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.

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.

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.

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.

Ultrafine PdCo bimetallic nanoclusters confined in N-doped porous carbon for the efficient semi-hydrogenation of alkynes.

Semi-hydrogenation of alkynes to prepare alkenes is an important reaction in the petrochemical and fine chemical industries. The use of conventional Pd nanoparticle-based catalysts is limited by alkyne over-hydrogenation and low Pd utilization. In this study, a nitrogen-doped mesoporous carbon material (m-NC), which was rich in defect sites after Zn volatilization, was fabricated by the carbonization of ZIF-8. Ultrafine PdCo bimetallic nanoclusters with Co atom-modified Pd active site electronic and compositional structure were highly dispersed and confined in m-NC. As-obtained Pd0.43Co1/m-NC was used for the semi-hydrogenation of alkynes and it exhibited high selectivity with high conversion under mild reaction conditions. Pd0.43Co1/m-NC also exhibited excellent stability in leaching tests and maintained its catalytic activity for at least nine reaction cycles. The highly dispersed active sites in Pd0.43Co1/m-NC served as the active sites for the catalytic semi-hydrogenation of alkynes; as a regulator, the second metal Co effectively improved selectivity, and m-NC endowed the catalyst with excellent stability. The research work presented here may provide a foundation for the design of highly active, selective, and stable Pd-based bimetallic catalysts for selective hydrogenation.

The association between congenital cytomegalovirus infection and cerebral palsy: A systematic review and meta-analysis.

Cytomegalovirus (CMV) is the most common cause of congenital infection, affecting 1% of all live births. Intrauterine infection such as CMV infection is a risk factor for developing cerebral palsy. This study aims to investigate the association between congenital CMV infection and the development of cerebral palsy. A systematic literature search was conducted in PubMed, Web of Science and Ovid SP to identify relevant studies. The quality of studies was assessed using the Newcastle-Ottawa Scale. The random-effect model was used to calculate the pooled prevalence. The generic inverse variance method was used for statistical analysis. A total of 12 studies were included in this systematic review and meta-analysis. The overall pooled prevalence of cerebral palsy among patients diagnosed with congenital CMV infection was 26% (95% confidence interval (CI), 13-40%). The overall pooled prevalence of congenital CMV infection among patients with cerebral palsy was 10.9% (95% CI, 5-16%). Congenital CMV infection was significantly associated with the development of cerebral palsy in children. Routine follow-ups should be offered to screen for cerebral palsy.

Quantum gas microscopy of Kardar-Parisi-Zhang superdiffusion.

The Kardar-Parisi-Zhang (KPZ) universality class describes the coarse-grained behavior of a wealth of classical stochastic models. Surprisingly, KPZ universality was recently conjectured to also describe spin transport in the one-dimensional quantum Heisenberg model. We tested this conjecture by experimentally probing transport in a cold-atom quantum simulator via the relaxation of domain walls in spin chains of up to 50 spins. We found that domain-wall relaxation is indeed governed by the KPZ dynamical exponent z = 3/2 and that the occurrence of KPZ scaling requires both integrability and a nonabelian SU(2) symmetry. Finally, we leveraged the single-spin-sensitive detection enabled by the quantum gas microscope to measure an observable based on spin-transport statistics. Our results yield a clear signature of the nonlinearity that is a hallmark of KPZ universality.

Realizing Distance-Selective Interactions in a Rydberg-Dressed Atom Array.

Measurement-based quantum computing relies on the rapid creation of large-scale entanglement in a register of stable qubits. Atomic arrays are well suited to store quantum information, and entanglement can be created using highly-excited Rydberg states. Typically, isolating pairs during gate operation is difficult because Rydberg interactions feature long tails at large distances. Here, we engineer distance-selective interactions that are strongly peaked in distance through off-resonant laser coupling of molecular potentials between Rydberg atom pairs. Employing quantum gas microscopy, we verify the dressed interactions by observing correlated phase evolution using many-body Ramsey interferometry. We identify atom loss and coupling to continuum modes as a limitation of our present scheme and outline paths to mitigate these effects, paving the way towards the creation of large-scale entanglement.

Perioperative nivolumab monotherapy versus nivolumab plus ipilimumab in resectable hepatocellular carcinoma: a randomised, open-label, phase 2 trial.

BACKGROUND: Hepatocellular carcinoma has high recurrence rates after surgery; however, there are no approved standard-of-care neoadjuvant or adjuvant therapies. Immunotherapy has been shown to improve survival in advanced hepatocellular carcinoma; we therefore aimed to evaluate the safety and tolerability of perioperative immunotherapy in resectable hepatocellular carcinoma. METHODS: In this single-centre, randomised, open-label, phase 2 trial, patients with resectable hepatocellular carcinoma were randomly assigned (1:1) to receive 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery at 6 weeks) followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for 2 years, or 240 mg of nivolumab intravenously every 2 weeks (for up to three doses before surgery) plus one dose of 1 mg/kg of ipilimumab intravenously concurrently with the first preoperative dose of nivolumab, followed in the adjuvant phase by 480 mg of nivolumab intravenously every 4 weeks for up to 2 years plus 1 mg/kg of ipilimumab intravenously every 6 weeks for up to four cycles. Patients were randomly assigned to the treatment groups by use of block randomisation with a random block size. The primary endpoint was the safety and tolerability of nivolumab with or without ipilimumab. Secondary endpoints were the proportion of patients with an overall response, time to progression, and progression-free survival. This trial is registered with ClinicalTrials.gov (NCT03222076) and is completed. FINDINGS: Between Oct 30, 2017, and Dec 3, 2019, 30 patients were enrolled and 27 were randomly assigned: 13 to nivolumab and 14 to nivolumab plus ipilimumab. Grade 3-4 adverse events were higher with nivolumab plus ipilimumab (six [43%] of 14 patients) than with nivolumab alone (three [23%] of 13). The most common treatment-related adverse events of any grade were increased alanine aminotransferase (three [23%] of 13 patients on nivolumab vs seven [50%] of 14 patients on nivolumab plus ipilimumab) and increased aspartate aminotransferase (three [23%] vs seven [50%]). No patients in either group had their surgery delayed due to grade 3 or worse adverse events. Seven of 27 patients had surgical cancellations, but none was due to treatment-related adverse events. Estimated median progression-free survival was 9·4 months (95% CI 1·47-not estimable [NE]) with nivolumab and 19·53 months (2·33-NE) with nivolumab plus ipilimumab (hazard ratio [HR] 0·99, 95% CI 0·31-2·54); median time to progression was 9·4 months (95% CI 1·47-NE) in the nivolumab group and 19·53 months (2·33-NE) in the nivolumab plus ipilimumab group (HR 0·89, 95% CI 0·31-2·54). In an exploratory analysis, three (23%) of 13 patients had an overall response with nivolumab monotherapy, versus none with nivolumab plus ipilimumab. Three (33%) of nine patients had a major pathological response (ie, ≥70% necrosis in the resected tumour area) with nivolumab monotherapy compared with three (27%) of 11 with nivolumab plus ipilimumab. INTERPRETATION: Perioperative nivolumab alone and nivolumab plus ipilimumab appears to be safe and feasible in patients with resectable hepatocellular carcinoma. Our findings support further studies of immunotherapy in the perioperative setting in hepatocellular carcinoma. FUNDING: Bristol Myers Squibb and the US National Institutes of Health.