Competitive SPR chaser assay to study biomolecular interactions with very slow binding dissociation rate constant.

Binding kinetics of drug and its target protein is crucial for the efficacy and safety of the drug. Using surface plasmon resonance (SPR) technology, we performed a competitive SPR chaser assay, a method to study biomolecular interactions with very slow dissociation rate constants (kd < 1E-4 s-1). This report described the principle and the experimental setup of the chaser assay, which involves using a competitive probe (chaser) to detect changes in target occupancy by a test molecule over time. We demonstrated the applicability of the chaser assay for both small and large molecules and compared the results with conventional SPR kinetic analysis and other methods. We suggest that the chaser assay is a useful and robust technique to characterize very tight biomolecular interactions, and that it can also be used to study cooperativity in ternary complex formation.

Divergent mechanisms of reduced growth performance in Betula ermanii saplings from high-altitude and low-latitude range edges.

The reduced growth performance of individuals from range edges is a common phenomenon in various taxa, and considered to be an evolutionary factor that limits the species' range. However, most studies did not distinguish between two mechanisms that can lead to this reduction: genetic load and adaptive selection to harsh conditions. To address this lack of understanding, we investigated the climatic and genetic factors underlying the growth performance of Betula ermanii saplings transplanted from 11 populations including high-altitude edge and low-latitude edge population. We estimated the climatic position of the populations within the overall B. ermanii's distribution, and the genetic composition and diversity using restriction-site associated DNA sequencing, and measured survival, growth rates and individual size of the saplings. The high-altitude edge population (APW) was located below the 95% significance interval for the mean annual temperature range, but did not show any distinctive genetic characteristics. In contrast, the low-latitude edge population (SHK) exhibited a high level of linkage disequilibrium, low genetic diversity, a distinct genetic composition from the other populations, and a high relatedness coefficient. Both APW and SHK saplings displayed lower survival rates, heights and diameters, while SHK saplings also exhibited lower growth rates than the other populations' saplings. The low heights and diameters of APW saplings was likely the result of adaptive selection to harsh conditions, while the low survival and growth rates of SHK saplings was likely the result of genetic load. Our findings shed light on the mechanisms underlying the reduced growth performance of range-edge populations.

HIV risk behavior and testing among MS M in Bangkok 2015-2019: a short report.

Men who have sex with men (MSM) in Thailand have high HIV prevalence. This analysis used three years of data from the Behavioral Surveillance Survey (BSS) to examine the behaviors and biomedical interventions among MSM in Bangkok. Percent MSM with an HIV or STI test in the past 12 months decreased from 50.8% to 29.8%, and 42.2% to 33.0%, respectively. The frequency of HIV/STI testing was higher among those who had university-level education, as well as among those who reported higher AIDS knowledge, and had utilized prevention services. Additionally, awareness of PrEP peaked in 2017 (74.1%). The study found an increasing trend of men who had sex without a condom the last time they had anal sex with a man, and/or with multiple partners. Nearly two-thirds of the sample were reached by HIV prevention interventions. One-third had correct AIDS knowledge. These findings suggest that, after an increase of sex behavior risk, a decrease in PrEP awareness, and unknown HIV status, HIV prevalence among MSM in Bangkok may have begun to increase again. Intensified prevention interventions are urgently needed to reduce HIV behavioral risk for MSM since that is a major driver of the HIV epidemic in Thailand.

Effect of tyrosine kinase inhibitors on cell migration and epithelial-to-mesenchymal transition in Asian head and neck cancer cell lines.

BACKGROUND: We investigated the role of epidermal growth factor (EGF) and transforming growth factor α (TGFα) on Asian head and neck cancer patient cell lines; in terms of epithelial-to-mesenchymal transition (EMT) and cell migration to determine whether these changes could be reversed using tyrosine kinase inhibitors (Gefitinib and Erlotinib). METHODS: Cell migration, protrusion and EMT were assessed using both Scatter assay and Scratch assay. Protein expression and localisation were evaluated using immunofluorescence, SDS-PAGE and Western blotting techniques to identify the involvement of phosphorylated MAPK (Thr202/Tyr204), phosphorylated EGFR (Y1068) and phosphorylated AKT (Ser473) protein expression. RESULTS: EGF and TGFα induced an EMT-like phenotypical change, cellular protrusion and cell migration while Gefitinib and Erlotinib blocked these morphological changes and cell migration. We also examined the effect of EGF/TGF α± tyrosine kinase inhibitors on phosphorylation sites Y1068 of epidermal growth factor receptor (EGFR). Y1068 was phosphorylated in all test conditions, and all tested concentrations of inhibitors did not inhibit Y1068 phosphorylation. EGF and TGFα increased phosphorylation of MAPK (Thr202/Tyr204) residues compared with serum-free control while a one-hour pre-treatment with tyrosine kinase inhibitor(s) before addition of growth factors completely blocked this phosphorylation. Phosphorylation of Akt Ser 473 was also induced by EGF and TGFα, and a one-hour pre-treatment with the tyrosine kinas inhibitor(s) reduced this phosphorylation. CONCLUSION: These data suggest that Gefitinib and Erlotinib prevent activation of downstream signalling proteins MAPK (Thr202/Tyr204) and Akt (Ser473) thereby blocking phenotypic change and cell migration. This study supports the potential therapeutic value of Gefitinib and Erlotinib in targeting head and neck cancer.

Autonomous conformational regulation of ß3 integrin and the conformation-dependent property of HPA-1a alloantibodies.

Integrin α/ß heterodimer adopts a compact bent conformation in the resting state, and upon activation undergoes a large-scale conformational rearrangement. During the inside-out activation, signals impinging on the cytoplasmic tail of ß subunit induce the α/ß separation at the transmembrane and cytoplasmic domains, leading to the extended conformation of the ectodomain with the separated leg and the opening headpiece that is required for the high-affinity ligand binding. It remains enigmatic which integrin subunit drives the bent-to-extended conformational rearrangement in the inside-out activation. The ß3 integrins, including αIIbß3 and αVß3, are the prototypes for understanding integrin structural regulation. The Leu33Pro polymorphism located at the ß3 PSI domain defines the human platelet-specific alloantigen (HPA) 1a/b, which provokes the alloimmune response leading to clinically important bleeding disorders. Some, but not all, anti-HPA-1a alloantibodies can distinguish the αIIbß3 from αVß3 and affect their functions with unknown mechanisms. Here we designed a single-chain ß3 subunit that mimics a separation of α/ß heterodimer on inside-out activation. Our crystallographic and functional studies show that the single-chain ß3 integrin folds into a bent conformation in solution but spontaneously extends on the cell surface. This demonstrates that the ß3 subunit autonomously drives the membrane-dependent conformational rearrangement during integrin activation. Using the single-chain ß3 integrin, we identified the conformation-dependent property of anti-HPA-1a alloantibodies, which enables them to differently recognize the ß3 in the bent state vs. the extended state and in the complex with αIIb vs. αV This study provides deeper understandings of integrin conformational activation on the cell surface.

Mackay Heart Failure Study: Examining the Root Causes, Compliance With Guideline-Based Therapy and Prognosis.

INTRODUCTION: Heart failure patients have poor outcomes comparable to some malignancies; however, the modern guideline directed medical therapy (GDMT) has improved its outcomes. The clinical characteristics and prescribers' compliance with GDMT for heart failure patients have not been studied in the Mackay region. METHODS: A retrospective cohort study of 115 consecutive adult heart failure patients was conducted at our institution. RESULTS: The study cohort consisted of 80% (n=92) males. Ischaemia was the leading cause accounting for 54% (n=62) of the cohort, followed by idiopathic cardiomyopathy at 32% (n=37). Drug-induced and Takotsubo cardiomyopathies were responsible for 11% and 1% respectively. Two (2) patients (2%) had valvular heart disease. Hypertension was present in 57% while diabetes and atrial fibrillation were present in 32% and 43% of patients. Fifty-nine per cent (59%) had a smoking history. All, except four patients, had reduced left ventricular ejection fraction (LVEF <50%) at diagnosis. Among patients with coronary ischaemia, 37% and 31% were revascularised with percutaneous coronary interventions and bypass graft surgeries, respectively. Renin-angiotensin-aldosterone system inhibitors and beta blockers were prescribed in 94% and 95% of the patients, respectively. Mineralocorticoid inhibitors were used in 25% while ivabradine was given to 8% of patients. Nine per cent (9%) of patients received cardiac resynchronisation therapy. Most patients had improvement in functional class and LVEF during follow-up. There were very few mortalities at 3% (n=3) at the median follow-up of 403 (IQR 239-896) days. CONCLUSION: Our study has shed light on heart failure epidemiology in the Mackay region. We found excellent compliance with GDMT and good prognosis for most patients in terms of both symptom and survival.

Structure of an extended ß3 integrin.

Cells use adhesion receptor integrins to communicate with their surroundings. Integrin activation and cellular signaling are coupled with change from bent to extended conformation. ß3 integrins, including αIIbß3, which is essential for the function of platelets in hemostasis and thrombosis, and αVß3, which plays multiple roles in diverse cell types, have been prototypes in understanding integrin structure and function. Despite extensive structural studies, a high-resolution integrin structure in an extended conformation remains to be determined. The human ß3 Leu33Pro polymorphism, located at the PSI domain, defines human platelet-specific alloantigens 1a and 1b (HPA-1a/b), immune response to which is a cause of posttransfusion purpura and fetal/neonatal alloimmune thrombocytopenia. Leu33Pro substitution has also been suggested to be a risk factor for thrombosis. Here we report the crystal structure of the ß3 headpiece in either Leu33 or Pro33 form, both of which reveal intermediate and fully extended conformations coexisting in 1 crystal. These were used to build high-resolution structures of full-length ß3 integrin in the intermediate and fully extended states, agreeing well with the corresponding conformations observed by electron microscopy. Our structures reveal how ß3 integrin becomes extended at its ß-knee region and how the flexibility of ß-leg domains is determined. In addition, our structures reveal conformational changes of the PSI and I-EGF1 domains upon ß3 extension, which may affect the binding of conformation-dependent anti-HPA-1a alloantibodies. Our structural and functional data show that Leu33Pro substitution does not directly alter the conformation or ligand binding of ß3 integrin.

Geographic distribution and utilisation of CT and MRI services at public hospitals in Myanmar.

BACKGROUND: Diagnosis by computed tomography (CT) and magnetic resonance imaging (MRI) is important for patient care. However, the geographic distribution and utilisation of these machines in countries with limited resources, such as Myanmar, have not been sufficiently studied. Therefore, this study aims to identify the geographic distribution and utilisation of CT and MRI services at public hospitals in Myanmar. METHODS: This nationwide, cross-sectional study was conducted at 43 public hospitals in Myanmar. Data were collected retrospectively using a prepared form from 1st January 2015 to 31st December 2017 at public hospitals in Myanmar. A descriptive analysis was performed to calculate the number of CT and MRI units per million population in each state and region of Myanmar. The distribution of CT and MRI units was assessed using the Lorenz curve and Gini coefficient, which are indicators of inequality in distribution. RESULTS: In total, 45 CT and 14 MRI units had been installed in public hospitals in Myanmar by 2017. In total, 205,570 CT examinations and 18,981 MRI examinations have been performed within the study period. CT units per million population in 2017 varied from 0.30 in Rakhine State to 3.22 in Kayah State. However, MRI units were available only in public hospitals in five states/regions. The Gini coefficient for CT and MRI was 0.35 and 0.69, respectively. An upward trend in the utilisation rate of CT and MRI was also observed during the study period, especially among patients aged between 36 and 65 years. CONCLUSIONS: Throughout Myanmar, CT units were more equally distributed than MRI units. CT and MRI units were mostly concentrated in the Yangon and Mandalay Regions, where the population density is higher. The geographic distribution and utilisation rate of CT and MRI units varied among states, regions, and patients' age group. However, the utilisation rates of CT and MRI increased annually in all states and regions during the review period. The Ministry of Health and Sports in Myanmar should consider the utilisation and population coverage of CT and MRI as an important factor when there will be procurement of those medical equipment in the future.

A pivotal role for a conserved bulky residue at the α1-helix of the αI integrin domain in ligand binding.

The ligand-binding ßI and αI domains of integrin are the best-studied von Willebrand factor A domains undergoing significant conformational changes for affinity regulation. In both ßI and αI domains, the α1- and α7-helixes work in concert to shift the metal-ion-dependent adhesion site between the resting and active states. An absolutely conserved Gly in the middle of the α1-helix of ßI helps maintain the resting ßI conformation, whereas the homologous position in the αI α1-helix contains a conserved Phe. A functional role of this Phe is structurally unpredictable. Using αLß2 integrin as a model, we found that the residue volume at the Phe position in the α1-helix is critical for αLß2 activation because trimming the Phe by small amino acid substitutions abolished αLß2 binding with soluble and immobilized intercellular cell adhesion molecule 1. Similar results were obtained for αMß2 integrin. Our experimental and molecular dynamics simulation data suggested that the bulky Phe acts as a pawl that stabilizes the downward ratchet-like movement of ß6-α7 loop and α7-helix, required for high-affinity ligand binding. This mechanism may apply to other von Willebrand factor A domains undergoing large conformational changes. We further demonstrated that the conformational cross-talk between αL αI and ß2 ßI could be uncoupled because the ß2 extension and headpiece opening could occur independently of the αI activation. Reciprocally, the αI activation does not inevitably lead to the conformational changes of the ß2 subunit. Such loose linkage between the αI and ßI is attributed to the αI flexibility and could accommodate the αLß2-mediated rolling adhesion of leukocytes.

The dual structural roles of the membrane distal region of the α-integrin cytoplasmic tail during integrin inside-out activation.

Studies on the mechanism of integrin inside-out activation have been focused on the role of ß-integrin cytoplasmic tails, which are relatively conserved and bear binding sites for the intracellular activators including talin and kindlin. Cytoplasmic tails for α-integrins share a conserved GFFKR motif at the membrane-proximal region and this forms a specific interface with the ß-integrin membrane-proximal region to keep the integrin inactive. The α-integrin membrane-distal regions, after the GFFKR motif, are diverse both in length and sequence and their roles in integrin activation have not been well-defined. In this study, we report that the α-integrin cytoplasmic membrane-distal region contributes to maintaining integrin in the resting state and to integrin inside-out activation. Complete deletion of the α-integrin membrane-distal region diminished talin- and kindlin-mediated integrin ligand binding and conformational change. A proper length and suitable amino acids in α-integrin membrane-distal region was found to be important for integrin inside-out activation. Our data establish an essential role for the α-integrin cytoplasmic membrane-distal region in integrin activation and provide new insights into how talin and kindlin induce the high-affinity integrin conformation that is required for fully functional integrins.

Creation of a Patient Information Video to Improve the Patient Experience of the Surgical Assessment Unit.

BACKGROUND: Patients who attend emergency surgical services are entering an unfamiliar environment whilst often being unwell and in pain. Patient satisfaction in emergency surgical units is often low due to poor communication with attendees and long wait times. METHODS: A pilot patient questionnaire identified areas where patient satisfaction was low during attendance at the surgical assessment unit (SAU). The aim of this intervention was to improve patient satisfaction with their experience whilst attending the SAU. An education video was filmed to address the areas where services were falling short of expectations, and this was played in the waiting room. Further questionnaire results tailored the frequency of the video to achieve maximum impact. RESULTS: Data were collected at three time points: firstly, prior to the introduction of the video (n=34); secondly, with the video played hourly (n=15); and finally with the video played every 30 minutes at a higher volume (n=15). Mean satisfaction scores after the final cycle improved to 7.3 from 4.9 (p=0.0009). Additionally, 94% of patients agreed that the video was in keeping with their personal experience of the SAU and agreed that the video improved their understanding of what to expect from the visit. CONCLUSIONS: Interventions that improve communication with patients and adjust their expectations play an important role in improving patient satisfaction and their overall perception of care. This can be achieved with a simple patient information video.

Real-world experience of nintedanib for progressive fibrosing interstitial lung disease in the UK.

Background: Nintedanib slows progression of lung function decline in patients with progressive fibrosing (PF) interstitial lung disease (ILD) and was recommended for this indication within the United Kingdom (UK) National Health Service in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date, there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting. Methods: 26 UK centres were invited to take part in a national service evaluation between 17 November 2021 and 30 September 2022. Summary data regarding underlying diagnosis, pulmonary function tests, diagnostic criteria, radiological appearance, concurrent immunosuppressive therapy and drug tolerability were collected via electronic survey. Results: 24 UK prescribing centres responded to the service evaluation invitation. Between 17 November 2021 and 30 September 2022, 1120 patients received a multidisciplinary team recommendation to commence nintedanib for PF-ILD. The most common underlying diagnoses were hypersensitivity pneumonitis (298 out of 1120, 26.6%), connective tissue disease associated ILD (197 out of 1120, 17.6%), rheumatoid arthritis associated ILD (180 out of 1120, 16.0%), idiopathic nonspecific interstitial pneumonia (125 out of 1120, 11.1%) and unclassifiable ILD (100 out of 1120, 8.9%). Of these, 54.4% (609 out of 1120) were receiving concomitant corticosteroids, 355 (31.7%) out of 1120 were receiving concomitant mycophenolate mofetil and 340 (30.3%) out of 1120 were receiving another immunosuppressive/modulatory therapy. Radiological progression of ILD combined with worsening respiratory symptoms was the most common reason for the diagnosis of PF-ILD. Conclusion: We have demonstrated the use of nintedanib for the treatment of PF-ILD across a broad range of underlying conditions. Nintedanib is frequently co-prescribed alongside immunosuppressive and immunomodulatory therapy. The use of nintedanib for the treatment of PF-ILD has demonstrated acceptable tolerability in a real-world setting.

Hazardous Child Labour, Psychosocial Functioning, and School Dropouts among Children in Bangladesh: A Cross-Sectional Analysis of UNICEF's Multiple Indicator Cluster Surveys (MICS).

Child labour is a common financial coping strategy in poor households, especially in low-and middle-income countries with many children working under hazardous conditions. Little is known about the linkages between hazardous work conditions and psycho-social and educational outcomes. We analysed the Bangladesh Multiple Indicator Cluster Survey (BMICS) round 6 to assess the association between the exposure variables, including child labour, hazardous child labour (HZCL) and hazardous work, and outcome variables, including psychosocial functioning difficulty and school dropout, in children aged 5 to 17 years. We conducted bivariable and multivariable analyses to examine the association. In the adjusted analyses, children engaged in HZCL had increased odds of psychosocial functioning difficulty (aOR: 1.41; 95% CI: 1.16-1.72) and school dropout (aOR: 5.65; 95% CI: 4.83-6.61) among 5-14-year-olds compared to children who did not engage in child labour and hazardous work. Other independent factors associated with psychosocial functioning difficulty and school dropout included being male, living in a deprived neighbourhood, being exposed to violent punishment, the caregiver's attitude towards physical punishment, the mother's functional difficulty and lower maternal education. The linkages between hazardous work and psychosocial functioning difficulty appear more prominent among children not in school. Further, the evidence on the relationship between hazardous work and school dropout is stronger among children with psychosocial functioning difficulty. Policies and programmes that target the most hazardous forms of work are likely to have the greatest benefits for children's mental health, social well-being and educational attainment.

Overexpression of microRNA-205-5p promotes cholangiocarcinoma growth by reducing expression of homeodomain-interacting protein kinase 3.

The microRNA miR-205-5p has diverse effects in different malignancies, including cholangiocarcinoma (CCA), but its effects on CCA progression is unclear. Here we investigated the role and function of miR-205-5p in CCA. Three CCA cell lines and human serum samples were found to have much higher expression levels of miR-205-5p than seen in typical cholangiocyte cell lines and healthy controls. Inhibition of miR-205-5p suppressed CCA cell motility, invasion and proliferation of KKU-213B whereby overexpression of miR-205-5p promoted cell proliferation and motility of KKU-100 cells. Bioinformatics tools (miRDB, TargetScan, miRWalk, and GEPIA) all predicted various miR-205-5p targets. Experiments using miR-205-5p inhibitor and mimic indicated that homeodomain-interacting protein kinase 3 (HIPK3) was a potential direct target of miR-205-5p. Overexpression of HIPK3 using HIPK3 plasmid cloning DNA suppressed migration and proliferation of KKU-100 cells. Notably, HIPK3 expression was lower in human CCA tissues than in normal adjacent tissues. High HIPK3 expression was significantly associated with longer survival time of CCA patients. Multivariate regression analysis indicated tissue HIPK3 levels as an independent prognostic factor for CCA patients. These findings indicate that overexpression of miR-205-5p promotes CCA cells proliferation and migration partly via HIPK3-dependent way. Therefore, targeting miR-205-5p may be a potential treatment approach for CCA.

A single F153Sß3 mutation causes constitutive integrin αIIbß3 activation in a variant form of Glanzmann thrombasthenia.

This report identifies a novel variant form of the inherited bleeding disorder Glanzmann thrombasthenia, exhibiting only mild bleeding in a physically active individual. The platelets cannot aggregate ex vivo with physiologic agonists of activation, although microfluidic analysis with whole blood displays moderate ex vivo platelet adhesion and aggregation consistent with mild bleeding. Immunocytometry shows reduced expression of αIIbß3 on quiescent platelets that spontaneously bind/store fibrinogen, and activation-dependent antibodies (ligand-induced binding site-319.4 and PAC-1) report ß3 extension suggesting an intrinsic activation phenotype. Genetic analysis reveals a single F153Sß3 substitution within the ßI-domain from a heterozygous T556C nucleotide substitution of ITGB3 exon 4 in conjunction with a previously reported IVS5(+1)G>A splice site mutation with undetectable platelet messenger RNA accounting for hemizygous expression of S153ß3. F153 is completely conserved among ß3 of several species and all human ß-integrin subunits suggesting that it may play a vital role in integrin structure/function. Mutagenesis of αIIb-F153Sß3 also displays reduced levels of a constitutively activated αIIb-S153ß3 on HEK293T cells. The overall structural analysis suggests that a bulky aromatic, nonpolar amino acid (F,W)153ß3 is critical for maintaining the resting conformation of α2- and α1-helices of the ßI-domain because small amino acid substitutions (S,A) facilitate an unhindered inward movement of the α2- and α1-helices of the ßI-domain toward the constitutively active αIIbß3 conformation, while a bulky aromatic, polar amino acid (Y) hinders such movements and restrains αIIbß3 activation. The data collectively demonstrate that disruption of F153ß3 can significantly alter normal integrin/platelet function, although reduced expression of αIIb-S153ß3 may be compensated by a hyperactive conformation that promotes viable hemostasis.

An Unusual Presentation of Adrenocortical Carcinoma (ACC): Panic Attacks and Psychosis.

BACKGROUND Adrenocortical carcinoma (ACC) is a very rare disease, with an incidence of 1.02 per million population per year. The most commonly secreted hormone in ACC is cortisol, often presenting as a rapidly progressive Cushing syndrome (CS). We describe a case of ACC with an unusual presentation, mainly with psychiatric manifestations, including panic attacks and hallucinations. CASE REPORT A 52-year-old woman presented with episodes of acute anxiety, hallucinations, palpitations, hot flashes, gastrointestinal upset associated with paroxysmal hypertension, tachycardia, and flushing for 1 week. The initial workup was aimed at ruling out causes of acute psychosis and/or anxiety such as substance use, and organic diseases such as pheochromocytoma (PCC). Our initial suspicion of PCC was ruled out based on the negative serum and urinary metanephrines (MN) and normetanephrines (NMN). Recurrent metabolic alkalosis and hypokalemia despite fluid and potassium supplementation prompted us to work up for hyperaldosteronism. Her renin level was elevated and the aldosterone level was appropriately suppressed. Elevated cortisol, positive dexamethasone (DXM) suppression test, low adrenocorticotropic hormone (ACTH), imaging revealing an adrenal mass, and postoperative histology confirmed the diagnosis of cortisol-producing ACC. CONCLUSIONS It is essential to recognize psychiatric presentations of CS to achieve early diagnosis and prevent mortality and morbidity. Panic attacks, a common presentation of CS, can present with features mimicking pheochromocytoma (PCC), including palpitations, sweating, tachycardia, and paroxysmal hypertension. A comprehensive workup is warranted to reach a diagnosis, with a combination of hormonal levels, imaging, and histology.

Child Domestic Work, Violence, and Health Outcomes: A Rapid Systematic Review.

This rapid systematic review describes violence and health outcomes among child domestic workers (CDWs) taken from 17 studies conducted in low- and middle-income countries. Our analysis estimated the median reported rates of violence in CDWs aged 5-17-year-olds to be 56.2% (emotional; range: 13-92%), 18.9% (physical; range: 1.7-71.4%), and 2.2% (sexual; range: 0-62%). Both boys and girls reported emotional abuse and sexual violence with emotional abuse being the most common. In Ethiopia and India, violence was associated with severe physical injuries and sexual insecurity among a third to half of CDWs. CDWs in India and Togo reported lower levels of psycho-social well-being than controls. In India, physical punishment was correlated with poor psycho-social well-being of CDWs [OR: 3.6; 95% CI: 3.2-4; p < 0.0001]. Across the studies, between 7% and 68% of CDWs reported work-related illness and injuries, and one third to half had received no medical treatment. On average, children worked between 9 and 15 h per day with no rest days. Findings highlight that many CDWs are exposed to abuse and other health hazards but that conditions vary substantially by context. Because of the often-hidden nature of child domestic work, future initiatives will need to be specifically designed to reach children in private households. Young workers will also benefit from strategies to change social norms around the value and vulnerability of children in domestic work and the long-term implications of harm during childhood.

Mental health of adolescents in Myanmar: A systematic review of prevalence, determinants and interventions.

Adolescence is a developmental phase where mental disorders typically manifest and where platforms for response (including schools and health services) change rapidly. However, data to inform public mental health responses are limited, including in countries like Myanmar which has a large adolescent population and where mental health has been identified as a priority of policy. In this paper we sought to systematically review the peer-reviewed and grey literature to determine (i) the prevalence of mental disorder among adolescents in Myanmar, (ii) determinants of mental disorder and (iii) interventions that have been implemented and evaluated. Nine publications met inclusion criteria (7 peer-reviewed and 2 grey literature) that included 7 publications reporting prevalence, 6 reporting correlates and one an intervention. The available data from the 2016 Global School-based Health Survey highlight that depression (27.2%) and suicidal ideation (9.4%) are prevalent in Myanmar, and these rates are substantially higher than regional averages. The limited available data on correlates identified violence and bullying, alcohol and substance use, and home, family and community security and cohesion as being closely related to mental health for adolescents. Only one study focussed on interventions and this found mindfulness meditation training to be an effective approach for young people whose parents were affected by HIV. These findings underscore the need to address adolescent mental health in Myanmar, but also to invest in better data collection efforts.

Adverse Childhood Experiences and Prevalence of Cigarette and E-Cigarette Use Among Adolescents in Bangkok, Thailand.

Currently, e-cigarettes are the most popular tobacco product among adolescents. The purpose of this study was to explore the relationship between exposure to adverse childhood experiences (ACEs) and use of cigarettes, e-cigarettes, and dual use in a sample of adolescents in Bangkok, Thailand. The sample comprises 6167 students from 48 schools (grades 9, 11, and vocational year 2) who participated in the 2019 round of the Behavior Surveillance Survey. History of 11 ACEs was used to calculate a cumulative ACE score (range 0-11). Multinomial logistic regression was used to assess the relationship between history of ACEs and smoking. In the sample, 7.0% reported using e-cigarettes only and 9.5% used e-cigarettes and cigarettes (dual use). After controlling for sociodemographic characteristics, history of ACEs was associated with increased odds of dual use. The odds of cigarette, e-cigarette, and dual use was significantly greater if the adolescent had a history of ≥4 ACEs. Special attention is needed to prevent smoking of different types among those with a history of ACEs.

Utilisation and Determinants of Epidermal Growth Factor Receptor Mutation Testing in Patients with Non-small Cell Lung Cancer in Routine Clinical Practice: A Global Systematic Review.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation testing is recommended for selecting patients with non-squamous non-small cell lung cancer (NSCLC) for EGFR tyrosine kinase inhibitor drug treatment. OBJECTIVE: The objective of this article was to systematically review available evidence on the utilisation and determinants of EGFR mutation testing of patients with NSCLC in routine clinical practice. PATIENTS AND METHODS: Searches were made of five electronic databases (Web of Science, MEDLINE [Ovid], Science Direct, EMBASE and Scopus), bibliographies of relevant articles, studies that cited included studies and relevant cancer websites. Studies were included if they: (1) reported the rate of uptake of EGFR testing in patients with NSCLC; (2) were conducted in routine clinical practice settings; (3) were published in English prior to July 2017; and (4) had full text available. Studies were appraised using the STROBE and the National Institutes of Health (National Heart, Lung and Blood Institute) checklists. RESULTS: Eighteen eligible studies were identified for this systematic review, published between 2011 and 2017, from the USA (n = 7), Canada (n = 2), Republic of Korea (n = 2), Norway (n = 1), Sweden (n = 1), Germany (n = 1), Spain (n = 1), New Zealand (n = 1), China (n = 1) and multiple countries from the Asia-Pacific region (n = 1). Overall, testing for EGFR mutations was undertaken in 16,146 of 52,257 study patients (31%), although testing rates varied widely between different studies (from 7.8% to 78.3%). Single institution retrospective audits reported higher rates of testing (median 65.7%, range 31.3-78.3%) than population-based retrospective cohort analyses (median 23%, range 11-69%) and multi-institutional cross-sectional practitioner surveys (median 19.8%, range 7.8-31.8%). Nine studies reported increasing rates of testing over the study period but maximum testing rates remained less than 75% in most studies. Factors associated with higher testing uptake rates included: female sex; younger age; former/no smoking; advanced stage of lung cancer; adenocarcinoma histology; better mobility; radiation therapy; available tissue specimen; and private insurance. Among 16,146 tested patients, EGFR mutations were detected in 4328 patients (26.8%). However, estimates of mutation prevalence were biased by incomplete and selective testing in many studies. CONCLUSIONS: The uptake of EGFR mutation testing of patients with NSCLC is suboptimal in many parts of the world. Incomplete uptake of testing is fuelled by selective testing referral practices, sample limitations, and funding constraints.