Improving psychosocial distress for young adolescents in rural schools of Pakistan: study protocol of a cluster randomised controlled trial.

INTRODUCTION: Emotional problems are leading contributors to health burden among adolescents worldwide. There is an urgent need for evidence-based psychological interventions for young people. This study aims to evaluate the effectiveness of a school-based, group psychological intervention, Early Adolescent Skills for Emotions (EASE) developed by the WHO to improve psychosocial distress in Pakistani adolescents. METHOD AND ANALYSIS: A two-arm, single-blinded, cluster randomised controlled trial, with a wait-list control arm is being conducted in school settings of rural Pakistan. Forty eligible public-school clusters have been randomised (stratified by gender) on a 1:1 allocation ratio into intervention (n=20) and control arm (n=20). Following informed consent, 564 adolescents with psychosocial distress (Youth-reported Paediatric Symptoms Checklist, cut-off ≥28) from 40 schools have been enrolled into the trial (14±3 average cluster size) between 2 November 2021 and 30th November 2021. Participants in the intervention arm will receive EASE in 7-weekly adolescents and 3-biweekly caregivers group sessions in schools. The adolescent sessions involve the components of psychoeducation, stress management, behavioural activation, problem-solving and relapse prevention. Caregivers will receive training to learn and implement active listening; spending quality time and using praise as a strategy to help their children. The primary outcome is reduction in psychosocial distress at 3 months postintervention. Secondary outcomes include symptoms of depression and anxiety, caregiver-adolescent relationship and caregivers' well-being. Outcomes will be assessed at baseline, immediate 1 week and 3-months postintervention. Qualitative process evaluation will explore barriers and facilitators to programme implementation in low-resource school settings. ETHICS: Ethics approval has been obtained from Central Ethics Committee of University of Liverpool, UK, Ethics Review Committee of WHO Geneva and from the Institutional Review Board of Human Development Research Foundation (HDRF), Pakistan. DISSEMINATION: The findings of the study will be disseminated by WHO and through peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN17755448.

Feasibility and acceptability of a multicomponent, group psychological intervention for adolescents with psychosocial distress in public schools of Pakistan: a feasibility cluster randomized controlled trial (cRCT).

BACKGROUND: Child and adolescent mental health problems are a global public mental health priority. However, there is a lack of evidence-based scalable psychological interventions for adolescents living in low resource settings. This trial was designed to evaluate the feasibility and acceptability of delivering the World Health Organization's Early Adolescent Skills for Emotions (EASE) intervention at public schools in a rural sub-district in Rawalpindi, Pakistan. METHODS: A two arm, single blinded, feasibility cluster randomized controlled trial with mixed-methods evaluation was conducted with 59 adolescents and their caregivers from 8 public schools. In the 4 intervention arm schools, 6 non-specialist facilitators delivered the culturally-adapted EASE group sessions to the adolescents (n = 29) and their caregivers with desired fidelity under the supervision of in-country supervisors. RESULTS: The participation rate of adolescents in the intervention sessions was 83%. The intervention strategies were implemented by the adolescents. However, attending biweekly sessions at schools was challenging for caregivers with only 50% caregivers attending the sessions. CONCLUSIONS: The results of this study support the feasibility and acceptability of delivering this culturally adapted intervention through non-specialist facilitators in school settings in Pakistan and pave the way to conduct a fully powered cluster randomized controlled trial to test the effectiveness of intervention to improve psychological outcomes in adolescents. Trial registration Trial registered with Clinicaltrials.gov prospectively; NCT04254393.

Effectiveness of relaxation techniques 'as an active ingredient of psychological interventions' to reduce distress, anxiety and depression in adolescents: a systematic review and meta-analysis.

BACKGROUND: Adolescent depression and anxiety are among the leading contributors to health burden worldwide. 'Relaxation Techniques (RTs)' are a "set of strategies to improve physiological response to stress" and are frequently cited as an active ingredient of trans-diagnostic, psychosocial interventions for scaling-up care for preventing and treating these conditions in adolescents. However, there is a little evidence on the effectiveness of 'relaxation techniques' for this age group. AIM: As a part of the Wellcome Trust's Active Ingredients commission, we did a systematic review and meta-analysis to evaluate the effectiveness of RTs to reduce the symptoms of distress, anxiety and depression in young people, aged 14 to 24 years old, globally. METHODS: We searched 10 academic databases to include 65 Randomized Controlled Trials (RCTs) of relaxation-based interventions for young people with the symptoms of anxiety and depression. Primary outcomes were reduction in symptoms of distress, anxiety and/or depression. We employed the Cochrane risk of bias tool and GRADE (Grading of Recommendations, Assessment, Development and Evaluations) guidelines to assess certainty of outcomes pertaining to anxiety, depression and distress. Standardized mean difference was estimated using effect size. RESULTS: The analysis of 65 RCTs with 8009 young people showed that RTs were highly effective in treating anxiety (pooled effect size of (Standardized Mean Difference-SMD) - 0.54 (95% CI - 0.69 to - 0.40); moderately effective in reducing distress (SMD = - 0.48, 95% CI - 0.71 to - 0.24) and had only a weak effect on improving depression in young people (SMD = - 0.28 (95% CI - 0.40% to - 0.15). Face-to-face delivered relaxation techniques yielded higher effect size (SMD = - 0.47, 95% CI - 0.64 to - 0.30) compared to online delivery (SMD = - 0.22, 95% CI - 0.48 to 0.04) for anxiety. CONCLUSION: Most of the included studies were from High Income Countries (HICs) and had a high risk of bias. Further high-quality studies with low risk of bias, especially from low resource settings are needed to evaluate the evidence for effectiveness of RTs as an active ingredient of psychological interventions to reduce the symptoms of distress, anxiety and depression in young people.

Effectiveness of a technology-assisted, family volunteers delivered, brief, multicomponent parents' skills training intervention for children with developmental disorders in rural Pakistan: a cluster randomized controlled trial.

BACKGROUND: Globally, there is a large documented gap between needs of families and children with developmental disorders and available services. We adapted the World Health Organization's mental health Gap-Intervention Guidelines (mhGAP-IG) developmental disorders module into a tablet-based android application to train caregivers of children with developmental disorders. We aimed to evaluate the effectiveness of this technology-assisted, family volunteers delivered, parents' skills training intervention to improve functioning in children with developmental disorders in a rural community of Rawalpindi, Pakistan. METHODS: In a single-blinded, cluster randomized controlled trial, 30 clusters were randomised (1:1 ratio) to intervention (n = 15) or enhanced treatment as usual (ETAU) arm (n = 15). After screening, 540 children (18 participants per cluster) aged 2-12 years, with developmental disorders and their primary caregivers were recruited into the trial. Primary outcome was child's functioning, measured by Childhood Disability Assessment Schedule for Developmental Disorders (DD-CDAS) at 6-months post-intervention. Secondary outcomes were parents' health related quality of life, caregiver-child joint engagement, socio-emotional well-being of children, family empowerment and stigmatizing experiences. Intention-to-treat analyses were done using mixed-models adjusted for covariates and clusters. RESULTS: At 6-months post-intervention, no statistically significant mean difference was observed on DD-CDAS between intervention and ETAU (mean [SD], 47.65 [26.94] vs. 48.72 [28.37], Adjusted Mean Difference (AMD), - 2.63; 95% CI - 6.50 to 1.24). However, parents in the intervention arm, compared to ETAU reported improved health related quality of life (mean [SD] 65.56 [23.25] vs. 62.17 [22.63], AMD 5.28; 95% CI 0.44 to 10.11). The results were non-significant for other secondary outcomes. CONCLUSIONS: In the relatively short intervention period of 6 months, no improvement in child functioning was observed; but, there were significant improvements in caregivers' health related quality of life. Further trials with a longer follow-up are recommended to evaluate the impact of intervention. Trial registration Clinicaltrials.gov, NCT02792894. Registered April 4, 2016, https://clinicaltrials.gov/ct2/show/NCT02792894.

Scaling-up school mental health services in low resource public schools of rural Pakistan: the Theory of Change (ToC) approach.

BACKGROUND: Ninety percent of children with mental health problems live in low or middle-income countries (LMICs). School-based programs offer opportunities for early identification and intervention, however implementation requires cross-sector collaboration to assure sustainable delivery of quality training, ongoing supervision, and outcomes monitoring at scale. In Pakistan, 35% of school-aged children are reported to have emotional and behavioral problems. As in many other LMICs, the government agencies who must work together to mount school-based programs have limited resources and a limited history of collaboration. The "Theory of Change" (ToC) process offers a way for new partners to efficiently develop mutual goals and long-term prospects for sustainable collaboration. OBJECTIVE: Develop a model for scale-up of school based mental health services in public schools of Pakistan. METHODS: We used ToC workshops to develop an empirically supported, 'hypothesized pathway' for the implementation of WHO's School Mental Health Program in the public schools of rural Pakistan. Three workshops included 90 stakeholders such as policy makers from education and health departments, mental health specialists, researchers, head teachers, teachers and other community stakeholders including non-governmental organizations. RESULTS: The ToC process linked implementers, organizations, providers and consumers of school mental health services to develop common goals and relate them (improved child socioemotional wellbeing, grades and participation in activities) to interventions (training, monitoring and supervision of teachers; collaboration with parents, teachers and primary health care facilities and schools). Key testable assumptions developed in the process included buy-in from health care providers, education officials and professionals, community-based organizations and families. For example, teachers needed skills for managing children's problems, but their motivation might come from seeking improved school performance and working conditions. Poverty, stigma and lack of child mental health literacy among teachers, administration, and parents were identified as key hypothesized barriers. Children and their families were identified as key stakeholders to make such a program successful. DISCUSSION: ToC workshops assisted in team building and served as a stakeholders' engagement tool. They helped to develop and support testable hypotheses about the structures, collaborations, and knowledge most important to scaling-up school based mental health services in Pakistan.

An immunostaining panel of C-reactive protein, N-cadherin, and S100 calcium binding protein P is useful for intrahepatic cholangiocarcinoma subtyping.

This study aimed to establish an immunohistochemical panel useful for subclassification of intrahepatic cholangiocarcinoma (iCCA) into small- and large-duct types. Fifty surgical cases of iCCA consisting of small- (n = 31) and large-duct types (n = 19) were examined. To imitate liver needle biopsies, tissue microarrays were constructed using three tissue cores (2 mm in diameter) obtained from one representative paraffin block of each case. Immunostaining for C-reactive protein (CRP), N-cadherin, tubulin beta-III (TUBB3), neural cell adhesion molecule (NCAM), and S100 calcium binding protein P (S100P) was conducted. Most cases of small-duct iCCA were immunoreactive to CRP and N-cadherin, whereas expressions of these markers were markedly less common in large-duct iCCA (CRP, 97% vs. 5%, P < 0.001; N-cadherin, 87% vs. 16%, P < 0.001). TUBB3 and NCAM were also more frequently expressed in small-duct iCCA (65% vs. 32%, P = 0.006; 58% vs. 5%, P < 0.001), but their sensitivities were lower than those of CRP and N-cadherin. S100P was more commonly expressed in large-duct iCCA than in small-duct iCCA (95% vs. 29%, P < 0.001), and diffuse expressions were observed in 17 of 19 cases of large-duct iCCA (90%). All cases with a CRP+/S100P- immunophenotype were of small-duct type, whereas all but one case with a CRP-/S100P+ immunophenotype were of large-duct type. Of 10 cases with a double-positive or double-negative immunophenotype, 7 were appropriately classified based on immunoreactivity to N-cadherin. In conclusion, CRP, N-cadherin, and S100P form a useful immunohistochemical panel for iCCA subclassification, and correct subclassification was possible in 92% of cases based on a proposed, simple algorithm.

Technology-Assisted Teachers' Training to Promote Socioemotional Well-Being of Children in Public Schools in Rural Pakistan.

BACKGROUND: The World Health Organization's (WHO) Eastern Mediterranean Regional Office (EMRO) developed a school mental health program (SMHP) to help reduce the burden of youth mental health problems. Designed in collaboration with international consultants, the SMHP draws on evidence-based interventions to train personnel to identify students in need, respond therapeutically, and engage families in seeking care. METHODS: Teams from Pakistan, Egypt, Iran, and Jordan collaborated with the WHO EMRO and British and U.S. universities to form the School Health Implementation Network: Eastern Mediterranean Region (SHINE), a National Institute of Mental Health-funded global mental health hub. SHINE partners used a "theory of change" process to adapt the SMHP to be more readily adopted by school personnel and replicated with fidelity. The adapted SMHP more directly addresses teachers' priorities and uses technology to facilitate training. RESULTS: A cluster-randomized implementation effectiveness trial enrolling 960 children ages 8-13 in 80 Pakistani schools will test the adapted SMHP against the original. Children who screen positive on first the teacher and subsequently the parent Strengths and Difficulties Questionnaires (SDQs) will be enrolled and tracked for 9 months. The primary trial outcome is reduction in parent-rated SDQ total difficulties scores. Secondary outcomes include children's well-being, academic performance, absenteeism, and perceived stigma; parent-teacher interaction; teachers' self-efficacy and subjective well-being; and school environment. Implementation outcomes include change in teachers' behavior and sense of program acceptability, cultural appropriateness, feasibility, penetration, and sustainability. NEXT STEPS: The trial began in October 2019, and the expected completion date is March 2021. Outcomes will inform dissemination of the SMHP in Pakistan and elsewhere.

Measuring the implementation strength of a perinatal mental health intervention delivered by peer volunteers in rural Pakistan.

The South Asian region, including Pakistan, reports one of the highest rates of perinatal depression. Effective task-shifting perinatal mental health interventions exist and are gaining attention of policy makers, as a potential solution to bridge the existing treatment gap. However, no specific indicators are available to gauge the level of implementation for such interventions in the South Asian region. The Thinking Healthy Programme Peer-delivered (THPP) is a perinatal mental health intervention delivered, at scale, by peer volunteers (PVs). An effectiveness trial for THPP based on 570 depressed pregnant women was conducted in rural Rawalpindi, Pakistan. In addition, we also examined the implementation processes of THPP in order to develop an index to gauge implementation strength of this intervention. The key components of this index are based on four important intervention processes related to service provision which include; i) the competence of PVs, ii) supervisions attended by PVs and iii) number and iv) duration of THPP sessions. We attempt to inform an implementation strength index which best correlates with reduced perinatal depression and disability at 6 months post childbirth. Knowledge of such an implementation strength index for a task-shifted perinatal depression intervention carries implications for scale up strategies.

Implementation and effectiveness of adolescent life skills programs in low- and middle-income countries: A critical review and meta-analysis.

BACKGROUND: Adolescence represents an unprecedented opportunity to invest in health. Individual adolescent life skills programs in low- and middle-income countries (LMICs) have demonstrated success but neither their relative effectiveness across multiple health arenas, including mental health, nor their key ingredients have been examined. METHODS: We conducted a systematic review and meta-analysis to identify key implementation processes and effectiveness of life skills programs among adolescents in LMICs which targeted at least one mental health outcome, as well as their relative effectiveness. Six academic databases, including PubMed and PsychInfo and bibliographies of related reviews, were systematically searched until July 1, 2016, with no restrictions on language or publication year. Studies were excluded if they were conducted in HIC settings, among chronically ill populations or lacking adolescents aged 10-19 years. Data from published reports related to the characteristics of RCTs and their implementation processes related to 'who, what, how and where' were extracted, including the development of a taxonomy to determine which life skills constituted each program. Meta-analyses with random effects models examined the overall trial effectiveness, as determined by their primary outcomes. Subsequent exploratory analyses determined which implementation processes predicted trial effectiveness (PROSPERO CRD42016043448). RESULTS: We included 50 eligible RCTs from 45 articles with a focus on an adolescent health program, which targeted at least one or more mental health outcomes. Most of the RCTs, conducted across 19 LMICs, targeted students (82%) and refugees (7%), and both genders (71%). Most of the interventions were delivered by teachers (n = 12), and specialist providers (n = 11), and most were focused on high-risk groups rather than clinically-disordered populations. These interventions were effective in reducing symptoms of anger (SMD = 1.234), improving life skills (SMD = 0.755) and functioning (SMD = 0.491), and decreasing PTSD (SMD = 0.327), depression and anxiety (SMD = 0.305). Trial effectiveness was positively associated with the following life skills: interventions focused on parent-child interactions (ß = 0.557, p < 0.05), assessing interpersonal relations (ß = 0.204, p < 0.05) and stress management (ß = 0.216, p < 0.05). DISCUSSION: Our results demonstrate the benefits of life skills programs targeting one or more mental health outcomes and co-occurring risk factors in school and community settings. Comprehensive programs focusing on multiple life skills related to the individual, his or her social environment and, in particular, interventions promoting parent-child interactions may hold particular promise in LMICs to address the burden of poor mental health and other health arenas.

A Validation Study for the Use of ROS1 Immunohistochemical Staining in Screening for ROS1 Translocations in Lung Cancer.

INTRODUCTION: The presence of ROS proto-oncogene 1, receptor tyrosine kinase gene (ROS1) rearrangements in lung cancers confers sensitivity to ROS kinase inhibitors, including crizotinib. However, they are rare abnormalities (in ∼1% of non-small cell lung carcinomas) that are typically identified by fluorescence in situ hybridization (FISH), and so screening using immunohistochemical (IHC) staining would be both cost- and time-efficient. METHODS: A cohort of lung tumors negative for other common mutations related to targeted therapies were screened to assess the sensitivity and specificity of IHC staining in detecting ROS1 gene rearrangements, enriched by four other cases first identified by FISH. A review of published data was also undertaken. RESULTS: IHC staining was 100% sensitive (95% confidence interval: 48-100) and 83% specific (95% confidence interval: 86-100) overall when an h-score higher than 100 was used. Patients with ROS1 gene rearrangements were younger and typically never-smokers, with the tumors all being adenocarcinomas with higher-grade architectural features and focal signet ring morphologic features (two of five). Four patients treated with crizotinib showed a partial response, with three also showing a partial response to pemetrexed. Three of four patients remain alive at 13, 27, and 31 months, respectively. CONCLUSION: IHC staining can be used to screen for ROS1 gene rearrangements, with patients herein showing a response to crizotinib. Patients with tumors that test positive according to IHC staining but negative according to FISH were also identified, which may have implications for treatment selection.

In Silico Characterization of the Binding Affinity of Dendrimers to Penicillin-Binding Proteins (PBPs): Can PBPs be Potential Targets for Antibacterial Dendrimers?

We have shown that novel silver salts of poly (propyl ether) imine (PETIM) dendron and dendrimers developed in our group exhibit preferential antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus. This led us to examine whether molecular modeling methods could be used to identify the key structural design principles for a bioactive lead molecule, explore the mechanism of binding with biological targets, and explain their preferential antibacterial activity. The current article reports the conformational landscape as well as mechanism of binding of generation 1 PETIM dendron and dendrimers to penicillin-binding proteins (PBPs) in order to understand the antibacterial activity profiles of their silver salts. Molecular dynamics at different simulation protocols and conformational analysis were performed to elaborate on the conformational features of the studied dendrimers, as well as to create the initial structure for further binding studies. The results showed that for all compounds, there were no significant conformational changes due to variation in simulation conditions. Molecular docking calculations were performed to investigate the binding theme between the studied dendrimers and PBPs. Interestingly, in significant accordance with the experimental data, dendron and dendrimer with aliphatic cores were found to show higher activity against S. aureus than the dendrimer with an aromatic core. The latter showed higher activity against MRSA. The findings from this computational and molecular modeling report together with the experimental results serve as a road map toward designing more potent antibacterial dendrimers against resistant bacterial strains.

Is home delivery really preferred? a mixed-methods national study in Pakistan.

BACKGROUND: Pakistan has a high maternal mortality ratio and a low rate of skilled birth attendants (SBAs). To address these two important issues, the Pakistan Maternal Newborn and Child Health (MNCH) programme launched the community midwives (CMW) initiative in 2007. CMWs are supposed to conduct deliveries at community level outside health facilities. The purpose of the current study is to document perceptions about CMWs and preferences for birthing place. METHODS: A mixed-methods study was conducted covering four provinces. For the quantitative survey, households were selected through a multistage sampling technique from rural districts. In 1,450 rural households, preferences of respondents about CMW-conducted deliveries were recorded. Qualitative data were obtained through focus group discussions (FGDs) and in-depth interviews (IDIs) with women, community elders, CMWs, and MNCH programme personnel in the same areas where the quantitative study was carried out. In both studies, preferences and the reasons behind particular respondent preferences were recorded. Frequencies of responses were analysed for the quantitative study. Narration and quotes from various types of participants were used to present findings from FGDs and IDIs. RESULTS: In the quantitative study, 42% of respondents expressed a preference for birthing stations, i.e. a place where CMWs conduct deliveries; 22% preferred home deliveries. Birthing stations were favoured because of the availability of space and equipment and the proximity to women's homes. These findings were largely supported by the qualitative component, although a range of views about where a CMW should conduct deliveries were expressed. CONCLUSION: Insights into where CMWs might provide delivery services were obtained through this study. Birthing stations may be an option as a preferred location for delivery care and should be considered as part of Pakistan's national CMW programme.

Nanoengineered drug delivery systems for enhancing antibiotic therapy.

Formulation scientists are recognizing nanoengineered drug delivery systems as an effective strategy to overcome limitations associated with antibiotic drug therapy. Antibiotics encapsulated into nanodelivery systems will contribute to improved management of patients with various infectious diseases and to overcoming the serious global burden of antibiotic resistance. An extensive review of several antibiotic-loaded nanocarriers that have been formulated to target drugs to infectious sites, achieve controlled drug release profiles, and address formulation challenges, such as low-drug entrapment efficiencies, poor solubility and stability is presented in this paper. The physicochemical properties and the in vitro/in vivo performances of various antibiotic-loaded delivery systems, such as polymeric nanoparticles, micelles, dendrimers, liposomes, solid lipid nanoparticles, lipid-polymer hybrid nanoparticles, nanohybirds, nanofibers/scaffolds, nanosheets, nanoplexes, and nanotubes/horn/rods and nanoemulsions, are highlighted and evaluated. Future studies that will be essential to optimize formulation and commercialization of these antibiotic-loaded nanosystems are also identified. The review presented emphasizes the significant formulation progress achieved and potential that novel nanoengineered antibiotic drug delivery systems have for enhancing the treatment of patients with a range of infections.