: 18-27), communicating (19%; 95% CI: 15-23) and self-care (13%; 95% CI: 10-17). Lower perceived mental health was associated with increased functional difficulties with remembering/concentrating. ASD diagnosis at a lower age and lower perceived general health were associated with increased functional difficulty with communication. Parental expectations for postsecondary education were associated with decreased functional difficulty for self-care. Conclusion: One or more functional difficulties from the WG-SS was present in 39% of Canadian children/youth aged 5 to 17 years with ASD. Functional difficulties with remembering/concentrating, communication and self-care were most common. [ABSTRACT FROM AUTHOR]