Does Hospital Operative Volume Influence the Outcomes of Patients After Heated Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis?

BACKGROUND: For some cancer operations, center volume is associated with improved patient outcomes. Whether this association is true for cytoreductive surgery/heated intraperitoneal chemotherapy (CRS/HIPEC) is unclear. Given the rapidly expanding use of CRS/HIPEC, the aim of this analysis was to determine whether a volume-outcome relationship exists for this strategy. METHODS: The Vizient Clinical Database® was queried for CRS/HIPEC cases from January 2020 through December 2022. Low-, medium-, and high-volume designations were made by sorting hospitals by case volume and creating equal tertiles based on total number of cases. Analysis was performed via one-way ANOVA with post-hoc Tukey test, as indicated. RESULTS: In the 36-month study period, 5165 cases were identified across 149 hospitals. Low- (n = 113), medium- (n = 25), and high-volume (n = 11) centers performed a median of 4, 21, and 47 cases per annum, respectively. Most cases were performed for appendiceal (39.3%) followed by gynecologic neoplasms (20.4%). Groups were similar with respect to age, gender, race, comorbidities, and histology. Low-volume centers were more likely to utilize the ICU post-operatively (59.6% vs. 40.5% vs. 36.3%; p = 0.02). No differences were observed in morbidity (9.4% vs. 7.1% vs. 9.0%, p = 0.71), mortality (0.9% vs. 0.6% vs. 0.7%, p = 0.93), length of stay (9.3 vs. 9.4 vs. 10 days, p = 0.83), 30-day readmissions (5.6% vs. 5.6% vs. 5.6%, p = 1.0), or total cost among groups. CONCLUSIONS: No association was found between CRS/HIPEC hospital volume and post-operative outcomes. These data suggest that in academic medical centers with HIPEC programs, outcomes for commonly treated cancers are not associated with hospital volume.

PTK2-associated gene signature could predict the prognosis of IPF.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with a poor prognosis. Current/available clinical prediction tools have limited sensitivity and accuracy when evaluating clinical outcomes of IPF. Research has shown that focal adhesion kinase (FAK), produced by the protein tyrosine kinase 2 (PTK2) gene, is crucial in IPF development. FAK activation is a characteristic of lesional fibroblasts; Thus, FAK may be a valuable therapeutic target or prognostic biomarker for IPF. This study aimed to create a gene signature based on PTK2-associated genes and microarray data from blood cells to predict disease prognosis in patients with IPF. PTK2 levels were found to be higher in lung tissues of IPF patients compared to healthy controls, and PTK2 inhibitor Defactinib was found to reduce TGFß-induced FAK activation and increase α-smooth muscle actin. Although the blood PTK2 levels were higher in IPF patients, blood PTK level alone could not predict IPF prognosis. From 196 PTK2-associated genes, 11 genes were prioritized to create a gene signature (PTK2 molecular signature) and a risk score system using univariate and multivariate Cox regression analysis. Patients were divided into high-risk and low-risk groups using PTK2 molecular signature. Patients in the high-risk group experienced decreased survival rates compared to patients in the low-risk group across all discovery and validation cohorts. Further functional enrichment and immune cell proportion analyses revealed that the PTK2 molecular signature strongly reflected the activation levels of immune pathways and immune cells. These findings suggested that PTK2 is a molecular target of IPF and the PTK2 molecular signature is an effective IPF prognostic biomarker.

Regulation of CHK1 inhibitor resistance by a c-Rel and USP1 dependent pathway.

Previously, we discovered that deletion of c-Rel in the Eµ-Myc mouse model of lymphoma results in earlier onset of disease, a finding that contrasted with the expected function of this NF-κB subunit in B-cell malignancies. Here we report that Eµ-Myc/cRel-/- cells have an unexpected and major defect in the CHK1 pathway. Total and phospho proteomic analysis revealed that Eµ-Myc/cRel-/- lymphomas highly resemble wild-type (WT) Eµ-Myc lymphomas treated with an acute dose of the CHK1 inhibitor (CHK1i) CCT244747. Further analysis demonstrated that this is a consequence of Eµ-Myc/cRel-/- lymphomas having lost expression of CHK1 protein itself, an effect that also results in resistance to CCT244747 treatment in vivo. Similar down-regulation of CHK1 protein levels was also seen in CHK1i resistant U2OS osteosarcoma and Huh7 hepatocellular carcinoma cells. Further investigation revealed that the deubiquitinase USP1 regulates CHK1 proteolytic degradation and that its down-regulation in our model systems is responsible, at least in part, for these effects. We demonstrate that treating WT Eµ-Myc lymphoma cells with the USP1 inhibitor ML323 was highly effective at reducing tumour burden in vivo. Targeting USP1 activity may thus be an alternative therapeutic strategy in MYC-driven tumours.

Control of cerebral ischemia with magnetic nanoparticles.

The precise manipulation of microcirculation in mice can facilitate mechanistic studies of brain injury and repair after ischemia, but this manipulation remains a technical challenge, particularly in conscious mice. We developed a technology that uses micromagnets to induce aggregation of magnetic nanoparticles to reversibly occlude blood flow in microvessels. This allowed induction of ischemia in a specific cortical region of conscious mice of any postnatal age, including perinatal and neonatal stages, with precise spatiotemporal control but without surgical intervention of the skull or artery. When combined with longitudinal live-imaging approaches, this technology facilitated the discovery of a feature of the ischemic cascade: selective loss of smooth muscle cells in juveniles but not adults shortly after onset of ischemia and during blood reperfusion.

A lifestyle intervention programme for the prevention of Type 2 diabetes mellitus among South Asian women with gestational diabetes mellitus [LIVING study]: protocol for a randomized trial.

AIM: This study aims to determine whether a resource- and culturally appropriate lifestyle intervention programme in South Asian countries, provided to women with gestational diabetes (GDM) after childbirth, will reduce the incidence of worsening of glycaemic status in a manner that is affordable, acceptable and scalable. METHODS: Women with GDM (diagnosed by oral glucose tolerance test using the International Association of the Diabetes and Pregnancy Study Groups criteria) will be recruited from 16 hospitals in India, Sri Lanka and Bangladesh. Participants will undergo a repeat oral glucose tolerance test at 6 ± 3 months postpartum and those without Type 2 diabetes, a total sample size of 1414, will be randomly allocated to the intervention or usual care. The intervention will consist of four group sessions, 84 SMS or voice messages and review phone calls over the first year. Participants requiring intensification of the intervention will receive two additional individual sessions over the latter half of the first year. Median follow-up will be 2 years. The primary outcome is the proportion of women with a change in glycaemic category, using the American Diabetes Association criteria: (i) normal glucose tolerance to impaired fasting glucose, or impaired glucose tolerance, or Type 2 diabetes; or (ii) impaired fasting glucose or impaired glucose tolerance to Type 2 diabetes. Process evaluation will explore barriers and facilitators of implementation of the intervention in each local context, while trial-based and modelled economic evaluations will assess cost-effectiveness. DISCUSSION: The study will generate important new evidence about a potential strategy to address the long-term sequelae of GDM, a major and growing problem among women in South Asia. (Clinical Trials Registry of India No: CTRI/2017/06/008744; Sri Lanka Clinical Trials Registry No: SLCTR/2017/001; and ClinicalTrials.gov Identifier No: NCT03305939).

Women's and healthcare providers' perceptions of long-term complications associated with hypertension and diabetes in pregnancy: a qualitative study.

OBJECTIVES: A diagnosis of hypertensive disorders during pregnancy (HDPs) or gestational diabetes mellitus (GDM) is highly predictive of women at increased risk of developing chronic hypertension, Type 2 diabetes, and cardiovascular disease. This study investigates perceptions of women and healthcare providers in rural India regarding these long-term risks. DESIGN: Qualitative study using modified grounded theory. SETTING: Two states in rural India: Haryana and Andhra Pradesh. POPULATION: Pregnant and postpartum women, community health workers (CHWs), primary care physicians, obstetricians, laboratory technicians, and healthcare officials. METHODS: In-depth interviews and focus group discussions explored: (1) priorities for high-risk pregnant women; (2) detection and management of HDPs and GDM; (3) postpartum management, and (4) knowledge of long-term sequelae of high-risk conditions. A thematic analysis was undertaken. RESULTS: Seven focus group discussions and 11 in-depth interviews (n = 71 participants) were performed. The key priority area for high-risk pregnant women was anaemia. Blood pressure measurement was routinely embedded in antenatal care; however, postpartum follow up and knowledge of the long-term complications were limited. GDM was not considered a common problem, although significant variations and challenges to GDM screening were identified. Knowledge of the long-term sequelae of GDM with regard to an increased risk of Type 2 diabetes and cardiovascular disease among doctors was minimal. CONCLUSIONS: There is a need for improved education, standardisation of testing and postpartum follow up of HDPs and GDM in rural Indian settings. FUNDING: SN is supported by an MRC Clinical Research Training Fellowship (MR/R017182/1). The George Institute for Global Health Global Women's Health programme provided financial support for the research assistant and fieldwork costs in India. TWEETABLE ABSTRACT: Improved education and postpartum care of women with hypertension and diabetes in pregnancy in rural India are needed to prevent long-term risks.

What do Accredited Social Health Activists need to provide comprehensive care that incorporates non-communicable diseases? Findings from a qualitative study in Andhra Pradesh, India.

BACKGROUND: The Indian National Program for Cardiovascular Disease, Diabetes, Cancer and Stroke (NPCDCS) was introduced to provide non-communicable disease (NCD) care through primary healthcare teams including Accredited Social Health Activists (ASHAs). Since ASHAs are being deployed to provide NCD care on top of their regular work for the first time, there is a need to understand the current capacity and challenges faced by them. METHODS: A desktop review of NPCDCS and ASHA policy documents was conducted. This was followed by group discussions with ASHAs, in-depth interviews with their supervisors and medical officers and group discussions with community members in Guntur, Andhra Pradesh, India. The multi-stakeholder data were analysed for themes related to needs, capacity, and challenges of ASHAs in providing NCD services. RESULTS: This study identified three key themes-first, ASHAs are unrecognised as part of the formal NPCDCS service delivery team. Second, they are overburdened, since they deliver several NPCDCS activities without receiving training or remuneration. Third, they aspire to be formally recognised as employees of the health system. However, ASHAs are enthusiastic about the services they provide and remain an essential link between the health system and the community. CONCLUSION: ASHAs play a key role in providing comprehensive and culturally appropriate care to communities; however, they are unrecognised and overburdened and aspire to be part of the health system. ASHAs have the potential to deliver a broad range of services, if supported by the health system appropriately. TRIAL REGISTRATION: The study was registered with "Clinical Trials Registry - India" (identifier CTRI/2018/03/012425 ).

Dynamic Clustering of Dyneins on Axonal Endosomes: Evidence from High-Speed Darkfield Imaging.

One of the fundamental features that govern the cooperativity of multiple dyneins during cargo trafficking in cells is the spatial distribution of these dyneins on the cargo. Geometric considerations and recent experiments indicate that clustered distributions of dyneins are required for effective cooperation on micron-sized cargos. However, very little is known about the spatial distribution of dyneins and their cooperativity on smaller cargos, such as vesicles or endosomes <200 nm in size, which are not amenable to conventional immunostaining and optical trapping methods. In this work, we present evidence that dyneins can dynamically be clustered on endosomes in response to load. Using a darkfield imaging assay, we measured the repeated stalls and detachments of retrograde axonal endosomes under load with <10 nm localization accuracy at imaging rates up to 1 kHz for over a timescale of minutes. A three-dimensional stochastic model was used to simulate the endosome motility under load to gain insights on the mechanochemical properties and spatial distribution of dyneins on axonal endosomes. Our results indicate that 1) the distribution of dyneins on endosomes is fluid enough to support dynamic clustering under load and 2) the detachment kinetics of dynein on endosomes differs significantly from the in vitro measurements possibly due to an increase in the unitary stall force of dynein on endosomes.

Conversion of gestational diabetes mellitus to future Type 2 diabetes mellitus and the predictive value of HbA1c in an Indian cohort.

AIM: To investigate the distribution of and risk factors for dysglycaemia (Type 2 diabetes and prediabetes) in women with previous gestational diabetes mellitus in India. METHODS: All women (n = 989) from two obstetric units in New Delhi and Hyderabad with a history of gestational diabetes were invited to participate, of whom 366 (37%) agreed. Sociodemographic, medical and anthropometric data were collected and 75-g oral glucose tolerance test were carried out. RESULTS: Within 5 years (median 14 months) of the pregnancy in which they were diagnosed with gestational diabetes, 263 (72%) women were dysglycaemic, including 119 (32%) and 144 (40%) with Type 2 diabetes and prediabetes, respectively. A higher BMI [odds ratio 1.16 per 1-kg/m2 greater BMI (95% CI 1.10, 1.28)], presence of acanthosis nigricans [odds ratio 3.10, 95% CI (1.64, 5.87)], postpartum screening interval [odds ratio 1.02 per 1 month greater screening interval 95% CI (1.01, 1.04)] and age [odds ratio 1.10 per 1-year older age 95% CI (1.04, 1.16)] had a higher likelihood of having dysglycaemia. The American Diabetes Association-recommended threshold HbA1c value of ≥ 48 mmol/mol (6.5%) had a sensitivity and specificity of 81.4 and 90.7%, respectively, for determining the presence of Type 2 diabetes postpartum. CONCLUSION: The high post-pregnancy conversion rates of gestational diabetes to diabetes reported in the present study reinforce the need for mandatory postpartum screening and identification of strategies for preventing progression to Type 2 diabetes. Use of the American Diabetes Association-recommended HbA1c threshold for diabetes may lead to significant under-diagnosis.

Retrograde NGF axonal transport--motor coordination in the unidirectional motility regime.

We present a detailed motion analysis of retrograde nerve growth factor (NGF) endosomes in axons to show that mechanical tugs-of-war and intracellular motor regulation are complimentary features of the near-unidirectional endosome directionality. We used quantum dots to fluorescently label NGF and acquired trajectories of retrograde quantum-dot-NGF-endosomes with <20-nm accuracy at 32 Hz in microfluidic neuron cultures. Using a combination of transient motion analysis and Bayesian parsing, we partitioned the trajectories into sustained periods of retrograde (dynein-driven) motion, constrained pauses, and brief anterograde (kinesin-driven) reversals. The data shows many aspects of mechanical tugs-of-war and multiple-motor mechanics in NGF-endosome transport. However, we found that stochastic mechanical models based on in vitro parameters cannot simulate the experimental data, unless the microtubule-binding affinity of kinesins on the endosome is tuned down by 10 times. Specifically, the simulations suggest that the NGF-endosomes are driven on average by 5-6 active dyneins and 1-2 downregulated kinesins. This is also supported by the dynamics of endosomes detaching under load in axons, showcasing the cooperativity of multiple dyneins and the subdued activity of kinesins. We discuss the possible motor coordination mechanism consistent with motor regulation and tugs-of-war for future investigations.

Neurotrophin signaling via long-distance axonal transport.

Neurotrophins are a family of target-derived growth factors that support survival, development, and maintenance of innervating neurons. Owing to the unique architecture of neurons, neurotrophins that act locally on the axonal terminals must convey their signals across the entire axon for subsequent regulation of gene transcription in the cell nucleus. This long-distance retrograde signaling, a motor-driven process that can take hours or days, has been a subject of intense interest. In the last decade, live-cell imaging with high sensitivity has significantly increased our capability to track the transport of neurotrophins, their receptors, and subsequent signals in real time. This review summarizes recent research progress in understanding neurotrophin-receptor interactions at the axonal terminal and their transport dynamics along the axon. We emphasize high-resolution studies at the single-molecule level and also discuss recent technical advances in the field.

An examination of public support for 35 nutrition interventions across seven countries.

BACKGROUND: Public support for evidence-based nutrition interventions can be an important determinant of government willingness to develop and implement such interventions. The aim of this study was to assess support for a broad range of nutrition interventions across seven countries: Australia, Canada, China, India, New Zealand, the United Kingdom, and the United States. Assessed interventions included those relating to food availability, affordability, reformulation, labelling, and promotion. METHODS: Approximately 1000 adults per country (total n = 7559) completed an online survey assessing support for 35 nutrition interventions/policies. ANOVA analyses were used to identify differences between countries on overall levels of support and by intervention category. Multiple regression analyses assessed demographic and diet-related factors associated with higher levels of support across the total sample and by country. RESULTS: Substantial levels of public support were found for the assessed interventions across the seven countries and five intervention categories. The highest levels were found in India (Mean across all interventions of 4.16 (standard deviation (SD) 0.65) on a 5-point scale) and the lowest in the United States (Mean = 3.48, SD = 0.83). Support was strongest for interventions involving food labelling (Mean = 4.20, SD = 0.79) and food reformulation (Mean = 4.17, SD = 0.87), and weakest for fiscal interventions (Mean = 3.52, SD = 1.06). Consumer characteristics associated with stronger support were higher self-rated health, higher educational attainment, female sex, older age, and perceptions of consuming a healthy diet. CONCLUSION: The results indicate substantial support for a large range of nutrition interventions across the assessed countries, and hence governments could potentially be more proactive in developing and implementing such initiatives.

"La Perla Del Mar": A Case Report on Subcutaneous Penile Implants.

The purpose of this report is to alert and inform the medical community about the presence and practice of subcutaneous penile implants (SPIs), which are used with the intent of increasing sexual pleasure. This case aspires to deflect plausible misconceptions in the specific populations who use the SPIs. This case study was performed in January 2023 at a tertiary care center in Miami, Florida. A 61-year-old Cuban male admitted for a routine hernia repair with an incidental finding of a benign SPI was interviewed and examined; an extended collection of historical information regarding the patient's penile implant was ascertained. The patient stated that there was a tradition among the men and adolescent individuals living along coastal cities/towns of Cuba such as Havana and Matanzas who would elect to have pieces of stones or gems or any solid objects shaped and molded into round objects that are used for the intent of increasing sexual pleasure. The patient referred to the implant as "La Perla Del Mar," which translates directly into "Pearl of the Sea." Upon visualization of the nodule on examination, a differential diagnosis may include infection (such as syphilis), granulomas, sarcoidosis, dermatofibroma, epithelial inclusion cyst, or malignancy. However, an appropriate workup informed us about the penile implant. Clinicians should employ caution in investigating a penile nodule by taking a detailed social and sexual history and physical exam from the patient if possible. This case and the literature review cited to bolster the notion of a lack of chronic symptoms due to the inserted objects. Several provocations for the implantation of an artificial penile nodule, in this case, maybe extrapolated, such as the desire for a prospective partner's pleasure/displeasure, group identification, or masculine embodiment. The main takeaways from this case report are the considerations that should be taken in the older Caribbean population for patients with the "Perla Del Mar" implantation and bolstering the notion of complete sexual education for clinicians regarding specific populations to enhance patient care.

Cell surface marker-based capture of neoantigen-reactive CD8+ T-cell receptors from metastatic tumor digests.

BACKGROUND: Cellular immunotherapies using autologous tumor-infiltrating lymphocytes (TIL) can induce durable regression of epithelial cancers in selected patients with treatment-refractory metastatic disease. As the genetic engineering of T cells with tumor-reactive T-cell receptors (TCRs) comes to the forefront of clinical investigation, the rapid, scalable, and cost-effective detection of patient-specific neoantigen-reactive TIL remains a top priority. METHODS: We analyzed the single-cell transcriptomic states of 31 neoantigen-specific T-cell clonotypes to identify cell surface dysfunction markers that best identified the metastatic transcriptional states enriched with antitumor TIL. We developed an efficient method to capture neoantigen-reactive TCRs directly from resected human tumors based on cell surface co-expression of CD39, programmed cell death protein-1, and TIGIT dysfunction markers (CD8+ TILTP). RESULTS: TILTP TCR isolation achieved a high degree of correlation with single-cell transcriptomic signatures that identify neoantigen-reactive TCRs, making it a cost-effective strategy using widely available resources. Reconstruction of additional TILTP TCRs from tumors identified known and novel antitumor TCRs, showing that at least 39.5% of TILTP TCRs are neoantigen-reactive or tumor-reactive. Despite their substantial enrichment for neoantigen-reactive TCR clonotypes, clonal dynamics of 24 unique antitumor TILTP clonotypes from four patients indicated that most in vitro expanded TILTP populations failed to demonstrate neoantigen reactivity, either by loss of neoantigen-reactive clones during TIL expansion, or through functional impairment during cognate neoantigen recognition. CONCLUSIONS: While direct usage of in vitro-expanded CD8+ TILTP as a source for cellular therapy might be precluded by profound TIL dysfunction, isolating TILTP represents a streamlined effective approach to rapidly identify neoantigen-reactive TCRs to design engineered cellular immunotherapies against cancer.

Brown Carbon from Photo-Oxidation of Glyoxal and SO2 in Aqueous Aerosol.

Aqueous-phase dark reactions during the co-oxidation of glyoxal and S(IV) were recently identified as a potential source of brown carbon (BrC). Here, we explore the effects of sunlight and oxidants on aqueous solutions of glyoxal and S(IV), and on aqueous aerosol exposed to glyoxal and SO2. We find that BrC is able to form in sunlit, bulk-phase, sulfite-containing solutions, albeit more slowly than in the dark. In more atmospherically relevant chamber experiments where suspended aqueous aerosol particles are exposed to gas-phase glyoxal and SO2, the formation of detectable amounts of BrC requires an OH radical source and occurs most rapidly after a cloud event. From these observations we infer that this photobrowning is caused by radical-initiated reactions as evaporation concentrates aqueous-phase reactants and aerosol viscosity increases. Positive-mode electrospray ionization mass spectrometric analysis of aerosol-phase products reveals a large number of CxHyOz oligomers that are reduced rather than oxidized (relative to glyoxal), with the degree of reduction increasing in the presence of OH radicals. This again suggests a radical-initiated redox mechanism where photolytically produced aqueous radical species trigger S(IV)-O2 auto-oxidation chain reactions, and glyoxal-S(IV) redox reactions especially if aerosol-phase O2 is depleted. This process may contribute to daytime BrC production and aqueous-phase sulfur oxidation in the atmosphere. The BrC produced, however, is about an order of magnitude less light-absorbing than wood smoke BrC at 365 nm.

Correction to Brown Carbon from Photo-Oxidation of Glyoxal and SO2 in Aqueous Aerosol.

[This corrects the article DOI: 10.1021/acsearthspacechem.3c00035.].

Phenotypic signatures of circulating neoantigen-reactive CD8+ T cells in patients with metastatic cancers.

Circulating T cells from peripheral blood (PBL) can provide a rich and noninvasive source for antitumor T cells. By single-cell transcriptomic profiling of 36 neoantigen-specific T cell clones from 6 metastatic cancer patients, we report the transcriptional and cell surface signatures of antitumor PBL-derived CD8+ T cells (NeoTCRPBL). Comparison of tumor-infiltrating lymphocyte (TIL)- and PBL-neoantigen-specific T cells revealed that NeoTCRPBL T cells are low in frequency and display less-dysfunctional memory phenotypes relative to their TIL counterparts. Analysis of 100 antitumor TCR clonotypes indicates that most NeoTCRPBL populations target the same neoantigens as TILs. However, NeoTCRPBL TCR repertoire is only partially shared with TIL. Prediction and testing of NeoTCRPBL signature-derived TCRs from PBL of 6 prospective patients demonstrate high enrichment of clonotypes targeting tumor mutations, a viral oncogene, and patient-derived tumor. Thus, the NeoTCRPBL signature provides an alternative source for identifying antitumor T cells from PBL of cancer patients, enabling immune monitoring and immunotherapies.

Protocol for process evaluation of SMART Mental Health cluster randomised control trial: an intervention for management of common mental disorders in India.

INTRODUCTION: In India about 95% of individuals who need treatment for common mental disorders like depression, stress and anxiety and substance use are unable to access care. Stigma associated with help seeking and lack of trained mental health professionals are important barriers in accessing mental healthcare. Systematic Medical Appraisal, Referral and Treatment (SMART) Mental Health integrates a community-level stigma reduction campaign and task sharing with the help of a mobile-enabled electronic decision support system (EDSS)-to reduce psychiatric morbidity due to stress, depression and self-harm in high-risk individuals. This paper presents and discusses the protocol for process evaluation of SMART Mental Health. METHODS AND ANALYSIS: The process evaluation will use mixed quantitative and qualitative methods to evaluate implementation fidelity and identify facilitators of and barriers to implementation of the intervention. Case studies of six intervention and two control clusters will be used. Quantitative data sources will include usage analytics extracted from the mHealth platform for the trial. Qualitative data sources will include focus group discussions and interviews with recruited participants, primary health centre doctors, community health workers (Accredited Social Health Activits) who participated in the project and local community leaders. The design and analysis will be guided by Medical Research Council framework for process evaluations, the Reach, Effectiveness, Adoption, Implementation and Maintenance (RE-AIM) framework, and the normalisation process theory. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee of the George Institute for Global Health, India and the Institutional Ethics Committee, All India Institute of Medical Sciences (AIIMS), New Delhi. Findings of the study will be disseminated through peer-reviewed publications, stakeholder meetings, digital and social media platforms. TRIAL REGISTRATION NUMBER: CTRI/2018/08/015355.

How do diverse low-income and middle-income countries implement primary healthcare team integration to support the delivery of comprehensive primary health care? A mixed-methods study protocol from India, Mexico and Uganda.

INTRODUCTION: Attainment of universal health coverage is feasible via strengthened primary health systems that are comprehensive, accessible, people-centred, continuous and coordinated. Having an adequately trained, motivated and equipped primary healthcare workforce is central to the provision of comprehensive primary healthcare (CPHC). This study aims to understand PHC team integration, composition and organisation in the delivery of CPHC in India, Mexico and Uganda. METHODS AND ANALYSIS: A parallel, mixed-methods study (integration of quantitative and qualitative results) will be conducted to gain an understanding of PHC teams. Methods include: (1) Policy review on PHC team composition, organisation and expected comprehensiveness of PHC services, (2) PHC facility review using the WHO Service Availability and Readiness Assessment, and (3) PHC key informant interviews. Data will be collected from 20, 10 and 10 PHCs in India, Mexico and Uganda, respectively, and analysed using descriptive methods and thematic analysis approach. Outcomes will include an in-depth understanding of the health policies for PHC as well as understanding PHC team composition, organisation and the delivery of comprehensive PHC. ETHICS AND DISSEMINATION: Approvals have been sought from the Institutional Ethics Committee of The George Institute for Global Health, India for the Indian sites, School of Medicine Research Ethics Committee at Makerere University for the sites in Uganda and the Research, Ethics and Biosecurity Committees of the Mexican National Institute of Public Health for the sites in Mexico. Results will be shared through presentations with governments, publications in peer-reviewed journals and presentations at conferences.