Caveats Regarding the Test-Negative Design to Study Mpox (monkeypox) Risk Factors and Vaccine Effectiveness.

The test-negative design (TND) has been commonly used to study vaccine effectiveness (notably regarding COVID-19 and influenza vaccines) and has been recently proposed as a valid design to study causal risk factors of diseases during an outbreak. In April 2022, mpox (previously monkeypox) led to a worldwide outbreak that resulted in an international public health emergency. The TND could be used to study vaccine effectiveness and risk factors of mpox using epidemiologic databases, and a few studies have already done so. However, several issues prevent such study design from being valid for this end. Problems stem from stigma surrounding mpox, which impacts a person's decision to look for healthcare. This poses a challenge to the "similar healthcare seeking behaviour" assumption that is central for test negative studies. Further limitations include the differential diagnoses of mpox, which have notable differences from mpox that may be easily detected by clinicians or patients but are unlikely to be included in epidemiologic databases or electronic health records. Herein I discuss caveats regarding the use of the TND in the context of the mpox outbreak, as well as potential steps that may allow it to be used effectively.

Prevalence and spectrum of germline pathogenic variants in cancer susceptibility genes among mexican patients with exocrine pancreatic cancer.

BACKGROUND: Although universal germline genetic testing is recommended for patients with exocrine pancreatic cancer (PC), access to genetic testing remains limited in low- and middle-income countries. This study aims to narrow the gap in our understanding of the spectrum of germline pathogenic and likely pathogenic variants (PVs) in cancer susceptibility genes in the Mexican population. METHODS: The landscape of PVs in cancer susceptibility genes was identified by next-generation sequencing multigene panel assays among patients with PC who were enrolled in the Clinical Cancer Genomics Community Research Network prospective registry in Mexico City. RESULTS: From August 2019 to April 2023, 137 patients underwent genetic testing. The median age at diagnosis was 60 years (range 36-85), 58.4 % were women, and 38.7 % were metastatic at diagnosis. The frequency of germline PVs was 16 % (n = 22): ATM 36.4 % (n = 8), CDKN2A/p16INK4A 27.3 % (n = 6), BRCA2 9.1 % (n = 2), PALB2 9.1 % (n = 2), CHEK2 9.1 % (n = 2), TP53 4.5 % (n = 1), and NF1 4.5 % (n = 1). Additionally, 2 carriers of monoallelic germline variants in MUTYH were identified. No significant differences were observed between carriers and non-carriers in terms of family history of pancreatic cancer. CONCLUSIONS: We identified a significant frequency of actionable germline PVs in Mexicans with PC, wherein the majority were in a broad spectrum of genes associated with the homologous recombination DNA repair mechanism. Most pancreatic cancer associated PVs were detected in non-BRCA genes, so our findings support the recommendation of multigene panel testing for genetic cancer risk assessment of Mexican individuals with PC.

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.

Preventable sources of bias in subgroup analyses and secondary outcomes of randomized trials.

BACKGROUND: Randomized controlled trials are the gold standard for determining treatment efficacy in medicine. To deter harmful practices such as p-hacking and hypothesizing after the results are known, any analysis of subgroups and secondary outcomes must be documented and pre-specified. However, they can still introduce bias (and routinely do) if they are not treated with the same consideration as the primary analysis. METHODS: We describe several sources of bias that affect subgroup and secondary outcome analyses using published randomized trials and causal directed acyclic graphs (DAGs). RESULTS: We use the RECOVERY and START trials to elucidate sources of bias in analyses of subgroups and secondary outcomes. Chance imbalance can occur if the distribution of prognostic variables is not sought for any given subgroup analysis as for the main analysis. This differential distribution of prognostic variables can also occur in analyses of secondary outcomes. Selection bias can occur if the subgroup variable is causally related to staying in the trial. Given loss to follow up is not normally addressed in subgroups, attrition bias can pass unnoticed in these cases. In every case, the solution is to take the same considerations for these analyses as we do for primary analyses. CONCLUSIONS: Approval of treatments and clinical decisions can occur based on results from subgroup or secondary outcome analyses. Thus, it is important to give them the same treatment as primary analyses to avoid preventable biases.

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.

Comparative Effectiveness of Switching to Bictegravir From Dolutegravir-, Efavirenz-, or Raltegravir-Based Antiretroviral Therapy Among Individuals With HIV Who are Virologically Suppressed.

Background: We aimed to determine the effectiveness of switching to bictegravir in maintaining an undetectable viral load (<50 copies/mL) among people with HIV (PWH) as compared with continuing dolutegravir-, efavirenz-, or raltegravir-based antiretroviral therapy using nationwide observational data from Mexico. Methods: We emulated 3 target trials comparing switching to bictegravir vs continuing with dolutegravir, efavirenz, or raltegravir. Eligibility criteria were PWH aged ≥16 years with a viral load <50 copies/mL and at least 3 months of current antiretroviral therapy (dolutegravir, efavirenz, or raltegravir) between July 2019 and September 2021. Weekly target trials were emulated during the study period, and individuals were included in every emulation if they continued to be eligible. The main outcome was the probability of an undetectable viral load at 3 months, which was estimated via an adjusted logistic regression model. Estimated probabilities were compared via differences, and 95% CIs were calculated via bootstrap. Outcomes were also ascertained at 12 months, and sensitivity analyses were performed to test our analytic choices. Results: We analyzed data from 3 028 619 PWH (63 581 unique individuals). The probability of an undetectable viral load at 3 months was 2.9% (95% CI, 1.9%-3.8%), 1.3% (95% CI, .9%-1.6%), and 1.2% (95% CI, .8%-1.7%) higher when switching to bictegravir vs continuing with dolutegravir, efavirenz, and raltegravir, respectively. Similar results were observed at 12 months and in other sensitivity analyses. Conclusions: Our findings suggest that switching to bictegravir could be more effective in maintaining viral suppression than continuing with dolutegravir, efavirenz, or raltegravir.