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Abstract Tuberculosis (TB) poses a significant global health threat, with high mortality rates if left untreated. Current sputum-based TB treatment monitoring methods face numerous challenges, particularly in relation to sample collection and analysis. This pilot study explores the potential of TB status assessment using DNA methylation (DNAm) signatures, which are gaining recognition as diagnostic and predictive tools for various diseases. We collected buccal swab samples from pulmonary TB patients at the commencement of TB treatment (n = 10), and at one, two, and six-month follow-up intervals. We also collected samples from healthy controls (n = 10) and individuals exposed to TB (n = 10). DNAm patterns were mapped using the Illumina Infinium Methylation EPIC 850 K platform. A DNAm profile distinct from controls was discovered in the oral mucosa of TB patients at the start of treatment, and this profile changed throughout the course of TB treatment. These findings were corroborated in a separate validation cohort of TB patients (n = 41), monitored at two and six months into their TB treatment. We developed a machine learning model to predict symptom scores using the identified DNAm TB profile. The model was trained and evaluated on the pilot, validation, and two additional independent cohorts, achieving an R2 of 0.80, Pearson correlation of 0.90, and mean absolute error of 0.13. While validation is needed in larger cohorts, the result opens the possibility of employing DNAm-based diagnostic and prognostic tools for TB in future clinical practice.

Abstract Background Access to essential diagnostics is crucial for primary healthcare (PHC) in low-and-middle income countries (LMICs). Many LMICs have invested in equipping PHC with point-of-care (PoC) diagnostics for infectious diseases, however there has been no similar investment to improve PHC capacities for clinical chemistry. The biochemistry gap is among the deterrents to universal health coverage. Methods A social sciences project was conducted with the aim to understand the key PHC stakeholders’ insights on the pertinence of PoC biochemistry for PHC in LMICs. Data generation was conducted between July-November 2023 in Mongolia, Nigeria and Peru. Decision-makers in healthcare delivery, healthcare professionals, and patient and community advocates were engaged using a combination of sampling techniques. Unstructured individual and group conversations, and non-participant observation were conducted. Analysis involved an inductive line-by-line coding on printed transcripts, followed by a deductive coding and theme-by-theme analysis on digitized transcripts. Results Fifteen, 51 and 20 informants from Mongolia, Nigeria and Peru, respectively, participated. Fifty-five of the 94 informants were female. Most informants considered that PoC biochemistry in PHC would be pertinent, from a clinical and a resources-saving perspective. Those households that currently bear the burden of referrals (i.e., the poor, the bedridden, the older adults) would benefit the most from the deployment of PoC biochemistry for essential biochemistry parameters. Improved access to PoC glycated hemoglobin (HbA1c), lipid, liver and kidney profile was perceived as helpful to inform clinicians’ decision-taking. The value of PoC biochemistry for the management of noncommunicable diseases (diabetes, hypertension) and infectious conditions (dengue, malaria, tuberculosis), to improve child health outcomes (severe dehydration in children with diarrhea and/or malnutrition) and to reduce preventable causes of death (dengue-related renal failure) was highlighted. Conclusions PoC biochemistry holds potential to revert the impact that the biochemistry gap has for patient care in some LMICs’ PHC settings. PoC equipment for parameters such as HbA1c, urea, creatinine or electrolytes could enhance community-level management of preventable causes of mortality, improve service delivery for patients affected by locally-prevalent infectious conditions, and improve the psychosocial and economic wellbeing of patients facing the burden of referrals to remote biochemistry-equipped centers. Trial Registration Not applicable.

This review provides a comprehensive summary of evidence to explore the role and value of differential diagnosis in the management of Acute Respiratory Infections (ARIs) through point-of-care (POC) rapid testing in a post-pandemic scenario, paying particular attention to coronavirus disease 2019 (COVID-19), influenza, and respiratory syncytial virus (RSV). The document builds on a review of literature and policies and a process of validation and feedback by a group of seven experts from Latin America (LATAM). Evidence was collected to understand scientific and policy perspectives on the differential diagnosis of ARIs and POC rapid testing, with a focus on seven countries: Argentina, Brazil, Chile, Colombia, Costa Rica, Mexico, and Peru. The evidence indicates that POC rapid testing can serve to improve ARI case management, epidemiological surveillance, research and innovation, and evidence-based decision-making. With multiple types of rapid tests available for POC, decisions regarding which tests to use require the consideration of the testing purpose, available resources, and test characteristics regarding accuracy, accessibility, affordability, and results turnaround time. Based on the understanding of the current situation, this document provides a set of recommendations for the implementation of POC rapid testing in LATAM, supporting decision-making and guiding efforts by a broad range of stakeholders.

ObjectivesThe COVID-19 pandemic caused a global shortage of nasopharyngeal (NP) swabs, required for RT-PCR testing. Canadian manufacturers were contacted to share NP swab innovations. The primary objective was to determine whether novel NP test swabs were comparable to commercially available swabs regarding user characteristics, ability to collect a specimen, and diagnostic performance using RT-PCR testing.MethodsParticipants were randomized by swab (test/control) and nostril (left/right). A calculated positive percent agreement ≥90% was considered successful. Mean Ct values of viral genes and housekeeping gene (RNase P) were considered similar if a Ct difference ≤ 2 between control and test group was obtained. There also was a qualitative assessment of swabs usability.Results647 participants were enrolled from Huaycan Hospital in Lima, Peru, distributed over 8 NP swabs brands. Seven brands agreed to share their results. There were no statistically significant differences between the test swabs of these 7 brands and control swabs.ConclusionAll the seven brands are comparable to the commercially available flocked swabs used for SARS-CoV-2 regarding test results agreement, ability to collect a specimen, and user characteristics.

There are initiatives to promote the creation of predictive COVID-19 fatality models to assist decision-makers. The study aimed to develop prediction models for COVID-19 fatality using population data recorded in the national epidemiological surveillance system of Peru. A retrospective cohort study was conducted (March to September of 2020). The study population consisted of confirmed COVID-19 cases reported in the surveillance system of nine provinces of Lima, Peru. A random sample of 80% of the study population was selected, and four prediction models were constructed using four different strategies to select variables: 1) previously analyzed variables in machine learning models; 2) based on the LASSO method; 3) based on significance; and 4) based on a post-hoc approach with variables consistently included in the three previous strategies. The internal validation was performed with the remaining 20% of the population. Four prediction models were successfully created and validate using data from 22,098 cases. All models performed adequately and similarly; however, we selected models derived from strategy 1 (AUC 0.89, CI95% 0.87-0.91) and strategy 4 (AUC 0.88, CI95% 0.86-0.90). The performance of both models was robust in validation and sensitivity analyses. This study offers insights into estimating COVID-19 fatality within the Peruvian population. Our findings contribute to the advancement of prediction models for COVID-19 fatality and may aid in identifying individuals at increased risk, enabling targeted interventions to mitigate the disease. Future studies should confirm the performance and validate the usefulness of the models described here under real-world conditions and settings.

Objective The objective of this study was to identify trajectories of depressive symptoms (DSs) during the first half of drug-sensitive pulmonary tuberculosis (PTB) treatment and examine their association with loss to follow-up (LTFU) in the second half.Design This study involved a secondary analysis of longitudinal data to identify potential trajectories of DS and their relationship with LTFU.Setting The study was conducted in first and second-level health centres located in San Juan de Lurigancho, Lima, Peru.Participants Anonymised data from 265 individuals, including monthly measures of DSs from diagnosis to the completion of treatment, initiation of treatment for multidrug resistant TB, LTFU or death, were collected.Results Three trajectories were identified: ‘declining’, ‘growth’ and ‘high’. These trajectories were observed in 182 (68.7%), 53 (20%) and 30 (11.3%) of the 265 individuals, respectively, during the first half of PTB treatment. Compared with those with a ‘declining’ trajectory, individuals with a ‘growth’ trajectory had a higher likelihood of experiencing LTFU during the second half of PTB treatment, after controlling for sociodemographic factors and at least weekly alcohol use (OR 3.9; 95% CI 1.09 to 13.97, p=0.036).Conclusions The findings suggest that a trajectory of increasing DSs during the first half of PTB treatment is associated with a higher risk of LTFU during the second half.

Serological assays have been used in seroprevalence studies to inform the dynamics of COVID-19. Lateral flow immunoassay (LFIA) tests are a very practical technology to use for this objective; however, one of their challenges may be variable diagnostic performance. Given the numerous available LFIA tests, evaluation of their accuracy is critical before real-world implementation. We performed a retrospective diagnostic evaluation study to independently determine the diagnostic accuracy of 4 different antibody-detection LFIA tests: Now Check (Bionote), CareStart (Access bio), Covid-19 BSS (Biosynex) and OnSite (CTK Biotech). The sample panel was comprised of specimens collected and stored in biobanks; specifically, specimens that were RT-PCR positive for SARS-CoV-2 collected at various times throughout the COVID-19 disease course and those that were collected before the pandemic, during 2018 or earlier, from individuals with upper respiratory symptoms but were negative for tuberculosis. Clinical performance (sensitivity and specificity) was analyzed overall, and subset across individual antibody isotypes, and days from symptoms onset. A very high specificity (98% - 100%) was found for all four tests. Overall sensitivity was variable, ranging from 29% [95% CI: 21%-39%] to 64% [95% CI: 54%-73%]. When considering detection of IgM only, the highest sensitivity was 42% [95% CI: 32%-52%], compared to 57% [95% CI: 47%-66%] for IgG only. When the analysis was restricted to at least 15 days since symptom onset, across any isotype, the sensitivity reached 90% for all four brands. All four LFIA tests proved effective for identifying COVID-19 antibodies when two conditions were met: 1) at least 15 days have elapsed since symptom onset and 2) a sample is considered positive when either IgM or IgG is present. With these considerations, the use of this assays could help in seroprevalence studies or further exploration of its potential uses.

ObjectivesIn order to generate independent performance data regarding accuracy of COVID-19 antigen-based rapid diagnostic tests (Ag-RDTs), prospective diagnostic evaluation studies across multiple sites are required to evaluate their performance in different clinical settings. This report describes the clinical evaluation the GENEDIA W COVID-19 Ag Device (Green Cross Medical Science Corp., Chungbuk, Korea) and the ActiveXpress+ COVID-19 Complete Testing Kit (Edinburgh Genetics Ltd, UK), in two testing sites Peru and the United Kingdom.MethodsNasopharyngeal swabs collected from 456 symptomatic patients at primary points of care in Lima, Peru and 610 symptomatic participants at a COVID-19 Drive-Through testing site in Liverpool, England were analyzed by Ag-RDT and compared to RT-PCR. Analytical evaluation of both Ag-RDTs was assessed using serial dilutions of direct culture supernatant of a clinical SARS-CoV-2 isolate from the B.1.1.7 lineage.ResultsFor GENEDIA brand, the values of overall sensitivity and specificity were 60.4% [95% CI 52.4-67.9%], and 99.2% [95% CI 97.6-99.7%] respectively; and for Active Xpress+ the overall values of sensitivity and specificity were 66.2% [95% CI 54.0-76.5%], and 99.6% [95% CI 97.9-99.9%] respectively. The analytical limit of detection was determined at 5.0 x 102 pfu/ml what equals to approximately 1.0 x 104 gcn/ml for both Ag-RDTs. The UK cohort had lower median Ct values compared to that of Peru during both evaluations. When split by Ct, both Ag-RDTs had optimum sensitivities at CtConclusionsWhilst the overall clinical sensitivity of the Genedia did not meet WHO minimum performance requirements for rapid immunoassays in either cohort, the ActiveXpress+ did so for the small UK cohort. This study illustrates comparative performance of Ag-RDTs across two global settings and considers the different approaches in evaluation methods.

Abstract Tuberculosis (TB), caused by Mycobacterium tuberculosis, spreads via aerosols and the first encounter with the immune system is with the pulmonary-resident immune cells. The role of epigenetic regulations in the immune cells is emerging and we have previously shown that macrophages capacity to kill M. tuberculosis is reflected in the DNA methylome. The aim of this study was to investigate epigenetic modifications in alveolar macrophages and T cells in a cohort of medical students with an increased risk of TB exposure, longitudinally. DNA methylome analysis revealed that a unique DNA methylation profile was present in healthy subjects who later developed latent TB during the study. The profile was reflected in a different overall DNA methylation distribution as well as a distinct set of differentially methylated genes (DMGs). The DMGs were over-represented in pathways related to metabolic reprogramming of macrophages and T cell migration and IFN-γ production, pathways previously reported important in TB control. In conclusion, we identified a unique DNA methylation signature in individuals, with no peripheral immune response to M. tuberculosis antigen who later developed latent TB. Together the study suggests that the DNA methylation status of pulmonary immune cells can reveal who will develop latent TB infection.

Abstract Background In Peru, 32,970 people were diagnosed with tuberculosis (TB) in 2019. Although TB treatment is effective, 3.4%–13% is associated with significant adverse drug reactions (ADR), considering drug‐induced liver injury (DILI) as the most prevalent. Among the first‐line anti‐TB drugs, isoniazid (INH) is primarily responsible for the occurrence of DILI. INH is metabolized in the liver by the enzymes N‐acetyltransferase‐2 (NAT2) and Cytochrome P450 2E1 (CYP2E1). Based on the previous studies, we hypothesized that the interactions between slow CYP2E1 genotype and NAT2 slow acetylators will induce DILI in TB patients. Methods In this cross‐sectional study, all 377 participants completed their anti‐TB treatment, and we genotyped SNPs: rs1041983, rs1801280, rs1799929, rs1799930, rs1208, and rs1799931 for NAT2 and rs3813867 and rs2031920 for CYP2E1. Results We found that rapid, intermediate, and slow NAT2 acetylator were 15%, 38%, and 47%, respectively, in the general population. Intermediate NAT2 acetylator is the least prevalent among patients with adverse reactions (p = 0.024). We did not confirm our hypothesis, however, we found that the combination of intermediate NAT2 acetylators and CYP2E1 c1/c1 genotype significantly protected (OR = 0.16; p = 0.049) against the development of DILI in our population. Conclusion We propose that the presence of NAT2 intermediate and CYP2E1 c1/c1 genotype could help in therapeutic drug monitoring, and optimize its therapeutic benefits while minimizing its risk for side effects or toxicity.

Abstract Objective The objective of this study was to characterize the composition of the gut microbiota in type 2 Diabetes Mellitus (T2DM) patients with adequate and inadequate metabolic control, and its relationship with fiber consumption. Results A total of 26 patients with type 2 diabetes mellitus (T2DM) were enrolled, of which 7 (26.9%) cases had adequate metabolic control (HbA1c

Tuberculosis is one of the leading causes of death worldwide, primarily affecting low- and middle income countries and individuals with limited-resources within fractured health care systems. Unfortunately, the COVID-19 pandemic has only served to aggravate the already existing diagnostic gap, decreasing the number of people who get diagnosed and thereby complete successful treatment. In addition to this, comorbidities act as an external component that when added to the TB management equation, renders it even more complex. Among the various comorbidities that interact with TB disease, diabetes mellitus and depression are two of the most prevalent among non-communicable diseases within the TB population and merits a thoughtful consideration when the healthcare system provides care for them. TB patients with diabetes mellitus (TB-DM) or depression both have an increased risk of mortality, relapse and recurrence. Both of these diseases when in presence of TB present a ‘vicious-circle-like’ mechanism, meaning that the effect of each disease can negatively add up, in a synergistic manner, complicating the patient’s health state. Among TB-DM patients, high glucose blood levels can decrease the effectiveness of anti-tuberculosis drugs; however, higher doses of anti-tuberculous drugs could potentially decrease the effects of DM drugs. Among the TB-depression patients, not only do we have the adherence to treatment problems, but depression itself can biologically shift the immunological profile responsible for TB containment, and the other way around, TB itself can alter the hormonal balance of several neurotransmitters responsible for depression. In this paper, we review these and other important aspects such as the pharmacological interactions found in the treatment of TB-DM and TB-depression patients and the implication on TB care and pharmacological considerations.

Abstract Growing evidence suggests pollution and other environmental factors have a role in the development of tuberculosis (TB), however, such studies have never been conducted in Peru. Considering the association between air pollution and specific geographic areas, our objective was to determine the spatial distribution and clustering of TB incident cases in Lima and their co-occurrence with clusters of fine particulate matter (PM2.5) and poverty. We found co-occurrences of clusters of elevated concentrations of air pollutants such as PM2.5, high poverty indexes, and high TB incidence in Lima. These findings suggest an interplay of socio-economic and environmental in driving TB incidence.

Abstract Background To evaluate the effectiveness and safety of the World Health Organization antibiotic regimen for the treatment of paucibacillary (PB) and multibacillary (MB) leprosy compared to other available regimens. Methods We performed a search from 1982 to July 2018 without language restriction. We included randomized controlled trials, quasi-randomized trials, and comparative observational studies (cohorts and case-control studies) that enrolled patients of any age with PB or MB leprosy that were treated with any of the leprosy antibiotic regimens established by the WHO in 1982 and used any other antimicrobial regimen as a controller. Primary efficacy outcomes included: complete clinical cure, clinical improvement of the lesions, relapse rate, treatment failure. Data were pooled using a random effects model to estimate the treatment effects reported as relative risk (RR) with 95% confidence intervals (CI). Results We found 25 eligible studies, 11 evaluated patients with paucibacillary leprosy, while 13 evaluated patients with MB leprosy and 1 evaluated patients of both groups. Diverse regimen treatments and outcomes were studied. Complete cure at 6 months of multidrug therapy (MDT) in comparison to rifampin-ofloxacin-minocycline (ROM) found RR of 1.06 (95% CI 0.88–1.27) in five studies. Whereas six studies compare the same outcome at different follow up periods between 6 months and 5 years, according to the analysis ROM was not better than MDT (RR of 1.01 (95% CI 0.78–1.31)) in PB leprosy. Conclusion Not better treatment than the implemented by the WHO was found. Diverse outcome and treatment regimens were studied, more statements to standardized the measurements of outcomes are needed.

Summary: Peru celebrates 200 years of independence in 2021. Over this period of independent life, and despite the turbulent socio-political scenarios, from internal armed conflict to economic crisis to political instability over the last 40 years, Peru has experienced major changes on its epidemiological and population health profile. Major advancements in maternal and child health as well as in communicable diseases have been achieved in recent decades, and today Peru faces an increasing burden of non-communicable diseases including mental health conditions. In terms of the configuration of the public health system, Peru has also strived to secure country-wide optimal health care, struggling in particular to improve primary health care and intercultural services. The science and technology infrastructure has also evolved, although the need for substantial investments remains if advancing science is to be a national priority. Climate change will also bring significant challenges to population health given Peru's geographical and microclimates diversity. Looking back over the 200-years of independence, we present a summary of key advances in selected health-related fields, thus serving as the basis for reflections on pending agendas and future challenges, in order to look forward to ensuring the future health and wellbeing of the Peruvian population. Resumen (translated abstract): El Perú cumple 200 años de independencia en 2021. Durante estos dos siglos de vida independiente, junto con periodos sociales y políticos turbulentos, incluyendo un conflicto armado interno, hiperinflación y la inestabilidad política de los últimos 40 años, el Perú ha experimentado importantes cambios en su perfil epidemiológico con repercusiones directas en la salud de la población. En las últimas décadas, los indicadores de salud materno-infantil y de las enfermedades transmisibles muestran mejoría importante, pero el país se enfrenta de manera simultánea a una carga cada vez mayor de enfermedades no transmisibles y de salud mental. En cuanto a los sistemas de salud pública, se han realizado esfuerzos por aumentar la cobertura y calidad de la atención de salud en todo el país, apostándose en particular por mejorar la atención primaria. La ciencia y tecnología relacionadas con la salud también han mejorado, aunque si se quiere que la ciencia sea una prioridad nacional, son necesarias inversiones sustanciales. El cambio climático traerá importantes desafíos para la salud de la población, dada la diversidad geográfica y de microclimas del país. Para conmemorar los 200 años de vida independiente del Perú, presentamos un resumen de avances clave en diversas áreas y temas relacionados con la salud. Este repaso sirve como base para reflexionar sobre agendas y desafíos pendientes y futuros, con el fin de asegurar la salud y el bienestar de la población peruana en las próximas décadas.

Abstract Objectives The primary objective is to determine the effect of a daily dose of ivermectin administered in three consecutive days to non-severe COVID-19 patients with no more than 96 hours of symptoms, on the detection of SARS-CoV-2 RNA by PCR from nasopharyngeal swabs at day seven post-treatment initiation. The secondary objectives are: 1. To assess the efficacy of ivermectin to reduce the SARS-CoV-2 viral load in the nasopharyngeal swab on days 4, 7, 14 and 21 post-treatment initiation 2. To assess the efficacy of ivermectin on the improvement of symptoms 3. To assess the proportion of seroconversions at day 21 4. To assess the safety of ivermectin at the proposed dose 5. To determine the magnitude of the immune response against SARS-CoV-2 6. To assess correlation of the presence of intestinal helminths on participants on baseline and day 14 with COVID-19 progression and treatment. Trial design SAINT PERU is a triple-blinded, randomized, placebo-controlled trial with two parallel arms to evaluate the efficacy of ivermectin in negativizing nasopharyngeal PCR in patients with SARS-CoV-2 infection. Participants The trial is conducted in two national hospitals in Lima-Peru. The study population is patients with a positive PCR test for SARS-CoV-2 in a nasopharyngeal specimen, symptomatic for 96 hours or less, with non-severe COVID-19 disease at baseline, regardless of the presence of risk factors for progression to severity. The study will not include pregnant women or minors (17 years old or younger). Inclusion criteria 1. COVID-19 symptomatology (cough, fever, anosmia, etc.) lasting no more than 96 hours, with a positive nasopharyngeal swab PCR test for SARS-CoV-2. 2. 18 years or older. 3. No use of ivermectin in the month prior to the visit. 4. No known history of ivermectin allergy. 5. Capable to give informed consent. 6. Not current use of CYP 3A4 or P-gp inhibitor drugs such as quinidine, amiodarone, diltiazem, spironolactone, verapamil, clarithromycin, erythromycin, itraconazole, ketoconazole, cyclosporine, tacrolimus, indinavir, ritonavir, cobicistat or critical CYP3A4 substrate drugs such as warfarin. Exclusion criteria 1. COVID-19 pneumonia diagnosed by the attending physician (oxygen saturation < 95% or lung examination) 2. Positive pregnancy test for women at childbearing age. 3. Positive IgG against SARS-CoV-2 by rapid diagnostic test at screening. Participants will be recruited by the investigators at the emergency services of the study sites. They are expected to remain in the trial for a period of 21 days. Follow-up visits will be conducted by the trial medical staff at the participant's home or at a hospital in case of hospitalization. Follow-up visits will assess clinical and laboratory parameters of the patients. Intervention and comparator Ivermectin (300 mcg/kg) or placebo will be administered in one daily dose for three consecutive days. Currently, there is no solid data on the efficacy of ivermectin against the virus in vivo; therefore the use of placebo in the control group is ethically justified. Main outcomes Primary Proportion of patients with a positive SARS-CoV-2 PCR from a nasopharyngeal swab at day 7 post-treatment. Secondary 1. Mean viral load as determined by PCR cycle threshold (Ct) on days 4, 7, 14, and 21 2. Proportion of patients with fever and cough at days 4, 7, 14, and 21 as well as proportion of patients progressing to severe disease or death during the trial 2. Proportion of patients with a positive rapid diagnostic test at day 21 3. Proportion of drug-related adverse events during the trial 4. Median levels of IgG, IgM, IgA measured by Luminex Randomization Participants will be randomized to receive one dose of 300 mcg/kg ivermectin or placebo daily for three consecutive days. The epidemiologist will generate a list of correlative numbers, in randomized blocks of size 4, with the assignment to the treatment groups (a and b). The randomization list will be kept in an encrypted file accessible only to the trial statistician. This list will be handed directly to the pharmacist. Independently, the principal investigator will randomly assign the intervention (ivermectin) to one of the two groups (a or b) by tossing a coin, and will inform the pharmacist of the result of this process. The pharmacist will prepare and label the treatment vials according to the randomization list prepared by the epidemiologist and the treatment assignment given by the principal investigator. Eligible patients will be allocated in a 1:1 ratio using this randomization list. Blinding (masking) The clinical trial team, the statistician, and the patients will be blinded as to arm allocation. The vials with placebo will be visibly identical to the ones with the active drug. Treatment will be administered by staff not involved in the clinical care or participant’s follow up. Numbers to be randomized (sample size) The planned sample size is 186 SARS-CoV-2 PCR positive patients: 93 patients to treatment and 93 to the placebo group. Trial Status Current protocol version: 2.0 dated January 15th, 2021. Recruitment started on Aug 29th, 2020. Recruitment is expected to be completed April 30th 2021. Trial registration “Ensayo Clínico aleatorizado de Fase IIa para comparar la efectividad de la ivermectina versus placebo en la negativización del PCR en pacientes en fase temprana de COVID-19” Peru National Health Institute REPEC with number: PER-034-20 , registered July 17th 2020 (National Peruvian Registration before the first participant enrolled). “Randomized Phase IIA Clinical Trial to Evaluate the Efficacy of Ivermectin to Obtain Negative PCR Results in Patients With Early Phase COVID-19” Clinicaltrials.gov: NCT04635943 , retrospectively registered in November 19th 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Summary: Background: Bartonella bacilliformis is the aetiological agent of Carrión's disease, a biphasic and highly lethal illness formerly restricted to the South American Andes that is now spreading to adjacent areas. Reliable serodiagnostic approaches and vaccines are urgently needed. In this study, we aimed to identify immunodominant proteins of B bacilliformis and to establish novel and reliable serodiagnostic tools. Methods: We used a reverse vaccinology approach in combination with an analysis of heterologous genomic expression libraries to identify immunodominant proteins, on the basis of the genome sequences of B bacilliformis strains KC583 and KC584. Antigens were screened with serum samples collected from Peruvian patients with B bacilliformis infections and from German healthy blood donors without history of travel to South America. We further analysed immunoreactive proteins of B bacilliformis with immunoblotting and line blots. We used selected target proteins to develop a diagnostic ELISA. To assess the performance of this ELISA, we did receiver operating characteristic analyses to assess the area under the curve, cutoff values, sensitivities, and specificities with 95% CIs. Findings: We used serum samples obtained between Dec 23, 1990, and May 5, 2018, from 26 Peruvian patients with B bacilliformis infections and serum samples taken between Aug 28 and Aug 31, 2020, from 96 healthy German blood donors. 21 potentially immunodominant proteins were identified and recombinantly expressed, and their reactivity was assessed with immunoblotting and line blots. Of these 21 antigens, 14 were found to be immunoreactive. By using serum samples of Peruvian patients with Carrión's disease and of healthy German blood donors, we identified three antigens (porin B, autotransporter E, and hypothetical protein B) as suitable immunodominant antigens, and we applied them in a diagnostic ELISA using two different antigen combinations (porin B plus autotransporter E and porin B plus autotransporter E plus hypothetical protein B). For the combination of porin B and autotransporter E, with optical density measured at 450 nm (OD450) cutoff value of 0·29, sensitivity was 80·8% (95% CI 60·7–93·5) and specificity was 94·8% (88·3–98·3) for all Peruvian patient samples. For a combination of porin B, autotransporter E, and hypothetical protein B, with an OD450 cutoff of 0·34, sensitivity was 76·9% (56·4–91·0) and specificity was 93·8% (86·9–97·7) for all Peruvian patient samples. Interpretation: This novel ELISA could represent a useful serodiagnostic tool for future epidemiological studies of B bacilliformis in endemic areas. Additionally, the immunodominant antigens we have identified could provide a first basis for future vaccine development to prevent the highly lethal Carrión's disease. Funding: DRUID (Novel Drug Targets against Poverty-Related and Neglected Tropical Infectious Diseases) Initiative and Robert Koch Institute. Translations: For the Spanish and Quechua translations of the abstract see Supplementary Materials section.

Abstract Background In 2014 the World Health Organization (WHO) launched the “End TB Strategy”, setting new ambitious goals for elimination of tuberculosis (TB). In contrast with previous efforts to control TB, the new strategy adopted the protection and promotion of human rights in TB prevention and care as a core pillar. This mandated the development of national programmes that are sensitive to the characteristics of populations and responsive to structural factors that put people at increased risk of exposure to TB, limit access to good quality health services and make people more vulnerable to TB infection. Indigenous people living in the Peruvian Amazon have been identified as a TB vulnerable group by Peruvian health authorities. This article examines the barriers faced by indigenous people and rural settlers from the Peruvian Amazon in obtaining a TB diagnosis and appropriate TB treatment, through the principles of the human rights based approach of accessibility, availability, affordability, adaptability and quality, and thus provides evidence of the utility of such approach in Peru. Methods This is a qualitative study. We combined information from policy documents and legal regulations and in-depth interviews with health workers and health authorities. We used Atlas-ti to conduct a thematic analysis and identify interviewees responses to pre-defined topics. Results Despite having a strong legal framework to protect the right to health of indigenous people and people affected by TB, there are underlying structural factors contributing to delays in detection, diagnosis and TB treatment, which are mostly related to having a health system poorly prepared to provide care for people living in dispersed rural communities. This article shows the limited level of integration of the “End TB Strategy” principles in the Peruvian National TB Programme and identifies the weakness of the health system to improve health care provision for indigenous people and rural settlers from the Peruvian Amazon. Conclusions Our study shows the need to go beyond developing a strong legal framework to ensure vulnerable populations such as indigenous people are able to realize their right to health. Governments need to allocate funds, improve training and adapt healthcare provision to the cultural, geographical, and social context of indigenous people.

Introducción. Las complicaciones crónicas por diabetes mellitus tipo 2 (DMT2) elevan la mortalidad y carga de enfermedad en Perú, siendo necesario evaluar su prevalencia y factores asociados. Métodos. Estudio transversal, analítico, en registros de 212 pacientes adultos con DMT2 atendidos por consulta externa en un hospital general del Seguro Social del Perú, durante el año 2017. Resultados. El 71,6% de los pacientes fueron mayores de 60 años y con un tiempo de enfermedad menor de 6 años (40,5%). El 38,7% de los pacientes tuvieron alguna complicación crónica, principalmente nefropatía (48,8%) y neuropatía (45,1%). La hipertensión arterial (52,4%) y la obesidad (43,7%) fueron las comorbilidades más frecuentes en pacientes con complicaciones crónicas. Las complicaciones por DMT2 estuvieron asociadas al número de consultas médicas y monitoreo glicémico. Conclusiones. Existen factores de riesgos asociados a las complicaciones crónicas de DMT2.

BACKGROUND Tuberculosis (TB) kills more people than any other infection, and new diagnostic tests to identify active cases are required. We aimed to discover and verify novel markers for TB in nondepleted plasma.METHODS We applied an optimized quantitative proteomics discovery methodology based on multidimensional and orthogonal liquid chromatographic separation combined with high-resolution mass spectrometry to study nondepleted plasma of 11 patients with active TB compared with 10 healthy controls. Prioritized candidates were verified in independent UK (n = 118) and South African cohorts (n = 203).RESULTS We generated the most comprehensive TB plasma proteome to date, profiling 5022 proteins spanning 11 orders-of-magnitude concentration range with diverse biochemical and molecular properties. We analyzed the predominantly low–molecular weight subproteome, identifying 46 proteins with significantly increased and 90 with decreased abundance (peptide FDR ≤ 1%, q ≤ 0.05). Verification was performed for novel candidate biomarkers (CFHR5, ILF2) in 2 independent cohorts. Receiver operating characteristics analyses using a 5-protein panel (CFHR5, LRG1, CRP, LBP, and SAA1) exhibited discriminatory power in distinguishing TB from other respiratory diseases (AUC = 0.81).CONCLUSION We report the most comprehensive TB plasma proteome to date, identifying novel markers with verification in 2 independent cohorts, leading to a 5-protein biosignature with potential to improve TB diagnosis. With further development, these biomarkers have potential as a diagnostic triage test.FUNDING Colciencias, Medical Research Council, Innovate UK, NIHR, Academy of Medical Sciences, Program for Advanced Research Capacities for AIDS, Wellcome Centre for Infectious Diseases Research.

BackgroundDepression is a common comorbidity of tuberculosis (TB) and is associated with poor adherence to treatment of multiple disorders. We conducted a systematic review to synthesize the existing evidence on the relationship between depression and negative outcomes of TB treatment.MethodsWe systematically reviewed studies that evaluated depressive symptoms (DS) directly or indirectly through psychological distress (PD) and measured negative treatment outcomes of drug-sensitive pulmonary TB, defined as death, loss to follow-up, or non-adherence. Sources included PubMed, Global Health Library, Embase, Scopus and Web of Science from inception to August 2019.ResultsOf the 2,970 studies initially identified, eight articles were eligible for inclusion and two were used for the primary outcome meta-analysis. We found a strong association between DS and negative TB treatment outcomes (OR = 4.26; CI95%:2.33-7.79; I2 = 0%). DS were also associated with loss to follow-up (OR = 8.70; CI95%:6.50-11.64; I2 = 0%) and death (OR = 2.85; CI95%:1.52-5.36; I2 = 0%). Non-adherence was not associated with DS and PD (OR = 1.34; CI95%:0.70-2.72; I2 = 94.36) or PD alone (OR = 0.92; CI95%:0.81-1.05; I2 = 0%).ConclusionsDS are associated with the negative TB treatment outcomes of death and loss to follow-up. Considerable heterogeneity exists in the definition of depression and outcomes such as non-adherence across the limited number of studies on this topic.

Abstract Background Genitourinary tuberculosis is the third most common form of extrapulmonary tuberculosis. Diagnosis is difficult because of unspecific clinical manifestations and low accuracy of conventional tests. Unfortunately, the delayed diagnosis impacts the urinary tract severely. Nucleic acid amplification tests yield fast results, and among these, new technologies can also detect drug resistance. There is lack of consensus regarding the use of these tests in genitourinary tuberculosis; we therefore aimed to assess the accuracy of nucleic acid amplification tests in the diagnosis of genitourinary tuberculosis and to evaluate the heterogeneity between studies. Methods We did a systematic review and meta-analysis of research articles comparing the accuracy of a reference standard and a nucleic acid amplification test for diagnosis of urinary tract tuberculosis. We searched Medline, EMBASE, Web of Science, LILACS, Cochrane Library, and Scopus for articles published between Jan 1, 1990, and Apr 14, 2016. Two investigators identified eligible articles and extracted data for individual study sites. We analyzed data in groups with the same index test. Then, we generated pooled summary estimates (95% CIs) for sensitivity and specificity by use of random-effects meta-analysis when studies were not heterogeneous. Results We identified eleven relevant studies from ten articles, giving information on PCR, LCR and Xpert MTB/RIF tests. All PCR studies were “in-house” tests, with different gene targets and had several quality concerns therefore we did not proceed with a pooled analysis. Only one study used LCR. Xpert studies were of good quality and not heterogeneous, pooled sensitivity was 0·87 (0·66–0·96) and specificity was 0·91 (0·84–0·95). Conclusion PCR studies were highly heterogeneous. Among Xpert MTB/RIF studies, specificity was favorable with an acceptable confidence interval, however new studies can update meta-analysis and get more precise estimates. Further high-quality studies are urgently needed to improve diagnosis of genitourinary tuberculosis. Protocol registration PROSPERO CRD42016039020.

ABSTRACT OBJECTIVE To evaluate the effectiveness of interventions aimed at the prevention of risk factors and incidence of type 2 diabetes in the workers population. METHODS Systematic review of interventions aimed at adult workers at risk of type 2 diabetes published in Medline, Embase, Web of Science, Central Cochrane Registry of Controlled Trials, and Lilacs. Randomized trials, quasi-experimental research and cohort studies were selected; in English, Spanish and Portuguese; published from 2000 to 2017. Intervention effectiveness was evaluated concerning the incidence of type 2 diabetes and a significant reduction in body weight, or another anthropometric or metabolic parameter. RESULTS 3,024 articles were generated, of which 2,825 that did not answer the research question were eliminated, as well as 130 that did not evaluate original interventions, 57 carried out outside the workplace and two reviews; so that 10 selected items remained. Interventions based on structured programs previously evaluated and integrated into the workplace had a favorable impact on the reduction of body weight and other risk factors. CONCLUSIONS The effectiveness of lifestyle interventions for the prevention of type 2 diabetes should be based on structured programs with proven effectiveness and adapted to the workplace, with employer participation in the provision of schedules and work environments.

Background: We conducted a systematic review to study the association between diabetes and malaria as well as malaria severity. Methods: The search was conducted in Embase, Global Health, MEDLINE, Scopus and Web of Science. Titles and abstracts were screened, full-text studied and information extracted for qualitative synthesis. Risk of bias was assessed with ROBINS-I criteria. The exposure was diabetes and the outcome malaria or malaria severity. Results: Of 1992 results, three studies were included (n=7,226). Two studies found strong associations: people with diabetes had higher odds of malaria (adjusted odds ratio (aOR): 1.46 (95% CI: 1.06-2.03)) and severe malaria (aOR: 2.98 (95% CI: 1.25-7.09)). One study did not find conclusive evidence: aOR for severe malaria was 0.95 (95% CI: 0.71-1.28). Risk of bias was high in all the studies. Conclusions: Although the available evidence on the association between diabetes and malaria is limited, the results may suggest there is a non-trivial positive relationship between these conditions.

Background: Cutaneous leishmaniasis is a prevalent communicable disease in low- and middle-income countries, where non-communicable diseases like skin cancer are on the rise. However, the study of multi-morbidity or co-morbidity between communicable and non-communicable diseases is limited, and even null for some tropical or neglected diseases. Nevertheless, looking at these conditions together instead of as isolated entities in places where these illnesses exist, could show new prevention and treatment paths. We aimed to summarize and critically appraise the epidemiological evidence on the association between cutaneous leishmaniasis and skin cancer. Methods: Following the PRISMA guidelines, we conducted a systematic review using five search engines (Embase, Medline, Global Health, Scopus and Web of Science). We sought observational studies in which the outcome was skin cancer whilst the exposure was cutaneous leishmaniasis; these conditions should have had laboratory or pathology confirmation. Results: No epidemiological investigations have studied the association between cutaneous leishmaniasis and skin cancer. Most of the evidence about the association of interest is still based on case reports and other clinical observations rather than strong epidemiological observational studies. Conclusions: Research is much needed to verify the repeatedly clinical observation that cutaneous leishmaniasis may be a risk factor for skin cancer. This evidence could inform and guide early diagnosis or prevention of skin cancer in survivors of cutaneous leishmaniasis or where cutaneous leishmaniasis is still highly prevalent. Registration: PROSPERO ID CRD42018111230; registered on 16/10/18.

BackgroundLeptospirosis is a worldwide prevalent zoonosis and chronic kidney disease (CKD) is a leading global disease burden. Because of pathophysiological changes in the kidney, it has been suggested that these conditions may be associated. However, the extent of this interaction has not been synthetized. We aimed to systematically review and critically appraise the evidence on the association between leptospirosis and CKD.Methodology/principal findingsObservational studies with a control group were selected. Leptospirosis, confirmed with laboratory methods, and CKD also based on a laboratory assessment, were the exposures and outcomes of interest. The search was conducted in EMBASE, MEDLINE, Global Health, Scopus and Web of Science. Studies selected for qualitative synthesis were assessed for risk of bias following the Newcastle-Ottawa Scale. 5,981 reports were screened, and 2 (n = 3,534) were included for qualitative synthesis. The studies were conducted in Taiwan and Nicaragua; these reported cross-sectional and longitudinal estimates. In the general population, the mean estimated glomerular filtration rate (eGFR) was lower (pConclusionAlthough the available evidence suggests there may be a positive association between leptospirosis and CKD, whereby leptospirosis could be a risk factor for CKD, it is still premature to draw conclusions. There is an urgent need for research on this association.

The prevalence of non-communicable diseases is increasing worldwide, which coincides with the persistence of infectious diseases including tuberculosis. These can synergistically affect individual and population health. Three non-communicable diseases that are relevant because of their associated morbidity, mortality and disability are type 2 diabetes mellitus, chronic kidney disease and rheumatoid arthritis. There is some evidence that patients with these conditions are at increased risk of acquiring latent tuberculosis infection (LTBI) and of this progressing to active disease. Unfortunately, evidence on accurate testing and effective prophylactic treatment in these populations is lacking. This review discusses current evidence and recommendations for management of LTBI in these patients. Keywords: Tuberculosis, Diabetes mellitus type 2, Chronic kidney disease and Rheumatoid arthritis

The contribution made by the private sector to health care in a low- or middle-income country may affect levels of physician emigration from that country. The increasing importance of the private sector in health care in the developing world has resulted in newfound academic interest in that sector's influences on many aspects of national health systems. The growth in physician emigration from the developing world has led to several attempts to identify both the factors that cause physicians to emigrate and the effects of physician emigration on primary care and population health in the countries that the physicians leave. When the relevant data on the emerging economies of Ghana, India and Peru were investigated, it appeared that the proportion of physicians participating in private health-care delivery, the percentage of health-care costs financed publicly and the amount of private health-care financing per capita were each inversely related to the level of physician expatriation. It therefore appears that private health-care delivery and financing may decrease physician emigration. There is clearly a need for similar research in other low- and middle-income countries, and for studies to see if, at the country level, temporal trends in the contribution made to health care by the private sector can be related to the corresponding trends in physician emigration. The ways in which private health care may be associated with access problems for the poor and therefore reduced equity also merit further investigation. The results should be of interest to policy-makers who aim to improve health systems worldwide.

BACKGROUND:Bartonellosis affects small Andean communities in Peru, Colombia and Ecuador. Research in this area has been limited. METHODS:Retrospective review of 191 cases of bartonellosis managed in Caraz District Hospital, Peru, during the last outbreak (2003). RESULTS:The majority of cases (65%) were 14 years old and younger. There was a peak in acute cases after the rainy season; chronic cases presented more constantly throughout the year. The sensitivity of blood smear against blood culture in acute disease was 25%. The most commonly used treatment for chronic disease was rifampicin; chloramphenicol was used to treat most acute cases. Complications arose in 6.8% and there were no deaths. CONCLUSIONS:Diagnostic and treatment algorithms for acute and chronic bartonellosis have been developed without a strong evidence base. Preparation of ready-to-go operational research protocols for future outbreaks would strengthen the evidence base for diagnostic and treatment strategies and enhance opportunities for control.

Pulmonary cavities, the hallmark of tuberculosis (TB), are characterized by high mycobacterial load and perpetuate the spread of M. tuberculosis. The mechanism of matrix destruction resulting in cavitation is not well defined. Neutrophils are emerging as key mediators of TB immunopathology and their influx are associated with poor outcomes. We investigated neutrophil-dependent mechanisms involved in TB-associated matrix destruction using a cellular model, a cohort of 108 patients, and in separate patient lung biopsies. Neutrophil-derived NF-kB-dependent matrix metalloproteinase-8 (MMP-8) secretion was up-regulated in TB and caused matrix destruction both in vitro and in respiratory samples of TB patients. Collagen destruction induced by TB infection was abolished by doxycycline, a licensed MMP inhibitor. Neutrophil extracellular traps (NETs) contain MMP-8 and are increased in samples from TB patients. Neutrophils lined the circumference of human pulmonary TB cavities and sputum MMP-8 concentrations reflected TB radiological and clinical disease severity. AMPK, a central regulator of catabolism, drove neutrophil MMP-8 secretion and neutrophils from AMPK-deficient patients secrete lower MMP-8 concentrations. AMPK-expressing neutrophils are present in human TB lung biopsies with phospho-AMPK detected in nuclei. These data demonstrate that neutrophil-derived MMP-8 has a key role in the immunopathology of TB and is a potential target for host-directed therapy in this infectious disease.

Proton-pump inhibitors (PPIs) are among the most frequently prescribed medications. Community-acquired pneumonia (CAP) is a common cause of morbidity, mortality and healthcare spending. Some studies suggest an increased risk of CAP among PPI users. We conducted a systematic review and meta-analysis to determine the association between outpatient PPI therapy and risk of CAP in adults.We conducted systematic searches of MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Scopus and Web of Science on February 3, 2014. Case-control studies, case-crossover, cohort studies and randomized controlled trials reporting outpatient PPI exposure and CAP diagnosis for patients ≥18 years old were eligible. Our primary outcome was the association between CAP and PPI therapy. A secondary outcome examined the risk of hospitalization for CAP and subgroup analyses evaluated the association between PPI use and CAP among patients of different age groups, by different PPI doses, and by different durations of PPI therapy.Systematic review of 33 studies was performed, of which 26 studies were included in the meta-analysis. These 26 studies included 226,769 cases of CAP among 6,351,656 participants. We observed a pooled risk of CAP with ambulatory PPI therapy of 1.49 (95% CI 1.16, 1.92; I2 99.2%). This risk was increased during the first month of therapy (OR 2.10; 95% CI 1.39, 3.16), regardless of PPI dose or patient age. PPI therapy also increased risk for hospitalization for CAP (OR 1.61; 95% CI: 1.12, 2.31).Outpatient PPI use is associated with a 1.5-fold increased risk of CAP, with the highest risk within the first 30 days after initiation of therapy. Providers should be aware of this risk when considering PPI use, especially in cases where alternative regimens may be available or the benefits of PPI use are uncertain.

Pulmonary tuberculosis (TB) persists an important contributor to the burden of diseases in developing countries. TB control success is based on the patient's compliance to the treatment. Depressive disorders have been negatively associated with compliance of therapeutic schemes for chronic diseases. This study aimed to estimate the significance and magnitude of major depressive episode as a hazard factor for negative outcomes (NO), including abandon or death in patients receiving TB treatment.A longitudinal study was conducted to evaluate the association of major depressive episode (MDE), as measured by a 5-item version of the Center for Epidemiological Studies Depression Scale (CES-D) with NO to TB treatment. Patients with confirmed TB were enrolled before the start of TB treatment. Baseline measurements included socio-demographic variables as well as the CES-D, which was also applied every month until the end of the treatment. Death and treatment default were assessed monthly. Survivor function (SF) for NO according to MDE status (CES-D≥6) at baseline (MDEb) was estimated. Cox's Regression was performed for bivariate analyses as well as for the multivariate model. A total of 325 patients accepted to participate in the study, of which 34 where excluded for diagnosis of MDR-TB. NO was observed in 24 patients (8.2%); 109 (37%) presented MDEb. Statistically significant difference was found on the SF of patients with and without MDEb (0.85 vs. 0.96, p-value = 0.002). The hazard ratio for NO, controlled for age, sex, marital status and instruction level was 3.54 (95%CI 1.43-8.75; p-value = 0.006).The presence of MDE at baseline is associated to NO of TB treatment. Targeting detection and treatment of MDE may improve TB treatment outcomes.