Understanding integrated HPV testing and treatment of pre-cancerous cervical cancer in Burkina Faso, Cote d'Ivoire, Guatemala and Philippines: study protocol.

BACKGROUND: Many low- and-middle-income countries are disproportionately burdened by cervical cancer, resulting in high morbidity and mortality. HPV-DNA testing coupled with treatment with thermal ablation is a recommended screening and precancer treatment strategy, but not enough is known about how this can be effectively implemented in the context of integrated services. The (Scale Up Cervical Cancer Elimination by Secondary prevention Strategy, (SUCCESS) project is conducting a study to understand this approach, integrated into existing women's health services in Burkina Faso, Cote d'Ivoire, Guatemala, and the Philippines (2020-2024). METHODS: A hybrid effectiveness-implementation type III mixed-methods observational study design is used to assess feasibility, acceptability, and costs of integrated service delivery in 10 sites per country, selected considering urban/rural location, facility level, onsite/offsite laboratories, and health services type. In each country, a sample size of 2227 women aged 25-49 years will be enrolled with about 20% being women living with HIV. The primary outcome is proportion of HPV positive women completing precancer treatment, if eligible, within three months of screening. Data collection and analysis includes; facility and client exit surveys, key informant and client interviews, registries and project records extractions, and costing data analysis. Analysis includes descriptive statistics, context description, thematic analysis, and document analysis. Quantitative analyses will be stratified by participant's HIV status. DISCUSSION: Recruitment of study participants started in April 2022 (Burkina Faso and Côte d'Ivoire) and August 2022 (Guatemala and the Philippines). Enrolment targets for women screened, client exit, in-depth and key informant interviews conducted were reached in Burkina Faso and Cote d'Ivoire in November 2022. Guatemala and Philippines are expected to complete enrolment by June 2023. Follow-up of study Participants 12-months post-treatment is ongoing and is expected to be completed for all countries by August 2024. In LMICs, integrating cervical cancer secondary prevention services into other health services will likely require specific rather than incidental recruitment of women for screening. Reconfiguration of laboratory infrastructure and planning for sample management must be made well in advance to meet induced demand for screening. Trail Registration ClinicalTrials.Gov ID: NCT05133661 (24/11/2021).

Acute promyelocytic leukaemia: population-based study of epidemiology and outcome with ATRA and oral-ATO from 1991 to 2021.

BACKGROUND: The epidemiology and treatment of acute promyelocytic leukaemia (APL) are changing. We have incorporated oral arsenic trioxide (oral-ATO) into induction/maintenance. METHODS: Newly-diagnosed APL from 1991 to 2021 divided into three 10-year periods were studied to define its epidemiology and how oral-ATO impacted on its outcome. Primary endpoints included APL incidence, early deaths (ED, first 30 days), and overall survival (OS). Secondary endpoints included post-30-day OS, relapse-free survival (RFS), and incidence of second cancers. RESULTS: APL occurred in 374 males and 387 females at a median age of 44 (1-97) years. Annual incidences increased progressively, averaging 0.32 per 100,000 people. All-trans retinoic acid (ATRA)-based and oral-ATO-based regimens were used in 469 and 282 patients. There were 144 EDs, occurring almost exclusively in ATRA-based inductions (N = 139), being more with males, age > 50 years, leucocyte > 10 × 109/L, diagnosis during 1991-2009 and fewer with oral-ATO-based regimens. After a median of 75 (interquartile range: 14-161) months, 5-year and 10-year OS were 68.1% and 63.3%, inferior with males, age > 50 years, leucocyte > 10 × 109/L, high-risk Sanz score and superior with oral-ATO-based regimens. Factoring out EDs, 5-year and 10-year post-30-day OS were 84.0% and 78.1%, inferior with males and superior with oral-ATO-based regimens. In 607 CR1 patients, the 5-year RFS was 83.8%, superior with diagnosis in 2010-2021 and oral-ATO-based regimens. Second cancers developed in 21 patients, unrelated to oral-ATO-based regimens. CONCLUSIONS: There was an increasing incidence of APL, and all survivals were superior with the use of oral-ATO-based regimens. This study formed part of the Acute Promyelocytic Leukaemia Asian Consortium Project (ClinicalTrials.gov identifier: NCT04251754).

At the frontlines of digitisation: a qualitative study on the challenges and opportunities in maintaining accurate, complete and timely digital health records in India's government health system.

OBJECTIVES: To understand factors underpinning the accuracy and timeliness of mobile phone numbers and other health information captured in India's government registry for pregnant and postpartum women. Accurate and timely registration of mobile phone numbers is necessary for beneficiaries to receive mobile health services. SETTING: Madhya Pradesh and Rajasthan states in India at the community, clinical, and administrative levels of the health system. PARTICIPANTS: Interviews (n=59) with frontline health workers (FLHWs), data entry operators, and higher level officials. Focus group discussions (n=12) with pregnant women to discuss experiences with sharing data in the health system. Observations (n=9) of the process of digitization and of interactions between stakeholders for data collection. PRIMARY AND SECONDARY OUTCOME MEASURES: Thematic analysis identified how key actors experienced the data collection and digitisation process, reasons for late or inaccurate data, and mechanisms that can bolster timeliness and accuracy. RESULTS: Pregnant women were comfortable sharing mobile numbers with health workers, but many were unaware that their data moved beyond their FLHW. FLHWs valued knowing up-to-date beneficiary mobile numbers, but felt little incentive to ensure accuracy in the digital record system. Delays in registering pregnant women in the online portal were attributed to slow movement of paper records into the digital system and difficulties in gathering required documents from beneficiaries. Data, including women's phone numbers, were handwritten and copied multiple times by beneficiaries and health workers with variable literacy. Supervision tended to focus on completeness rather than accuracy. Health system actors noted challenges with the digital system but valued the broader project of digitisation. CONCLUSIONS: Increased focus on training, supportive supervision, and user-friendly data processes that prioritise accuracy and timeliness should be considered. These inputs can build on existing positive patient-provider relationships and health system actors' enthusiasm for digitisation.

Population risk factors for severe disease and mortality in COVID-19: A global systematic review and meta-analysis.

AIM: COVID-19 clinical presentation is heterogeneous, ranging from asymptomatic to severe cases. While there are a number of early publications relating to risk factors for COVID-19 infection, low sample size and heterogeneity in study design impacted consolidation of early findings. There is a pressing need to identify the factors which predispose patients to severe cases of COVID-19. For rapid and widespread risk stratification, these factors should be easily obtainable, inexpensive, and avoid invasive clinical procedures. The aim of our study is to fill this knowledge gap by systematically mapping all the available evidence on the association of various clinical, demographic, and lifestyle variables with the risk of specific adverse outcomes in patients with COVID-19. METHODS: The systematic review was conducted using standardized methodology, searching two electronic databases (PubMed and SCOPUS) for relevant literature published between 1st January 2020 and 9th July 2020. Included studies reported characteristics of patients with COVID-19 while reporting outcomes relating to disease severity. In the case of sufficient comparable data, meta-analyses were conducted to estimate risk of each variable. RESULTS: Seventy-six studies were identified, with a total of 17,860,001 patients across 14 countries. The studies were highly heterogeneous in terms of the sample under study, outcomes, and risk measures reported. A large number of risk factors were presented for COVID-19. Commonly reported variables for adverse outcome from COVID-19 comprised patient characteristics, including age >75 (OR: 2.65, 95% CI: 1.81-3.90), male sex (OR: 2.05, 95% CI: 1.39-3.04) and severe obesity (OR: 2.57, 95% CI: 1.31-5.05). Active cancer (OR: 1.46, 95% CI: 1.04-2.04) was associated with increased risk of severe outcome. A number of common symptoms and vital measures (respiratory rate and SpO2) also suggested elevated risk profiles. CONCLUSIONS: Based on the findings of this study, a range of easily assessed parameters are valuable to predict elevated risk of severe illness and mortality as a result of COVID-19, including patient characteristics and detailed comorbidities, alongside the novel inclusion of real-time symptoms and vital measurements.

CAR T-cell therapy is effective for CD19-dim B-lymphoblastic leukemia but is impacted by prior blinatumomab therapy.

Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell product targeting CD19 is approved for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, the impact of pretreatment variables, such as CD19 expression level, on leukemic blasts, the presence of CD19- subpopulations, and especially prior CD19-targeted therapy, on the response to CAR T-cell therapy has not been determined. We analyzed 166 patients treated with CAR T-cell therapy at our institution. Eleven patients did not achieve a minimal residual disease (MRD)- deep remission, whereas 67 patients had a recurrence after achieving a MRD- deep remission: 28 patients with CD19+ leukemia and 39 patients with CD19- leukemia. Return of CD19+ leukemia was associated with loss of CAR T-cell function, whereas CD19- leukemia was associated with continued CAR T-cell function. There were no significant differences in efficacy of CAR T cells in CD19-dim B-ALL, compared with CD19-normal or -bright B-ALL. Consistent with this, CAR T cells recognized and lysed cells with very low levels of CD19 expression in vitro. The presence of dim CD19 or rare CD19- events by flow cytometry did not predict nonresponse or recurrence after CAR T-cell therapy. However, prior therapy with the CD19-directed, bispecific T-cell engager blinatumomab was associated with a significantly higher rate of failure to achieve MRD- remission or subsequent loss of remission with antigen escape. Finally, immunophenotypic heterogeneity and lineage plasticity were independent of underlying clonotype and cytogenetic abnormalities.

Tackling socioeconomic inequalities and non-communicable diseases in low-income and middle-income countries under the Sustainable Development agenda.

Five Sustainable Development Goals (SDGs) set targets that relate to the reduction of health inequalities nationally and worldwide. These targets are poverty reduction, health and wellbeing for all, equitable education, gender equality, and reduction of inequalities within and between countries. The interaction between inequalities and health is complex: better economic and educational outcomes for households enhance health, low socioeconomic status leads to chronic ill health, and non-communicable diseases (NCDs) reduce income status of households. NCDs account for most causes of early death and disability worldwide, so it is alarming that strong scientific evidence suggests an increase in the clustering of non-communicable conditions with low socioeconomic status in low-income and middle-income countries since 2000, as previously seen in high-income settings. These conditions include tobacco use, obesity, hypertension, cancer, and diabetes. Strong evidence from 283 studies overwhelmingly supports a positive association between low-income, low socioeconomic status, or low educational status and NCDs. The associations have been differentiated by sex in only four studies. Health is a key driver in the SDGs, and reduction of health inequalities and NCDs should become key in the promotion of the overall SDG agenda. A sustained reduction of general inequalities in income status, education, and gender within and between countries would enhance worldwide equality in health. To end poverty through elimination of its causes, NCD programmes should be included in the development agenda. National programmes should mitigate social and health shocks to protect the poor from events that worsen their frail socioeconomic condition and health status. Programmes related to universal health coverage of NCDs should specifically target susceptible populations, such as elderly people, who are most at risk. Growing inequalities in access to resources for prevention and treatment need to be addressed through improved international regulations across jurisdictions that eliminate the legal and practical barriers in the implementation of non-communicable disease control.

Retrospective study of the prevalence and progression of monoclonal gammopathy in HIV positive versus HIV negative patients.

The significance of HIV associated paraproteins and their risk of progression to hematological malignancies remains unclear. We compared the development of hematological malignancies among HIV+ (n = 266) and HIV- (n = 537) patients with monoclonal gammopathies. HIV+ and HIV- patients with a positive serum protein electrophoresis test (SPEP) were studied. HIV+ SPEP+ were more likely to have faint and oligoclonal paraproteins (F-SPEP) and less likely to have discrete bands (D-SPEP) compared to HIV- SPEP+. The incidence of hematological malignancies was significantly lower in the HIV+ compared to the HIV- (6.4% vs 15.4%, p < 0.0002). Upon subgroup analysis, the lower incidence of hematological malignancies was noted for HIV+ patients with F-SPEP but not for those with D-SPEP. Copyright © 2015 John Wiley & Sons, Ltd.

Viral co-infections and paraproteins in HIV: effect on development of hematological malignancies.

The role of viral co-infections and paraproteins in the development of hematological malignancies (HMs) in HIV remains unclear. Using our large database of HIV+ patients, we investigated whether co-infection and paraproteinemia increase the risk of HM. Data on demographics, hepatitis B (HBV) and hepatitis C virus (HCV) co-infections, paraproteinemia, HIV characteristics, and biopsy proven malignant hematological disorders for HIV+ patients were collected over a 10-year period in a large urban hospital setting. We identified 10,293 HIV+ patients who were followed for a median duration of 53 months. Of the 10,293 patients with HIV, 229 (2.2 %) were diagnosed with a HM. Over 85 % of patients in both groups were tested; no significant difference in the prevalence of chronic HBV or HCV was noted between the HM positive (n = 229) and HM negative (n = 9992) patients. The serum protein electrophoresis test was performed for 1371 of the 10,221 patients. HM positive patients, compared to HM negative, were more likely to be tested for paraproteins (OR 3.3, 95 % CI 2.5-4.4) and more likely to have a discrete paraprotein band (OR 3.3, 95 % CI 1.2-8.9). Discrete paraproteins exclusively correlated with the development of plasma cell malignancies. Faint or oligoclonal protein bands were seen in high grade B cell lymphomas but did not show a significant correlation with HM development. Chronic hepatitis B or C infections did not correlate with the development of HM in HIV; however, viral influence on host gene transformation may have been impacted by anti-viral therapy limiting the duration of high viremic states.

Supply-side dimensions and dynamics of integrating HIV testing and counselling into routine antenatal care: a facility assessment from Morogoro Region, Tanzania.

BACKGROUND: Integration of HIV into RMNCH (reproductive, maternal, newborn and child health) services is an important process addressing the disproportionate burden of HIV among mothers and children in sub-Saharan Africa. We assess the structural inputs and processes of care that support HIV testing and counselling in routine antenatal care to understand supply-side dynamics critical to scaling up further integration of HIV into RMNCH services prior to recent changes in HIV policy in Tanzania. METHODS: This study, as a part of a maternal and newborn health program evaluation in Morogoro Region, Tanzania, drew from an assessment of health centers with 18 facility checklists, 65 quantitative and 57 qualitative provider interviews, and 203 antenatal care observations. Descriptive analyses were performed with quantitative data using Stata 12.0, and qualitative data were analyzed thematically with data managed by Atlas.ti. RESULTS: Limitations in structural inputs, such as infrastructure, supplies, and staffing, constrain the potential for integration of HIV testing and counselling into routine antenatal care services. While assessment of infrastructure, including waiting areas, appeared adequate, long queues and small rooms made private and confidential HIV testing and counselling difficult for individual women. Unreliable stocks of HIV test kits, essential medicines, and infection prevention equipment also had implications for provider-patient relationships, with reported decreases in women's care seeking at health centers. In addition, low staffing levels were reported to increase workloads and lower motivation for health workers. Despite adequate knowledge of counselling messages, antenatal counselling sessions were brief with incomplete messages conveyed to pregnant women. In addition, coping mechanisms, such as scheduling of clinical activities on different days, limited service availability. CONCLUSION: Antenatal care is a strategic entry point for the delivery of critical tests and counselling messages and the framing of patient-provider relations, which together underpin care seeking for the remaining continuum of care. Supply-side deficiencies in structural inputs and processes of delivering HIV testing and counselling during antenatal care indicate critical shortcomings in the quality of care provided. These must be addressed if integrating HIV testing and counselling into antenatal care is to result in improved maternal and newborn health outcomes.

Program synergies and social relations: implications of integrating HIV testing and counselling into maternal health care on care seeking.

BACKGROUND: Women and children in sub-Saharan Africa bear a disproportionate burden of HIV/AIDS. Integration of HIV with maternal and child services aims to reduce the impact of HIV/AIDS. To assess the potential gains and risks of such integration, this paper considers pregnant women's and providers' perceptions about the effects of integrated HIV testing and counselling on care seeking by pregnant women during antenatal care in Tanzania. METHODS: From a larger evaluation of an integrated maternal and newborn health care program in Morogoro, Tanzania, this analysis included a subset of information from 203 observations of antenatal care and interviews with 57 providers and 190 pregnant women from 18 public health centers in rural and peri-urban settings. Qualitative data were analyzed manually and with Atlas.ti using a framework approach, and quantitative data of respondents' demographic information were analyzed with Stata 12.0. RESULTS: Perceptions of integrating HIV testing with routine antenatal care from women and health providers were generally positive. Respondents felt that integration increased coverage of HIV testing, particularly among difficult-to-reach populations, and improved convenience, efficiency, and confidentiality for women while reducing stigma. Pregnant women believed that early detection of HIV protected their own health and that of their children. Despite these positive views, challenges remained. Providers and women perceived opt out HIV testing and counselling during antenatal services to be compulsory. A sense of powerlessness and anxiety pervaded some women's responses, reflecting the unequal relations, lack of supportive communications and breaches in confidentiality between women and providers. Lastly, stigma surrounding HIV was reported to lead some women to discontinue services or seek care through other access points in the health system. CONCLUSION: While providers and pregnant women view program synergies from integrating HIV services into antenatal care positively, lack of supportive provider-patient relationships, lack of trust resulting from harsh treatment or breaches in confidentiality, and stigma still inhibit women's care seeking. As countries continue rollout of Option B+, social relations between patients and providers must be understood and addressed to ensure that integrated delivery of HIV counselling and services encourages women's care seeking in order to improve maternal and child health.

Cytogenetic testing of iris melanoma using fine needle aspiration biopsy in 17 patients.

PURPOSE: To determine the incidence of Chromosome 3 monosomy in iris melanoma using fine needle aspiration biopsy. METHODS: Noncomparative case series of 17 patients. Fine needle aspiration biopsy was performed intraoperatively immediately before treatment of iris melanoma. Genetic analysis using DNA amplification and microsatellite assay was performed in the specimen. RESULTS: Clinical features and outcomes related to Chromosome 3 monosomy were reviewed. Disomy 3 was found in 5 melanomas (29%), partial Monosomy 3 in 7 melanomas (41%), and complete Monosomy 3 in 5 melanomas (29%). The only feature statistically associated with partial/complete Monosomy 3 (vs. Disomy 3) was older patients' age (median, 60 vs. 46 years, P = 0.03). A comparison of clinical features showed Monosomy 3 (vs. Disomy 3) tumors to be thinner (median, 2.8 vs. 4.2 mm) and with smaller base (median, 5.1 vs. 10 mm) but with greater iris seeding (mean, 5.7 vs. 2.4 clock hours) and greater angle seeding (mean, 3.2 vs. 0 clock hours), producing elevated intraocular pressure <22 mmHg (17 vs. 0%). Monosomy 3 tumors showed mixed/epithelioid cell type in 80% versus 0% in Disomy 3 (P = 0.14). No patients developed local melanoma recurrence or melanoma-related metastasis or death in the short 16-month mean follow-up. CONCLUSION: Using fine needle aspiration biopsy, cytogenetic analysis can be achieved in iris melanoma. Iris melanoma demonstrated partial or complete Monosomy 3 in 71%, and this statistically correlated with increasing patients' age. Mixed/epithelioid cell type was far more commonly seen in patients with Monosomy 3, although this did not reach statistical significance.