Filling the simulation-to-reality gap: high-degree-of-freedom AI-optimized photonic crystal nanobeam resonators with fabrication tolerance.

In this work, we unveil a novel, to the best of our knowledge, AI-based design method (AIDN1) specifically developed for photonic crystal resonator designs, capable of handling complex designs with over 10 degrees of freedom (DoFs) and considering practical fabrication uncertainties to minimize the common simulation-to-reality (sim2real) gap. Especially, we introduce an ultrashort (<5 µm) curved nanobeam resonator, which obtains an ultrahigh theoretical quality factor (Q-factor) of 2 × 107 and maintains a theoretical Q-factor above 105 even under high fabrication variations. Importantly, we emphasize that AIDN1 is generalizable and our work serves as a solid foundation for future laser fabrication endeavors beyond the realm of ultrashort 1D photonic crystal (PhC) resonators.

Topical treatment of tyrosine kinase 2 inhibitor through borneol-embedded hydrogel: Evaluation for preventive, therapeutic, and Recurrent management of psoriasis.

Psoriasis, an immune-mediated inflammatory skin disorder characterized by a chronically relapsing-remitting course, continues to be primarily managed through topical therapy. While oral administration of tyrosine kinase 2 inhibitors (TYK2i) stands as an effective approach for psoriasis treatment, the potential efficacy of topical application of TYK2i remains unexplored. Herein, the carbomer/alginic acid hydrogel is embedded with borneol (BO) as a new topical carrier of TYK2i for achieving enhanced transdermal permeation and anti-psoriasis efficacy. The hydrogel system, i.e., TYK2i-BO-gel, exhibits significantly improved preventative and therapeutic effects in mice models of psoriasiform dermatitis, as evidenced by phenotypical images, psoriasis severity score index (PSI), histology, immunohistochemical staining, and PCR analysis. Remarkably, TYK2i-BO-gel outperforms conventional topical corticosteroid therapy by significantly preventing psoriatic lesion recurrence as measured by a nearly 50 % reduction in ear thickness changes (p < 0.0001), PSI (p < 0.0001) and epidermal thickness (p < 0.05). Moreover, a strengthened anti-inflammatory effect caused by TYK2i-BO-gel is seen in a human skin explant model, implying its potential application for human patients. With the addition of BO, the TYK2i-BO-gel not only increases skin permeability but also inhibits the expression of antimicrobial peptides in keratinocytes and facilitates the anti-Th17 response of TYK2i with suppressed activation of STAT3. Therefore, this work represents the accessibility and effectiveness of TYK2i-BO-hydrogel as a new topical formulation for anti-psoriasis management and shows great potential for clinical application.

CD11b suppresses TLR7-driven inflammatory signaling to protect against lupus nephritis.

Lupus Nephritis (LN) is a severe complication of systemic lupus erythematosus (SLE) that affects kidney function. Here, we investigated the role of CD11b, a protein encoded by the ITGAM gene, in the development of LN and its functional activation as a therapeutic strategy. Genetic coding variants of ITGAM significantly increase the risk for SLE and LN by producing a less active CD11b and leading to elevated levels of type I interferon (IFN I). However, a molecular mechanism for how these variants increase LN risk has been unclear. Here, we determined that these variants also significantly associate with elevations in soluble urokinase plasminogen activator receptor (suPAR), a known biomarker linked to kidney disease, suggesting a novel molecular connection. Pharmacologic activation of CD11b with a novel, clinical-stage agonist ONT01 significantly suppressed suPAR production in myeloid cells and reduced systemic inflammation and kidney damage in multiple experimental models of LN. Importantly, delaying treatment with ONT01 until after disease onset also significantly reduced serum suPAR and inflammatory cytokines, and decreased immune complex deposition in the glomerulus, glomerulonephritis and albuminuria, suggesting that CD11b activation is therapeutic for LN. Genetic activation of CD11b via a gain-of-function CD11b mutation also showed complete protection from LN, whereas genetic deletion of CD11b worsened the disease in mice, providing further evidence of the role of CD11b activation in regulating LN. Finally, transfer of human LN PBMCs generated human LN like disease in mice that was significantly reduced by ONT01. Together, these data provide strong evidence that ONT01 mediated CD11b activation can therapeutically modulate TLR7-driven inflammation and protect against LN. These findings support clinical development of CD11b agonists as novel therapeutics for treating lupus nephritis in human patients.

FGF1 Suppresses Allosteric Activation of ß3 Integrins by FGF2: A Potential Mechanism of Anti-Inflammatory and Anti-Thrombotic Action of FGF1.

Several inflammatory cytokines bind to the allosteric site (site 2) and allosterically activate integrins. Site 2 is also a binding site for 25-hydroxycholesterol, an inflammatory lipid mediator, and is involved in inflammatory signaling (e.g., TNF and IL-6 secretion) in addition to integrin activation. FGF2 is pro-inflammatory and pro-thrombotic, and FGF1, homologous to FGF2, has anti-inflammatory and anti-thrombotic actions, but the mechanism of these actions is unknown. We hypothesized that FGF2 and FGF1 bind to site 2 of integrins and regulate inflammatory signaling. Here, we describe that FGF2 is bound to site 2 and allosterically activated ß3 integrins, suggesting that the pro-inflammatory action of FGF2 is mediated by binding to site 2. In contrast, FGF1 bound to site 2 but did not activate these integrins and instead suppressed integrin activation induced by FGF2, indicating that FGF1 acts as an antagonist of site 2 and that the anti-inflammatory action of FGF1 is mediated by blocking site 2. A non-mitogenic FGF1 mutant (R50E), which is defective in binding to site 1 of αvß3, suppressed ß3 integrin activation by FGF2 as effectively as WT FGF1.

Symmetry-preserving modeling for lithographic imaging.

In computational imaging and lithography, it has been a challenge for a numerical model to faithfully preserve symmetries in the physical imaging system. In this Letter, we present a project-to-symmetry-subspace (PTSS) method to prevent symmetry loss during the iterative generation of optical kernels. Essentially, PTSS is to project iterative vectors onto a predefined symmetric subspace when decomposing the transmission cross coefficient (TCC). Simulation results demonstrate the PTSS-generation of a truncated set of optical kernels that are substantially free of symmetry error, regardless of the order of truncation.

Prevalence and clinical significance of late gadolinium enhancement in children and adolescents with hypertrophic cardiomyopathy: a systematic review and meta-analysis.

OBJECTIVES: Hypertrophic cardiomyopathy is the leading cause of sudden cardiac death among the paediatric population. The aim of this study is to investigate the prevalence and clinical significance of late gadolinium enhancement, as assessed by cardiac MRI, in paediatric hypertrophic cardiomyopathy. METHODS: A systematic literature search was conducted in PubMed, SCOPUS, and Ovid SP to identify relevant studies. Pooled estimates with a 95% confidence interval were calculated using the random-effects generic inverse variance model. Statistical analysis was performed using Review Manager v5.4 and R programming. RESULTS: Seventeen studies were included in this meta-analysis, encompassing a total of 778 patients. Late gadolinium enhancement was highly prevalent in paediatric hypertrophic cardiomyopathy, with a pooled prevalence of 51% (95% confidence interval, 40-62%). The estimated extent of focal fibrosis expressed as a percentage of left ventricular mass was 4.70% (95% confidence interval, 2.11-7.30%). The presence of late gadolinium enhancement was associated with an increased risk of adverse cardiac events (pooled odds ratio 3.49, 95% confidence interval 1.10-11.09). The left ventricular mass index of late gadolinium enhancement-positive group was higher than the negative group, with a standardised mean difference of 0.91 (95% confidence interval, 0.42-1.41). CONCLUSION: This meta-analysis demonstrates that prevalence of late gadolinium enhancement in paediatric hypertrophic cardiomyopathy is similar to that in the adult population. The presence and extent of late gadolinium enhancement are independent predictors of adverse cardiac events, underscoring their prognostic significance among the paediatric population.

Pulmonary Complications of Cytomegalovirus Infection in Neonates and Infants: A Systematic Review of Case Reports and Pooled Analysis.

BACKGROUND: Cytomegalovirus (CMV) causes intrauterine infections in 0.67% of neonates, with 12.7% displaying symptoms at birth. CMV can lead to severe multiorgan involvement, and mortality in symptomatic cases is around 30%. Pulmonary complications are rare in infants with CMV. This review assesses pulmonary complications and outcomes in infants with CMV infection. METHODS: A systematic literature search was conducted using PubMed, SCOPUS and Ovid SP to retrieve case reports on pulmonary complications in infants with congenital or perinatal CMV infection. Descriptive analysis and pooled analysis were conducted for the case reports. RESULTS: A total of 28 articles with 38 patients were included in this systematic review. The reported pulmonary complications in the case reports were CMV pneumonitis (34.2%), persistent pulmonary hypertension of the newborn (18.4%), emphysema and chronic lung disease (15.8%), diaphragmatic dysfunction (13.2%), lung cysts and calcifications (10.5%), Pneumocystis jirovecii infection (7.9%), pulmonary hypoplasia (5.3%) and bronchial atresia (2.6%). Seven (18.4%) of 38 patients passed away because of the pulmonary complications of CMV infection. Congenital transmission ( P = 0.0108), maternal CMV ( P = 0.0396) and presence of neonatal comorbidities ( P = 0.0398) were independent risk factors for mortality. CONCLUSIONS: This systematic review demonstrated infrequent occurrence of severe pulmonary involvement in CMV infection but should be considered in infants with persistent or severe respiratory symptoms.

Adeno-Associated Virus Type 9-Mediated Gene Therapy of Choline Acetyltransferase-Deficient Mice.

The enzyme choline acetyltransferase (ChAT) synthesizes acetylcholine from acetyl-CoA and choline at the neuromuscular junction and at the nerve terminals of cholinergic neurons. Mutations in the ChAT gene (CHAT) result in a presynaptic congenital myasthenic syndrome (CMS) that often associates with life-threatening episodes of apnea. Knockout mice for Chat (Chat-/-) die at birth. To circumvent the lethality of this model, we crossed mutant mice possessing loxP sites flanking Chat exons 4 and 5 with mice that expressed Cre-ERT2. Injection of tamoxifen (Tx) at postnatal (P) day 11 in these mice induced downregulation of Chat, autonomic failure, weakness, and death. However, a proportion of Chatflox/flox-Cre-ERT2 mice receiving at birth an intracerebroventricular injection of 2 × 1013 vg/kg adeno-associated virus type 9 (AAV9) carrying human CHAT (AAV9-CHAT) survived a subsequent Tx injection and lived to adulthood without showing signs of weakness. Likewise, injection of AA9-CHAT by intracisternal injection at P28 after the onset of weakness also resulted in survival to adulthood. The expression of Chat in spinal motor neurons of Chatflox/flox-Cre-ERT2 mice injected with Tx was markedly reduced, but AAV-injected mice showed a robust recovery of ChAT expression, which was mainly translated by the human CHAT RNA. The biodistribution of the viral genome was widespread but maximal in the spinal cord and brain of AAV-injected mice. No significant histopathological changes were observed in the brain, liver, and heart of AAV-injected mice after 1 year follow-up. Thus, AAV9-mediated gene therapy may provide an effective and safe treatment for patients severely affected with CHAT-CMS.

Photocatalyzed Enantioselective Functionalization of C(sp3)-H Bonds.

Owing to its diverse activation processes including single-electron transfer (SET) and hydrogen-atom transfer (HAT), visible-light photocatalysis has emerged as a sustainable and efficient platform for organic synthesis. These processes provide a powerful avenue for the direct functionalization of C(sp3)-H bonds under mild conditions. Over the past decade, there have been remarkable advances in the enantioselective functionalization of the C(sp3)-H bond via photocatalysis combined with conventional asymmetric catalysis. Herein, we summarize the advances in asymmetric C(sp3)-H functionalization involving visible-light photocatalysis and discuss two main pathways in this emerging field: (a) SET-driven carbocation intermediates are followed by stereospecific nucleophile attacks; and (b) photodriven alkyl radical intermediates are further enantioselectively captured by (i) chiral π-SOMOphile reagents, (ii) stereoselective transition-metal complexes, and (iii) another distinct stereoscopic radical species. We aim to summarize key advances in reaction design, catalyst development, and mechanistic understanding, to provide new insights into this rapidly evolving area of research.

Uncovering a dose-response relationship between positive fecal immunochemical test (FIT) and all-cause, cardiovascular and cancer-related mortality.

BACKGROUND: Fecal immunochemical test (FIT) is for colorectal cancer (CRC) screening. Its association with non-CRC mortality has been overlooked. Given the quantitative FIT values, its dose-response relationships with different causes of deaths and years of life shortened were assessed. METHODS: This retrospective study included 546,214 adults aged ≥ 20 who attended a health surveillance program from 1994 to 2017 and were followed up until the end of 2020. FIT ≥ 20 µg Hb/g was defined as positive. The Cox model was used to assess adjusted hazard ratios (aHR). RESULTS: Positive FIT was associated with increased all-cause mortality (aHR: 1.34, 95 % CI: 1.25-1.44) and all-cancer mortality (aHR: 1.71, 95 % CI: 1.55-1.89), with a reduction of life expectancy by 4 years. The association remained even with CRC excluded. With each 10 µg Hb/g increase in FIT above 20 µg Hb/g, life expectancy was reduced by one year, and mortality increased by 4 %. About 18.6 % of deaths with positive FIT were attributed to cardiovascular disease (CVD), followed by CRC (13.5 %) and upper gastrointestinal (GI) cancers (4.5 %). The all-cause mortality rate after excluding CRC for positive FIT was 3.56/1,000 person-year, comparable to the all-cause mortality rate of 3.69/1,000 person-year for hypertension. CONCLUSION: Positive FIT was associated with increased mortality in a dose-response manner and shortened life expectancy by 4 years, an overlooked risk comparable to hypertension, even with CRC excluded. After a negative colonoscopy, subjects with positive FIT should undergo a workup on CVD risk factors and look for other upper GI cancers.

Organic photoredox catalyzed C(sp3)-H functionalization of saturated aza-heterocycles via a cross-dehydrogenative coupling reaction.

Herein we present a novel protocol to access α-functionalized saturated aza-heterocycles, and a variety of nucleophilic groups, such as indole, naphthol, phenol, pyrrole, furyl, nitromethyl, and cyano, could be easily installed into saturated aza-heterocycles. Furthermore, a range of biologically valuable 3,3'-diindolylmethane derivatives could also be readily accessed under mild photocatalytic conditions.

Private Equity: An Emerging Practice Model.

Private equity acquisitions are increasing among orthopedic practices. The concepts and vocabulary surrounding these deals may be foreign to physicians. There are both potential risks and potential benefits to physicians at the center of these complex deals, and a clear understanding of any proposed private equity acquisition is crucial. Short-term data on private equity acquisition in other procedure-based outpatient specialties have shown that private equity ownership consistently increased the number of patients seen per provider, allowed amount per claim, and utilization of advanced practice practitioners. These studies did not show consistent changes in the rates of invasive procedures or negative impacts on patient care. Each practice will need to carefully consider any potential private equity involvements.

The International Map of Axial Spondyloarthritis Survey: A US Patient Perspective on Diagnosis and Burden of Disease.

OBJECTIVE: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that causes inflammation in the axial skeleton, resulting in structural damage and disability. We aimed to understand the effect of axSpA on work activity, day-to-day function, mental health, relationships, and quality of life and to examine barriers to early diagnosis. METHODS: A 30-minute quantitative US version of the International Map of Axial Spondyloarthritis survey was administered online to US patients aged 18 years and older with a diagnosis of axSpA who were under the care of a health care provider from July 22 to November 10, 2021. This analysis describes demographics, clinical characteristics, journey to axSpA diagnosis, and disease burden. RESULTS: We surveyed 228 US patients with axSpA. Patients had a mean diagnostic delay of 8.8 years, with a greater delay in women versus men (11.2 vs. 5.2 years), and 64.5% reported being misdiagnosed before receiving an axSpA diagnosis. Most patients (78.9%) had active disease (Bath Ankylosing Spondylitis Disease Activity Index score ≥4), reported psychological distress (57.0%; General Health Questionnaire 12 score ≥3), and experienced a high degree of impairment (81.6%; Assessment of Spondyloarthritis International Society Health Index score ≥6). Overall, 47% of patients had a medium or high limitation in activities of daily living, and 46% were not employed at survey completion. CONCLUSION: The majority of US patients with axSpA had active disease, reported psychological distress, and reported impaired function. US patients experienced a substantial delay in time to diagnosis of axSpA that was twice as long in women versus men.

Elucidating the Origin of Plasmon-Generated Hot Holes in Water Oxidation.

Plasmon-generated hot electrons in metal/oxide heterostructures have been used extensively for driving photochemistry. However, little is known about the origin of plasmon-generated hot holes in promoting photochemical reactions. Herein, we discover that, during the nonradiative plasmon decay, the interband excitation rather than the intraband excitation generates energetic hot holes that enable to drive the water oxidation at the Au/TiO2 interface. Distinct from lukewarm holes via the intraband excitation that only remain on Au, hot holes from the interband excitation are found to be transferred from Au into TiO2 and stabilized by surface oxygen atoms on TiO2, making them available to oxidize adsorbed water molecules. Taken together, our studies provide spectroscopic evidence to clarify the photophysical process for exciting plasmon-generated hot holes, unravel their atomic-level accumulation sites to maintain the strong oxidizing power in metal/oxide heterostructures, and affirm their crucial functions in governing photocatalytic oxidation reactions.

Injury severity analysis of time-of-day fluctuations and temporal volatility in reverse sideswipe collisions: A random parameter model with heterogeneous means and heteroscedastic variances.

PROBLEM: Sideswipe collisions in the opposite direction often result in more severe injuries than the typical same-direction crashes, especially when light trucks are involved. This study investigates the time-of-day fluctuations and temporal volatility of potential factors that affect the injury severity of reverse sideswipe collisions. METHODS: A series of random parameters logit models with heterogeneous means and heteroscedastic variances are developed and utilized to explore unobserved heterogeneity inherent in variables and preclude biased parameter estimation. The segmentation of estimated results is also examined through temporal instability tests. RESULTS: Based on crash data in North Carolina, a number of contributing factors are identified that have profound associations with obvious and moderate injuries. Meanwhile, significant temporal volatility is observed in the marginal effects of several factors such as driver restraint, alcohol or drugs impact, Sport Utility Vehicle (SUV) at fault, and adverse road surface across three different periods. Fluctuations in the time of day indicate that restraint with belts is more effective in mitigating the obvious injury in the nighttime, and high-class roadway sustains a higher probability of resulting in more serious injury compared to the daytime. PRACTICAL APPLICATIONS: The findings of this study could help further guide the implementation of safety countermeasures related to atypical sideswipe collisions.

Modeling pedestrian injury severity in pedestrian-vehicle crashes considering different land use patterns: Mixed logit approach.

OBJECTIVE: The objective of this study is to identify and compare the contributing factors to pedestrian injury severity in pedestrian-vehicle crashes considering different land use patterns. METHODS: The pedestrian-vehicle crash data from 2007 to 2018 were collected from the North Carolina Department of Transportation (NCDOT). A total number of 15,807 observations with 72 categorical variables were included in the final dataset. Two mixed logit models were developed to analyze the crash dataset with segmentations of two dominant land use areas (i.e., residential and commercial). Fixed and random parameters were found in both models. Estimation results and marginal effects of significant explanatory variables were investigated. RESULTS: In general, the residential model has 24 fixed parameters and 3 random parameters. The commercial model has 31 fixed parameters and 3 random parameters. According to the estimated results, elder or drunk factors are found to have more impacts on severe injuries in residential areas. Large and mid-size vehicles increase the probability of severe injuries in commercial areas. The marginal effect values for severe injury at non-intersections have opposite signs in the two models. Besides, speed limits between 40 and 45 mph and factors related to poor visibility are more likely to result in severe pedestrian injuries. Coarse asphalt pavement can reduce the probability of severe pedestrian injuries. CONCLUSIONS: This study investigated the pedestrian injury severity in pedestrian-vehicle crashes considering two types of land use using a mixed logit approach. Based on the discussions of factors contributing to the pedestrian injury severity, policies and countermeasures to improve traffic safety are suggested. Above all, a mixed-use land development policy is recommended. Other suggestions are summarized below: (1) giving more considerations to older pedestrians when planning and designing residential areas; (2) strengthening laws and education against drunk driving and even drunk walking on/across the roadways; (3) increasing the frequency of the patrols and alcohol tests; (4) improving lighting conditions and road alignments; (5) establishing a limited-truck-passing-period policy especially in commercial areas; and (6) improving the pavement conditions wherever needed.

Morphological and Functional Changes of Cerebral Cortex in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by early-onset impairments in socialization, communication, repetitive behaviors, and restricted interests. ASD exhibits considerable heterogeneity, with clinical presentations varying across individuals and age groups. The pathophysiology of ASD is hypothesized to be due to abnormal brain development influenced by a combination of genetic and environmental factors. One of the most consistent morphological parameters for assessing the abnormal brain structures in patients with ASD is cortical thickness. Studies have shown changes in the cortical thickness within the frontal, temporal, parietal, and occipital lobes of individuals with ASD. These changes in cortical thickness often correspond to specific clinical features observed in individuals with ASD. Furthermore, the aberrant brain anatomical features and cortical thickness alterations may lead to abnormal brain connectivity and synaptic structure. Additionally, ASD is associated with cortical hyperplasia in early childhood, followed by a cortical plateau and subsequent decline in later stages of development. However, research in this area has yielded contradictory findings regarding the cortical thickness across various brain regions in ASD.