Methodology for adapting a co-created early childhood development intervention and implementation strategies for use by frontline workers in India and Guatemala: a systematic application of the FRAME-IS framework.

There is little evidence on optimizing the effectiveness and implementation of evidence-based early childhood development (ECD) interventions when task-shifted to frontline workers. In this Methods Forum paper, we describe our adaptation of the International Guide for Monitoring Child Development (GMCD) for task-shifting to frontline workers in Guatemala and India. In 2021-2022, implementers, trainers, frontline workers, caregivers, and international GMCD experts collaborated to adapt the GMCD for a task shifted implementation by frontline workers. We used an eight-step co-creating process: assembling a multidisciplinary team, training on the existing package, working groups to begin modifications, revision of draft modifications, tailoring of visual materials and language, train-the-trainers activities, pilot frontline worker trainings, final review and feedback. Preliminary effectiveness of adaptations was evaluated through narrative notes and group-based qualitative feedback following pilot trainings with 16 frontline workers in India and 6 in Guatemala. Final adaptations included: refining training techniques to match skill levels and learning styles of frontline workers; tailoring all visual materials to local languages and contexts; design of job aids for providing developmental support messages; modification of referral and triage processes for children in need of enhanced support and speciality referral; and creation of post-training support procedures. Feedback from pilot trainings included: (1) group consensus that training improved ECD skills and knowledge across multiple domains; and (2) feedback on ongoing needed adjustments to pacing, use of video-based vs. role-playing materials, and time allocated to small group work. We use the Framework for Reporting Adaptations and Modifications to Evidence-based Implementation Strategies (FRAME-IS) framework to document our adaptations. The co-creating approach we use, as well as systematic documentation of adaptation decisions will be of use to other community-based early childhood interventions and implementation strategies.

Main findings: The International Guide for Monitoring Child Development, an early childhood development support and monitoring tool, was successfully adapted for use by frontline workers in rural India and Guatemala.Added knowledge: Our Methods Forum paper uses a detailed framework to document the collaborative, co-creating process used and the adaptive decisions taken.Global health impact for policy and action: Evidence on how best to adapt and optimize early childhood interventions for frontline workers will be useful or scaling up support for children globally.

Consensus Statement of the IAP - Neurodevelopmental Chapter On Neurodevelopmental Disorders Habilitation Process: Strategic Plan for Prevention, Early Detection and Early Intervention.

JUSTIFICATION: Neurodevelopmental disorders, as per DSM-V, are described as a group of conditions with onset in the development period of childhood. There is a need to distinguish the process of habilitation and rehabilitation, especially in a developing country like India, and define the roles of all stakeholders to reduce the burden of neurodevelopmental disorders. PROCESS: Subject experts and members of Indian Academy of Pediatrics (IAP) Chapter of Neurodevelopmental Pediatrics, who reviewed the literature on the topic, developed key questions and prepared the first draft on guidelines. The guidelines were then discussed by the whole group through online meetings, and the contentious issues were discussed until a general consensus was arrived at. Following this, the final guidelines were drafted by the writing group and approved by all contributors. OBJECTIVES: These guidelines aim to provide practical clinical guidelines for pediatricians on the prevention, early diagnosis and management of neurodevelopmental disorders (NDDs) in the Indian settings. It also defines the roles of developmental pediatricians and development nurse counselor. STATEMENT: There is a need for nationwide studies with representative sampling on epidemiology of babies with early NDD in the first 1000 days in India. Specific learning disability (SLD) has been documented as the most common NDD after 6 years in India, and special efforts should be made to establish the epidemiology of infants and toddlers at risk for SLD, where ever measures are available. Preconception counseling as part of focusing on first 1000 days; Promoting efforts to organize systematic training programs in Newborn Resuscitation Program (NRP); Lactation management; Developmental follow-up and Early stimulation for SNCU/ NICU graduates; Risk stratification of NICU graduates, Newborn Screening; Counseling parents; Screening for developmental delay by trained professionals using simple validated Indian screening tools at 4, 8, 12, 18 and 24 months; Holistic assessment of 10 NDDs at child developmental clinics (CDCs) / district early intervention centre (DEICs) by multidisciplinary team members; Confirmation of diagnosis by developmental pediatrician/developmental neurologist/child psychiatrist using clinical/diagnostic tools; Providing parent guided low intensity multimodal therapies before 3 years age as a center-based or home-based or community-based rehabilitation; Developmental pediatrician to seek guidance of pediatric neurologist, geneticist, child psychiatrist, physiatrist, and other specialists, when necessary; and Need to promote ongoing academic programs in clinical child development for capacity building of community based therapies, are the chief recommendations.

Activating Inducible T-cell Costimulator Yields Antitumor Activity Alone and in Combination with Anti-PD-1 Checkpoint Blockade.

In recent years, there has been considerable interest in mAb-based induction of costimulatory receptor signaling as an approach to combat cancer. However, promising nonclinical data have yet to translate to a meaningful clinical benefit. Inducible T-cell costimulator (ICOS) is a costimulatory receptor important for immune responses. Using a novel clinical-stage anti-ICOS immunoglobulin G4 mAb (feladilimab), which induces but does not deplete ICOS+ T cells and their rodent analogs, we provide an end-to-end evaluation of the antitumor potential of antibody-mediated ICOS costimulation alone and in combination with programmed cell death protein 1 (PD-1) blockade. We demonstrate, consistently, that ICOS is expressed in a range of cancers, and its induction can stimulate growth of antitumor reactive T cells. Furthermore, feladilimab, alone and with a PD-1 inhibitor, induced antitumor activity in mouse and humanized tumor models. In addition to nonclinical evaluation, we present three patient case studies from a first-time-in-human, phase I, open-label, dose-escalation and dose-expansion clinical trial (INDUCE-1; ClinicalTrials.gov: NCT02723955), evaluating feladilimab alone and in combination with pembrolizumab in patients with advanced solid tumors. Preliminary data showing clinical benefit in patients with cancer treated with feladilimab alone or in combination with pembrolizumab was reported previously; with example cases described here. Additional work is needed to further validate the translation to the clinic, which includes identifying select patient populations that will benefit from this therapeutic approach, and randomized data with survival endpoints to illustrate its potential, similar to that shown with CTLA-4 and PD-1 blocking antibodies. Significance: Stimulation of the T-cell activation marker ICOS with the anti-ICOS agonist mAb feladilimab, alone and in combination with PD-1 inhibition, induces antitumor activity across nonclinical models as well as select patients with advanced solid tumors.

Diagnosis and Management of Global Development Delay: Consensus Guidelines of Growth, Development and Behavioral Pediatrics Chapter, Neurology Chapter and Neurodevelopment Pediatrics Chapter of the Indian Academy of Pediatrics.

JUSTIFICATION: Global developmental delay (GDD) is a relatively common neurodevelopmental disorder; however, paucity of published literature and absence of uniform guidelines increases the complexity of clinical management of this condition. Hence, there is a need of practical guidelines for the pediatrician on the diagnosis and management of GDD, summarizing the available evidence, and filling in the gaps in existing knowledge and practices. PROCESS: Seven subcommittees of subject experts comprising of writing and expert group from among members of Indian Academy of Pediatrics (IAP) and its chapters of Neurology, Neurodevelopment Pediatrics and Growth Development and Behavioral Pediatrics were constituted, who reviewed literature, developed key questions and prepared the first draft on guidelines after multiple rounds of discussion. The guidelines were then discussed by the whole group in an online meeting. The points of contention were discussed and a general consensus was arrived at, after which final guidelines were drafted by the writing group and approved by all contributors. The guidelines were then approved by the Executive Board of IAP. Guidelines: GDD is defined as significant delay (at least 2 standard deviations below the mean with standardized developmental tests) in at least two developmental domains in children under 5 years of age; however, children whose delay can be explained primarily by motor issues or severe uncorrected visual/hearing impairment are excluded. Severity of GDD can be classified as mild, moderate, severe and profound on adaptive functioning. For all children, in addition to routine surveillance, developmental screening using standardized tools should be done at 9-12 months,18-24 months, and at school entry; whereas, for high risk infants, it should be done 6-monthly till 24 months and yearly till 5 years of age; in addition to once at school entry. All children, especially those diagnosed with GDD, should be screened for ASD at 18-24 months, and if screen negative, again at 3 years of age. It is recommended that investigations should always follow a careful history and examination to plan targeted testing and, vision and hearing screening should be done in all cases prior to standardized tests of development. Neuro-imaging, preferably magnetic resonance imaging of the brain, should be obtained when specific clinical indicators are present. Biochemical and metabolic investigations should be targeted towards identifying treatable conditions and genetic tests are recommended in presence of clinical suspicion of a genetic syndrome and/or in the absence of a clear etiology. Multidisciplinary intervention should be initiated soon after the delay is recognized even before a formal diagnosis is made, and early intervention for high risk infants should start in the nursery with developmentally supportive care. Detailed structured counselling of family regarding the diagnosis, etiology, comorbidities, investigations, management, prognosis and follow-up is recommended. Regular targeted follow-up should be done, preferably in consultation with a team of experts led by a developmental pediatrician/ pediatric neurologist.

Global Trends in Telehealth Among Clinicians in Developmental-Behavioral Pediatric Practice: A COVID-19 Snapshot.

OBJECTIVE: This study aims to describe the extent of telehealth use by global developmental-behavioral pediatrics (DBP) clinicians and barriers (if any) in adopting telehealth during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: A survey was disseminated to DBP clinicians through contact with international professional organizations to determine the use of telehealth in DBP care, before and since the beginning of the COVID-19 pandemic. Descriptive statistics and χ2 tests were used for analysis. RESULTS: A total of 271 respondents from 38 countries completed the survey. The number of respondents offering telehealth increased from 36% to 88% after the pandemic, with the greatest shift to telehealth among high-income countries (HICs). Among respondents using telehealth, 75.1% were conducting interactive video visits, with HICs using more telehealth modalities embedded in electronic health records. Most patients (98.7%) were at home for the telehealth encounter. Almost half (46.5%) could not include an interpreter in telehealth visits. Barriers reported by telehealth users included concerns about limited patient access to technology (74.3%), home environment distractions (56.5%), preference for in-person care (53.6%), telehealth effectiveness (48.1%), workflow efficiency (42.2%), and cost/reimbursement (32.1%). CONCLUSION: Global DBP clinicians rapidly adopted telehealth and continued to have interprofessional practice while doing so, with the largest adoption occurring in HICs. Provider concerns about effectiveness and patient access to technology emerged as key organizational and patient barriers, respectively. Increased provider confidence in telehealth and its sustained use in the future depends on supportive regulatory policies and availability and use of measures to monitor quality and effectiveness.

A guiding process to culturally adapt assessments for participation-focused pediatric practice: the case of the Participation and Environment Measures (PEM).

PURPOSE: There is unprecedented opportunity to evaluate children's participation in diverse cultural contexts, to enhance cross-cultural research, advance the delivery of culturally responsive pediatric rehabilitation, and translate new knowledge on a global scale. The participation concept is complex and heavily influenced by a child's context. Therefore, effectively capturing the participation concept requires valid, reliable, and culturally sensitive participation-focused measures. This perspective paper proposes a structured process for culturally adapting measures of participation for children and youth with disabilities. METHODS: Elements of the Applied Cultural Equivalence Framework and Beaton and colleagues' six-step process were used to create a guiding process for culturally adapting a Participation and Environment Measure (PEM) while drawing on two distinct cultural contexts. This process included forward and back language translations, and semi-structured cognitive interviews, to develop adapted versions of the PEM that are ready for psychometric validation. RESULTS: Common challenges to culturally adapting PEM content and administration are identified and methodological strategies to mitigate these challenges are proposed. CONCLUSIONS: The proposed process can guide rehabilitation specialists and researchers in adapting participation measures that are suitable for their culture. Such a process can facilitate scalable implementation of evidence-based tools to support participation-based practice in the rehabilitation field.Implications for RehabilitationThe use of a systematic process can harmonize efforts by rehabilitation researchers and service providers to effectively culturally adapt pediatric participation measures to optimize its impact for culturally sensitive research and practice targeting participation.Two distinct, yet complementary, illustrative exemplars showcase the range of considerations and strategies, such as by conducting consecutive rounds of cognitive interviews, when teams use this systematic process to cultural adapt a pediatric participation measure.The systematic process outlined in this paper promotes rigor in achieving all elements of cultural equivalency, when feasible, to best ensure that the participation measure is suitable for use in the target cultural context.

Adaptation of the Measure of Processes of Care for the Evaluation of Family-Centeredness of Services in India.

OBJECTIVE: This study aims to (1) adapt the Measure of Processes of Care (MPOC-20) for use in India and (2) evaluate family-centered services for children with disabilities and their caregivers in an urban Indian context. METHODS: In this cross-sectional observational study, we translated the MPOC-20 into Hindi. Caregivers of children diagnosed with developmental disabilities who read and/or understood Hindi and had received services for ≥6 months were recruited. The psychometric properties of the Hindi MPOC-20 were assessed using factor analysis followed by reliability analyses. The Hindi MPOC-20 was used to assess caregiver perceptions about the family-centeredness of services delivered between October 2016 and February 2017 at Ummeed Child Development Center. RESULTS: Of the 170 eligible children, 141 (83%) comprised the study sample. Most were boys (66%) with a median age of 67 months. Factor analyses yielded a 4-factor scale with items loading differently from the original measure. The resulting Hindi MPOC-20 had acceptable to good internal consistency (Cronbach's alpha of scales: 0.71-0.86). On the Hindi MPOC-20, Respectful and Coordinated Care, Enabling Partnership, and Providing Specific Information were identified as strengths and Providing General Information as a relative limitation of the service by caregivers across different income and education groups. CONCLUSION: The Hindi MPOC-20 shows acceptable psychometric properties for use with caregivers of children with disabilities in India. The availability of Hindi MPOC-20 paves the way for the assessment of the family-centeredness of services in India and provides a roadmap for adaptations in other low- and middle-income countries.

Providing Services for Children With Developmental Difficulties, Delay or Disability - Early Diagnosis and Interventions at the Community Level.

This paper describes two programs using the recommended tiered approach - World Health Organization's (WHO) Nurturing Care Framework (NCF), viz., Early Childhood Champions (ECC) program and Child Development Aide (CDA) program delivered by Ummeed Child Development Center, a non-governmental organization in Mumbai. The ECC program builds capacity in community health workers (CHWs) employed by community based organizations in urban, semi-urban and rural areas to deliver the responsive caregiving and early learning components of WHO-NCF framework to all children (universal services) and those with or at risk for disabilities (targeted and indicated services). The CDA program trains CHWs to become disability workers in communities where rehabilitation services are scarce or nonexistent. ECC and CDA programs integrate ECD services into the existing work of established CHWs in the communities and have preliminary evidence of reach, effectiveness and acceptability. Till date, the 145 CHWs trained by the ECC program have reached 7073 children, of whom 835 (7.4%) have been identified with developmental delays. The ECC program meets the well-recognized need for training packages on responsive caregiving and early learning components of WHO NCF framework.

Hybrid type 1 effectiveness/implementation trial of the international Guide for Monitoring Child Development: protocol for a cluster-randomised controlled trial.

Introduction: More than 40% of children under 5 years of age in low-income and middle-income countries are at risk of not reaching their developmental potential. The international Guide for Monitoring Child Development (GMCD) early intervention package is a comprehensive programme to address developmental difficulties using an individualised intervention plan for young children and their families. We will conduct a hybrid type 1 effectiveness-implementation evaluation of the GMCD intervention in rural India and Guatemala. Methods and analysis: Using a cluster-randomised design, 624 children aged 0-24 months in 52 clusters (26 in India, 26 in Guatemala) will be assigned to usual care or the GMCD intervention plus usual care delivered by frontline workers for 12 months. After 12 months, the usual care arm will cross over to the intervention, which will continue for 12 additional months (24 total). The intervention will be delivered using a digital mobile device interface. Effectiveness will be assessed for developmental functioning (Bayley Scales of Infant Development, 3rd edition) and nurturing care (Home Observation for Measurement of the Environment Scale) outcomes. Implementation will be assessed using the Reach, Effectiveness, Adoption, Implementation, Maintenance framework. Explanatory qualitative analysis guided by the Consolidated Framework for Implementation Research will explore determinants between clusters with high versus low implementation effectiveness. Ethics and dissemination: The study has been approved by the Institutional Review Boards of Brigham and Women's Hospital, Mahatma Gandhi Institute of Medical Sciences and Maya Health Alliance; and by the Indian Council of Medical Research/Health Ministry Screening Committee. Key study findings will be published in international open-access journals. Trial registration number: NCT04665297, CTRI/2020/12/029748. Protocol version: 1.0 (12 November 2020).

Belantamab Mafodotin (GSK2857916) Drives Immunogenic Cell Death and Immune-mediated Antitumor Responses In Vivo.

B-cell maturation antigen (BCMA) is an attractive therapeutic target highly expressed on differentiated plasma cells in multiple myeloma and other B-cell malignancies. GSK2857916 (belantamab mafodotin, BLENREP) is a BCMA-targeting antibody-drug conjugate approved for the treatment of relapsed/refractory multiple myeloma. We report that GSK2857916 induces immunogenic cell death in BCMA-expressing cancer cells and promotes dendritic cell activation in vitro and in vivo GSK2857916 treatment enhances intratumor immune cell infiltration and activation, delays tumor growth, and promotes durable complete regressions in immune-competent mice bearing EL4 lymphoma tumors expressing human BCMA (EL4-hBCMA). Responding mice are immune to rechallenge with EL4 parental and EL4-hBCMA cells, suggesting engagement of an adaptive immune response, immunologic memory, and tumor antigen spreading, which are abrogated upon depletion of endogenous CD8+ T cells. Combinations with OX40/OX86, an immune agonist antibody, significantly enhance antitumor activity and increase durable complete responses, providing a strong rationale for clinical evaluation of GSK2857916 combinations with immunotherapies targeting adaptive immune responses, including T-cell-directed checkpoint modulators.

International Interprofessional Collaborative Office Rounds (iiCOR): Addressing Children's Developmental, Behavioral, and Emotional Health Using Distance Technology.

Developmental, behavioral, and emotional issues are highly prevalent among children across the globe. Among children living in low- and middle-income countries, these conditions are leading contributors to the global burden of disease. A lack of skilled professionals limits developmental and mental health care services to affected children globally. Collaborative Office Rounds are interprofessional groups that meet regularly to discuss actual cases from the participants' practices using a non-hierarchical, peer-mentoring approach. In 2017, International Interprofessional Collaborative Office Rounds was launched with several goals: to improve the knowledge and skills of practicing child health professionals in high and low resourced settings regarding developmental and mental health care, to support trainees and clinicians in caring for these children, and to promote best practice in diagnosis and management of these conditions. Five nodes, each comprised of 3-4 different sites with an interprofessional team, from 8 countries in North America, Africa, Asia, and South America met monthly via videoconferencing. This report describes and evaluates the first 2 years' experience. Baseline surveys from participants (N = 141) found that 13 disciplines were represented. Qualitative analysis of 51 discussed cases, revealed that all cases were highly complex. More than half of the cases (N = 26) discussed children with autism or traits of autism and almost all (N = 49) had three or more themes discussed. Frequently occurring themes included social determinants of health (N = 31), psychiatric co-morbidity (N = 31), aggression and self-injury (N = 25), differences with the healthcare provider (N = 17), cultural variation in accepting diagnosis or treatment (N = 19), and guidance on gender and sexuality issues (N = 8). Participants generally sought recommendations on next steps in clinical care or management. A survey of participants after year 1 (N = 47) revealed that 87% (N = 41) had expectations that were completely or mostly met by the program. Our experience of regular meetings of interprofessional groups from different countries using distance-learning technology allowed participants to share on overlapping challenges, meet continuing educational needs while learning about different approaches in high- and low-resourced settings. International Interprofessional Collaborative Office Rounds may prove a useful strategy for increasing the work force capacity for addressing developmental, behavioral, and emotional conditions worldwide. More systematic studies are needed.

Cross-Cultural Adaptation and Evaluation of the Participation and Environment Measure for Children and Youth to the Indian Context-A Mixed-Methods Study.

Culturally appropriate measures enable knowledge transfer and quality improvement of rehabilitation services in diverse contexts. The Applied Cultural Equivalence Framework (ACEF) was used in a two-phased mixed methods study to adapt and evaluate the Participation and Environment Measure-Children and Youth (PEM-CY) in India. Cognitive interviews with caregivers of children with disabilities (n = 15) aged 5-17 years established conceptual, item, semantic, and operational equivalence of the Indian PEM-CY. Construct validity was assessed by comparing PEM-CY scores of children with and without disabilities (n = 130) using a case-control design. Cognitive interviews resulted in operational (60.3%), semantic (26.4%), and item-level (13.2%) modifications in the PEM-CY with no changes at the conceptual level. Internal consistency (n = 130) was acceptable to excellent (0.61-0.87) on most scales. Test-retest reliability (n = 30) was good to excellent (ICC ≥ 0.75, Kappa 0.6-1.0) for most scales. Significant differences in all PEM-CY summary scores were found between children with and without disabilities, except for environmental supports. Children with disabilities had lower scores on frequency and involvement in activities across all settings; their caregivers desired greater change in participation and reported experiencing more environmental barriers across settings. Findings suggest the adapted PEM-CY is a valid and reliable measure for assessing the participation of Indian children.

T Cell- and Monocyte-Specific RNA-Sequencing Analysis in Septic and Nonseptic Critically Ill Patients and in Patients with Cancer.

Sepsis is characterized as life-threatening organ dysfunction caused by a dysregulated host immune response to infection. The purpose of this investigation was to determine the differential effect of sepsis on innate versus adaptive immunity, in humans, by examining RNA expression in specific immune cell subsets, including monocytes/macrophages and CD4 and CD8 T cells. A second aim was to determine immunosuppressive mechanisms operative in sepsis that might be amenable to immunotherapy. Finally, we examined RNA expression in peripheral cells from critically ill nonseptic patients and from cancer patients to compare the unique immune response in these disorders with that occurring in sepsis. Monocytes, CD4 T cells, and CD8 T cells from septic patients, critically ill nonseptic patients, patients with metastatic colon cancer, and healthy controls were analyzed by RNA sequencing. Sepsis induced a marked phenotypic shift toward downregulation of multiple immune response pathways in monocytes suggesting that impaired innate immunity may be fundamental to the immunosuppression that characterizes the disorder. In the sepsis cohort, there was a much more pronounced effect on gene transcription in CD4 T cells than in CD8 T cells. Potential mediators of sepsis-induced immunosuppression included Arg-1, SOCS-1, and SOCS-3, which were highly upregulated in multiple cell types. Multiple negative costimulatory molecules, including TIGIT, Lag-3, PD-1, and CTLA-4, were also highly upregulated in sepsis. Although cancer had much more profound effects on gene transcription in CD8 T cells, common immunosuppressive mechanisms were present in all disorders, suggesting that immunoadjuvant therapies that are effective in one disease may also be efficacious in the others.

Anti-OX40 Antibody Directly Enhances The Function of Tumor-Reactive CD8+ T Cells and Synergizes with PI3Kß Inhibition in PTEN Loss Melanoma.

PURPOSE: OX40 agonist-based combinations are emerging as a novel avenue to improve the effectiveness of cancer immunotherapy. To better guide its clinical development, we characterized the role of the OX40 pathway in tumor-reactive immune cells. We also evaluated combining OX40 agonists with targeted therapy to combat resistance to cancer immunotherapy.Experimental Design: We utilized patient-derived tumor-infiltrating lymphocytes (TILs) and multiple preclinical models to determine the direct effect of anti-OX40 agonistic antibodies on tumor-reactive CD8+ T cells. We also evaluated the antitumor activity of an anti-OX40 antibody plus PI3Kß inhibition in a transgenic murine melanoma model (Braf mutant, PTEN null), which spontaneously develops immunotherapy-resistant melanomas. RESULTS: We observed elevated expression of OX40 in tumor-reactive CD8+ TILs upon encountering tumors; activation of OX40 signaling enhanced their cytotoxic function. OX40 agonist antibody improved the antitumor activity of CD8+ T cells and the generation of tumor-specific T-cell memory in vivo. Furthermore, combining anti-OX40 with GSK2636771, a PI3Kß-selective inhibitor, delayed tumor growth and extended the survival of mice with PTEN-null melanomas. This combination treatment did not increase the number of TILs, but it instead significantly enhanced proliferation of CD8+ TILs and elevated the serum levels of CCL4, CXCL10, and IFNγ, which are mainly produced by memory and/or effector T cells. CONCLUSIONS: These results highlight a critical role of OX40 activation in potentiating the effector function of tumor-reactive CD8+ T cells and suggest further evaluation of OX40 agonist-based combinations in patients with immune-resistant tumors.

Validation of the International Guide for Monitoring Child Development demonstrates good sensitivity and specificity in four diverse countries.

AIM: It is of critical importance to have internationally constructed tools to address early childhood development. The aim of this second phase of a two-phase study was to examine the sensitivity and specificity of the Guide for Monitoring Child Development (GMCD) in identifying developmental delay in four diverse countries. METHODS: The first phase of this 2011-2015 back-to-back study included 4949 children up to 42 months of age from primary healthcare centres in Argentina, India, South Africa and Turkey. Distribution curves were generated to show the ages when the children attained GMCD milestones and those that could be used across sexes and countries were placed in age ranges corresponding to the 85th and 97th percentile point estimates. Phase two examined a separately recruited sample of children in those countries to determine sensitivity and specificity of the GMCD. RESULTS: The validation phase of the 85 milestones in the GMCD identified delayed development in 30% of the 1731 children in the four countries. The sensitivity and specificity ranged from 0.71-0.94 and 0.69-0.82, respectively, for the total sample and the different age groups. CONCLUSION: The GMCD standardised in four diverse countries has appropriate accuracy for identification of children with developmental delay.

Tumor-immune profiling of murine syngeneic tumor models as a framework to guide mechanistic studies and predict therapy response in distinct tumor microenvironments.

Mouse syngeneic tumor models are widely used tools to demonstrate activity of novel anti-cancer immunotherapies. Despite their widespread use, a comprehensive view of their tumor-immune compositions and their relevance to human tumors has only begun to emerge. We propose each model possesses a unique tumor-immune infiltrate profile that can be probed with immunotherapies to inform on anti-tumor mechanisms and treatment strategies in human tumors with similar profiles. In support of this endeavor, we characterized the tumor microenvironment of four commonly used models and demonstrate they encompass a range of immunogenicities, from highly immune infiltrated RENCA tumors to poorly infiltrated B16F10 tumors. Tumor cell lines for each model exhibit different intrinsic factors in vitro that likely influence immune infiltration upon subcutaneous implantation. Similarly, solid tumors in vivo for each model are unique, each enriched in distinct features ranging from pathogen response elements to antigen presentation machinery. As RENCA tumors progress in size, all major T cell populations diminish while myeloid-derived suppressor cells become more enriched, possibly driving immune suppression and tumor progression. In CT26 tumors, CD8 T cells paradoxically increase in density yet are restrained as tumor volume increases. Finally, immunotherapy treatment across these different tumor-immune landscapes segregate into responders and non-responders based on features partially dependent on pre-existing immune infiltrates. Overall, these studies provide an important resource to enhance our translation of syngeneic models to human tumors. Future mechanistic studies paired with this resource will help identify responsive patient populations and improve strategies where immunotherapies are predicted to be ineffective.

Similarities and differences in child development from birth to age 3 years by sex and across four countries: a cross-sectional, observational study.

BACKGROUND: Knowledge about typical development is of fundamental importance for understanding and promoting child health and development. We aimed to ascertain when healthy children in four culturally and linguistically different countries attain developmental milestones and to identify similarities and differences across sexes and countries. METHODS: In this cross-sectional, observational study, we recruited children aged 0-42 months and their caregivers between March 3, 2011, and May 18, 2015, at 22 health clinics in Argentina, India, South Africa, and Turkey. We obtained a healthy subsample, which excluded children with a low birthweight, perinatal complications, chronic illness, undernutrition, or anaemia, and children with missing health data. Using the Guide for Monitoring Child Development, caregivers described their child's development in seven domains: expressive and receptive language, gross and fine motor, play, relating, and self-help. Clinicians examining the children also completed a checklist about the child's health status. We used logit and probit regression models based on the lowest deviance information criterion to generate Bayesian point estimates and 95% credible intervals for the 50th percentile ages of attainment of 106 milestones. We assessed the significance of differences between sexes and countries using predefined criteria and regions of practical equivalence. FINDINGS: Of 10 246 children recruited, 4949 children (48·3%) were included in the healthy subsample. For the 106 milestones assessed, the median age of attainment was equivalent for 102 (96%) milestones across sexes and 81 (76%) milestones across the four countries. Across countries, median ages of attainment were equivalent for all play milestones, 20 (77%) of 26 expressive language milestones, ten (67%) of 15 receptive language milestones, nine (82%) of 11 fine motor milestones, 14 (88%) of 16 gross motor milestones, and eight (73%) of 11 relating milestones. However, across the four countries the median age of attainment was equivalent for only two (22%) of nine milestones in the self-help domain. INTERPRETATION: The ages of attainment of developmental milestones in healthy children, and the similarities and differences across sexes and country samples might aid the development of international tools to guide policy, service delivery, and intervention research, particularly in low-income and middle-income countries. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Big opportunities for small molecules in immuno-oncology.

The regulatory approval of ipilimumab (Yervoy) in 2011 ushered in a new era of cancer immunotherapies with durable clinical effects. Most of these breakthrough medicines are monoclonal antibodies that block protein-protein interactions between T cell checkpoint receptors and their cognate ligands. In addition, genetically engineered autologous T cell therapies have also recently demonstrated significant clinical responses in haematological cancers. Conspicuously missing from this class of therapies are traditional small-molecule drugs, which have previously served as the backbone of targeted cancer therapies. Modulating the immune system through a small-molecule approach offers several unique advantages that are complementary to, and potentially synergistic with, biologic modalities. This Review highlights immuno-oncology pathways and mechanisms that can be best or solely targeted by small-molecule medicines. Agents aimed at these mechanisms--modulation of the immune response, trafficking to the tumour microenvironment and cellular infiltration--are poised to significantly extend the scope of immuno-oncology applications and enhance the opportunities for combination with tumour-targeted agents and biologic immunotherapies.

Incorporating developmental screening and surveillance of young children in office practice.

CONTEXT: Developmental concerns voiced by parents need to be responded to by structured developmental screening. Screening is the use of validated developmental screening tools to identify children with high risk of developmental delay out of an apparently normal population, while surveillance is the process of monitoring children identified as high risk by screening. Absence of routine screening can be attributed to problems at the level of parents, pediatricians or National policies. Hence vulnerable children are not detected early, and are denied benefit from appropriate developmental interventions. There are no definite guidelines for screening or for suitable tools for screening and surveillance. OBJECTIVES: To review existing developmental screening and monitoring tools for children validated in Indian under-five children, and provide a proposed practice paradigm for developmental screening in office practice. EVIDENCE ACQUISITION: Scientific papers were retrieved by an electronic database search using MeSH terms 'screening tool', 'developmental delay', and filter of 'children under 5 years'. Those relevant to office practice and validated internationally or in Indian children were reviewed. RESULTS: Screening tools applicable to Indian office practice have been compared and certain tools have been recommended according to the level of risk of developmental delay. An algorithmic approach to screening has been given along with strategies for incorporation. CONCLUSIONS: Screening and surveillance for high risk of developmental delay are essential components of child health care. It is possible to incorporate both into routine practice.