Challenges to the HIV Care Continuum During the COVID-19 Pandemic in Mexico: A Mixed Methods Study.

The COVID-19 pandemic has been reported to disrupt the access to care of people who live with HIV (PWH). The impact of the pandemic on the longitudinal HIV care continuum, however, has not been properly evaluated. We performed a mixed-methods study using data from the Mexican System of Distribution, Logistics, and ART Surveillance on PWH that are cared for in the state of Oaxaca. We evaluated the number of HIV diagnoses performed in the state before and during the pandemic with an interrupted time series. We used the longitudinal HIV care continuum framework to describe the stages of HIV care before and during the pandemic. Finally, we performed a qualitative analysis to determine which were the challenges faced by staff and users regarding HIV care during the pandemic. New HIV diagnoses were lower during the first year of the pandemic compared with the year immediately before. Among 2682 PWH with enough information to determine their status of care, 728 started receiving care during the COVID-19 pandemic and 1954 before the pandemic. PWH engaged before the pandemic spent 42825 months (58.2% of follow-up) in optimal HIV control compared with 3061 months (56.1% of follow-up) for those engaged in care during the pandemic. Staff and users reported decreases in the frequency of appointments, prioritisation of unhealthy users, larger disbursements of ART medication, and novel communication strategies with PWH. Despite challenges due to government cutbacks, changes implemented by staff helped maintain HIV care due to higher flexibility in ART delivery and individualised attention.

The importance of using disease causal models in studies of preventive interventions: Learning from preeclampsia research.

OBJECTIVE: Interventions aimed at preventing disease are commonly studied as strategies of primary or secondary prevention. Unfortunately, this dichotomy can be misleading, and studies might unknowingly exclude people at high risk of the disease that could benefit from the intervention. Here I use the example of aspirin for prevention of preeclampsia to illustrate this problem. METHODS: I use directed acyclic graphs to represent several causal models of aspirin and preeclampsia, each making different assumptions regarding the causal relation between previous preeclampsia, aspirin, and subsequent preeclampsia. Afterwards, I discuss the implications of each model. RESULTS: Aspirin started being recommended to pregnant women that had presented preeclampsia in previous pregnancies, but not to women at high risk due to other factors. Studies started evaluating aspirin in women at high risk due to these other causes and found it also reduced the risk of preeclampsia in them. Thanks to a shift towards risk-based interventions, guidelines started recommending aspirin to all women considered at high risk of preeclampsia. Furthermore, recent studies have begun using blood markers in women without classic risk factors to identify additional women that might benefit from aspirin. With such advances, performing "secondary prevention" once the first event occurred will increasingly represent a failure to intervene on time. CONCLUSIONS: Explicitly illustrating disease causal models helps to identify those individuals that are most likely to benefit from risk reduction, regardless of whether they were previously afflicted by the disease. This is beneficial when designing studies and when implementing preventive interventions.

Pyridostigmine reduces mortality of patients with severe SARS-CoV-2 infection: A phase 2/3 randomized controlled trial.

BACKGROUND: Respiratory failure in severe coronavirus disease 2019 (COVID-19) is associated with a severe inflammatory response. Acetylcholine (ACh) reduces systemic inflammation in experimental bacterial and viral infections. Pyridostigmine increases the half-life of endogenous ACh, potentially reducing systemic inflammation. We aimed to determine if pyridostigmine decreases a composite outcome of invasive mechanical ventilation (IMV) and death in adult patients with severe COVID-19. METHODS: We performed a double-blinded, placebo-controlled, phase 2/3 randomized controlled trial of oral pyridostigmine (60 mg/day) or placebo as add-on therapy in adult patients admitted due to confirmed severe COVID-19 not requiring IMV at enrollment. The primary outcome was a composite of IMV or death by day 28. Secondary outcomes included reduction of inflammatory markers and circulating cytokines, and 90-day mortality. Adverse events (AEs) related to study treatment were documented and described. RESULTS: We recruited 188 participants (94 per group); 112 (59.6%) were men; the median (IQR) age was 52 (44-64) years. The study was terminated early due to a significant reduction in the primary outcome in the treatment arm and increased difficulty with recruitment. The primary outcome occurred in 22 (23.4%) participants in the placebo group vs. 11 (11.7%) in the pyridostigmine group (hazard ratio, 0.47, 95% confidence interval 0.24-0.9; P = 0.03). This effect was driven by a reduction in mortality (19 vs. 8 deaths, respectively). CONCLUSION: Our data indicate that adding pyridostigmine to standard care reduces mortality among patients hospitalized for severe COVID-19.

Seizures following COVID-19 vaccination in Mexico: A nationwide observational study.

The COVID-19 pandemic led to the development and emergency approval of an array of effective vaccines against SARS-CoV-2. Given the relatively small number of patients included in vaccine trials, postapproval epidemiological surveillance is crucial to detect infrequent vaccine-related adverse events. We conducted a nationwide retrospective descriptive study evaluating the incidence of seizures among recipients of SARS-CoV-2 vaccines in Mexico from December 24, 2020 (date of administration of first doses nationwide) to October 29, 2021. Among 81 916 351 doses of any vaccine that were administered, we documented seizures in 53 patients, of which 31 (60%) were new onset seizures. The incidence rate of seizures per million doses was highest for mRNA-1273 (Moderna) with 2.73 per million, followed by BNT162b2 (Pfizer-BioNTech) with 1.02 per million, and Ad5-nCoV (CanSino) with 1.01 per million. Thus, we found that seizures following SARS-CoV-2 vaccination are exceedingly rare events.

Incidence of Guillain-Barré syndrome following SARS-CoV-2 immunization: Analysis of a nationwide registry of recipients of 81 million doses of seven vaccines.

BACKGROUND AND PURPOSE: Information on Guillain-Barré syndrome (GBS) as an adverse event following immunization (AEFI) against SARS-CoV-2 remains scarce. We aimed to report GBS incidence as an AEFI among adult (≥18 years) recipients of 81,842,426 doses of seven anti-SARS-CoV-2 vaccines between December 24, 2020, and October 29, 2021, in Mexico. METHODS: Cases were retrospectively collected through passive epidemiological surveillance. The overall observed incidence was calculated according to the total number of administered doses. Vaccines were analyzed individually and by vector as mRNA-based (mRNA-1273 and BNT162b2), adenovirus-vectored (ChAdOx1 nCov-19, rAd26-rAd5, Ad5-nCoV, and Ad26.COV2-S), and inactivated whole-virion-vectored (CoronaVac) vaccines. RESULTS: We identified 97 patients (52 males [53.6%]; median [interquartile range] age 44 [33-60] years), for an overall observed incidence of 1.19/1,000,000 doses (95% confidence interval [CI] 0.97-1.45), with incidence higher among Ad26.COV2-S (3.86/1,000,000 doses, 95% CI 1.50-9.93) and BNT162b2 recipients (1.92/1,00,000 doses, 95% CI 1.36-2.71). The interval (interquartile range) from vaccination to GBS symptom onset was 10 (3-17) days. Preceding diarrhea was reported in 21 patients (21.6%) and mild COVID-19 in four more (4.1%). Only 18 patients were tested for Campylobacter jejuni (positive in 16 [88.9%]). Electrophysiological examinations were performed in 76 patients (78.4%; axonal in 46 [60.5%] and demyelinating in 25 [32.8%]); variants were similar across the platforms. On admission, 91.8% had a GBS disability score ≥3. Seventy-five patients (77.3%) received intravenous immunoglobulin, received seven plasma exchange (7.2%), and 15 (15.5%) were treated conservatively. Ten patients (10.3%) died, and 79.1% of survivors were unable to walk independently. CONCLUSIONS: Guillain-Barré syndrome was an extremely infrequent AEFI against SARS-CoV-2. The protection provided by these vaccines outweighs the risk of developing GBS.

Result Turnaround Time of RT-PCR for SARS-CoV-2 is the Main Cause of COVID-19 Diagnostic Delay: A Country-Wide Observational Study of Mexico and Colombia.

BACKGROUND: Delay in COVID-19 diagnosis due to late real-time reverse transcription-polymerase chain reaction reporting has been described to be an important cause of suboptimal COVID-19 surveillance and outbreak containment. OBJECTIVE: The objective of the study was to determine the duration of diagnostic delay due to test turnaround time and its association with marginalization status. METHODS: In this observational study using national open data of Mexico and Colombia, we quantified the delay in COVID-19 diagnosis that occurred in both countries. We considered two periods that contributed to the delay in diagnosis: the time from symptom onset until testing (delay-one) and test turnaround time (delay-two). Marginalization status was determined according to country-specific scores. RESULTS: Among 3,696,773 patients from Mexico and Colombia, delay-two was generally longer than delay-one. Median delay-one was 3 days and delay-two 7 days in Colombia, while in Mexico, they were 3 days and 4 days, respectively. In Colombia, worse marginalization status prolonged delaytwo. In Mexico, a lower number and percentage of rapid tests were performed in areas with worse marginalization. CONCLUSION: Diagnostic delay was mostly due to test turnaround time. Marginalization status was an important barrier to diagnostic test access.

Common hematological values predict unfavorable outcomes in hospitalized COVID-19 patients.

COVID-19 can range from asymptomatic to life-threatening. Early identification of patients who will develop severe disease is crucial. A number of scores and indexes have been developed to predict severity. However, most rely on measurements not readily available. We evaluated hematological and biochemical markers taken on admission and determined how predictive they were of development of critical illness or death. We observed that higher values of readily available tests, including neutrophil:lymphocyte ratio; derived neutrophil index; and troponin I were associated with a higher risk of death or critical care admission (P < 0.001). We show that common hematological tests can be helpful in determining early in the course of illness which patients are likely to develop severe forms, as well as allocating resources to those patients early, while avoiding overuse of limited resources in patients with reduced risk of progression to severe disease.

Neurologic adverse events among 704,003 first-dose recipients of the BNT162b2 mRNA COVID-19 vaccine in Mexico: A nationwide descriptive study.

mRNA vaccines against SARS-CoV-2 are remarkably effective. Limited information exists about the incidence of adverse events following immunization (AEFI) with their use. We conducted a prospective observational study including data from 704,003 first-doses recipients; 6536 AEFI were reported, of whom 65.1% had at least one neurologic AEFI (non-serious 99.6%). Thirty-three serious events were reported; 17 (51.5%) were neurologic (observed frequency, 2.4/100,000 doses). At the time of writing this report, 16/17 cases had been discharged without deaths. Our data suggest that the BNT162b2 mRNA COVID-19 vaccine is safe; its individual and societal benefits outweigh the low percentage of serious neurologic AEFI. This information should help to dissipate hesitancy towards this new vaccine platform.

A parallel-group, multicenter randomized, double-blinded, placebo-controlled, phase 2/3, clinical trial to test the efficacy of pyridostigmine bromide at low doses to reduce mortality or invasive mechanical ventilation in adults with severe SARS-CoV-2 infection: the Pyridostigmine In Severe COvid-19 (PISCO) trial protocol.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the causative agent of coronavirus disease 2019 (COVID-19), may lead to severe systemic inflammatory response, pulmonary damage, and even acute respiratory distress syndrome (ARDS). This in turn may result in respiratory failure and in death. Experimentally, acetylcholine (ACh) modulates the acute inflammatory response, a neuro-immune mechanism known as the inflammatory reflex. Recent clinical evidence suggest that electrical and chemical stimulation of the inflammatory reflex may reduce the burden of inflammation in chronic inflammatory diseases. Pyridostigmine (PDG), an ACh-esterase inhibitor (i-ACh-e), increases the half-life of endogenous ACh, therefore mimicking the inflammatory reflex. This clinical trial is aimed at evaluating if add-on of PDG leads to a decrease of invasive mechanical ventilation and death among patients with severe COVID-19. METHODS: A parallel-group, multicenter, randomized, double-blinded, placebo-controlled, phase 2/3 clinical trial to test the efficacy of pyridostigmine bromide 60 mg/day P.O. to reduce the need for invasive mechanical ventilation and mortality in hospitalized patients with severe COVID-19. DISCUSSION: This study will provide preliminary evidence of whether or not -by decreasing systemic inflammation- add-on PDG can improve clinical outcomes in patients with severe COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04343963 (registered on April 14, 2020).

Impact of RT-PCR Test False-Negative Results for SARS-CoV-2 Surveillance in Mexico.

Background: Underestimation of the number of cases during the coronavirus disease 2019 (COVID-19) pandemic has been a constant concern worldwide. Detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA using realtime reverse-transcription polymerase chain reaction (RT-PCR) is the most common method to confirm a case. However, these tests have suboptimal sensitivity. Objective: The objective of the study was to estimate the number of COVID-19 confirmed cases, intensive care unit (ICU) admissions and deaths in Mexico, accounting for the probabilities of false-negative tests. Methods: We used publicly available, national databases of all SARS-CoV-2 tests performed at public laboratories in Mexico between February 27 and October 31, 2020. We used the estimated probabilities of false-negative tests based on the day of clinical sample collection after symptom initiation calculated previously. With the resulting model, we estimated the corrected daily number of cases, ICU admissions, and deaths. Results: Among 2,024,822 people tested in Mexico between February 27 and October 31 with an available result, we estimated 1,248,583 (95% confidence interval 1,094,850-1,572,818) cases, compared to 902,343 cases reported with positive tests. ICU admissions and deaths were 15% and 8% higher than reported, respectively. Conclusion: Accounting for SARS-CoV-2 RT-PCR-based diagnostic tests' precision is a simple way to improve estimations for the true number of COVID-19 cases among tested persons.

Role of immunotherapy in castration-resistant prostate cancer (CRPC).

Initial therapy for metastatic prostate cancer consists of androgenic suppression. However, this is only a palliative treatment with an effective duration that usually lasts 12-24 months. Historically, castration-resistant prostate cancer (CRPC) had been considered a chemoresistant tumour. In 2004, docetaxel received USA Food and Drug Administration approval as a first-line treatment for metastatic prostate cancer, after two independent phase III trials showed an increased survival benefit. Recently, five new drugs have shown increased survival in CRPC: sipuleucel-T (assymptomatic or minimally symptomatic), abiraterone acetate (before and after docetaxel), cabazitaxel (after docetaxel), MDV3100 (after docetaxel) and radium-223 (not suitable for docetaxel or after docetaxel). The identification of antigens in normal prostate tissue or prostate cancer that are recognised by immune effectors cells has resulted in several new studies based on immunotherapy. Prostate cancer disease provides a test system to determine the efficacy of vaccines for different reasons. This cancer is a tumour that grows relatively slowly. Recurrence is often diagnosed early (with many patients presenting only with biochemical progression), there is a biological marker that can predict prognosis and outcome (PSA doubling time), various specific antigens have been identified and characterised, and vaccines can be used with a good safety profile combined with anti-androgen therapy, chemotherapy, or radiotherapy. Here we provide a review of the main important immune treatments in CRPC.

Retiring the term AIDS for more descriptive language.

The term acquired immunodeficiency syndrome (AIDS) was coined to describe a condition marked by weakened cell-mediated immunity in the absence of a clear cause. Due to unfortunate messaging during the early days of the HIV epidemic, this term became loaded with stigma. After the discovery of HIV, the term AIDS became redundant, but its use has persisted and has come to embody negative connotations in the current landscape of the HIV epidemic. People commonly associate AIDS with a terminal illness. This misconception promotes stigma by others, including health-care workers, but also self-stigma, which can prevent individuals from accessing health care. Also, the link between AIDS and gay men generated during the early epidemic with use of the term gay-related immune disorder is misleading regarding which populations are at risk, which can delay diagnosis. The use of the term AIDS is now discouraged by several professional associations, some of which ironically have the word as part of their name. Ending use of the term AIDS would not eradicate stigma. However, this term has outlasted its usefulness, and we should transition towards more descriptive language that aligns with contemporary challenges in HIV.

Genetic Network Design Automation with LOICA.

Genetic design automation (GDA) is the use of computer-aided design (CAD) in designing genetic networks. GDA tools are necessary to create more complex synthetic genetic networks in a high-throughput fashion. At the core of these tools is the abstraction of a hierarchy of standardized components. The components' input, output, and interactions must be captured and parametrized from relevant experimental data. Simulations of genetic networks should use those parameters and include the experimental context to be compared with the experimental results.This chapter introduces Logical Operators for Integrated Cell Algorithms (LOICA), a Python package used for designing, modeling, and characterizing genetic networks using a simple object-oriented design abstraction. LOICA represents different biological and experimental components as classes that interact to generate models. These models can be parametrized by direct connection to the Flapjack experimental data management platform to characterize abstracted components with experimental data. The models can be simulated using stochastic simulation algorithms or ordinary differential equations with varying noise levels. The simulated data can be managed and published using Flapjack alongside experimental data for comparison. LOICA genetic network designs can be represented as graphs and plotted as networks for visual inspection and serialized as Python objects or in the Synthetic Biology Open Language (SBOL) format for sharing and use in other designs.

Flapjack: Data Management and Analysis for Genetic Circuit Characterization.

Flapjack presents a valuable solution for addressing challenges in the Design, Build, Test, Learn (DBTL) cycle of engineering synthetic genetic circuits. This platform provides a comprehensive suite of features for managing, analyzing, and visualizing kinetic gene expression data and associated metadata. By utilizing the Flapjack platform, researchers can effectively integrate the test phase with the build and learn phases, facilitating the characterization and optimization of genetic circuits. With its user-friendly interface and compatibility with external software, the Flapjack platform offers a practical tool for advancing synthetic biology research.This chapter provides an overview of the data model employed in Flapjack and its hierarchical structure, which aligns with the typical steps involved in conducting experiments and facilitating intuitive data management for users. Additionally, this chapter offers a detailed description of the user interface, guiding readers through accessing Flapjack, navigating its sections, performing essential tasks such as uploading data and creating plots, and accessing the platform through the pyFlapjack Python package.

Clinical features and outcomes of mpox in people with and without HIV: a national comparative study.

BACKGROUND: People who live with HIV (PWLH) have been one of the most affected groups during the current mpox outbreak. They are hypothesized to have a more severe clinical course than people without HIV but comparative data is scarce. We aimed to compare clinical features and outcomes of mpox in people with and without HIV in Mexico. SETTING: Country-wide study in Mexico. METHODS: We performed an observational study using nation-wide epidemiological data. We included all people with confirmed mpox diagnosed between May and November 2022 in Mexico. Clinical and sociodemographic characteristics were compared between people with and without HIV. Multivariable logistic regression models were preformed to determine the association between HIV, clinical features, and outcomes and reported with odds ratios (ORs) and 95% confidence intervals (95% CI). ORs for rare outcomes were interpreted as risk ratios. RESULTS: Among 3291 people with mpox, 59% were PWLH. PWLH had an increased risk of severe mpox (OR 2.6, 2.4-2.9) and death (OR 10.8, 9.7-11.9). They also had a higher risk of otalgia, proctitis, and urethritis. Eleven individuals died, of whom ten were PWLH. All deaths were directly attributed to mpox. CONCLUSION: People with HIV have a higher risk of severe mpox and death due to mpox.

Home or hospital? An observational study of what affects the place of death of people with COVID-19 in Mexico.

BACKGROUND: Out-of-hospital deaths increased during peak coronavirus disease 2019 (COVID-19) pandemic periods. However, aside from COVID-19 severity, which variables are related to being hospitalized have not been properly studied. We examine the association of several variables with dying at home from COVID-19 as opposed to in a hospital. METHODS: We used COVID-19 open data from Mexico City from March 2020 until February 2021. A causal model was prespecified to identify variables of interest. Adjusted logistic regressions were performed to calculate ORs for associations between variables of interest and dying out of hospital due to COVID-19. RESULTS: Among 61 112 people who died due to COVID-19, 8080 died out of hospital. Older age (OR 3.49, age 90 vs 60 y), male sex (OR 1.18) and higher bed occupancy (OR 2.68, 90% vs 50% occupancy) were positively associated with dying outside of hospital. CONCLUSION: Older age could confer different patient wishes or less ability to look for healthcare. Higher bed occupancy may have prevented hospital admission from people who required in-hospital care.