Monomeric structures of hexokinase I

Hexokinase I, the pacemaker of glycolysis in brain tissue, is composed of two structurally similar halves connected by an [Alpha]-helix. The enzyme dimerizes at elevated protein concentrations in solution and in crystal structures; however, almost all published data reflect the properties of a hexokinase I monomer in solution. Crystal structures of mutant forms of recombinant human hexokinase I, presented here, reveal the enzyme monomer for the first time. The mutant hexokinases bind both glucose 6-phosphate and glucose with high affinity to their N- and C-terminal halves, and ADP, also with high affinity, to a site near the N-terminus of the polypeptide chain. Exposure of the monomer crystals to ADP in the complete absence of glucose 6-phosphate reveals a second binding site for adenine nucleotides at the putative active site (C-half), with conformational changes extending 15 Å to the contact interface between the N- and C-halves. The structures reveal a flexible region of the C-half and a rigid-body rotation of the N-half, as possible elements of a structure-based mechanism for allosteric regulation of catalysis

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication

The Role of Mother’s and Child’s Self-Regulation on Bidirectional Links between Harsh Parenting and Child Externalizing Problems

The authors examined task-based (i.e., executive function), surveyed (i.e., effortful control), and physiological (i.e., resting cardiac respiratory sinus arrhythmia [RSA]) measures of child and maternal regulation as distinct moderators of longitudinal bidirectional links between child externalizing (EXT) behaviors and harsh parenting (HP) from 6 to 9 years. The sample size was 299 (50.9% female; 1% Asian, 4% multiple races; 14% Black; 78% White), and participants were recruited in the United States (a rural college town in Virginia and a midsized city in North Carolina). Higher child EXT at 6 years predicted higher HP at 7–8 years, which predicted higher EXT at 9 years. Also, this path was moderated by 6-year child effortful control, 6-year resting RSA, and 9-year executive function. In contrast, there was no moderating effect of any measure of maternal regulation. Findings suggest it is important to consider child self-regulation when examining bidirectionality in parent and child effects for HP and child EXT. (PsycInfo Database Record (c) 2024 APA, all rights reserved)Peer reviewe

National burden of pediatric abusive injuries: patterns vary by age

Child abuse is often unrecognized by healthcare practitioners. This study sought to characterize pediatric abuse injury patterns and associated mortality rates in a nationwide cohort.The Kids' Inpatient Database (1997-2012) was queried for patients  39,000 children were hospitalized for abuse from 1997 to 2012. The majority were Caucasian (36%), male (51%) and < 4 years old (70%). Most sustained physical abuse (53%), followed by AHT (14%), sexual (9%) and emotional abuse (2%). Multiple injuries were sustained by 44% of patients. Mortality was 4% (n = 1476). Burns (2%) and intrathoracic (2%) injuries had the highest mortality compared to other injuries (21% and 19%, respectively; both P < 0.001). Emotional abuse (5%) and neglect (1%) were highest in those ≥ 13 years old (both P  = 0.001).Physical injuries are less common in adolescents (13-18 years) hospitalized for abuse. However, they are more likely to report emotional abuse and neglect, which has not been compared in previous studies. Intrathoracic injuries and AHT are associated with significant mortality

Radical Resection of Pediatric Fibrosarcoma Is Not Associated With Survival Benefit: A Nationwide Database Analysis

Introduction: Fibrosarcoma is one of the most common nonrhabdomyosarcoma soft tissue sarcomas in the pediatric population. Surgical resection is the cornerstone of treatment; however, optimal factors regarding the extent of fibrosarcoma resection in localized versus regional disease is poorly understood. Methods: The Surveillance, Epidemiology, and End Results database was queried for pa-tients who are 19 y old or younger with a diagnosis of fibrosarcoma from 1975 to 2016. Kaplan-Meier analyses were performed for disease-specific survival on clinical and pathologic variables. Multivariate analysis was performed based on significant predictors of disease-specific survival.Results: There were 1290 patients (median age 13 [7-17] y) identified with fibrosarcoma. The overall survival rate at 20 y was 93%. Radical resection was performed on 22%, 40%, and 52% of patients with localized, regional, and distant Surveillance, Epidemiology, and End Results disease stage, respectively. Chemotherapy (P < 0.001), radiation (P < 0.001), his-tology (P < 0.001), and stage (P = 0.004) were significant predictors of increased mortality using univariate Kaplan-Meier analysis. Most patients (86%) with localized or regional stage who underwent radiation had fibrosarcomas of nondermatofibrosarcoma histology (P < 0.001). Dermatofibrosarcoma subtype comprised most radical resections (41%). Excluding distant stage, nondermatofibroma histology (hazard ratio 16.94, 95% confidence interval 3.77-76.01) and regional stage (hazard ratio 8.15, 95% confidence interval 2.93-22.69) were independent prognostic factors of mortality (both P < 0.001). Radical resection was not a significant independent prognostic indicator of survival.Conclusions: Nondermatofibrosarcoma subtype is independently associated with increased mortality. Although surgery remains the mainstay of treatment, the extent of resection is not a predictor of survival for patients with the localized and regional stage of disease. 2022 Elsevier Inc. All rights reserved

Multiplatform analyses reveal distinct drivers of systemic pathogenesis in adult versus pediatric severe acute COVID-19

In this work, authors take a multiomics and microfluidics-based approach to elucidate the mechanism of endothelial damage in critical illness associated with SARS-CoV-2

Surgical site infection after gastrointestinal surgery in children : an international, multicentre, prospective cohort study

Introduction Surgical site infection (SSI) is one of the most common healthcare-associated infections (HAIs). However, there is a lack of data available about SSI in children worldwide, especially from low-income and middle-income countries. This study aimed to estimate the incidence of SSI in children and associations between SSI and morbidity across human development settings. Methods A multicentre, international, prospective, validated cohort study of children aged under 16 years undergoing clean-contaminated, contaminated or dirty gastrointestinal surgery. Any hospital in the world providing paediatric surgery was eligible to contribute data between January and July 2016. The primary outcome was the incidence of SSI by 30 days. Relationships between explanatory variables and SSI were examined using multilevel logistic regression. Countries were stratified into high development, middle development and low development groups using the United Nations Human Development Index (HDI). Results Of 1159 children across 181 hospitals in 51 countries, 523 (45 center dot 1%) children were from high HDI, 397 (34 center dot 2%) from middle HDI and 239 (20 center dot 6%) from low HDI countries. The 30-day SSI rate was 6.3% (33/523) in high HDI, 12 center dot 8% (51/397) in middle HDI and 24 center dot 7% (59/239) in low HDI countries. SSI was associated with higher incidence of 30-day mortality, intervention, organ-space infection and other HAIs, with the highest rates seen in low HDI countries. Median length of stay in patients who had an SSI was longer (7.0 days), compared with 3.0 days in patients who did not have an SSI. Use of laparoscopy was associated with significantly lower SSI rates, even after accounting for HDI. Conclusion The odds of SSI in children is nearly four times greater in low HDI compared with high HDI countries. Policies to reduce SSI should be prioritised as part of the wider global agenda.Peer reviewe

Policy as normative influence? On the relationship between parental leave policy and social norms in gender division of childcare across 48 countries

In the present work, we addressed the relationship between parental leave policies and social norms. Using a pre-registered, cross-national approach, we examined the relationship between parental leave policies and the perception of social norms for the gender division of childcare. In this study, 19,259 students (11,924 women) from 48 countries indicated the degree to which they believe childcare is (descriptive norm) and should be (prescriptive norm) equally divided among mothers and fathers. Policies were primarily operationalized as the existence of parental leave options in the respective country. The descriptive and prescriptive norms of equal division of childcare were stronger when parental leave was available in a country - also when controlling for potential confounding variables. Moreover, analyses of time since policy change suggested that policy change may initially affect prescriptive norms and then descriptive norms at a later point. However, due to the cross-sectional nature of the data, drawing causal inferences is difficult