DNA damage triggers Golgi dispersal via DNA-PK and GOLPH3.

The response to DNA damage, which regulates nuclear processes such as DNA repair, transcription, and cell cycle, has been studied thoroughly. However, the cytoplasmic response to DNA damage is poorly understood. Here, we demonstrate that DNA damage triggers dramatic reorganization of the Golgi, resulting in its dispersal throughout the cytoplasm. We further show that DNA-damage-induced Golgi dispersal requires GOLPH3/MYO18A/F-actin and the DNA damage protein kinase, DNA-PK. In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents. Identification of the DNA-damage-induced Golgi response reveals an unexpected pathway through DNA-PK, GOLPH3, and MYO18A that regulates cell survival following DNA damage.

RUNX1 isoform disequilibrium promotes the development of trisomy 21-associated myeloid leukemia.

Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR-CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the pathognomonic Gata1s mutation during leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium in patient-derived xenografts in vitro and in vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.

The megakaryocytic transcription factor ARID3A suppresses leukemia pathogenesis.

Given the plasticity of hematopoietic stem and progenitor cells, multiple routes of differentiation must be blocked in the the pathogenesis of acute myeloid leukemia, the molecular basis of which is incompletely understood. We report that posttranscriptional repression of the transcription factor ARID3A by miR-125b is a key event in the pathogenesis of acute megakaryoblastic leukemia (AMKL). AMKL is frequently associated with trisomy 21 and GATA1 mutations (GATA1s), and children with Down syndrome are at a high risk of developing the disease. The results of our study showed that chromosome 21-encoded miR-125b synergizes with Gata1s to drive leukemogenesis in this context. Leveraging forward and reverse genetics, we uncovered Arid3a as the main miR-125b target behind this synergy. We demonstrated that, during normal hematopoiesis, this transcription factor promotes megakaryocytic differentiation in concert with GATA1 and mediates TGFß-induced apoptosis and cell cycle arrest in complex with SMAD2/3. Although Gata1s mutations perturb erythroid differentiation and induce hyperproliferation of megakaryocytic progenitors, intact ARID3A expression assures their megakaryocytic differentiation and growth restriction. Upon knockdown, these tumor suppressive functions are revoked, causing a blockade of dual megakaryocytic/erythroid differentiation and subsequently of AMKL. Inversely, restoring ARID3A expression relieves the arrest of megakaryocytic differentiation in AMKL patient-derived xenografts. This work illustrates how mutations in lineage-determining transcription factors and perturbation of posttranscriptional gene regulation can interact to block multiple routes of hematopoietic differentiation and cause leukemia. In AMKL, surmounting this differentiation blockade through restoration of the tumor suppressor ARID3A represents a promising strategy for treating this lethal pediatric disease.

GOLPH3 bridges phosphatidylinositol-4- phosphate and actomyosin to stretch and shape the Golgi to promote budding.

Golgi membranes, from yeast to humans, are uniquely enriched in phosphatidylinositol-4-phosphate (PtdIns(4)P), although the role of this lipid remains poorly understood. Using a proteomic lipid-binding screen, we identify the Golgi protein GOLPH3 (also called GPP34, GMx33, MIDAS, or yeast Vps74p) as a PtdIns(4)P-binding protein that depends on PtdIns(4)P for its Golgi localization. We further show that GOLPH3 binds the unconventional myosin MYO18A, thus connecting the Golgi to F-actin. We demonstrate that this linkage is necessary for normal Golgi trafficking and morphology. The evidence suggests that GOLPH3 binds to PtdIns(4)P-rich trans-Golgi membranes and MYO18A conveying a tensile force required for efficient tubule and vesicle formation. Consequently, this tensile force stretches the Golgi into the extended ribbon observed by fluorescence microscopy and the familiar flattened form observed by electron microscopy.

Prevalence of subclinical lung cancer detected at autopsy: a systematic review.

BACKGROUND: Lung cancer screening in high-risk populations with low-dose computed tomography is supported by international associations and recommendations. Overdiagnosis is considered a risk of screening with associated harms. The aim of this paper is to determine the prevalence of subclinical lung cancer diagnosed post-mortem to better understand the reservoir of subclinical lung cancer. METHODS: We searched EMBASE, PubMed, and MEDLINE databases from inception until March 2022 with no language restrictions. We considered all studies with ≥100 autopsies in adults. Two reviewers independently assessed eligibility of studies, extracted data, and assessed risk of bias of included studies. We performed a meta-analysis using a random-effects model for prevalence of subclinical lung cancer diagnosed post-mortem with sensitivity and subgroup analyses. RESULTS: A total of 13 studies with 16 730 autopsies were included. Pooled prevalence was 0.4% (95% CI 0.20 to 0.82%, I2 = 84%, tau2 = 1.19, low certainty evidence,16 730 autopsies). We performed a sensitivity analysis excluding studies which did not specify exclusion of children in their cohort, with a pooled prevalence of subclinical lung cancer of 0.87% (95% CI 0.48 to 1.57%, I2 = 71%, tau2 = 0.38, 6998 autopsies, 8 studies). CONCLUSIONS: This is the first published systematic review to evaluate the prevalence of post-mortem subclinical lung cancer. Compared to autopsy systematic reviews in breast, prostate and thyroid cancers, the pooled prevalence is lower in lung cancer for subclinical cancer. This result should be interpreted with caution due to the included studies risk of bias and heterogeneity, with further high-quality studies required in target screening populations.

Anti-Trypanosomal Bufadienolides from the Oocytes of the Toad Rhinella alata (Anura, Bufonidae).

Amphibians are widely known as a prolific source of bioactive metabolites. In this work, we isolated and characterized compounds with antiparasitic activity from the oocytes of the toad Rhinella alata collected in Panama. Bio-guided isolation and structural elucidation were carried out using chromatographic and spectroscopic techniques, respectively. The organic extract was subjected to solid phase extraction followed by HPLC purification of the fraction with in vitro activity against Trypanosoma cruzi trypomastigotes. Seven steroids (1-7) of the bufadienolide family were isolated, and their structures were determined using NMR and MS analyses; of these 19-formyl-dyscinobufotalin, (3) is reported as a new natural product. Compounds 1 and 3-7 resulted in a good anti-trypanosomal activity profile. Among these, 16ß-hydroxyl-hellebrigenin (1) and bufalin (7) showed significant selectivity values of >5 and 2.69, respectively, while the positive control benznidazole showed a selectivity of 18.81. Furthermore, molecular docking analysis showed compounds 1, 3 and 7 interact through H-bonds with the amino acid residues GLN-19, ASP-158, HIS-159 and TRP-177 from cruzipain at the catalytic site. Given the lack of therapeutic options to treat American trypanosomiasis, this work can serve as the basis for further studies that aim for the development of bufadienolides or their derivatives as drugs against Chagas disease.

A risk classification model for prioritising the management of quality issues relating to substandard medicines in Singapore.

BACKGROUND: Monitoring for substandard medicines by regulatory agencies is a key post-market surveillance activity. It is important to prioritise critical product defects for review to ensure that prompt risk mitigation actions are taken. METHODS: A regulatory risk impact prioritisation model for product defects (RISMED) with 11 factors considering the seriousness and extent of impact of a defect was developed. The model generated an overall score that categorised cases into high, medium or low impact. The model was further developed into a statistical risk scoring model (stat-RISMED) using multivariate logistic regression that classified cases into high and non-high impact. Both models were evaluated against an expert-derived gold standard annotation corpus and tested on an independent dataset. RESULTS: Product defect cases received from January 2011 to June 2020 (n = 660) were used to train stat-RISMED and cases from July 2020 to June 2021 (n = 220) for validation. The stat-RISMED identified four factors associated with high impact cases, namely defect classification based on MedDRA-HSA terms, therapeutic indication of product, detectability of defect and whether any overseas regulatory actions were performed. Compared to RISMED, stat-RISMED achieved an improved sensitivity (94% vs 42%) and positive predictive value (47% vs 43%) for the identification of high impact cases, against the gold standard labels. CONCLUSIONS: This study reported characteristics that predicts cases with high impact, and the use of a statistical model to identify such cases. The model may potentially be applied to prioritise product defect issues and strengthen overall surveillance efforts of substandard medicines.

A mobile health intervention to encourage physical activity in children: a randomised controlled trial.

BACKGROUND: Despite immense benefits of physical activity on health and developmental outcomes, few children achieve recommended daily levels of physical activity. Given more than half of families with children own a dog, we investigated the effect of a mobile health (mHealth) intervention to encourage dog-facilitated physical activity through increased family dog walking and children's active play with their dog. METHODS: The PLAYCE PAWS study was a three-armed randomised pilot trial conducted in Perth, Western Australia. Children aged 5-10 years with a family dog were randomised to 4 weeks of either 1) SMS-only intervention, 2) 'SMS + pedometer' intervention or 3) 'usual care' control. The mHealth intervention involved SMS messages to parents; the 'SMS + pedometer' group also received a dog pedometer and personalised dog steps diary. Parent-reported measures were collected at baseline, 1- and 3-months post intervention. The primary outcome was weekly frequency of family dog walking and dog play; secondary outcomes were child attachment to the dog and feasibility of the intervention. RESULTS: A total of 150 children were randomised in staggered blocks to SMS-only (n = 50), 'SMS + pedometer' (n = 50) or usual care (n = 50). No differences were observed in family dog walking and dog play at 1-month. SMS-only children (OR 2.6, 95% CI 1.17, 5.83, P = 0.019) and all intervention children (OR 1.97, 95% CI 1.01, 3.86, P = 0.048) were more likely to increase total dog-facilitated physical activity (sum of family dog walking and dog play responses) at 3-months. The positive associations with total dog-facilitated physical activity disappeared (all P > 0.05) after adjusting for socio-demographic factors. CONCLUSIONS: The PLAYCE PAWS mHealth intervention did not significantly affect dog-facilitated physical activity in children. Given high levels of dog ownership in the community, SMS prompts could be a low-cost intervention to encourage more physical activity in children. Further research is needed to understand how increased interaction with the family dog impacts on children's overall physical activity and other health and development outcomes. TRIAL REGISTRATION: ANZCTR, ACTRN12620000288921 , retrospectively registered on 4/3/2020.

Rapid growth in the COVID-19 era.

ABSTRACT: From Operation Warp Speed to the lipid mRNA vaccine, the COVID-19 pandemic has been a watershed moment for technological development, production, and implementation. The scale and pace of innovation and global collaboration has likely not been experienced since World War II. This article highlights some of the engineering accomplishments that occurred during the pandemic. We provide a broad overview of the technological achievements in vaccine design, antibody engineering, drug repurposing, and rapid diagnostic testing. We also discuss what the future of these technologies and the future of large-scale collaborations might look like moving forward.

The relationship between dog ownership, dog play, family dog walking, and pre-schooler social-emotional development: findings from the PLAYCE observational study.

BACKGROUND: Regular physical activity provides children with health and developmental benefits. This study investigated if active play and walking with the family dog was associated with better social-emotional development in young children. METHODS: We surveyed 1646 parents to ascertain if families with pre-schoolers owned a dog, and the frequency per week their child went on family dog walks or actively played with their dog. The parent-report version of the Strengths and Difficulties Questionnaire (SDQ) was used to measure children's social-emotional development. RESULTS: Children from dog-owning households had reduced likelihood of conduct problems (odds ratio (OR) = 0.70; 95% confidence interval (CI): 0.54, 0.90), peer problems (OR = 0.60; 95% CI: 0.46, 0.79), and total difficulties (OR = 0.77; 95% CI: 0.59, 0.99) and increased likelihood of prosocial behavior (OR = 1.34; 95% CI: 1.06, 1.68) compared with children without a dog. Within dog-owning households, family dog walking at least once/week (OR = 1.45; 95% CI: 1.02, 2.08) and active play with the family dog three or more times/week (OR = 1.74; 95% CI: 1.16, 2.59) increased the likelihood of prosocial behaviors. Family dog walking at least once/week also reduced the likelihood of total difficulties (OR = 0.64; 95% CI: 0.42, 0.96). CONCLUSIONS: Our findings highlight the possible physical activity and social-emotional developmental benefits of family dog ownership for pre-schoolers, and that these benefits may present in early childhood. IMPACT: Young children from dog-owning families had lower peer problems and conduct problems, and higher prosocial behaviors than children from non-dog-owning families. Children of dog-owning families who walked or played with their dog more often also had better prosocial behaviors. Positive social-emotional development was associated with dog ownership, family dog walking, and dog play in young children. Highlights that the social-emotional benefits of owning a dog may begin early in childhood. Due to the high level of pet ownership in households with children, these findings suggest having a dog and interacting with it through play and walking may be important mechanisms for facilitating young children's social-emotional development.

Semisynthesis, Antiplasmodial Activity, and Mechanism of Action Studies of Isocoumarin Derivatives.

In this study, eight natural isocoumarins (1-8) were isolated from a marine-derived Exserohilum sp. fungus. To explore their structure-activity relationship and discover potent antimalarial leads, a small library of 22 new derivatives (1a-1n, 2a, 3a-3c, 4a-4c, and 7a) were semisynthesized by varying the substituents of the aromatic ring and the aliphatic side chains. The natural compound (1) and three semisynthetic derivatives (1d, 1n, and 2a), possessing an all-cis stereochemistry, exhibited strong antiplasmodial activity with IC50 values of 1.1, 0.8, 0.4, and 2.6 µM, respectively. Mechanism studies show that 1n inhibits hemozoin polymerization and decreases the mitochondrial membrane potential but also inhibits P. falciparum DNA gyrase. 1n not only combines different mechanisms of action but also exhibits a high therapeutic index (CC50/IC50 = 675), high selectivity, and a notable drug-like profile.

A study protocol for a randomised controlled trial to evaluate the effectiveness of a dog-facilitated physical activity minimal intervention on young children's physical activity, health and development: the PLAYCE PAWS trial.

BACKGROUND: Pet ownership brings many health benefits to individuals. In children developmental benefits can extend to improved self-esteem, better social competence and decreased loneliness. The majority of households with children own a dog, however only a small proportion of children gain the benefits of dog ownership through dog walking and play. There are few intervention studies investigating the impact of dog-facilitated physical activity in children. The PLAYCE PAWS study aims to test a minimal-contact intervention through the use of mobile health ("mhealth") strategies, i.e. text (SMS) messages, to parents to encourage their children to walk and play with their dog more, and evaluate the impact on children's overall physical activity and development. METHODS/DESIGN: The PLAYCE PAWS intervention study will target parents in dog-owning families with children aged 5 to 8 years in Perth, Western Australia. Approximately 150 dog-owning parents and children will be randomly allocated into either one of two intervention groups or a 'usual care' control group. The first intervention group will receive SMS messages over 4 weeks to encourage and prompt parents to undertake dog walking and dog play with their child. The second intervention group will receive the same text messages, plus a dog pedometer and personalised 'dog steps' diary for their child to complete. Parent-reported outcome measures include changes in children's dog walking and play, overall physical activity, socio-emotional development, self-regulation, self-esteem, empathy, and level of attachment to their dog. DISCUSSION: The PLAYCE PAWS study appears to be the first to examine the effectiveness of a low-cost, mhealth intervention for increasing young children's physical activity through dog walking and play. Given the high prevalence of dogs as family pets, this study presents a valuable opportunity to investigate if mHealth interventions encourage children to walk and play with their dog more, and if there are any associated impact on children's overall physical activity and socio-emotional well-being. If effective, a larger trial or program could be implemented at low-cost and with wide reach in the community. TRIAL REGISTRATION: ANZCTR, ACTRN12620000288921 . Registered 4th March 2020 - Retrospectively registered.

Bufadienolides from the Skin Secretions of the Neotropical Toad Rhinella alata (Anura: Bufonidae): Antiprotozoal Activity against Trypanosoma cruzi.

Toads in the family Bufonidae contain bufadienolides in their venom, which are characterized by their chemical diversity and high pharmacological potential. American trypanosomiasis is a neglected disease that affects an estimated 8 million people in tropical and subtropical countries. In this research, we investigated the chemical composition and antitrypanosomal activity of toad venom from Rhinella alata collected in Panama. Structural determination using mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy led to the identification of 10 bufadienolides. Compounds identified include the following: 16ß-hydroxy-desacetyl-bufotalin-3-adipoyl-arginine ester (1), bufotalin (2), 16ß-hydroxy-desacetyl-bufotalin-3-pimeloyl-arginine ester (3), bufotalin-3-pimeloyl-arginine ester (4), 16ß-hydroxy-desacetyl-bufotalin-3-suberoyl-arginine ester (5), bufotalin-3-suberoyl-arginine ester (6), cinobufagin-3-adipoyl-arginine ester (7), cinobufagin-3-pimeloyl-arginine ester (8), cinobufagin-3-suberoyl-arginine ester (9), and cinobufagin (10). Among these, three new natural products, 1, 3, and 5, are described, and compounds 1-10 are reported for the first time in R. alata. The antitrypanosomal activity assessed in this study revealed that the presence of an arginyl-diacid attached to C-3, and a hydroxyl group at C-14 in the structure of bufadienolides that is important for their biological activity. Bufadienolides showed cytotoxic activity against epithelial kidney Vero cells; however, bufagins (2 and 10) displayed low mammalian cytotoxicity. Compounds 2 and 10 showed activity against the cancer cell lines MCF-7, NCI-H460, and SF-268.

Volume of Gadolinium Enhancement and Successful Repair of the Blood-Brain Barrier in Cerebral Adrenoleukodystrophy.

Up to 40% of boys with adrenoleukodystrophy develop a severe central nervous system demyelinating form (cALD) characterized by white matter changes and gadolinium enhancement on magnetic resonance imaging (MRI). Hematopoietic cell transplant (HCT) is the only proven means to attenuate cALD progression. The elimination of active neuroinflammation is indicated radiographically by the resolution of gadolinium (Gd) enhancement and correlates to speed of donor neutrophil recovery. We analyzed 66 boys with cALD undergoing HCT for biomarkers correlating with early (30 days post-HCT) Gd signal resolution. We found that log Gd volume (cm3) on pre-HCT MRI strongly positively correlated to day 30 Gd resolution (P = .0003) with smaller volume correlating to higher proportion resolved, as was the baseline gadolinium intensity score (P = .04), plasma chitotriosidase activity (P = .04), and faster absolute neutrophil count recovery (P = .03). In multivariate analysis, log Gd volume remained superior in determining which patients would have Gd signal resolution by 30 days post-HCT (P = .016). A final analysis indicated that early Gd resolution also correlated with less neurologic progression from baseline to 1 year following HCT (P = .006). MRI Gd volume may serve as a contributing biomarker to better delineate outcomes and an important metric in comparing therapies in the treatment of cALD.

Racial differences in prediabetes prevalence by test type for the US pediatric and adult population: NHANES 1999-2016.

BACKGROUND: Previous studies have shown that US estimates of prediabetes or diabetes differ depending on test type, fasting plasma glucose (FPG) vs hemoglobin A1c (HbA1c). Given age, race, and test differences reported in the literature, we sought to further examine these differences in prediabetes detection using a nationally representative sample. METHODS: Using the National Health and Nutrition Examination Survey (NHANES) 1999-2016, individuals were identified as having prediabetes with an HbA1c of 5.7% to 6.4% or a FPG of 100 to 125 mg/dL. We excluded individuals with measurements in the diabetic range. We ran generalized estimating equation logistic regressions to examine the relationship between age, race, and test type with interactions, controlling for sex and body mass index. We compared the difference in predicted prediabetes prevalence detected by impaired fasting glycemia (IFG) vs HbA1c by race/ethnicity among children and adults separately using adjusted Wald tests. RESULTS: The absolute difference in predicted prediabetes detected by IFG vs HbA1c was 19.9% for white adolescents, 0% for black adolescents, and 20.1% for Hispanic adolescents; 21.4% for white adults, -1.2% for black adults, and 19.2% for Hispanic adults. Using adjusted Wald tests, we found the absolute differences between black vs white and black vs Hispanic individuals to be significant, but, not between Hispanic and white individuals among children and adults separately. CONCLUSIONS: These observations highlight differences in test performance among racial/ethnic groups. Our findings corroborate the need for further studies to determine appropriate HbA1c cutoff levels for diagnosis of prediabetes by age group and race.

Refined sgRNA efficacy prediction improves large- and small-scale CRISPR-Cas9 applications.

Genome editing with the CRISPR-Cas9 system has enabled unprecedented efficacy for reverse genetics and gene correction approaches. While off-target effects have been successfully tackled, the effort to eliminate variability in sgRNA efficacies-which affect experimental sensitivity-is in its infancy. To address this issue, studies have analyzed the molecular features of highly active sgRNAs, but independent cross-validation is lacking. Utilizing fluorescent reporter knock-out assays with verification at selected endogenous loci, we experimentally quantified the target efficacies of 430 sgRNAs. Based on this dataset we tested the predictive value of five recently-established prediction algorithms. Our analysis revealed a moderate correlation (r = 0.04 to r = 0.20) between the predicted and measured activity of the sgRNAs, and modest concordance between the different algorithms. We uncovered a strong PAM-distal GC-content-dependent activity, which enabled the exclusion of inactive sgRNAs. By deriving nine additional predictive features we generated a linear model-based discrete system for the efficient selection (r = 0.4) of effective sgRNAs (CRISPRater). We proved our algorithms' efficacy on small and large external datasets, and provide a versatile combined on- and off-target sgRNA scanning platform. Altogether, our study highlights current issues and efforts in sgRNA efficacy prediction, and provides an easily-applicable discrete system for selecting efficient sgRNAs.

Juvenile-Onset Immunodeficiency Secondary to Anti-Interferon-Gamma Autoantibodies.

Immunodeficiency secondary to anti-interferon-gamma (anti-IFN-γ) autoantibodies was first described in 2004 as an acquired defect in the IFN-γ pathway leading to susceptibility to multiple opportunistic infections, including dimorphic fungi, parasites, and bacteria, especially tuberculosis and non-tuberculous mycobacterium (NTM) species. It has so far only been described in adult patients. We present 2 cases of disseminated NTM infections in otherwise immunocompetent children. A 16-year-old girl with Sweet's syndrome-like neutrophilic dermatosis developed recurrent fever and cervical lymphadenitis secondary to Mycobacterium abscessus. A 10-year-old boy with a history of prolonged fever, aseptic meningitis, aortitis, and arteritis in multiple blood vessels developed thoracic vertebral osteomyelitis secondary to Mycobacterium avium complex. Both patients were found to have positive serum neutralizing anti-IFNγ autoantibodies. Testing for anti-IFNγ autoantibodies should be considered in otherwise healthy immunocompetent hosts with recurrent or disseminated NTM infection. This represents a phenocopy of primary immunodeficiency which has been recently described only in adults. We report the first two cases of this phenomenon to affect children.

Remote ischaemic preconditioning modifies serum apolipoprotein D, met-enkephalin, adenosine, and nitric oxide in healthy young adults.

Remote ischaemic preconditioning (RIPC) has been employed as a non-invasive protective intervention against myocardial ischaemia-reperfusion injury in animal studies. However, the underlying mechanisms are incompletely defined in humans and its clinical efficacy has been inconclusive. As advanced age, disease, and drugs may confound RIPC mechanisms in patients, our aim is to measure whether RIPC evokes release of adenosine, bradykinin, met-enkephalin, nitric oxide, and apolipoproteins in healthy young adults. Healthy subjects (n = 18, 9 males, 23 ± 1.5 years old; 9 females, 23 ± 1.8 years old) participated after informed consent. RIPC was applied using a blood pressure cuff to the dominant arms for four cycles of 5-minute cuff inflation (ischaemia) and 5-minute cuff deflation (reperfusion). Blood was sampled at baseline and immediately after the final cuff deflation (Post-RIPC). Baseline and Post-RIPC plasma levels of adenosine, bradykinin, met-enkephalin, apolipoprotein A-1 (ApoA-1), apolipoprotein D (ApoD), and nitric oxide (as nitrite) were measured via ELISA and high-performance liquid chromatography. Mean (±SD) baseline levels of adenosine, bradykinin, met-enkephalin, ApoA-1, ApoD, and nitrite in healthy young adults were 13.8 ± 6.5 ng/mL, 2.6 ± 1.9 µg/mL, 594.1 ± 197.4 pg/mL, 3.0 ± 0.7 mg/mL, 22.2 ± 4.0 µg/mL, and 49.8 ± 13.4 nmol/L, respectively. Post-RIPC adenosine and nitrite levels increased (59.5 ± 37.9%, P < .0001; 32.2 ± 19.5%, P < .0001), whereas met-enkephalin and ApoD levels marginally decreased (5.3 ± 14.0%, P = .04; 10.8 ± 20.5%, P = .04). Post-RIPC levels were not influenced by sex, age, blood pressure, waist circumference, or BMI. RIPC produces increased levels of adenosine and nitrites, and decreased met-enkephalin and ApoD in the plasma of young healthy adults.

Evaluation of tranexamic acid in trauma patients: A retrospective quantitative analysis.

INTRODUCTION: Tranexamic acid (TXA) has been shown to decrease mortality in adult trauma patients with or at significant risk of hemorrhage when administered within 3 h of injury. The use and appropriateness of TXA in adult trauma patients presenting to Royal Columbian Hospital (RCH) was investigated. METHODS: This retrospective chart review utilized the British Columbia Trauma Registry to identify 100 consecutive trauma patients that presented to the emergency department at RCH between April 2012 to June 2015 and met the following indications for TXA: systolic blood pressure <90 mm Hg and/or heart rate >110 bpm and presentation within 8 h of injury. Primary outcomes included: percentage that met indications for TXA, received TXA according to the CRASH-2 protocol, received a pre-hospital dose, and received TXA ≤1, >1 to ≤3, or >3 h from injury. RESULTS: During the given time period, 117 subjects (2.7%) met indications for TXA. 67 patients (57%) received TXA in any dose, with 10 subjects (8.5%) receiving TXA according to the CRASH-2 protocol. Of the 67 patients who received any TXA, 76% did so ≤3 h. 22 patients (19%) received TXA as a pre-hospital dose. CONCLUSIONS: <10% of adult trauma patients that met the indication for TXA received it according to the CRASH-2 protocol. Of those patients that received TXA, 76% did so within 3 h. Further inquiry to identify reasons trauma patients are not receiving TXA as well as quality improvement initiatives in trauma care are required. LEVEL OF EVIDENCE: III STUDY TYPE: Therapeutic.

Effect of atopic dermatitis on quality of life and its psychosocial impact in Asian adolescents.

BACKGROUND/OBJECTIVES: Atopic dermatitis (AD) is a common condition affecting up to 20% of the paediatric population in Singapore. It is often associated with significant psychosocial morbidity and can affect patients' quality of life (QOL) tremendously. This study investigated the varying lifestyle impacts, and psychosocial domains most affected by AD in adolescent children in Singapore. METHODS: A prospective study evaluating the impact of AD on the QOL of adolescents was conducted over a 6-month period from July to December 2014. Adolescents aged 11-16 years with varying eczema severity were recruited. Eczema severity was determined by using the eczema area and severity index (EASI) scores. Lifestyle impact of AD was evaluated using patient-reported children's dermatology life quality index (CDLQI) scores. Statistical analysis was performed using an analysis of one-way variance and Student's t-test. RESULTS: A total of 50 patients were enrolled and divided into three groups: mild (<10.3), moderate (10.3-20.9) and severe (>20.9) eczema based on EASI scores. Patients with mild and moderate eczema had lower CDLQI scores. Adolescents were most affected by the disruption that their symptoms had on their leisure and physical activities and sleep as a result of itch and scratching, respectively. CONCLUSION: Chronic sufferers of severe eczema experience poorer QOL than those with mild or moderate eczema. They also experience significant psychosocial impact as a consequence of their condition.