µSim: A goal-driven framework for elucidating the neural control of movement through musculoskeletal modeling.

How does the motor cortex (MC) produce purposeful and generalizable movements from the complex musculoskeletal system in a dynamic environment? To elucidate the underlying neural dynamics, we use a goal-driven approach to model MC by considering its goal as a controller driving the musculoskeletal system through desired states to achieve movement. Specifically, we formulate the MC as a recurrent neural network (RNN) controller producing muscle commands while receiving sensory feedback from biologically accurate musculoskeletal models. Given this real-time simulated feedback implemented in advanced physics simulation engines, we use deep reinforcement learning to train the RNN to achieve desired movements under specified neural and musculoskeletal constraints. Activity of the trained model can accurately decode experimentally recorded neural population dynamics and single-unit MC activity, while generalizing well to testing conditions significantly different from training. Simultaneous goal- and data- driven modeling in which we use the recorded neural activity as observed states of the MC further enhances direct and generalizable single-unit decoding. Finally, we show that this framework elucidates computational principles of how neural dynamics enable flexible control of movement and make this framework easy-to-use for future experiments.

Burden of Disease in Psoriatic Arthritis in Latin America: a Systematic Literature Review.

INTRODUCTION: Psoriatic arthritis is a chronic inflammatory pathology that generates a substantial and progressive deterioration of functionality and quality of life. It is associated with comorbidities (cardiovascular and metabolic) and involvement of mental health. In Latin America, information regarding the disease is limited. This study reviews the burden of disease (disease activity, functional involvement, clinical manifestations, comorbidities, patient-reported outcomes, quality of life, and use of health resources) in PsA patients in Latin America. METHODS: Systematic literature review of publications in PUBMED, EMBASE, Cochrane Database of Systematic Reviews-CDSR/Database of Abstracts of Reviews of Effects, LILACS, Scielo, Redalyc, conference abstracts, and grey literature. Two independent assessors selected studies and extracted information. Quality was assessed according to the type of study. RESULTS: We identified 692 references, selecting 50 studies: 41 cross-sectional, four economic-studies, four cohort studies and one systematic review. The information comes mainly from Brazil, Argentina, and Mexico. The estimated disease prevalence for Latin America ranges from 0.004 to 0.08% (95% CI 0.02-0.20). Measurements with validated instruments suggest suboptimal assessment of disease domains, significant functional compromise, loss of productivity, and high frequency of comorbidities, including mental health. Methodological and population considerations limit the generalizability of the findings. CONCLUSIONS: The available information reports a considerable burden of disease in patients with PsA in Latin America, with involvement of quality of life associated with disability in relation to disease activity and its various manifestations. Future research and funding efforts should be aimed at generating more standardized information about the impact of PsA in the region. Key Points •The functional involvement related to disease activity, the impact on the quality of life, and the frequency of cardiometabolic and psychological comorbidities are remarkable in Latin American patients with PsA. •The current synthesis offers an overview of the burden of disease (disease activity, functional involvement, clinical manifestations, comorbidities, patient-reported outcomes, quality of life, and use of health resources) in PsA patients in Latin America. •Future research efforts and clinical strategies are required in order to generate standardized data on the patients and better estimate the burden of disease in the region.

The short-term cost-effectiveness of once-weekly semaglutide versus once-weekly dulaglutide for the treatment of type 2 diabetes mellitus in Colombian adults.

Background: Type 2 Diabetes Mellitus (T2DM) is a highly prevalent disease worldwide and in Colombia, representing one of the main causes of death and placing a considerable burden on healthcare systems. 13 classes of drugs are approved for the treatment of T2DM, with Glucagon-like Peptide-1 (GLP-1) receptor agonists being a first-line treatment option for patients with or at high risk of certain cardiovascular diseases and chronic kidney disease. The objective of this study is to conduct a short-term cost-effectiveness analysis of once-weekly semaglutide versus once-weekly dulaglutide in Colombian adults with T2DM, from a third-party payer perspective. Methods: Numbers needed to treat were calculated for different single and composite endpoints of the SUSTAIN 7 trial, annual costs for once weekly semaglutide 1.0 mg and dulaglutide 1.5 mg were extracted from the public SISMED database. With these inputs a cost of control model was developed, to obtain the annual cost of bringing one T2DM patient to relevant clinical outcomes by using semaglutide or dulaglutide. Results: Semaglutide was considered cost-effective compared to dulaglutide across all pre-specified endpoints, even in the different scenarios evaluated in the sensitivity analyses, and in a particularly pronounced manner for weight loss outcomes. Semaglutide at a dose of 1.0 mg once-weekly was cost-effective compared to dulaglutide 1.5 mg across all outcomes in the short-term, making it an appropriate first-line choice in the treatment of T2DM when deciding between these two GLP-1 receptor agonists. Conclusions: This is the first short-term cost-effectiveness study of semaglutide and dulaglutide in T2DM Colombian patients. Our modeled results suggest that once-weekly semaglutide represents a cost-effective option for treating individuals with T2DM in Colombia who are not achieving glycaemia control with metformin, and it would be expected to improve HbA1C, promote greater weight loss and reduce costs from a third-payer perspective compared with treatment with dulaglutide.

Evaluation of Vector-Enabled Xenosurveillance in Rural Guatemala.

Surveillance methods that permit rapid detection of circulating pathogens in low-resource settings are desperately needed. In this study, we evaluated a mosquito bloodmeal-based surveillance method ("xenosurveillance") in rural Guatemala. Twenty households from two villages (Los Encuentros and Chiquirines) in rural southwest Guatemala were enrolled and underwent weekly prospective surveillance from August 2019 to December 2019 (16 weeks). When febrile illness was reported in a household, recently blood-fed mosquitoes were collected from within dwellings and blood samples taken from each member of the household. Mosquitoes were identified to species and blood sources identified by sequencing. Shotgun metagenomic sequencing was used to identify circulating viruses. Culex pipiens (60.9%) and Aedes aegypti (18.6%) were the most abundant mosquitoes collected. Bloodmeal sources were most commonly human (32.6%) and chicken (31.6%), with various other mammal and avian hosts detected. Several mosquito-specific viruses were detected, including Culex orthophasma virus. Human pathogens were not detected. Therefore, xenosurveillance may require more intensive sampling to detect human pathogens in Guatemala and ecologically similar localities in Central America.

Clinical and Economic Impact of COVID-19 on Agricultural Workers, Guatemala1.

We evaluated clinical and socioeconomic burdens of respiratory disease in banana farm workers in Guatemala. We offered all eligible workers enrollment during June 15-December 30, 2020, and annually, then tracked them for influenza-like illnesses (ILI) through self-reporting to study nurses, sentinel surveillance at health posts, and absenteeism. Workers who had ILI submitted nasopharyngeal swab specimens for testing for influenza virus, respiratory syncytial virus, and SARS-CoV-2, then completed surveys at days 0, 7, and 28. Through October 10, 2021, a total of 1,833 workers reported 169 ILIs (12.0 cases/100 person-years), and 43 (25.4%) were laboratory-confirmed infections with SARS-CoV-2 (3.1 cases/100 person-years). Workers who had SARS-CoV-2‒positive ILIs reported more frequent anosmia, dysgeusia, difficulty concentrating, and irritability and worse clinical and well-being severity scores than workers who had test result‒negative ILIs. Workers who had positive results also had greater absenteeism and lost income. These results support prioritization of farm workers in Guatemala for COVID-19 vaccination.

Challenges and lessons learned from the rapid operationalization of a prospective cohort to study the natural history and neurodevelopmental outcomes of postnatal Zika virus infection among infants and children in rural Guatemala.

During the course of the 2015-2017 outbreak of Zika virus (ZIKV) in the Americas, the emerging virus was recognized as a congenital infection that could damage the developing brain. As the Latin American ZIKV outbreak advanced, the scientific and public health community questioned if this newly recognized neurotropic flavivirus could affect the developing brain of infants and young children infected after birth. We report here the study design, methods and the challenges and lessons learned from the rapid operationalization of a prospective natural history cohort study aimed at evaluating the potential neurological and neurodevelopmental effects of postnatal ZIKV infection in infants and young children, which had become epidemic in Central America. This study enrolled a cohort of 500 mothers and their infants, along with nearly 400 children 1.5-3.5 years of age who were born during the initial phase of the ZIKV epidemic in a rural area of Guatemala. Our solutions and lessons learned while tackling real-life challenges may serve as a guide to other researchers carrying out studies of emerging infectious diseases of public health priority in resource-constrained settings.

Repeated Rapid Active Sampling Surveys Demonstrated a Rapidly Changing Zika Seroprevalence among Children in a Rural Dengue-endemic Region in Southwest Guatemala during the Zika Epidemic (2015-2016).

Although Central America is largely dengue virus (DENV)-endemic, the 2015-2016 Zika virus (ZIKV) pandemic brought new urgency to develop surveillance approaches capable of characterizing the rapidly changing disease burden in resource-limited settings. We conducted a pediatric DENV surveillance study in rural Guatemala, including serial cross-sectional surveys from April through September 2015 (Survey 1), in October-November 2015 (Survey 2), and January-February 2016 (Survey 3). Serum underwent DENV IgM MAC ELISA and polymerase chain reaction testing. Using banked specimens from Surveys 2 and 3, we expanded testing to include DENV 1-4 and ZIKV microneutralization (MN50), DENV NS1 IgG ELISA, and ZIKV anti-NS1 antibody Blockage of Binding (BoB) ELISA testing. Demographic risk factors for ZIKV BoB positivity were explored using multivariable generalized linear regression models. Of Survey 2 and 3 samples available (N = 382), DENV seroprevalence slightly increased (+1%-10% depending on the assay) during the surveillance period and increased with age. In contrast, ZIKV seroprevalence consistently increased over the 3-month period, including from 6% to 34% (P < 0.0001) and 10%-37% (P < 0.0001) using the MN50 ≥100 and BoB ELISA assays, respectively. Independent risk factors for ZIKV seropositivity included older age (prevalence ratio (PR)/year = 1.12, 95% confidence interval (CI) = 1.07-1.17) and primary caregiver literacy (PR = 2.80, CI = 1.30-6.06). Rapid active surveillance (RAS) surveys demonstrated a nearly 30% increase in ZIKV prevalence and a slight (≤ 10%) increase in DENV seroprevalence from October to November 2015 to January to February 2016 in rural southwest Guatemala, regardless of serologic assay used. RAS surveys may be a useful "off-the-shelf" tool to characterize arboviruses and other emerging pathogens rapidly in resource-limited settings.

A novel multi-epitope recombinant protein elicits an antigen-specific CD8+ T cells response in Trypanosoma cruzi-infected mice.

About 6.5 million people worldwide are afflicted by Chagas disease, which is caused by the protozoan parasite Trypanosoma cruzi. The development of a therapeutic vaccine to prevent the progression of Chagasic cardiomyopathy has been proposed as an alternative for antiparasitic chemotherapy. Bioinformatics tools can predict MHC class I CD8 + epitopes for inclusion in a single recombinant protein with the goal to develop a multivalent vaccine. We expressed a novel recombinant protein Tc24-C4.10E harboring ten nonameric CD8 + epitopes and using Tc24-C4 protein as scaffold to evaluate the therapeutic effect in acute T. cruzi infection. T. cruzi-infected mice were immunized with Tc24-C4.10E or Tc24-C4 in a 50-day model of acute infection. Tc24-C4.10E-treated mice showed a decreased parasitemia compared to the Tc24-C4 (non-adjuvant) immunized mice or control group. Moreover, Tc24-C4.10E induced a higher stimulation index of CD8 + T cells producing IFNγ and IL-4 cytokines. These results suggest that the addition of the MHC Class I epitopes to Tc24-C4 can synergize the antigen-specific cellular immune responses, providing proof-of-concept that this approach could lead to the development of a promising vaccine candidate for Chagas disease.

Cervical Cancer Prevention in El Salvador: Gains to Date and Challenges for the Future.

Cervical cancer is preventable through vaccination, early detection, and the treatment of pre-cancerous lesions. However, global inequalities mean that the disease remains a leading cause of cancer death around the world, with over 80% of new cases and 90% of deaths occurring in low- and middle-income countries (LMICs). In El Salvador, joint efforts between the Ministry of Health (MoH) and the non-profit organization Basic Health International (BHI) have been in place since 2008, with the goal of reducing the country's disease burden. While the World Health Organization's (WHO) call to action to eliminate cervical cancer provided worldwide momentum to implement new public health initiatives, the COVID-19 pandemic disrupted ongoing programs and jeopardized plans for the future. The purpose of this manuscript is to describe the progress that El Salvador has achieved in improving cervical cancer prevention, the impact of the pandemic on current strategies, and potential solutions that can help the country meet the WHO's strategic targets by 2030 to accelerate the elimination of cervical cancer.

Clinical and Economic Impact of COVID-19 on Plantation Workers: Preliminary Results from the Guatemala Agricultural Workers and Respiratory Illness Impact (AGRI) Study.

We evaluated the clinical and socioeconomic burdens of respiratory disease in a cohort of Guatemalan banana plantation workers. All eligible workers were offered enrollment from June 15-December 30, 2020, and annually, then followed for influenza-like illnesses (ILI) through: 1) self-reporting to study nurses, 2) sentinel surveillance at health posts, and 3) absenteeism. Workers with ILI submitted nasopharyngeal swabs for influenza, RSV, and SARS-CoV-2 testing, then completed surveys at days 0, 7, and 28. Through October 10, 2021, 1,833 workers developed 169 ILIs (12.0/100 person-years) and 43 (25.4%) of these ILIs were laboratory-confirmed SARS-CoV-2 (3.1/100 person-years). Workers with SARS-CoV-2-positive ILI reported more anosmia (p<0.01), dysgeusia (p<0.01), difficulty concentrating (p=0.01), and irritability (p=0.01), and greater clinical and well-being severity scores (Flu-iiQ) than test-negative ILIs; they also had greater absenteeism (p<0.01) and lost income (median US$127.1, p<0.01). These results support the prioritization of Guatemalan farm workers for COVID-19 vaccination.

Hospital Adverse Event Reporting Systems: A Systematic Scoping Review of Qualitative and Quantitative Evidence.

INTRODUCTION: Reducing the incidence of reportable events with undesirable effects (REUE) is a priority in the hospital environment, which is why reporting systems have been implemented to identify and manage them. Information is required regarding the performance of reporting systems, barriers, or facilitators for reporting and strategies that improve passive reporting. METHODOLOGY: Systematic scoping review of the literature that included studies performed in the population exposed to the occurrence of REUE in the health system (teams, patients, and family). A search was performed in Cochrane Database of Systematic Reviews, Epistemonikos, MEDLINE (PubMed), MEDLINE In-Process and MEDLINE Daily Update, EMBASE, LILACS, and databases of the World Health Organization and Pan-American Health Organization. RESULTS: Fifteen studies were found, 1 systematic review, 2 clinical trials, 8 observational studies, 3 qualitative studies, and 1 mixed study. In 4 of them, the effectiveness of active versus passive reporting systems was compared. The measures to improve the passive systems were education about REUE, simplification of the reporting format, activities focused on increasing the motivation for self-report, adoption of self-report as an obligatory institutional policy, and using specific report formats for each service. CONCLUSIONS: There is information that allows to find differences between the performance of the active and passive reporting systems. The reviewed research articles found that passive techniques significantly underreported adverse events. It is recommended that institutions adopt both active and passive techniques in adverse event surveillance. New studies should be directed to answer the comparative efficiency of the reporting systems.

Outcomes for Step-Wise Implementation of a Human Papillomavirus Testing-Based Cervical Screen-and-Treat Program in El Salvador.

PURPOSE: The Cervical Cancer Prevention in El Salvador (CAPE) project is a public-sector intervention introducing lower-cost human papillomavirus (HPV) testing in all four departments of the Paracentral region that screened a total of 28,015 women. After demonstrating success of an HPV screen-and-treat (S&T) algorithm over colposcopy management in the first two phases, the third phase scaled up the S&T strategy. We present results from phase III and evaluate S&T components across the entire project. METHODS: During phase III, 17,965 women age 30-59 years underwent HPV testing. HPV-positive women were asked to return and, if eligible, received gas-based cryotherapy. We compare loss to follow-up and time intervals between S&T steps across the three phases. RESULTS: There were no differences in HPV positivity across phases (phase I, 11.9%; phase II, 11.4%; phase III, 12.3%; P = .173). Although most HPV-positive women completed indicated follow-up procedures within 6 months in phases I (93.3%, 111 of 119) and II (92.3%, 429 of 465), this proportion declined to 74.9% (1,659 of 2,214; P < .001) in phase III. Mean days between testing and delivery of results to patients increased over program phases (phase I, 23.2 days; phase II, 46.7 days; phase III, 99.8 days; P < .001). CONCLUSION: A public-sector implementation of an HPV-based S&T algorithm was successfully scaled up in El Salvador, albeit with losses in efficiency. After CAPE, the Ministry of Health changed its screening guidelines and procured additional tests to expand the program.

Simultaneous LC/MS Analysis of Carotenoids and Fat-Soluble Vitamins in Costa Rican Avocados (Persea americana Mill.).

Avocado (a fruit that represents a billion-dollar industry) has become a relevant crop in global trade. The benefits of eating avocados have also been thoroughly described as they contain important nutrients needed to ensure biological functions. For example, avocados contain considerable amounts of vitamins and other phytonutrients, such as carotenoids (e.g., ß-carotene), which are fat-soluble. Hence, there is a need to assess accurately these types of compounds. Herein we describe a method that chromatographically separates commercial standard solutions containing both fat-soluble vitamins (vitamin A acetate and palmitate, Vitamin D2 and D3, vitamin K1, α-, δ-, and γ-vitamin E isomers) and carotenoids (ß-cryptoxanthin, zeaxanthin, lutein, ß-carotene, and lycopene) effectively (i.e., analytical recoveries ranging from 80.43% to 117.02%, for vitamins, and from 43.80% to 108.63%). We optimized saponification conditions and settled at 80 °C using 1 mmol KOH L-1 ethanol during 1 h. We used a non-aqueous gradient that included methanol and methyl tert-butyl ether (starting at an 80:20 ratio) and a C30 chromatographic column to achieve analyte separation (in less than 40 min) and applied this method to avocado, a fruit that characteristically contains both types of compounds. We obtained a method with good linearity at the mid to low range of the mg L-1 (determination coefficients 0.9006-0.9964). To determine both types of compounds in avocado, we developed and validated for the simultaneous analysis of carotenoids and fat-soluble vitamins based on liquid chromatography and single quadrupole mass detection (LC/MS). From actual avocado samples, we found relevant concentrations for cholecalciferol (ranging from 103.5 to 119.5), δ-tocopherol (ranging from 6.16 to 42.48), and lutein (ranging from 6.41 to 15.13 mg/100 g dry weight basis). Simmonds cultivar demonstrated the higher values for all analytes (ranging from 0.03 (zeaxanthin) to 119.5 (cholecalciferol) mg/100 g dry weight basis).

Advancing Reliable Data for Cancer Control in the Central America Four Region.

The Central America Four (CA-4) region, comprising Guatemala, Honduras, El Salvador, and Nicaragua, is the largest low- and middle-income country region in the Western Hemisphere, with over 36 million inhabitants. The CA-4 nations share a common geography, history, language, and development indices, and unified with open borders in 2006. The growing CA-4 cancer burden among the noncommunicable diseases is expected to increase 73% by 2030, which argues for a regional approach to cancer control. This has driven efforts to establish population-based cancer registries as a central component of the cancer control plans. The involvement of international and academic partners in an array of initiatives to improve cancer information and control in the CA-4 has accelerated over the past several years. Existing data underscore that the infectious cancers (cervical, stomach, and liver) are a particular burden. All four countries have committed to establishing regional population-based cancer registries and have advanced significantly in pediatric cancer registration. The challenges common to each nation include the lack of national cancer control plans and departments, competing health priorities, lack of trained personnel, and sustainability strategies. General recommendations to address these challenges are outlined. The ongoing regional, international, and academic cooperation has proven helpful and is expected to continue to be a powerful instrument to contribute to the design and implementation of long-term national cancer control plans.

Fracaso renal agudo secundario a crisis de hipercalcemia muy severa por hiperparatiroidismo primario / Acute kidney failure secondary to very severe hypercalcaemia from primary hyperparathyroidism

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Magnesium sulphate reduces cell volume in physiological conditions but not in the cytotoxic oedema during global brain ischemia.

PRIMARY OBJECTIVE: To establish the effect of MgSO4 on brain cellular volume during physiological and global ischemia using impedanciometric method. RESEARCH DESIGN: Impedanciometric measure in the brain before and during global brain ischemia, with or without intravenous infusion of MgSO4. METHODS AND PROCEDURES: Male Sprague-Dawley rats were anaesthetized (thiobarbital, 60 mg kg-1 i.p.). Ringer solution (n=9) or MgSO4 (n=8; 1 mmol Kg-1) where i.v. isovolumetrically administered. Sub-cortical impedance was recorded before and after the infusion of ringer or MgSO4 and during global cerebral ischemia induced by a cardiopulmonary arrest. MAIN OUTCOMES AND RESULTS: In non-ischemic conditions, MgSO4 infusion induced higher voltage values than those of ringer infusion (Wilcoxon, Z=2.49; p=0.01). During global cerebral ischemia, the MgSO4 infused animals showed a fast drop of voltages (82%) in the first 5 minutes, 4-fold the values of ringer infused animals (p<0.0001). In the following 15 minutes no differences were found between ringer and MgSO4 infused animals. CONCLUSIONS: The results suggest that MgSO4 significantly reduced brain cell volume in physiological conditions but not in global brain ischemia.