Evaluation of height centile growth patterns compared with parental-adjusted target height following kidney transplantation.

BACKGROUND: Early steroid withdrawal (ESW) improves growth following kidney transplant (KT). It is not known whether these children achieve target height within mid-parental height range post-KT. METHODS: Retrospective analysis of growth patterns of KT recipients following ESW in our center between 2009 and 2020 had minimum follow-up period of 12 months. RESULTS: Forty-eight (female 29.2%) KT recipients, median age 5.3 years at first KT, were included. At KT, 29 (60.4%) recipients had normal height (SDS≥-1.88) and in 23 (47.9%), the height was within their target height (parental-adjusted height SDS within ±1.55). The proportion of children achieving normal height at 1-, 2-, 3-, and 5-years post-KT (median 5.5 years) were 75%, 83.3%, 86.5%, and 88% respectively. The proportion of children achieving target height measured at the same intervals was 68.8%, 73.8%, 73%, and 80%, respectively. Children <6 years were most growth impaired at KT but were most likely to achieve target height within first-year post-KT (72%; p = .023). All 19 children with short stature at KT received dialysis. Three children received growth hormone post-KT. Children who did not achieve target height post-KT (n = 14), five had eGFR <60 mL/min/1.73 m2 , and eight were on corticosteroid therapy at latest follow-up. CONCLUSIONS: Although vast majority of children achieved normal height post-KT following ESW during the first 5 years post-KT, 20% of these children had not achieved their target height post-KT.

Evaluation of Tebipenem Hydrolysis by ß-Lactamases Prevalent in Complicated Urinary Tract Infections.

Tebipenem pivoxil is the first orally available carbapenem antibiotic and has been approved in Japan for treating ear, nose, and throat and respiratory infections in pediatric patients. Its active moiety, tebipenem, has shown potent antimicrobial activity in vitro against clinical isolates of Enterobacterales species from patients with urinary tract infections (UTIs), including those producing extended-spectrum ß-lactamases (ESBLs) and/or AmpC ß-lactamase. In the present study, tebipenem was tested for stability to hydrolysis by a set of clinically relevant ß-lactamases, including TEM-1, AmpC, CTX-M, OXA-48, KPC, and NDM-1 enzymes. In addition, hydrolysis rates of other carbapenems, including imipenem, meropenem, and ertapenem, were determined for comparison. It was found that, similar to other carbapenems, tebipenem was resistant to hydrolysis by TEM-1, CTX-M, and AmpC ß-lactamases but was susceptible to hydrolysis by KPC, OXA-48, and NDM-1 enzymes with catalytic efficiency values (kcat/Km) ranging from 0.1 to 2 × 106 M-1s-1. This supports the reported results of antimicrobial activity of tebipenem against ESBL- and AmpC-producing but not carbapenemase-producing Enterobacterales isolates. Considering that CTX-M and AmpC ß-lactamases represent the primary determinants of multidrug-resistant complicated UTIs (cUTIs), the stability of tebipenem to hydrolysis by these enzymes supports the utility of its prodrug tebipenem, tebipenem pivoxil hydrobromide (TBP-PI-HBr), as an oral therapy for adult cUTIs.

Deep Sequencing of a Systematic Peptide Library Reveals Conformationally-Constrained Protein Interface Peptides that Disrupt a Protein-Protein Interaction.

Disrupting protein-protein interactions is difficult due to the large and flat interaction surfaces of the binding partners. The BLIP and BLIP-II proteins are unrelated in sequence and structure and yet each potently inhibit ß-lactamases. High-throughput oligonucleotide synthesis was used to construct a 12,470-member library containing overlapping linear and cyclic peptides ranging in size from 6 to 21 amino acids that scan through the sequences of BLIP and BLIP-II. Phage display affinity selections and deep sequencing revealed that, despite the differences in interaction surfaces with ß-lactamases, rapid enrichment of consensus peptide regions originating from both BLIP and BLIP-II contact residues in the binding interface occurred. BLIP and BLIP-II peptides that were enriched by affinity selection were shown to bind ß-lactamases and disrupt the BLIP/ß-lactamase interaction. The results suggest that peptides that bind at and disrupt PPI interfaces can be identified through systematic peptide library construction, affinity selection, and deep sequencing.

Parental sleep experiences on the pediatric oncology ward.

PURPOSE: Parents of pediatric oncology patients are encouraged to sleep on the ward with their child to provide additional care throughout the night. The purpose of this study was to provide the first prevalence estimates of self-reported sleep quantity and quality among parents accommodated on the pediatric oncology ward, compared to parents of age-matched controls. METHODS: Parents of children receiving in-patient cancer treatment and parents of healthy, age-matched children completed a self-report questionnaire, including validated measures of parental sleep and psychological distress, demographic, and clinical characteristics. RESULTS: In total, 114 parents participated (52 parents of children with cancer; 62 control parents; over all response rate 70 %). Parents on the pediatric oncology ward reported sleeping 5.7 h (SD = 1.8) on average, in comparison to control parents who reported sleeping 7.0 h at home (SD = 1.4; t = 4.3, p < 0.001). Parents reported waking an average of 4.6 times (SD = 0.3) per night on the ward, compared to control parents who reported 2.0 (SD = 0.2) nighttime awakenings (t = 7.69, p < 0.001). Parents of children with cancer were significantly more likely to report that they had slept "badly" (67.3 versus 21.0 %; χ(2) = 21.9, p < 0.001). Significant predictors of sleep duration included anxiety (p = 0.013) and caffeine consumption (p = 0.017). Parents who slept on the ward attributed poor sleep to feelings of anxiety, environmental noise, and child-related factors. CONCLUSIONS: Parents who sleep on the pediatric oncology ward experience poor sleep outcomes, including inadequate duration and frequent interruptions. The detrimental effects of sleep deprivation on parents' ability to cope during this challenging time require further investigation and intervention.

Mapping human norovirus antigens during infection reveals the breadth of the humoral immune response.

Human noroviruses (HuNoV) are the leading cause of acute gastroenteritis worldwide. The humoral immune response plays an important role in clearing HuNoV infections and elucidating the antigenic landscape of HuNoV during an infection can shed light on antibody targets to inform vaccine design. Here, we utilized Jun-Fos-assisted phage display of a HuNoV genogroup GI.1 genomic library and deep sequencing to simultaneously map the epitopes of serum antibodies of six individuals infected with GI.1 HuNoV. We found both unique and common epitopes that were widely distributed among both nonstructural proteins and the major capsid protein. Recurring epitope profiles suggest immunodominant antibody footprints among these individuals. Analysis of sera collected longitudinally from three individuals showed the presence of existing epitopes in the pre-infection sera, suggesting these individuals had prior HuNoV infections. Nevertheless, newly recognized epitopes surfaced seven days post-infection. These new epitope signals persisted by 180 days post-infection along with the pre-infection epitopes, suggesting a persistent production of antibodies recognizing epitopes from previous and new infections. Lastly, analysis of a GII.4 genotype genomic phage display library with sera of three persons infected with GII.4 virus revealed epitopes that overlapped with those identified in GI.1 affinity selections, suggesting the presence of GI.1/GII.4 cross-reactive antibodies. The results demonstrate that genomic phage display coupled with deep sequencing can characterize HuNoV antigenic landscapes from complex polyclonal human sera to reveal the timing and breadth of the human humoral immune response to infection.

15-keto-PGE2 alleviates nonalcoholic steatohepatitis through its covalent modification of NF-κB factors.

15-keto-PGE2 is one of the eicosanoids with anti-inflammatory properties. In this study, we demonstrated that 15-keto-PGE2 post-translationally modified the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) subunits p105/p50 and p65 at Cys59 and Cys120 sites, respectively, hence inhibiting the activation of NF-κB signaling in macrophages. In mice fed a high-fat and high-sucrose diet (HFHSD), 15-keto-PGE2 treatment reduced pro-inflammatory cytokines and fasting glucose levels. In mice with non-alcoholic steatohepatitis (NASH) induced by a prolonged HFHSD, 15-keto-PGE2 treatment significantly decreased liver inflammation, lowered serum levels of alanine transaminase (ALT) and aspartate transferase (AST), and inhibited macrophage infiltration. It also reduced lipid droplet size and downregulated key regulators of lipogenesis. These findings highlight the potential of 15-keto-PGE2, through NF-κB modification, in preventing the development and progression of steatohepatitis, emphasizing the significance of endogenous lipid mediators in the inflammatory response.

Family Resilience and Psychological Responses to COVID-19: A Study of Concordance and Dyadic Effects in Singapore Households.

The impacts of COVID-19 may be magnified in a shared environment like the household, especially with people spending extended time at home during the pandemic. Family resilience is the ability of a family to adapt to crisis and can be a protective factor against stress and negative affect. While there have been calls to address family resilience during the pandemic, there is a lack of empirical study on its benefit. In this dyadic observational study, we sought to investigate the concordance of family members' psychological responses to COVID-19, whether dyad members' risk factors (COVID-19 exposure and financial impact) mutually affected each other's psychological responses, and importantly, whether family resilience was a significant factor in these responses. A total of 200 family dyads from the same household completed the Family Resilience Assessment Scale and questionnaires on COVID-19 threat perception, impacts, and exposure. We found concordant dyad responses for COVID-19 threat perception, but not for psychological impact. Using the Actor-Partner-Interdependence Model framework, we found that one's psychological impact was affected by the financial impact from both dyad members. After controlling for risk factors and demographic covariates, we found that family resilience significantly associated with lower COVID-19 psychological impact, though not with threat perception. The findings suggest that both family and individual factors need to be addressed and there may be benefit in addressing multilevel risk and protective factors using an ecological systems approach, which may help prepare the population for future crises.

The validation of culturally appropriate scales to assess the family health climate in a multi-ethnic Asian population.

Background: The Family Health Climate (FHC) is a family environment attribute postulated to influence the health behaviors of family members. It can be measured by domain scales for physical activity (FHC-PA) and nutrition (FHC-NU), which have been validated and used to identify health climate patterns in families in Western populations. To extend the use of the scales to Asian settings, this study aimed to adapt and validate the instruments for use in the multi-ethnic population of Singapore, accounting for language and cultural differences. Methods: In Part A (n = 40) to adapt the scales for the Singapore population, we performed cognitive interviews, face validity testing and pre-testing of the instruments (n = 40). Besides English, the scales were translated into Chinese and Malay. In Part B (n = 400), we performed exploratory and confirmatory factor analyses respectively on two random samples. We also tested for item discriminant validity, internal consistency reliability, construct validity, and measurement invariance. Results: The findings from the cognitive interviews in Part A led to scale adaptations to accommodate cultural and linguistic factors. In Part B, EFA on Sample I resulted in a three-factor model for the PA scale (accounting for 71.2% variance) and a four-factor model for the NU scale (accounting for 72.8% variance). CFA on Sample II indicated acceptable model fits: FHC-PA: χ2 = 192.29, df = 101, p < 0.001, χ2/df = 1.90; SRMR = 0.049; RMSEA = 0.067; CFI = 0.969; TLI = 0.963; FHC-NU: χ2 = 170.46, df = 98, p < 0.001, χ2/df = 1.74; SRMR = 0.036; RMSEA = 0.061; CFI = 0.967; TLI = 0.960. The scores of family members demonstrated significant agreement on the FHC-PA (Sg) [ICC(2, 2) = 0.77] and FHC-NU (Sg) [ICC(2, 2) = 0.75] scales. Findings suggest good evidence for item discriminant validity, internal consistency reliability, construct validity, and measurement invariance. Short versions of the scales were also developed. Conclusion: We adapted, translated and validated the scales for assessing the health climate of families in Singapore, including the development of short versions. The results showed good psychometric properties and the constructs had significant relationships with health behaviors and routines. Improving our understanding of family influences on individual health behavior will be important in developing multi-level strategies for health promotion and chronic disease prevention.

Prevalence of eating disorder is lower in migrants than in the Australian-born population.

OBJECTIVES: There are limited data on the epidemiology of eating disorders (ED) in migrants. Recent Scandinavian research suggests that migrants are at lower risk of eating disorders, however, to our knowledge there have not been comparable studies exploring eating disorders in Australian adult populations. We sought to explore the prevalence of EDs in first-generation migrants to Australia in comparison with the Australian-born population. A secondary aim was to explore ED prevalence across first-generation migrants from different regions of birth (Europe, Asia, Africa, and Other). METHODS: We conducted sequential cross-sectional population surveys in South Australian individuals aged over 15 years in 2015 and 2016 (n = 6052). Demographic data were collected and migration status was inferred based on a country of birth outside Australia. Questions asked regarding disordered eating were based on the Eating Disorders Examination. FINDINGS: The 3-month prevalence of any ED was found to be significantly lower in first-generation migrants born outside Australia (4.5%, 95% CI 3.6-5.6) in comparison to the Australian-born population (6.4%, 95% CI 5.7-7.2). People born in countries in Africa (11.0% 95% CI 6.1-19.1) had a significantly higher prevalence of EDs than those born in Asia (4.0% 95% CI 2.7-5.8). CONCLUSIONS: First-generation migrants to Australia may be at lower risk of eating disorders compared to their Australia-born peers, suggesting support for a 'healthy immigrant effect'.

Enhancing intracellular accumulation and target engagement of PROTACs with reversible covalent chemistry.

Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton's Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy.

Cognitive and Motor Outcomes of Children With Prenatal Opioid Exposure: A Systematic Review and Meta-analysis.

Importance: Prenatal opioid exposure (POE) is one of the fastest-growing global health problems, but its association with long-term neurologic and physical development remains unknown. Objective: To assess the association between POE and cognitive and motor development in children from age 6 months to 18 years. Data Sources: Key search terms included prenatal opioid exposure, neonatal abstinence syndrome, and neurocognitive development. Studies were searched using PubMed and Embase, with no publication date restriction, through August 20, 2018. Study Selection: Only published cohort studies comparing the results of age-appropriate standardized cognitive and/or motor tests between children with any POE (aged 0-18 years) with drug-free controls were included. Data that were not convertible to means and SDs were excluded. Data Extraction and Synthesis: This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Data were pooled using a random-effects model. Main Outcomes and Measures: Standardized mean difference of cognitive and motor tests between POE and nonexposed children. Results: Twenty-six peer-reviewed cohort studies were included. Cognitive outcomes were compared for a total of 1455 children with POE and 2982 nonexposed children across 3 age groups (mean [SE] age at cognitive testing was 13 [1.58] months for the toddler group; 4.5 [0.38] years for the preschool group; and 13 [2.36] years for the school-aged group). Motor outcomes were compared for 688 children with POE and 1500 nonexposed children up to age 6 years (mean [SD] age at motor testing, 2 [0.45] years). Standardized mean difference was lower in cognitive tests for children with POE at 0 to 2 years (d = -0.52; 95% CI, -0.74 to -0.31; P < .001) and 3 to 6 years (d = -0.38; 95% CI, -0.69 to -0.07; P < .001); the difference was not significant for those aged 7 to 18 years (d = -0.44; 95% CI, -1.16 to 0.28; P = .23). Motor scores were lower in children with POE (d = 0.49; 95% CI, 0.23-0.74; P < .001). Conclusions and Relevance: Prenatal opioid exposure appeared to be negatively associated with neurocognitive and physical development from age 6 months, and this association persisted until adolescence. The cause and association of this with POE or other factors (eg, withdrawal treatment) are uncertain but suggest that POE necessitates long-term support and intervention.

Diagnostic Imaging: Ultrasound.

Diagnostic ultrasound imaging, particularly that which includes pulsed wave Doppler interrogation, is a safe, real-time modality by which the risk of developing preeclampsia can be refined, and the effects of established disease can be assessed. This chapter outlines the rationale and technique for Doppler interrogation of the maternal ophthalmic and uterine arteries and grayscale imaging of the maternal optic nerve sheath diameter.

Targeting the 15-keto-PGE2-PTGR2 axis modulates systemic inflammation and survival in experimental sepsis.

Sepsis is a systemic inflammation accompanied by multi-organ dysfunction due to microbial infection. Prostaglandins and their metabolites have long been studied for their importance in regulating the innate immune response. 15-keto-PGE2 (15k-PGE2) is a prostaglandin E2 (PGE2) metabolite, whose further processing is catalyzed by prostaglandin reductase 2 (PTGR2). We showed disruption of the Ptgr2 gene in mice improves the survival rate under both LPS- and cecum ligation/puncture (CLP)-induced experimental sepsis. Knockdown of PTGR2 showed significant accumulation of intracellular 15k-PGE2 in activated macrophages. Both PTGR2 knockdown and exogenous treatment with 15k-PGE2 resulted in reduced pro-inflammatory cytokines production in LPS-stimulated RAW264.7 cells or bone marrow-derived macrophages (BMDM). The same treatment in RAW264.7 and BMDM also led to increased levels of the anti-oxidative transcription factor, Nuclear factor (erythroid-2) related factor-2 (NRF2), augmented anti-oxidant response element (ARE)-mediated reporter activity and upregulated expression of the corresponding anti-oxidant genes. 15k-PGE2 further demonstrated modification to Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2, at cysteine 288 (Cys288) site post-translationally. Finally, 15k-PGE2-treated mice were found to be more resistant to experimental sepsis. Taken together, our study affirms the significance of PTGR2 and 15k-PGE2 in mitigating inflammatory responses and suggests a novel anti-oxidative and anti-inflammatory therapy for sepsis through targeting PTGR2 and administering15k-PGE2.

Prevention and treatment of diabetic foot ulcers.

The rising prevalence of diabetes estimated at 3.6 million people in the UK represents a major public health and socioeconomic burden to our National Health Service. Diabetes and its associated complications are of a growing concern. Diabetes-related foot complications have been identified as the single most common cause of morbidity among diabetic patients. The complicating factor of underlying peripheral vascular disease renders the majority of diabetic foot ulcers asymptomatic until latter evidence of non-healing ulcers become evident. Therefore, preventative strategies including annual diabetic foot screening and diabetic foot care interventions facilitated through a multidisciplinary team have been implemented to enable early identification of diabetic patients at high risk of diabetic foot complications. The National Diabetes Foot Care Audit reported significant variability and deficiencies of care throughout England and Wales, with emphasis on change in the structure of healthcare provision and commissioning, improvement of patient education and availability of healthcare access, and emphasis on preventative strategies to reduce morbidities and mortality of this debilitating disease. This review article aims to summarise major risk factors contributing to the development of diabetic foot ulcers. It also considers the key evidence-based strategies towards preventing diabetic foot ulcer. We discuss tools used in risk stratification and classifications of foot ulcer.

Genome-wide linkage analysis and regional fine mapping identified variants in the RYR3 gene as a novel quantitative trait locus for circulating adiponectin in Chinese population.

Adiponectin is adipocyte-secreted cytokine with potent insulin-sensitizing action in peripheral tissues. The heritability of plasma adiponectin is high in Han Chinese population.To identify genetic loci influencing plasma adiponectin levels in Chinese population, we performed a genome-wide linkage scan in 1949 Chinese participants of the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance family study and mapped a quantitative trail locus located on chromosome 15 at 31 cM (logarithm of odds = 3.04) with 1-logarithm of odds support interval at 24 to 34 cM. Within this mapped region, we further genotyped a total of 68 single-nucleotide polymorphisms in 12 genes. Association analysis revealed that haplotypes composed of single-nucleotide polymorphisms in the ryanodine receptor 3 (RYR3) gene had strongest association with plasma adiponectin. RYR3 haplotypes were also associated with systolic (P = 0.001) and diastolic (P = 7.1 × 10) blood pressure and high-density lipoprotein cholesterol (P = 1.4 × 10). Furthermore, an inverse relationship between expression of RYR3 and adiponectin was observed in human abdominal adipose tissue. In conclusion, a genome-wide linkage scan and regional association fine-mapping identified variants in the RYR3 gene as a quantitative trail locus for plasma adiponectin levels in Chinese population.

First-trimester uterine artery Doppler analysis in the prediction of later pregnancy complications.

Uterine artery Doppler waveform analysis has been extensively studied in the second trimester of pregnancy as a predictive marker for the later development of preeclampsia and fetal growth restriction. The use of Doppler interrogation of this vessel in the first trimester has gained momentum in recent years. Various measurement techniques and impedance indices have been used to evaluate the relationship between uterine artery Doppler velocimetry and adverse pregnancy outcomes. Overall, first-trimester Doppler interrogation of the uterine artery performs better in the prediction of early-onset than late-onset preeclampsia. As an isolated marker of future disease, its sensitivity in predicting preeclampsia and fetal growth restriction in low risk pregnant women is moderate, at 40-70%. Multiparametric predictive models, combining first-trimester uterine artery pulsatility index with maternal characteristics and biochemical markers, can achieve a detection rate for early-onset preeclampsia of over 90%. The ideal combination of these tests and validation of them in various patient populations will be the focus of future research.