Estimating the effect of realistic improvements of metformin adherence on COVID-19 mortality using targeted machine learning.

Background: Type 2 diabetes elevates the risk of severe outcomes in COVID-19 patients, with multiple studies reporting higher case fatality rates. Metformin is a widely used medication for glycemic management. We hypothesize that improved adherence to metformin may lower COVID-19 post-infection mortality risk in this group. Utilizing data from the Mexican Social Security Institute (IMSS), we investigate the relationship between metformin adherence and mortality following COVID-19 infection in patients with chronic metformin prescriptions. Methods: This is a retrospective cohort study consisting of 61,180 IMSS beneficiaries who received a positive polymerase chain reaction (PCR) or rapid test for SARS-CoV-2 and had at least two consecutive months of metformin prescriptions prior to the positive test. The hypothetical intervention is improved adherence to metformin, measured by proportion of days covered (PDC), with the comparison being the observed metformin adherence values. The primary outcome is all-cause mortality following COVID-19 infection. We defined the causal parameter using shift intervention, an example of modified treatment policies. We used the targeted learning framework for estimation of the target estimand. Findings: Among COVID-19 positive patients with chronic metformin prescriptions, we found that a 5% and 10% absolute increase in metformin adherence is associated with a respective 0.26% (95% CI: -0.28%, 0.79%) and 1.26% (95% CI: 0.72%, 1.80%) absolute decrease in mortality risk. Interpretation: Subject to the limitations of a real-world data study, our results indicate a causal association between improved metformin adherence and reduced COVID-19 post-infection mortality risk.

SARS-CoV-2 infection by trimester of pregnancy and adverse perinatal outcomes: a Mexican retrospective cohort study.

OBJECTIVE: Conflicting evidence for the association between COVID-19 and adverse perinatal outcomes exists. This study examined the associations between maternal COVID-19 during pregnancy and adverse perinatal outcomes including preterm birth (PTB), low birth weight (LBW), small-for-gestational age (SGA), large-for-gestational age (LGA) and fetal death; as well as whether the associations differ by trimester of infection. DESIGN AND SETTING: The study used a retrospective Mexican birth cohort from the Instituto Mexicano del Seguro Social (IMSS), Mexico, between January 2020 and November 2021. PARTICIPANTS: We used the social security administrative dataset from IMSS that had COVID-19 information and linked it with the IMSS routine hospitalisation dataset, to identify deliveries in the study period with a test for SARS-CoV-2 during pregnancy. OUTCOME MEASURES: PTB, LBW, SGA, LGA and fetal death. We used targeted maximum likelihood estimators, to quantify associations (risk ratio, RR) and CIs. We fit models for the overall COVID-19 sample, and separately for those with mild or severe disease, and by trimester of infection. Additionally, we investigated potential bias induced by missing non-tested pregnancies. RESULTS: The overall sample comprised 17 340 singleton pregnancies, of which 30% tested positive. We found that those with mild COVID-19 had an RR of 0.89 (95% CI 0.80 to 0.99) for PTB and those with severe COVID-19 had an RR of 1.53 (95% CI 1.07 to 2.19) for LGA. COVID-19 in the first trimester was associated with fetal death, RR=2.36 (95% CI 1.04, 5.36). Results also demonstrate that missing non-tested pregnancies might induce bias in the associations. CONCLUSIONS: In the overall sample, there was no evidence of an association between COVID-19 and adverse perinatal outcomes. However, the findings suggest that severe COVID-19 may increase the risk of some perinatal outcomes, with the first trimester potentially being a high-risk period.

How predictive of SARS-CoV-2 infection are clinical characteristics at presentation among individuals with COVID-like symptoms treated at the Mexican Institute of Social Security.

BACKGROUND: The COVID-19 pandemic has progressed rapidly, with the emergence of new virus variants that pose challenges in treating infected individuals. In Mexico, four epidemic waves have been recorded with varying disease severity. To understand the heterogeneity in clinical presentation over time and the sensitivity and specificity of signs and symptoms in identifying COVID-19 cases, an analysis of the changes in the clinical presentation of the disease was conducted. AIM: To analyze the changes in the clinical presentation of COVID-19 among 3.38 million individuals tested for SARS-CoV-2 at the Mexican Social Security Institute (IMSS) from March 2020 to October 2021 and evaluate the predictivity of signs and symptoms in identifying COVID-19 cases. METHODS: A retrospective analysis of clinical presentation patterns of COVID-19 among individuals treated at IMSS was performed, contrasting the signs and symptoms among SARS-CoV-2-positive individuals with those who tested negative for the virus but had respiratory infection symptoms. The sensitivity and specificity of each sign and symptom in identifying SARS-CoV-2 infection were estimated. RESULTS: The set of signs and symptoms reported for COVID-19-suspected patients treated at IMSS were not highly specific for SARS-CoV-2 positivity. The signs and symptoms exhibited variability based on age and epidemic wave. The area under the receiver operating characteristic (ROC) curve was 0.62 when grouping the five main symptoms (headache, dyspnea, fever, arthralgia, and cough). Most of the individual symptoms had ROC values close to 0.5 (16 out of 22 between 0.48 and 0.52), indicating non-specificity. CONCLUSIONS: The results highlight the difficulty in making a clinical diagnosis of COVID-19 due to the lack of specificity of signs and symptoms. The variability of clinical presentation over time and among age groups highlights the need for further research to differentiate whether the changes are due to changes in the virus, who is becoming infected, or the population, particularly with respect to prior infection and vaccination status.

Group psychedelic therapy: empirical estimates of cost-savings and improved access.

Objective: To compare group and individual psychedelic-assisted therapy in terms of clinician time, costs and patient access. Methods: Using 2023 data from two group therapy trial sites, one using 3,4-Methylenedioxymethamphetamine (MDMA) to treat posttraumatic stress disorder (PTSD), and one using psilocybin to treat major depressive disorder (MDD), we compared overall variable costs, clinician costs and clinician time required by therapy protocols utilizing groups versus individual patient therapy. Using published literature, we estimated the prevalence of adults with PTSD and MDD eligible for treatment with psychedelic therapy and projected the savings in time and cost required to treat these prevalent cases. Results: Group therapy saved 50.9% of clinician costs for MDMA-PTSD and 34.7% for psilocybin-MDD, or $3,467 and $981 per patient, respectively. To treat all eligible PTSD and MDD patients in the U.S. in 10 years with group therapy, 6,711 fewer full-time equivalent (FTE) clinicians for MDMA-PTSD and 1,159 fewer for FTE clinicians for psilocybin-MDD would be needed, saving up to $10.3 billion and $2.0 billion respectively, discounted at 3% annually. Conclusion: Adopting group therapy protocols where feasible would significantly reduce the cost of psychedelic-assisted therapies. By enhancing the number of patients served per clinician, group therapy could also ameliorate the anticipated shortage of appropriately trained clinicians, thereby accelerating access to these promising new therapies.

Changes in the epidemiological profile of SARS-CoV-2-positive individuals in Mexico across pandemic waves as an explanation of fatality reduction: a retrospective observational study.

OBJECTIVES: We aim to quantify shifts in hospitalisation and mortality and how those were related to the first three phases of the epidemic and individuals' demographics and health profile among those with a positive test for SARS-CoV-2 treated at the Mexican Social Security Institute's facilities from March 2020 to October 2021. DESIGN: Retrospective observational study using interrupted time series analysis to identify changes in hospitalisation rate and case fatality rate (CFR) by epidemic wave. SETTING: Data from the Mexican Institute of Social Security's (IMSS) Online Influenza Epidemiological Surveillance System (SINOLAVE) that include all individuals that sought care at IMSS facilities all over Mexico. PARTICIPANTS: All individuals included in the SINOLAVE with a positive PCR or rapid test for SARS-CoV-2. PRIMARY AND SECONDARY OUTCOME MEASURES: Monthly test positivity rates, hospitalisation rates, CFRs and prevalence of relevant comorbidities by age group. RESULTS: From March 2020 to October 2021, the CFR declined between 1% and 3.5%; the declines were significant for those 0-9, 20-29, 30-39, 40-49 and 70 and older. The decline was steep during the first wave and was less steep or was temporarily reversed at the beginning of the second and third waves (changes in the trend of about 0.3% and 3.8%, and between 0.7% and 3.8%, respectively, for some age groups), but then continued to the end of the analytical period. Prevalence of diabetes, hypertension and obesity among patients testing positive also declined-two for most age groups (reductions of up to 10 percentage points for diabetes, 12 percentage points for hypertension and 19 percentage points for obesity). CONCLUSION: Data suggest that the decrease in COVID-19 fatality rate is at least partially explained by a change in the profile of those contracting the disease, that is, a falling proportion of individuals with comorbidities across all age groups.

Evolution of differences in clinical presentation across epidemic waves among patients with COVID-like-symptoms who received care at the Mexican Social Security Institute.

Background: Timely monitoring of SARS-CoV-2 variants is crucial to effectively managing both prevention and treatment efforts. In this paper, we aim to describe demographic and clinical patterns of individuals with COVID-19-like symptoms during the first three epidemic waves in Mexico to identify changes in those patterns that may reflect differences determined by virus variants. Methods: We conducted a descriptive analysis of a large database containing records for all individuals who sought care at the Mexican Social Security Institute (IMSS) due to COVID-19-like symptoms from March 2020 to October 2021 (4.48 million records). We described the clinical and demographic profile of individuals tested (3.38 million, 32% with PCR and 68% with rapid test) by test result (positives and negatives) and untested, and among those tested, and the changes in those profiles across the first three epidemic waves. Results: Individuals with COVID-19-like symptoms were older in the first wave and younger in the third one (the mean age for those positive was 46.6 in the first wave and 36.1 in the third wave; for negatives and not-tested, the mean age was 41 and 38.5 in the first wave and 34.3 and 33.5 in the third wave). As the pandemic progressed, an increasing number of individuals sought care for suspected COVID-19. The positivity rate decreased over time but remained well over the recommended 5%. The pattern of presenting symptoms changed over time, with some of those symptoms decreasing over time (dyspnea 40.6 to 14.0%, cough 80.4 to 76.2%, fever 77.5 to 65.2%, headache 80.3 to 78.5%), and some increasing (odynophagia 48.7 to 58.5%, rhinorrhea 28.6 to 47.5%, anosmia 11.8 to 23.2%, dysgeusia 11.2 to 23.2%). Conclusion: During epidemic surges, the general consensus was that any individual presenting with respiratory symptoms was a suspected COVID-19 case. However, symptoms and signs are dynamic, with clinical patterns changing not only with the evolution of the virus but also with demographic changes in the affected population. A better understanding of these changing patterns is needed to improve preparedness for future surges and pandemics.

One vaccine to counter many diseases? Modeling the economics of oral polio vaccine against child mortality and COVID-19.

Introduction: Recent reviews summarize evidence that some vaccines have heterologous or non-specific effects (NSE), potentially offering protection against multiple pathogens. Numerous economic evaluations examine vaccines' pathogen-specific effects, but less than a handful focus on NSE. This paper addresses that gap by reporting economic evaluations of the NSE of oral polio vaccine (OPV) against under-five mortality and COVID-19. Materials and methods: We studied two settings: (1) reducing child mortality in a high-mortality setting (Guinea-Bissau) and (2) preventing COVID-19 in India. In the former, the intervention involves three annual campaigns in which children receive OPV incremental to routine immunization. In the latter, a susceptible-exposed-infectious-recovered model was developed to estimate the population benefits of two scenarios, in which OPV would be co-administered alongside COVID-19 vaccines. Incremental cost-effectiveness and benefit-cost ratios were modeled for ranges of intervention effectiveness estimates to supplement the headline numbers and account for heterogeneity and uncertainty. Results: For child mortality, headline cost-effectiveness was $650 per child death averted. For COVID-19, assuming OPV had 20% effectiveness, incremental cost per death averted was $23,000-65,000 if it were administered simultaneously with a COVID-19 vaccine <200 days into a wave of the epidemic. If the COVID-19 vaccine availability were delayed, the cost per averted death would decrease to $2600-6100. Estimated benefit-to-cost ratios vary but are consistently high. Discussion: Economic evaluation suggests the potential of OPV to efficiently reduce child mortality in high mortality environments. Likewise, within a broad range of assumed effect sizes, OPV (or another vaccine with NSE) could play an economically attractive role against COVID-19 in countries facing COVID-19 vaccine delays. Funding: The contribution by DTJ was supported through grants from Trond Mohn Foundation (BFS2019MT02) and Norad (RAF-18/0009) through the Bergen Center for Ethics and Priority Setting.

Non-communicable diseases and inequalities increase risk of death among COVID-19 patients in Mexico.

BACKGROUND: The SARS-CoV-2 pandemic compounds Mexico's pre-existing challenges: very high levels of both non-communicable diseases (NCD) and social inequity. METHODS AND FINDINGS: Using data from national reporting of SARS-CoV-2 tested individuals, we estimated odds of hospitalization, intubation, and death based on pre-existing non-communicable diseases and socioeconomic indicators. We found that obesity, diabetes, and hypertension are positively associated with the three outcomes in a synergistic manner. The municipal poverty level is also positively associated with hospitalization and death. CONCLUSIONS: Mexico's response to COVID-19 is complicated by a synergistic double challenge: raging NCDs and extreme social inequity. The response to the current pandemic must take both into account both to be effective and to ensure that the burden of COVID-19 not falls disproportionately on those who are already disadvantaged.

Willingness-to-accept reductions in HIV risks: conditional economic incentives in Mexico.

The objective of this study was to measure willingness-to-accept (WTA) reductions in risks for HIV and other sexually transmitted infections (STI) using conditional economic incentives (CEI) among men who have sex with men (MSM), including male sex workers (MSW) in Mexico City. A survey experiment was conducted with 1,745 MSM and MSW (18-25 years of age) who received incentive offers to decide first whether to accept monthly prevention talks and STI testing; and then a second set of offers to accept to stay free of STIs (verified by quarterly biological testing). The survey used random-starting-point and iterative offers. WTA was estimated with a maximum likelihood double-bounded dichotomous choice model. The average acceptance probabilities were: 73.9 % for the monthly model, and 80.4 % for the quarterly model. The incentive-elasticity of participation in the monthly model was 0.222, and 0.515 in the quarterly model. For a combination program with monthly prevention talks, and staying free of curable STI, the implied WTA was USD$ 288 per person per year, but it was lower for MSW: USD$ 156 per person per year. Thus, some of the populations at highest risk of HIV infection (MSM and MSW) seem well disposed to participate in a CEI program for HIV and STI prevention in Mexico. The average WTA estimate is within the range of feasible allocations for prevention in the local context. Given the potential impact, Mexico, a leader in conditional cash transfers for human development and poverty reduction, could extend that successful model to targeted HIV/STI prevention.

How the Avahan HIV prevention program transitioned from the Gates Foundation to the government of India.

Developing countries face diminishing development aid and time-limited donor commitments that challenge the long-term sustainability of donor-funded programs to improve the health of local populations. Increasing country ownership of the programs is one solution. Transitioning managerial and financial responsibility for donor-funded programs to governments and local stakeholders represents a highly advanced form of country ownership, but there are few successful examples among large-scale programs. We present a transition framework and describe how it was used to transfer the Bill & Melinda Gates Foundation's HIV/AIDS prevention program, the Avahan program, to the Government of India. Essential features recommended for the transition of donor-funded programs to governments include early planning with the government, aligning donor program components with government structures and funding models prior to transition, building government capacity through active technical and management support, budgeting for adequate support during and after the transition, and dividing the transition into phases to allow time for adjustments and corrections. The transition of programs to governments is an important sustainability strategy for efforts to scale up HIV prevention programs to reach the populations most at risk.

[Mixed design for the evaluation of the Mesoamerica Health 2015 initiative]. / Diseño mixto de evaluación de la iniciativa Salud Mesoamérica 2015.

Since the Salud Mesoamerica 2015 initiative (SM-2015) aim is to improve health and nutrition conditions of those most vulnerable in Mesoamerica, the goal of the evaluation is to generate evidence of the joint effectiveness of a package of interventions designed to improve the health conditions. We propose a mix design for the evaluation, which will allow to know the magnitude of changes attributable to the interventions, as well as the meanings of these changes for the target population, taking into account the specificities of each country. The main axis of this design is a locality panel where information about individuals, households, and health facilities (first and second level) will also be collected. The evaluation design described in this paper was developed between June and December, 2009, and it was integrated during workshops in Cuernavaca (Mexico), Managua (Nicaragua), and San Jose (Costa Rica). The proposed design will allow to generate evidence about the joint effectiveness of the package of interventions proposed for the SM-2015. The success of this design rests on the political commitment of countries and donors.

Diseño mixto de evaluación de la iniciativa Salud Mesoamérica 2015 / Mixed design for the evaluation of the Mesoamerica Health 2015 initiative

El propósito de la iniciativa Salud Mesoamérica 2015 (SM-2015) es mejorar el estado de salud y nutrición de la población con mayor grado de vulnerabilidad en Mesoamérica. El objetivo de la evaluación es generar evidencia sobre la efectividad conjunta de un paquete de intervenciones diseñadas para mejorar las condiciones de salud en la región. Se propone una evaluación de impacto con métodos mixtos, para conocer la magnitud de los cambios atribuibles a la SM-2015, e identificar los significados de estos cambios para la población objetivo, en el contexto de cada país. El eje conductor es un panel de localidades con el que se colectará información de individuos, hogares y unidades de salud de primero y segundo nivel de atención. El diseño que se describe en este documento fue desarrollado entre junio y diciembre de 2009, y su articulación se llevó a cabo en talleres realizados en Cuernavaca (México), Managua (Nicaragua), y San José (Costa Rica). El diseño propuesto permitirá generar evidencia sobre la efectividad conjunta del paquete de intervenciones propuesto en los planes maestros mesoamericanos. El éxito de este diseño radica en la voluntad y en el compromiso político de los países y los donantes.

Since the Salud Mesoamerica 2015 initiative (SM-2015) aim is to improve health and nutrition conditions of those most vulnerable in Mesoamerica, the goal of the evaluation is to generate evidence of the joint effectiveness of a package of interventions designed to improve the health conditions. We propose a mix design for the evaluation, which will allow to know the magnitude of changes attributable to the interventions, as well as the meanings of these changes for the target population, taking into account the specificities of each country. The main axis of this design is a locality panel where information about individuals, households, and health facilities (first and second level) will also be collected. The evaluation design described in this paper was developed between June and December, 2009, and it was integrated during workshops in Cuernavaca (Mexico), Managua (Nicaragua), and San Jose (Costa Rica). The proposed design will allow to generate evidence about the joint effectiveness of the package of interventions proposed for the SM-2015. The success of this design rests on the political commitment of countries and donors.

Optimizing HIV treatment programs.

PURPOSE OF REVIEW: Increasing demand for HIV treatment and limited resource availability will require the optimization of treatment programming to not only improve individual treatment outcomes, but also to maximize overall benefit for available resources. RECENT FINDINGS: Available research, although recognizing the importance of ensuring or improving treatment adherence, largely focuses on patient barriers or incentives. More research is necessary to examine how decisions made at all levels of treatment programming affect treatment outcomes. SUMMARY: Explicit decisions regarding treatment access, initiation, drug combinations, and potential termination of treatment along with addressing incentives and barriers to treatment adherence are necessary to maximize the overall benefit for available resources. This factor will depend on the involvement of the three main treatment actors, program managers, health practitioners, and patients.

[Cost-effectiveness of breast cancer screening policies in Mexico]. / Costo-efectividad de políticas para el tamizaje de cáncer de mama en México.

OBJECTIVE: Generate cost-effectiveness information to allow policy makers optimize breast cancer (BC) policy in Mexico. MATERIAL AND METHODS: We constructed a Markov model that incorporates four interrelated processes of the disease: the natural history; detection using mammography; treatment; and other competing-causes mortality, according to which 13 different strategies were modeled. RESULTS: Strategies (starting age, % of coverage, frequency in years)= (48, 25, 2), (40, 50, 2) and (40, 50, 1) constituted the optimal method for expanding the BC program, yielding 75.3, 116.4 and 171.1 thousand pesos per life-year saved, respectively. CONCLUSIONS: The strategies included in the optimal method for expanding the program produce a cost per life-year saved of less than two times the GNP per capita and hence are cost-effective according to WHO Commission on Macroeconomics and Health criteria.

HIV prevention cost-effectiveness: a systematic review.

BACKGROUND: After more than 25 years, public health programs have not been able to sufficiently reduce the number of new HIV infections. Over 7,000 people become infected with HIV every day. Lack of convincing evidence of cost-effectiveness (CE) may be one of the reasons why implementation of effective programs is not occurring at sufficient scale. This paper identifies, summarizes and critiques the CE literature related to HIV-prevention interventions in low- and middle-income countries during 2005-2008. METHODS: Systematic identification of publications was conducted through several methods: electronic databases, internet search of international organizations and major funding/implementing agencies, and journal browsing. Inclusion criteria included: HIV prevention intervention, year for publication (2005-2008), setting (low- and middle-income countries), and CE estimation (empirical or modeling) using outcomes in terms of cost per HIV infection averted and/or cost per disability-adjusted life year (DALY) or quality-adjusted life year (QALY). RESULTS: We found 21 distinct studies analyzing the CE of HIV-prevention interventions published in the past four years (2005-2008). Seventeen CE studies analyzed biomedical interventions; only a few dealt with behavioral and environmental/structural interventions. Sixteen studies focused on sub-Saharan Africa, and only a handful on Asia, Latin America and Eastern Europe. Many HIV-prevention interventions are very cost effective in absolute terms (using costs per DALY averted), and also in country-specific relative terms (in cost per DALY measured as percentage of GDP per capita). CONCLUSION: There are several types of interventions for which CE studies are still not available or insufficient, including surveillance, abstinence, school-based education, universal precautions, prevention for positives and most structural interventions. The sparse CE evidence available is not easily comparable; thus, not very useful for decision making. More than 25 years into the AIDS epidemic and billions of dollars of spending later, there is still much work to be done both on costs and effectiveness to adequately inform HIV prevention planning.