Total Synthesis of Incarnatapeptins A and B.

The first total synthesis of incarnatapeptins A and B, two novel marine natural products, was accomplished from readily available (S)-1-benzyloxycarbonylhexahydropyridazine-3-carboxylic acid. This route, whose longest linear sequence was 12 steps, provided the incarnatapeptins A and B in yields of 26.5 % and 19.7 %, respectively, and enabled the structure and stereochemistry of both natural products to be unambiguously confirmed. Highlights of our synthesis include the photoredox-mediated decarboxylative 1,4-addition reaction and a novel and practical N-acylation paradigm promoted by silver carbonate. The unusual facile atropisomerism of some linear peptidic intermediates was also observed by TLC analysis in the course of this work.

Total Synthesis of Nicrophorusamide A and Structural Disproof of the Proposed Noursamycin A.

Total synthesis of the proposed noursamycin A has been accomplished, which disproves the original structural assignments. The synthetic strategy described herein has also been employed in the first total synthesis of nicrophorusamide A, a cyclopeptide that is structurally related to noursamycin A.

Ultrasound has limited diagnostic utility in children with acute lymphoblastic leukemia developing pancreatitis.

PURPOSE: Acute pancreatitis (AP) due to chemotherapy-induced pancreatic injury is a common side effect of treatment for acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The American College of Radiology recommends ultrasound (US) for initial imaging of AP in all populations to assess for ductal obstruction. However, US may be insensitive to diagnose and assess chemotherapy-associated AP. METHODS AND MATERIALS: The institutional review board approved this retrospective study. Patients with ALL and AP were identified from protocol databases, using Common Terminology Criteria for Adverse Events (CTCAE) version 3. Chemotherapy dosing, amylase/lipase levels, clinical symptoms, and US/computed tomography (CT) reports within 10 days of diagnosis were recorded. All CT images were reviewed for revised Atlanta classification and CT severity index (CTSI). RESULTS: Sixty-nine patients, aged 2-21 years, experienced 88 episodes of AP, undergoing 98 US and 44 CT. Seventy-two events (82%) occurred within 30 days of asparaginase administration. Sixty-nine episodes (78%) were initially diagnosed by the presence of abdominal pain and pancreatic enzyme elevation. Overall sensitivities for AP detection were 47% using US and 98% for CT. US sensitivity was greatest in CTCAE grade 4 (86%) and necrotizing pancreatitis (67%). CONCLUSIONS: Most cases of AP in children with ALL can be diagnosed with clinical history and labs. US has limited sensitivity in detecting pancreatitis in this population. Imaging to diagnose AP in this patient population could be limited to clinically equivocal cases.

Total Synthesis and Structural Reassignment of Laingolide A.

The asymmetric total synthesis of four diastereomers of laingolide A was achieved, which led to the unambiguous assignment of the stereochemistry of the natural product. The salient features of the convergent, fully stereocontrolled approach were a copper-catalysed stereospecific Kumada-type coupling, a Julia-Kocienski olefination and an RCM/alkene migration sequence to access the desired macrocyclic enamide.

Total Synthesis of Pagoamide A.

The first total synthesis of the thiazole-containing cyclic depsipeptide pagoamide A, is detailed. The longest linear sequence of the liquid-phase synthesis comprises 9 long linear steps from simple known starting materials, which led to the unambiguous structural confirmation of pagoamide A.

Health, economic, and social implications of COVID-19 for China's rural population.

This study examines the effects of local and nationwide COVID-19 disease control measures on the health and economy of China's rural population. We conducted phone surveys with 726 randomly selected village informants across seven rural Chinese provinces in February 2020. Four villages (0.55%) reported infections, and none reported deaths. Disease control measures had been universally implemented in all sample villages. About 74% of informants reported that villagers with wage-earning jobs outside the village had stopped working due to workplace closures. A higher percentage of rural individuals could not work due to transportation, housing, and other constraints. Local governments had taken measures to reduce the impact of COVID-19. Although schools in all surveyed villages were closed, 71% of village informants reported that students were attending classes online. Overall, measures to control COVID-19 appear to have been successful in limiting disease transmission in rural communities outside the main epidemic area. Rural Chinese citizens, however, have experienced significant economic consequences from the disease control measures.

Biochemistry-Guided Prediction of the Absolute Configuration of Fungal Reduced Polyketides.

Highly reducing polyketide synthases (HR-PKSs) produce structurally diverse polyketides (PKs). The PK diversity is constructed by a variety of factors, including the ß-keto processing, chain length, methylation pattern, and relative and absolute configurations of the substituents. We examined the stereochemical course of the PK processing for the synthesis of polyhydroxy PKs such as phialotides, phomenoic acid, and ACR-toxin. Heterologous expression of a HR-PKS gene, a trans-acting enoylreductase gene, and a truncated non-ribosomal peptide synthetase gene resulted in the formation of a linear PK with multiple stereogenic centers. The absolute configurations of the stereogenic centers were determined by chemical degradation followed by comparison of the degradation products with synthetic standards. A stereochemical rule was proposed to explain the absolute configurations of other reduced PKs and highlights an error in the absolute configurations of a reported structure. The present work demonstrates that focused functional analysis of functionally related HR-PKSs leads to a better understanding of the stereochemical course.

Asymmetric Total Syntheses of Kopsane Alkaloids via a PtCl2 -Catalyzed Intramolecular [3+2] Cycloaddition.

A concise and asymmetric total synthesis of five kopsane alkaloids that share a unique heptacyclic caged ring system was accomplished. The key transformation in the sequence involved a remarkable PtCl2 -catalyzed intramolecular [3+2] cycloaddition, which allowed for the rapid assembly of pentacyclic carbon skeletons bearing 2,3-quaternary functionalized indoline. Expeditious construction of diverse indoline scaffolds with excellent control of diastereoselectivity demonstrated the broad scope and versatility of this key transformation.

Comprehensive Regression Model for Dissociation Equilibria of Cell-Specific Aptamers.

A comprehensive nonlinear regression model for dissociation equilibria of cell-specific aptamers is proposed by considering the effect of receptor expression level. Benefiting from the global regression of simultaneous equations, the fitted parameters reach a very significant level, indicating the statistical validity of this updated model. According to the fitting results, we found that dissociation constants fitted using the previous model are obviously larger than the updated values, which can be explained by the effect of receptor number on curve fitting. In addition, equivalent receptor density can be estimated using the updated model, which may lead to some new judgments about reported results of cell-SELEX.

Nickel-Catalyzed Cross-Coupling of Vinyl Dioxanones to Form Enantiomerically Enriched Cyclopropanes.

Under the conditions of nickel(0) catalysis, enantiomerically enriched vinyl dioxanones engage boroxines or B2(pin)2 in stereospecific cross-coupling to form diverse tetrasubstituted cyclopropanes bearing all-carbon quaternary stereocenters. The collective data corroborate a mechanism involving nickel(0)-mediated benzylic oxidative addition with inversion of stereochemistry followed by reversible olefin insertion to form a (cyclopropylcarbinyl)nickel complex, which upon reductive elimination releases the cyclopropane.

Total Synthesis and Stereochemical Assignment of Actinoranone.

The total synthesis of four actinoranone stereoisomers led to unambiguous assignment of relative and absolute stereochemistry of the natural product. Key features of the convergent, fully stereocontrolled route include the use of a Negishi carbozirconation/iodination, a Friedel-Crafts cyclization, a Felkin-controlled addition reaction, a Mitsunobu reaction, and a late-stage C-H oxidation.

Enantioselective Synthesis of Oxetanes Bearing All-Carbon Quaternary Stereocenters via Iridium-Catalyzed C-C Bond-Forming Transfer Hydrogenation.

Oxetanes bearing all-carbon quaternary stereocenters are readily prepared through the iridium-catalyzed anti-diastereo- and enantioselective C-C coupling of primary alcohols and isoprene oxide. Based on this methodology, an oxetane containing analogue of haloperidol was prepared. A related azetidine formation is also described.

Maternal empowerment, feeding knowledge, and infant nutrition: Evidence from rural China.

Background: Maternal empowerment - the capacity to make decisions within households - is linked to better child feeding and nutritional outcomes, but few studies have considered the mediating role of caregiver knowledge. Further, existing literature centres primarily on the husband-wife dyad while overlooking grandmothers as important childcare decision-makers. Methods: We collected primary data through household surveys in 2019 and 2021 from 1190 households with infants zero to six months living in rural western China. We identified the primary and secondary caregivers for each infant and assessed their feeding knowledge and practices, as well as infant nutritional status. We constructed a maternal empowerment index using a seven-item decision-making questionnaire and examined the relationship between maternal empowerment in childcare and household decisions, caregivers' feeding knowledge, and infant feeding practices and nutritional outcomes. Results: Mothers had significantly higher levels of feeding knowledge than secondary caregivers (most were grandmothers, 72.7%), with average knowledge scores of 5.4 vs. 4.1, respectively, out of 9. Mothers and secondary caregivers with higher levels of feeding knowledge had significantly higher exclusive breastfeeding rates by 13-15 percentage points (P < 0.01) and 11-13 percentage points (P < 0.01), respectively. The knowledge of secondary caregivers was even more strongly associated with not feeding formula (15 percentage points, P < 0.01). Mothers empowered to make childcare decisions were more likely to exclusively breastfeed (12-13 percentage points, P < 0.01), less likely to formula feed (9-10 percentage points, P < 0.05), and more likely to have children with higher Z-scores for length-for-age (0.32-0.33, P < 0.01) and weight-for-age (0.24-0.25, P < 0.05). Effects remained after controlling for maternal feeding knowledge. Conclusions: While mothers' and grandmothers' feeding knowledge was both important for optimal infant feeding, grandmothers' knowledge was particularly critical for practicing exclusive breastfeeding. Given the disparity in feeding knowledge between the two caregivers, our study further shows that mothers empowered in childcare decision-making were more likely to exclusively breastfeed their infants. This implies that some mothers with adequate knowledge may not practice optimal feeding because of lower decision-making power. Overall, our study highlights the role of secondary caregivers (grandmothers) in infant care and suggests that future child nutritional interventions may benefit from involving secondary caregivers (grandmothers). Registration: Parent trial registration: ISRCTN16800789.

The Relationship Between Health Insurance Status and Diabetic Retinopathy Progression.

Objective: To determine if baseline diabetic retinopathy (DR) severity mediates the relationship between health insurance status and DR progression. Design: Retrospective cohort study. Subjects: Seven hundred sixteen patients aged ≥ 18 years with a diagnosis of type 1 or 2 diabetes mellitus, and a diagnosis of nonproliferative DR (NPDR) were identified from the electronic health record of a tertiary academic center between June 2012 and February 2022. Methods: NPDR severity at baseline was the proposed mediator in the relationship between insurance status and proliferative DR (PDR) progression. Logistic regression was used to determine the association between insurance status and NPDR severity at baseline, and Cox proportional hazards regression was used to assess the association between insurance status and time to PDR progression. To analyze the mediation effect of NPDR severity at baseline, a counterfactual approach, which decomposes a total effect into a natural direct effect and a natural indirect effect was applied. Main Outcome Measures: Time to progression from first NPDR diagnosis to first PDR diagnosis. Results: Of the 716 patients, 581 (81%) had Medicare or private insurance, 107 (15%) had Medicaid, and 28 (4.0%) were uninsured at their baseline eye visit. Uninsured or Medicaid patients had a higher proportion of moderate or severe NPDR at their baseline eye visit and a higher proportion of progression to PDR. After adjusting for confounders and NPDR severity at baseline, patients who were uninsured had significantly greater risk of progression to PDR compared with that of patients with Medicare/private insurance (hazard ratio [HR]: 2.63; 95% confidence interval [CI]: 1.10-6.25). Patients with Medicaid also had an increased risk of progression to PDR compared with that of patients with Medicare/private insurance, although not statistically significant (HR: 1.53; 95% CI: 0.81-2.89). NPDR severity at baseline mediated 41% of the effect of insurance status (uninsured vs. Medicare/private insurance) on PDR progression. Conclusions: Patients who were uninsured were more likely to have an advanced stage of NPDR at their baseline eye visit and were at significantly greater risk of progression to PDR compared with patients who had Medicare or were privately insured. Mediation analysis revealed that differences in baseline NPDR severity by insurance explained a significant proportion of the relationship between insurance status and DR progression. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Performance and symptom validity indicators among children undergoing cognitive surveillance following treatment for craniopharyngioma.

Background: Performance validity tests (PVTs) and symptom validity tests (SVTs) are essential to neuropsychological evaluations, helping ensure findings reflect true abilities or concerns. It is unclear how PVTs and SVTs perform in children who received radiotherapy for brain tumors. Accordingly, we investigated the rate of noncredible performance on validity indicators as well as associations with fatigue and lower intellectual functioning. Methods: Embedded PVTs and SVTs were investigated in 98 patients with pediatric craniopharyngioma undergoing proton radiotherapy (PRT). The contribution of fatigue, sleepiness, and lower intellectual functioning to embedded PVT performance was examined. Further, we investigated PVTs and SVTs in relation to cognitive performance at pre-PRT baseline and change over time. Results: SVTs on parent measures were not an area of concern. PVTs identified 0-31% of the cohort as demonstrating possible noncredible performance at baseline, with stable findings 1 year following PRT. Reliable digit span (RDS) noted the highest PVT failure rate; RDS has been criticized for false positives in pediatric populations, especially children with neurological impairment. Objective sleepiness was strongly associated with PVT failure, stressing need to consider arousal level when interpreting cognitive performance in children with craniopharyngioma. Lower intellectual functioning also needs to be considered when interpreting task engagement indices as it was strongly associated with PVT failure. Conclusions: Embedded PVTs should be used with caution in pediatric craniopharyngioma patients who have received PRT. Future research should investigate different cut-off scores and validity indicator combinations to best differentiate noncredible performance due to task engagement versus variable arousal and/or lower intellectual functioning.

Histone lysine demethylase 4 family proteins maintain the transcriptional program and adrenergic cellular state of MYCN-amplified neuroblastoma.

Neuroblastoma with MYCN amplification (MNA) is a high-risk disease that has a poor survival rate. Neuroblastoma displays cellular heterogeneity, including more differentiated (adrenergic) and more primitive (mesenchymal) cellular states. Here, we demonstrate that MYCN oncoprotein promotes a cellular state switch in mesenchymal cells to an adrenergic state, accompanied by induction of histone lysine demethylase 4 family members (KDM4A-C) that act in concert to control the expression of MYCN and adrenergic core regulatory circulatory (CRC) transcription factors. Pharmacologic inhibition of KDM4 blocks expression of MYCN and the adrenergic CRC transcriptome with genome-wide induction of transcriptionally repressive H3K9me3, resulting in potent anticancer activity against neuroblastomas with MNA by inducing neuroblastic differentiation and apoptosis. Furthermore, a short-term KDM4 inhibition in combination with conventional, cytotoxic chemotherapy results in complete tumor responses of xenografts with MNA. Thus, KDM4 blockade may serve as a transformative strategy to target the adrenergic CRC dependencies in MNA neuroblastomas.

Associations of in-hospital postpartum feeding experiences with exclusive breastfeeding practices among infants in rural Sichuan, China.

BACKGROUND: In rural China, exclusive breastfeeding (EBF) prevalence is low and hospitals often fail to attain baby-friendly feeding objectives, such as ≥ 75% of newborns exclusively breastfed from birth to discharge. Empirical evidence for the impact of increased hospital compliance with recommended feeding guidelines on continued EBF in rural China is lacking. We sought to measure and model the association of newborns' in-hospital feeding experiences with EBF practice in infancy to inform policies for EBF promotion. METHODS: Data were cross-sectional from 785 caregivers of infants < 6 months of age, collected from November to December 2019 in four underdeveloped counties/districts in Sichuan Province. In-hospital feeding practices were determined, and prevalence of current infant feeding practices was calculated from 24-h recall and categorized according to WHO/UNICEF Infant and Young Child Feeding categories as EBF, breastfed with non-milk liquids, mixed feeding, breastfed with solids, and not breastfed. Relative risk ratios were estimated using adjusted multinomial logistic regression to examine risk factors for non-EBF practices compared to EBF, including in-hospital feeding experiences. The regression model was used to investigate change in EBF prevalence under alternative in-hospital experiences. RESULTS: Only 38.1% of under-six-month-old infants were being exclusively breastfed when data were collected; 61.8% and 77.6% had been fed water and infant formula, respectively, in the hospital. Infants who were fed water or formula before discharge were estimated as 2-3 times as likely to be non-EBF than EBF up to age six months. According to our model, EBF prevalence would have increased to 53.7% (95% confidence interval (CI) 46.1, 61.2) had ≥ 75% of infants been exclusively breastfed and water-based feeds eliminated in-hospital. CONCLUSIONS: Given the importance of infants' first feeding experiences in the establishment and continuation of EBF, it is imperative that rural Chinese hospitals actively seek to limit infant formula feeds to medically indicated situations and eliminate water-based feeds.

Developing and Validating Models to Predict Progression to Proliferative Diabetic Retinopathy.

Purpose: To develop models for progression of nonproliferative diabetic retinopathy (NPDR) to proliferative diabetic retinopathy (PDR) and determine if incorporating updated information improves model performance. Design: Retrospective cohort study. Participants: Electronic health record (EHR) data from a tertiary academic center, University of California San Francisco (UCSF), and a safety-net hospital, Zuckerberg San Francisco General (ZSFG) Hospital were used to identify patients with a diagnosis of NPDR, age ≥ 18 years, a diagnosis of type 1 or 2 diabetes mellitus, ≥ 6 months of ophthalmology follow-up, and no prior diagnosis of PDR before the index date (date of first NPDR diagnosis in the EHR). Methods: Four survival models were developed: Cox proportional hazards, Cox with backward selection, Cox with LASSO regression and Random Survival Forest. For each model, three variable sets were compared to determine the impact of including updated clinical information: Static0 (data up to the index date), Static6m (data updated 6 months after the index date), and Dynamic (data in Static0 plus data change during the 6-month period). The UCSF data were split into 80% training and 20% testing (internal validation). The ZSFG data were used for external validation. Model performance was evaluated by the Harrell's concordance index (C-Index). Main Outcome Measures: Time to PDR. Results: The UCSF cohort included 1130 patients and 92 (8.1%) patients progressed to PDR. The ZSFG cohort included 687 patients and 30 (4.4%) patients progressed to PDR. All models performed similarly (C-indices ∼ 0.70) in internal validation. The random survival forest with Static6m set performed best in external validation (C-index 0.76). Insurance and age were selected or ranked as highly important by all models. Other key predictors were NPDR severity, diabetic neuropathy, number of strokes, mean Hemoglobin A1c, and number of hospital admissions. Conclusions: Our models for progression of NPDR to PDR achieved acceptable predictive performance and validated well in an external setting. Updating the baseline variables with new clinical information did not consistently improve the predictive performance. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Effect of the mHealth-supported Healthy Future programme delivered by community health workers on maternal and child health in rural China: study protocol for a cluster randomised controlled trial.

INTRODUCTION: Millions of young rural children in China still suffer from poor health and malnutrition, partly due to a lack of knowledge about optimal perinatal and child care among rural mothers and caregivers. Meanwhile, there is an urgent need to improve maternal mental health in rural communities. Comprehensive home visiting programmes delivered by community health workers (CHWs) can bridge the caregiver knowledge gap and improve child health and maternal well-being in low-resource settings, but the effectiveness of this approach is unknown in rural China. Additionally, grandmothers play important roles in child care and family decision-making in rural China, suggesting the importance of engaging multiple caregivers in interventions. The Healthy Future programme seeks to improve child health and maternal well-being by developing a staged-based curriculum that CHWs deliver to mothers and caregivers of young children through home visits with the assistance of a tablet-based mHealth system. This protocol describes the design and evaluation plan for this programme. METHODS AND ANALYSIS: We designed a cluster-randomised controlled trial among 119 rural townships in four nationally designated poverty counties in Southwestern China. We will compare the outcomes between three arms: one standard arm with only primary caregivers participating in the intervention, one encouragement arm engaging primary and secondary caregivers and one control arm with no intervention. Families with pregnant women or infants under 6 months of age are invited to enrol in the 12-month study. Primary outcomes include children's haemoglobin levels, exclusive breastfeeding rates and dietary diversity in complementary feeding. Secondary outcomes include a combination of health, behavioural and intermediate outcomes. ETHICS AND DISSEMINATION: Ethical approval has been provided by Stanford University, Sichuan University and the University of Nevada, Reno. Trial findings will be disseminated through national and international peer-reviewed publications and conferences. TRIAL REGISTRATION NUMBER: ISRCTN16800789.

Asymmetric Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-yne-vinylcyclopropanes for bicyclo[3.3.0] compounds with a chiral quaternary carbon stereocenter and density functional theory study of the origins of enantioselectivity.

A highly enantioselective Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-yne-VCPs to bicyclo[3.3.0] compounds with an all-carbon chiral quaternary stereocenter at the bridgehead carbon was developed. DFT calculations of the energy surface of the catalytic cycle (complexation, cyclopropane cleavage, alkyne insertion, and reductive elimination) of the asymmetric [3 + 2] cycloaddition reaction indicated that the rate- and stereo-determining step is the alkyne-insertion step. Analysis of the alkyne-insertion transition states revealed that the serious steric repulsion between the substituents in the alkyne moiety of the substrates and the rigid H(8)-BINAP backbone is responsible for not generating the disfavored [3 + 2] cycloadducts.