Enablers and barriers to adopt the locally developed Masi mechanical ventilator amid COVID-19 pandemic in Peru.

Background: Limited supply of resources during the COVID-19 emergency encouraged the local development of the Masi mechanical ventilator (MV). Despite the efforts to promote Masi, adopting this innovation faced multiple obstacles, regardless of its performance. We explored the perceptions among healthcare personnel towards incorporating Masi to provide ventilatory support to COVID-19 patients during the second wave in Peru (January to June 2021). Methods: We conducted twelve in-depth virtual interviews. Topics included experience when handling Masi, the impact of the training received, confidence in the device, barriers perceived, and enablers identified. All participants provided verbal informed consent. Results: Most of the participants were male physicians. Participants belonged to seven hospitals that exhibited a wide range of healthcare capacities. Globally, the adoption of Masi MV was driven by the scarcity of ventilatory devices in the wards and reinforced by appropriate training and prompt technical support. Participants reported that Masi's structural and operational features played both advantages and disadvantages. Hospital infrastructure readiness, availability of commercial MVs, mistrust in its simple appearance, and resistance to change among healthcare personnel were perceived as barriers, while low-cost, prompt technical support and user-friendliness were valuable enablers. The first two enablers were observed in participants regardless of their attitude towards Masi. Despite the small number of participants for this qualitative study, it is important to note that the sample size was sufficient to reach saturation, as the topics discussed with participants became redundant and did not yield new information. Conclusions: The perceptions among healthcare personnel to incorporate Masi as a mechanical ventilator for COVID-19 patients showed that communication, training and experience, and peer encouragement were essential to secure its use and sustainability of the technology. A priori judgments and perceptions unrelated to the performance of the novel device were observed, and its proper management may define its further implementation. Altogether our study suggests that along with strengthening local technological development, strategies to improve their adoption process must be considered as early as possible in medical innovations.

Prediction of prostate cancer biochemical recurrence by using discretization supports the critical contribution of the extra-cellular matrix genes.

Due to its complexity, much effort has been devoted to the development of biomarkers for prostate cancer that have acquired the utmost clinical relevance for diagnosis and grading. However, all of these advances are limited due to the relatively large percentage of biochemical recurrence (BCR) and the limited strategies for follow up. This work proposes a methodology that uses discretization to predict prostate cancer BCR while optimizing the necessary variables. We used discretization of RNA-seq data to increase the prediction of biochemical recurrence and retrieve a subset of ten genes functionally known to be related to the tissue structure. Equal width and equal frequency data discretization methods were compared to isolate the contribution of the genes and their interval of action, simultaneously. Adding a robust clinical biomarker such as prostate specific antigen (PSA) improved the prediction of BCR. Discretization allowed classifying the cancer patients with an accuracy of 82% on testing datasets, and 75% on a validation dataset when a five-bin discretization by equal width was used. After data pre-processing, feature selection and classification, our predictions had a precision of 71% (testing dataset: MSKCC and GSE54460) and 69% (Validation dataset: GSE70769) should the patients present BCR up to 24 months after their final treatment. These results emphasize the use of equal width discretization as a pre-processing step to improve classification for a limited number of genes in the signature. Functionally, many of these genes have a direct or expected role in tissue structure and extracellular matrix organization. The processing steps presented in this study are also applicable to other cancer types to increase the speed and accuracy of the models in diverse datasets.

Bioprinting: A Strategy to Build Informative Models of Exposure and Disease.

Novel additive manufacturing techniques are revolutionizing fields of industry providing more dimensions to control and the versatility of fabricating multi-material products. Medical applications hold great promise to manufacture constructs of mixed biologically compatible materials together with functional cells and tissues. We reviewed technologies and promising developments nurturing innovation of physiologically relevant models to study safety of chemicals that are hard to reproduce in current models, or diseases for which there are no models available. Extrusion-, inkjet- and laser-assisted bioprinting are the most used techniques. Hydrogels as constituents of bioinks and biomaterial inks are the most versatile materials to recreate physiological and pathophysiological microenvironments. The highlighted bioprinted models were chosen because they guarantee post-printing cellular viability while maintaining desirable mechanical properties of their constitutive bioinks or biomaterial inks to ensure their printability. Bioprinting is being readily adopted to overcome ethical concerns of in vivo models and improve the automation, reproducibility, geometry stability of traditional in vitro models. The challenges for advancing the technological level readiness of bioprinting require overcoming heterogeneity, microstructural complexity, dynamism and integration with other models, to generate multi-organ platforms that can inform about biological responses to chemical exposure, disease development and efficacy of novel therapies.

Open-source perfusion system for medium-scale fabrication of demineralized bone matrix chip grafts.

Demineralized bone matrix (DBM) is considered one of the most reliable bone tissue grafts for regular surgical use, as it provides a scaffold that is structurally like native bone, and that enhances bone regeneration. However, commercially available DBM products are not suited for surgical restitutions of large bones. Therefore, each Tissue Bank is urged to implement their own demineralization protocol, which usually does not meet the high demand for bone grafting. In this project, we developed an open source system for medium-scale manufacturing of DBM grafts from human cadaveric donors to automate the demineralization protocol and improve its reproducibility. The device consists in (1) unidirectional flow reaction chamber, where the demineralization protocol takes place; (2) automated syringe pump, which controls the reagent́s inlet and vacuum; and (3) reagent dispenser, for the management of the reagents need for the demineralization protocol. Validation of the device included histological analysis, DNA quantification temperature regulation, electrochemiluminescence and colorimetric protocols, followed by the optimization of physicochemical parameters based on Response Surface Methodology. The results showed values of residual lipids and calcium within standardized ranges, and the maintenance of the structural integrity of the DBM, demonstrating the capacity of the system to support the proposed demineralization protocol.

Biomechanical in silico evaluation of a 3D novel total hip implant with cemented fixation using finite elements.

This paper presents the biomechanical evaluation of a proposed replacement implant for a total hip arthroplasty considering both the effect of the material and using a numerical tool. The use of titanium, alumina, polycarbonate urethane (PCU), and nitride titanium allows the manufacture of a cemented hip prosthesis with better resistance to corrosion, greater biocompatibility, greater mechanical resistance for physiological conditions, and does not present plastic deformation. This article provides an analysis of biomaterials and adequate geometries for a total hip prosthesis, with the aim of finding the optimal model, thus avoiding complications such as loosening or fatigue that current models present. Ultimately, the proposed design of the prosthesis was modeled using finite elements, simulating the static loads to which the prosthesis is subjected and evaluating the chosen biomaterials. Clinical Relevance - Osteoarthritis is a degenerative disease that affects 20% of the population above 60 years of age, particularly the hip joint, which is why, in most cases, a total arthroplasty of the expressed joint is required. In this procedure, the hip is replaced with an implant, which failure is usually related with either geometrical conditions or selected materials. An exponential increase of 136% in the incidence of total hip arthroplasty is expected by 2030.

Development of an Intervertebral Disc for Cervical Spondylosis Composed of Seeded Biomaterials.

Most of the current artificial disc prosthesis presented a restricted range of motion. Here we propose the design of a novel intervertebral disc composed of carbon fiber, hyaluronic methylcellulose hydrogel loaded with mesenchymal stem cells and polycaprolactone. The prosthesis was biomechanically evaluated under two static physiological conditions to study the mechanical influence of the material on the device. The results obtained in the simulations showed a not only a congruent behavior with preclinical condition, but also that the proposed materials met the desired biomechanical properties Clinical Relevance- Cervical spondylosis is a degenerative disease of the human spine that causes wear and tear of the cervical intervertebral discs. Nowadays, the proposed surgical solutions do not allow fully recovery of normal movement because the surgical intervention do not emulate the natural range of motion, may lack shock absorption mechanisms, show signs of fatigue over time affecting its durability, and do not have good bone adhesion. Therefore, hypermobility and problems of heterotopic ossification may restrict the range of motion.

Biological evaluation of a mechanical ventilator that operates by controlling an automated manual resuscitator. A descriptive study in swine.

The Covid-19 outbreak challenged health systems around the world to design and implement cost-effective devices produced locally to meet the increased demand of mechanical ventilators worldwide. This study evaluates the physiological responses of healthy swine maintained under volume- or pressure-controlled mechanical ventilation by a mechanical ventilator implemented to bring life-support by automating a resuscitation bag and closely controlling ventilatory parameters. Physiological parameters were monitored in eight sedated animals (t0) prior to inducing deep anaesthesia, and during the next six hours of mechanical ventilation (t1-7). Hemodynamic conditions were monitored periodically using a portable gas analyser machine (i.e. BEecf, carbonate, SaO2, lactate, pH, PaO2, PaCO2) and a capnometer (i.e. ETCO2). Electrocardiogram, echocardiography and lung ultrasonography were performed to detect in vivo alterations in these vital organs and pathological findings from necropsy were reported. The mechanical ventilator properly controlled physiological levels of blood biochemistry such as oxygenation parameters (PaO2, PaCO2, SaO2, ETCO2), acid-base equilibrium (pH, carbonate, BEecf), and perfusion of tissues (lactate levels). In addition, histopathological analysis showed no evidence of acute tissue damage in lung, heart, liver, kidney, or brain. All animals were able to breathe spontaneously after undergoing mechanical ventilation. These preclinical data, supports the biological safety of the medical device to move forward to further evaluation in clinical studies.

Monitoreo adecuado y comunicación inequívoca, son la mejor estrategia para proteger a las poblaciones afectadas por derrames de petróleo / Proper testing strategies and unambiguous communication is the best strategy to protect oil-spill affected populations

Estimado editor, Con respecto al lamentable derrame de petróleo ocurrido el pasado 15 de enero en nuestro mar y costa peruana, me gustaría comentar sobre la necesidad de formular un Plan de Acción proactivo para abordar las preocupaciones de Salud Ambiental a largo plazo y utilizar las mejores prácticas para comunicar los riesgos a las personas cuyos medios de subsistencia están estrechamente entrelazados con las áreas afectadas.

Dear Editor, Regarding the unfortunate oil spill occurred last January 15th on our coast, I would like to call the attention of your readership towards the need to formulate a proactive Plan of Action to address Environmental Health concerns and use the best practices to communicate risks for people whose livelihoods are closely intertwined with the affected areas.

Diabetes Status is Associated With Plantar Soft Tissue Stiffness Measured Using Ultrasound Reverberant Shear Wave Elastography Approach.

INTRODUCTION: The purpose of this study was to investigate the association between the mechanical properties of plantar soft tissue and diabetes status. METHOD: 51 (M/F: 21/30) participants with prediabetes onset (fasting blood sugar [FBS] level > 100 mg/dL), age >18 years, and no lower limb amputation were recruited after ethical approval was granted from Pontificia Universidad Catolica del Peru ethical review board. Ultrasound reverberant shear wave elastography was used to assess the soft tissue stiffness at the 1st metatarsal head (MTH), 3rd MTH, and the heel at both feet. RESULTS: Spearman's rank-order correlation (rho) test indicated a significant (P < .05) positive correlations between FBS level and the plantar soft tissue shear wave speed at the 1st MTH: rho = 0.402 (@400 Hz), rho = 0.373 (@450 Hz), rho = 0.474 (@500 Hz), rho= 0.395 (@550 Hz), and rho = 0.326 (@600 Hz) in the left foot and rho = 0.364 (@450 Hz) in the right foot. Mann-Whitney U test indicated a significantly (P < .05) higher shear wave speed in the plantar soft tissue with the following effect sizes (r) at the 1st MTH of the left foot at all tested frequencies: r = 0.297 (@450 Hz), r = 0.345 (@500 Hz), r = 0.322 (@550 Hz), and r = 0.275 (@600 Hz), and at the 1st MTH of right foot r = 0.286 (@400 Hz) in diabetes as compared with the age and body mass index matched prediabetes group. CONCLUSION: An association between fasting blood sugar level and the stiffness of the plantar soft tissue with higher values of shear wave speed in diabetes versus prediabetes group was observed. This indicated that the proposed approach can improve the assessment of the severity of diabetic foot complications with potential implications in patient stratification.

Plantar Soft Tissue Characterization Using Reverberant Shear Wave Elastography: A Proof-of-Concept Study.

Plantar soft tissue stiffness provides relevant information on biomechanical characteristics of the foot. Therefore, appropriate monitoring of foot elasticity could be useful for diagnosis, treatment or health care of people with complex pathologies such as a diabetic foot. In this work, the reliability of reverberant shear wave elastography (RSWE) applied to plantar soft tissue was investigated. Shear wave speed (SWS) measurements were estimated at the plantar soft tissue at the first metatarsal head, the third metatarsal head and the heel from both feet in five healthy volunteers. Experiments were repeated for a test-retest analysis with and without the use of gel pad using a mechanical excitation frequency range between 400 and 600 Hz. Statistical analysis was performed to evaluate the reliability of the SWS estimations. In addition, the results were compared against those obtained with a commercially available shear wave-based elastography technique, supersonic imaging (SSI). The results indicate a low coefficient of variation for test-retest experiments with gel pad (median: 5.59%) and without gel pad (median: 5.83%). Additionally, the values of the SWS measurements increase at higher frequencies (median values: 2.11 m/s at 400 Hz, 2.16 m/s at 450 Hz, 2.24 m/s at 500 Hz, 2.21 m/s at 550 Hz and 2.31 m/s at 600 Hz), consistent with previous reports at lower frequencies. The SWSs at the plantar soft tissue at the first metatarsal head, third metatarsal head and heel were found be significantly (p<0.05) different, with median values of 2.42, 2.16 and 2.03 m/s, respectively which indicates the ability of the method to differentiate between shear wave speeds at different anatomical locations. The results indicated better elastographic signal-to-noise ratios with RSWE compared to SSI because of the artifacts presented in the SWS generation. These preliminary results indicate that the RSWE approach can be used to estimate the plantar soft tissue elasticity, which may have great potential to better evaluate changes in biomechanical characteristics of the foot.

Targeting SUMOylation dependency in human cancer stem cells through a unique SAE2 motif revealed by chemical genomics.

Natural products (NPs) encompass a rich source of bioactive chemical entities. Here, we used human cancer stem cells (CSCs) in a chemical genomics campaign with NP chemical space to interrogate extracts from diverse strains of actinomycete for anti-cancer properties. We identified a compound (McM25044) capable of selectively inhibiting human CSC function versus normal stem cell counterparts. Biochemical and molecular studies revealed that McM025044 exerts inhibition on human CSCs through the small ubiquitin-like modifier (SUMO) cascade, found to be hyperactive in a variety of human cancers. McM025044 impedes the SUMOylation pathway via direct targeting of the SAE1/2 complex. Treatment of patient-derived CSCs resulted in reduced levels of SUMOylated proteins and suppression of progenitor and stem cell capacity measured in vitro and in vivo. Our study overcomes a barrier in chemically inhibiting oncogenic SUMOylation activity and uncovers a unique role for SAE2 in the biology of human cancers.

Biological bases of cancer immunotherapy.

Immunotherapy has changed the landscape of cancer treatment and has significantly improved the outcome of several cancer types including breast, lung, colorectal and prostate. Neoantigen recognition and immune checkpoint inhibitors are nowadays the milestones of different immunotherapeutic regimes; however, high cost, primary and acquired resistance and the high variability of responses make their extensive use difficult. The development of better predictive biomarkers that represent tumour diversity shows promise because there is a significant body of clinical data showing a spectrum of immunotherapeutic responses that might be related back to their specific characteristics. This article makes a conceptual and historical review to summarise the main advances in our understanding of the role of the immune system in cancer, while describing the methodological details that have been successfully implemented on cancer treatments and that may hold the key to improved therapeutic approaches.

Masi: A mechanical ventilator based on a manual resuscitator with telemedicine capabilities for patients with ARDS during the COVID-19 crisis.

In this article, we introduce a portable and low-cost ventilator that could be rapidly manufactured, to meet the increasing demand of ventilators worldwide produced by COVID-19 pandemic. These ventilators should be rapidly deployable and with functional capabilities to manage COVID-19 patients with severe acute respiratory distress syndrome (ARDS). Our implementation offers robustness, safety and functionality absent in existing solutions to the ventilator shortage (i.e., telemonitoring, easy-to-disinfect, modularity) by maintaining simplicity. The design makes use of a manual resuscitator as the core respiration component activated by a compression mechanism which consist of two electronically controlled paddles. The quality measurements obtained after testing on a calibrated artificial lung demonstrate repeatability and accuracy exceeding human capabilities of manual ventilation. The complete design files are provided in the supplementary materials to facilitate ventilator production even in resource-limited settings. The implementation of this mechanical ventilator could eliminate device rationing or splitting to serve multiple patients on ICUs.

Ética de la investigación con seres humanos en el Perú. Una tarea pendiente más / Ethics Of Human Research In Peru. Yet Another Pending Task

Actualmente estamos atravesando una segunda ola de casos durante las pandemias de COVID-19 en Perú. Ya nos acostumbramos a ver héroes anónimos que salen de sus casas todos los días ofrecer su trabajo para apoyar a sus familias y comunidades. Después de casi un año del inicio de esta Crisis de Salud Pública, se está exigiendo mucho más a los profesionales de la salud y afines. Importantes esfuerzos encaminados a mejorar la infraestructura y la orientación técnica de las innovaciones médicas se han visto obligados a avanzar y ser implementados en plazos sin precedentes, pero su visibilidad se ve obstaculizada por otra tarea pendiente en el Sistema de Salud Peruano relacionada con la Ética de la Investigación con Seres Humanos.

We are currently cruising through a second wave of cases during the pandemics of COVID-19 in Peru. Anonymous heroes leave their houses every day and keep offering their work to support their families and communities. After almost a year of the beginning of this Public Health Crisis, much more is being demanded from health and allied professionals. Important efforts leading to improvements on infrastructure and technical guidance for medical innovations have been forced to move forward and be implemented in unprecedented timelines, but their visibility is hindered by another pending task in the Peruvian Health System related to the Ethics of Human Research.

Tratamiento de quemaduras mediante plasma heterólogo rico en plaquetas (PRPh). A propósito de un caso pediátrico / Treatmen of burns by heterologous rich platelet plasma (hRPP). About a pediatric case report

Presentamos un caso en el que empleamos con éxito plasma rico en plaquetas heterólogo (PRPh) para la reparación de una quemadura de difícil evolución en un paciente pediátrico. Mostramos la seguridad y eficacia del uso del PRPh proveniente de la madre en un caso de quemadura AB-A por agua caliente. Se trata de una paciente de 3 años de edad que fue intervenida quirúrgicamente en otro centro, sin resultados positivos y profundizándose, por lo que se vio complicada su recuperación. El objetivo fue regenerar el tejido afectado e inducir de manera asistida la formación de tejido epitelial utilizando PRPh de la madre de la paciente. Aplicamos técnica de curación cerrada en 2 sesiones ambulatorias mediante la aplicación de PRPh sin necesidad de procedimientos adicionales. No se presentaron complicaciones, signos de rechazo ni infecciones y la recuperación se obtuvo en 14 días

The safety and efficacy of the use of heterologous rich platelet plasma (hRPP) from the mother is shown in a case of AB-A burn by hot water. This is a 3-year-old patient who was surgically operated in another center, without positive results and deepening, so recovery was complicated. The objective was to regenerate the affected tissue and to induce in an assisted way the formation of epithelial tissue using hRPP from the patient's mother. We apply the closed healing technique in 2 outpatient sessions by applying hRPP without the need for additional procedures. There were no complications, signs of rejection or infections, and their recovery was obtained in 14 days

Análisis del potencial de innovación en apósitos para tratar heridas crónicas en la ciudad de Lima, Perú / Analysis Of The Potential Of Innovation In Dressings To Treat Chronic Wounds In The City Of Lima, Peru

Objetivo: Analizar el potencial de innovación en apósitos para tratar heridas crónicas en la Ciudad de Lima. Métodos: Se realizó un estudio cualitativo mediante una encuesta y análisis de las entrevistas realizadas a expertos médicos y gestores de compras en insumos para el tratamiento de heridas de difícil resolución en 8 instituciones representativas de salud pública con categorías 1 ­ 4 dentro de las 54 existentes solo en Lima Metropolitana, Perú - 2018. Resultados: Se determinó que en las instituciones de salud pública son atendidos un promedio 17 pacientes mensualmente (60% provenientes de hospitalización y 40% de consultorio externo). Equivale decir que 11,016 pacientes presentan heridas crónicas de difícil resolución al año, los cuales requerirán de tratamiento especializado y una demanda anual promedio de 110,160 apósitos en stock. Los apósitos con mayor demanda corresponden a los Hidrogeles e Hidrocoloides, respectivamente que son utilizados por los resultados positivos que ofrecen en la curación de las heridas, aunque en ocasiones la limitante es el aspecto económico. En el mercado, el precio unitario oscila entre los 20 y 90 soles, esto representa una inversión económica de 1500 soles en promedio por paciente, produciendo en algunos casos complicaciones o abandono del tratamiento cuando los recursos son escasos. Conclusiones: La demanda de pacientes con heridas crónicas de difícil resolución en las instituciones de salud públicas de Lima metropolitana es alta. Es importante promover e incentivar la investigación de nuevas alternativas terapéuticas y/o dispositivos biomédicos que favorezcan su curación.

Objective: To analyze the potential for innovation in dressings to treat chronic wounds in the City of Lima. Methods: A qualitative study was carried out by means of interviews to medical experts and purchasing managers of medical supplies for the treatment of difficult-to-resolve wounds in 8 representative public health institutions with categories 1-4 within the only 54 of Lima, Peru - 2018. Results: It was determined that an average of 17 patients is treated in public health institutions on a monthly basis (60% from hospitalization and 40% from an outpatient office). It is equivalent to say that 11,016 patients present chronic wounds of difficult resolution each year, which will require specialized treatment and an average annual demand of 110,160 dressings in stock. The dressings with the highest demand correspond to the Hydrogels and Hydrocolloids, respectively; used because of the positive results they offer in wound healing, despite economic limitations. The market price per unit ranges between 20 and 90 soles (S/.), representing an economic investment of 1500 soles on average per patient, in some cases causing complications or abandonment of treatment when resources are scarce. Conclusions: There is a high demand for patients with chronic wounds of difficult resolution in the public health institutions of Lima. It is important to promote and incentivize the investigation of new therapeutic alternatives and / or biomedical devices that favor its treatment.

The Aryl Hydrocarbon Receptor Relays Metabolic Signals to Promote Cellular Regeneration.

While sensing the cell environment, the aryl hydrocarbon receptor (AHR) interacts with different pathways involved in cellular homeostasis. This review summarizes evidence suggesting that cellular regeneration in the context of aging and diseases can be modulated by AHR signaling on stem cells. New insights connect orphaned observations into AHR interactions with critical signaling pathways such as WNT to propose a role of this ligand-activated transcription factor in the modulation of cellular regeneration by altering pathways that nurture cellular expansion such as changes in the metabolic efficiency rather than by directly altering cell cycling, proliferation, or cell death. Targeting the AHR to promote regeneration might prove to be a useful strategy to avoid unbalanced disruptions of homeostasis that may promote disease and also provide biological rationale for potential regenerative medicine approaches.

GSK3 Deficiencies in Hematopoietic Stem Cells Initiate Pre-neoplastic State that Is Predictive of Clinical Outcomes of Human Acute Leukemia.

Initial pathway alternations required for pathogenesis of human acute myeloid leukemia (AML) are poorly understood. Here we reveal that removal of glycogen synthase kinase-3α (GSK-3α) and GSK-3ß dependency leads to aggressive AML. Although GSK-3α deletion alone has no effect, GSK-3ß deletion in hematopoietic stem cells (HSCs) resulted in a pre-neoplastic state consistent with human myelodysplastic syndromes (MDSs). Transcriptome and functional studies reveal that each GSK-3ß and GSK-3α uniquely contributes to AML by affecting Wnt/Akt/mTOR signaling and metabolism, respectively. The molecular signature of HSCs deleted for GSK-3ß provided a prognostic tool for disease progression and survival of MDS patients. Our study reveals that GSK-3α- and GSK-3ß-regulated pathways can be responsible for stepwise transition to MDS and subsequent AML, thereby providing potential therapeutic targets of disease evolution.