Systematic review on the implementation of metrological assurance systems for medical devices in Latin America.

Background: Metrology plays a crucial role in small healthcare service businesses to ensure the quality of products and services. While legal metrology in healthcare exists in some regions, it lacks harmonization. In other countries, there is limited presence of metrology in medical and biomedical engineering. We aimed to evaluate the implementation of metrological assurance systems for medical devices in Latin America. Methods: A systematic review was conducted following PRISMA 2020 guidelines and registered with PROSPERO (CRD42022359284). Searches were performed across 13 databases from October 30th to November 3rd, 2022. The search equation was "(((quality assurance) AND (metrology)) AND (medical devices))." A total of 7,789 documents were identified, of which only 16 met the inclusion criteria. Results: The majority of studies (75%) were conducted in Colombia, with a significant portion being undergraduate theses. The primary normative references used in the analyzed studies were ISO 10012 and ISO 17025, with the majority (68.75%) relying on national legislation for their approach. One study in Colombia referenced eight standards, and one in Brazil analyzed user involvement in medical device management. Among the included studies, 56.25% were conducted in healthcare institutions, mainly clinics. Most studies provided implementation guidelines, with ISO 10012 being prominent, alongside ISO 17025, which implicitly addresses ISO 9001 elements. Global bias was low across all studies. Conclusion: Our results underscore the importance of metrological assurance in managing medical devices in Latin America. The utilization of international standards and national legislation illustrates the diverse approaches adopted by different institutions. Future research should focus on optimizing metrological practices to enhance quality and safety in healthcare.

Rethinking the Role of Biodosimetry to Assess Risks for Acute Radiation Syndrome in Very Large Radiation Events: Reconsidering Legacy Concepts.

The development of effective uses of biodosimetry in large-scale events has been hampered by residual, i.e., "legacy" thinking based on strategies that scale up from biodosimetry in small accidents. Consequently, there remain vestiges of unrealistic assumptions about the likely magnitude of victims in "large" radiation events and incomplete analyses of the logistics for making biodosimetry measurements/assessments in the field for primary triage. Elements remain from an unrealistic focus on developing methods to use biodosimetry in the initial stage of triage for a million or more victims. Based on recent events and concomitant increased awareness of the potential for large-scale events as well as increased sophistication in planning and experience in the development of biodosimetry, a more realistic assessment of the most effective roles of biodosimetry in large-scale events is urgently needed. We argue this leads to a conclusion that the most effective utilization of biodosimetry in very large events would occur in a second stage of triage, after initially winnowing the population by identifying those most in need of acute medical attention, based on calculations of geographic sites where significant exposures could have occurred. Understanding the potential roles and limitations of biodosimetry in large-scale events involving significant radiation exposure should lead to development of the most effective and useful biodosimetric techniques for each stage of triage for acute radiation syndrome injuries, i.e., based on more realistic assumptions about the underlying event and the logistics for carrying out biodosimetry for large populations.

Optogenetic control of Nodal signaling patterns.

A crucial step in early embryogenesis is the establishment of spatial patterns of signaling activity. Tools to perturb morphogen signals with high resolution in space and time can help reveal how embryonic cells decode these signals to make appropriate fate decisions. Here, we present new optogenetic reagents and an experimental pipeline for creaHng designer Nodal signaling patterns in live zebrafish embryos. Nodal receptors were fused to the light-sensitive heterodimerizing pair Cry2/CIB1N, and the Type II receptor was sequestered to the cytosol. The improved optoNodal2 reagents eliminate dark activity and improve response kinetics, without sacrificing dynamic range. We adapted an ultra-widefield microscopy platform for parallel light patterning in up to 36 embryos and demonstrated precise spatial control over Nodal signaling activity and downstream gene expression. Patterned Nodal activation drove precisely controlled internalization of endodermal precursors. Further, we used patterned illumination to generate synthetic signaling patterns in Nodal signaling mutants, rescuing several characteristic developmental defects. This study establishes an experimental toolkit for systematic exploration of Nodal signaling patterns in live embryos.

Lipoxygenase-derived oxylipins are enriched in anti-citrullinated protein antibody (ACPA)-positive individuals at risk for developing rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is typically preceded by an extended preclinical period where circulating autoantibodies, particularly anti-citrullinated protein antibodies (ACPA), are detectable in the absence of clinical arthritis. Increased dietary intake of anti-inflammatory omega-3 (ω3) polyunsaturated fatty acids (PUFA) has been shown to be associated with a lower the risk of developing incident RA in large epidemiological studies. It is currently not known how changes in fatty acid (FA) metabolism may impact on the progression towards RA in at-risk individuals. To begin to address this question, we profiled serum FAs and oxylipins in an established cohort of at-risk ACPA-positive first-degree relatives (FDR) of RA patients (N = 31), some of whom developed RA (N = 4), and compared their profile to ACPA-negative FDR from the same population (N = 10). METHODS: Gas chromatography (GC) was used for FA quantitation. Oxylipins were extracted and quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC/MS/MS). RESULTS: Although we did not detect any meaningful differences in overall FA content between ACPA + and ACPA - FDR, the levels of oxylipins derived from FA metabolism demonstrated significant differences between the two groups, with the ACPA + group demonstrating enrichment in circulating arachidonic acid- and eicosapentaenoic acid-derived molecules. Compared with the ACPA - FDR group, the ACPA + FDR, including those who progressed into inflammatory arthritis, displayed higher levels of LOX-derived oxylipins. CONCLUSION: ACPA seropositivity in otherwise unaffected individuals at-risk for developing future RA based on family history (FDR) is associated with alterations in the serum oxylipin profile that suggests dysregulated LOX activity.

Species-specific oxylipins and the effects of ontogeny and predation on their emission from freshwater snails.

Chemical cues play important roles in mediating ecological interactions. Oxylipins, oxygenated metabolites of fatty acids, are one signalling molecule type that influences the physiology and function of species, suggesting their broader significance in chemical communication within aquatic systems. Yet, our current understanding of their function is restricted taxonomically and contextually making it difficult to infer their ecological significance. Snails and leeches are ubiquitous in freshwater ecosystems worldwide, yet little is known about their oxylipin profiles and the factors that cause their profiles to change. As snails and leeches differ taxonomically and represent different trophic groups, we postulated oxylipin profile differences. For snails, we hypothesized that ontogeny (non-reproductive vs reproductive) and predation (non-infested vs leech-infested) would affect oxylipin profiles. Oxylipins were characterized from water conditioned with the snail Planorbella duryi and leech Helobdella lineata, and included three treatment types (snails, leeches, and leech-infested snails) with the snails consisting of three size classes: small (5-6 mm, non-reproductive) and medium and large (13-14 and 19-20 mm, reproductive). The two species differed in the composition of their oxylipin profiles both in diversity and amounts. Further, ontogeny and predation affected the diversity of oxylipins emitted by snails. Our experimental profiles of oxylipins show that chemical cues within freshwater systems vary depending upon the species emitting the signals, the developmental stage of the species, as well as from ecological interactions such as predation. We also identified some candidates, like 9-HETE and PGE2, that could be explored more directly for their physiological and ecological roles in freshwater systems.

Valvular Prostaglandins Are Elevated in Severe Human Aortic Valve Stenosis.

BACKGROUND: Aortic valve stenosis (AVS) is the most common valvular disease in the developed world. AVS involves the progressive fibrocalcific remodeling of the aortic valve (AV), which impairs function and can ultimately lead to heart failure. Due to gaps in our understanding of the underlying mechanisms of AVS, there are no pharmacological treatments or dietary interventions known to slow AVS progression. Recent studies have begun to suggest oxylipins-a class of bioactive lipids-may be dysregulated in the valves of patients with AVS. METHODS: We utilized high-performance liquid chromatography-tandem mass spectrometry to conduct a targeted oxylipin analysis on human AV tissue and plasma from a cohort of 110 patients undergoing AV surgery. RESULTS: We identified 36 oxylipins in human AV tissue with all showing significant increase in patients with severe AVS. A multivariate model including patient characteristics and valvular oxylipins identified the arachidonic acid-COX (cyclooxygenase) pathway-derived prostanoids to be the most associated with AVS severity. Plasma oxylipin levels were measured in a subset of AV surgery patients and compared with a control group of healthy participants, showing distinct oxylipin profiles between control and disease. CONCLUSIONS: Our comprehensive analysis of oxylipins in the human AV identified the inflammatory and osteogenic regulating prostanoids to be positively correlated with AVS severity. This elucidation of prostanoid dysregulation warrants further research into COX inhibition to mitigate AVS.

Re-examining What the Results of "a Measurement of Oxygen Level in Tissues" Really Mean.

Within this special issue, many eminent investigators report on measurements of oxygen (O2) levels in tissues. Given the complexities of spatial and temporal heterogeneities of O2 in tissues and its many sources, this commentary draws attention to what such measurements do and do not actually assess regarding O2 levels in tissues. Given this limitation, it also discusses how these results can be used most effectively. To provide a convenient mechanism to discuss these issues more fully, this analysis focuses on measurements using EPR oximetry, but these considerations apply to all other techniques. The nature of the delivery of O2 to tissues and the mechanisms by which O2 is consumed necessarily result in very different levels of O2 within the volume of each voxel of a measurement. Better spatial resolution cannot fully resolve the problem because the variations include O2 gradients within each cell. Improved resolution of the time-dependent variation in O2 is also very challenging because O2 levels within tissues can have fluctuations of O2 levels in the range of milliseconds, while most methods require longer times to acquire the data from each voxel. Based on these issues, we argue that the values obtained inevitably are complex aggregates of averages of O2 levels across space and time in the tissue. These complexities arise from the complex physiology of tissues and are compounded by the limitations of the technique and its ability to acquire data. However, one often can obtain very meaningful and useful results if these complexities and limitations are taken into account. We illustrate this, using results obtained with in vivo EPR oximetry, especially utilizing its capacity to make repeated measurements to follow changes in O2 levels that occur with interventions and/or over time.

Reduced morbidity with early surgical ligation of patent ductus arteriosus in extremely low birth weight infants: a retrospective single-centre study.

INTRODUCTION: Failure of the patent ductus arteriosus to close is common among extremely low birth weight neonates and has been associated with increased morbidities. The objective of this study was to compare outcomes between early and late surgical ligation in extremely low birth weight patients. METHODS: This was a single-centre retrospective cohort study of infants who required surgical closure of patent ductus arteriosus between January 2017 and August 2022. RESULTS: A total of 43 neonates were identified with birth weight less than 1 kg that underwent surgical patent ductus arteriosus ligation. Compared to the late ligation group, the early ligation group experienced fewer total days of mechanical ventilation (43.9 days vs. 97.2 days, p < 0.05) and a shorter length of hospital stay (114.2 days vs. 169.0 days, p < 0.05). CONCLUSION: Early surgical ligation of haemodynamically significant patent ductus arteriosus in extremely low birth weight neonates may improve hospital morbidity, including improved ventilatory outcomes and a shorter length of stay.

In Vivo Verification of Electron Paramagnetic Resonance Biodosimetry Using Patients Undergoing Radiation Therapy Treatment.

PURPOSE: Electron paramagnetic resonance (EPR) biodosimetry, used to triage large numbers of individuals incidentally exposed to unknown doses of ionizing radiation, is based on detecting a stable physical response in the body that is subject to quantifiable variation after exposure. In vivo measurement is essential to fully characterize the radiation response relevant to a living tooth measured in situ. The purpose of this study was to verify EPR spectroscopy in vivo by estimating the radiation dose received in participants' teeth. METHODS AND MATERIALS: A continuous wave L-band spectrometer was used for EPR measurements. Participants included healthy volunteers and patients undergoing head and neck and total body irradiation treatments. Healthy volunteers completed 1 measurement each, and patients underwent measurement before starting treatment and between subsequent fractions. Optically stimulated luminescent dosimeters and diodes were used to determine the dose delivered to the teeth to validate EPR measurements. RESULTS: Seventy measurements were acquired from 4 total body irradiation and 6 head and neck patients over 15 months. Patient data showed a linear increase of EPR signal with delivered dose across the dose range tested. A linear least-squares weighted fit of the data gave a statistically significant correlation between EPR signal and absorbed dose (P < .0001). The standard error of inverse prediction (SEIP), used to assess the usefulness of fits, was 1.92 Gy for the dose range most relevant for immediate triage (≤7 Gy). Correcting for natural background radiation based on patient age reduced the SEIP to 1.51 Gy. CONCLUSIONS: This study demonstrated the feasibility of using spectroscopic measurements from radiation therapy patients to validate in vivo EPR biodosimetry. The data illustrated a statistically significant correlation between the magnitude of EPR signals and absorbed dose. The SEIP of 1.51 Gy, obtained under clinical conditions, indicates the potential value of this technique in response to large radiation events.

Bayesian Optimization-Based Inverse Finite Element Analysis for Atrioventricular Heart Valves.

Inverse finite element analysis (iFEA) of the atrioventricular heart valves (AHVs) can provide insights into the in-vivo valvular function, such as in-vivo tissue strains; however, there are several limitations in the current state-of-the-art that iFEA has not been widely employed to predict the in-vivo, patient-specific AHV leaflet mechanical responses. In this exploratory study, we propose the use of Bayesian optimization (BO) to study the AHV functional behaviors in-vivo. We analyzed the efficacy of Bayesian optimization to estimate the isotropic Lee-Sacks material coefficients in three benchmark problems: (i) an inflation test, (ii) a simplified leaflet contact model, and (iii) an idealized AHV model. Then, we applied the developed BO-iFEA framework to predict the leaflet properties for a patient-specific tricuspid valve under a congenital heart defect condition. We found that the BO could accurately construct the objective function surface compared to the one from a [Formula: see text] grid search analysis. Additionally, in all cases the proposed BO-iFEA framework yielded material parameter predictions with average element errors less than 0.02 mm/mm (normalized by the simulation-specific characteristic length). Nonetheless, the solutions were not unique due to the presence of a long-valley minima region in the objective function surfaces. Parameter sets along this valley can yield functionally equivalent outcomes (i.e., closing behavior) and are typically observed in the inverse analysis or parameter estimation for the nonlinear mechanical responses of the AHV. In this study, our key contributions include: (i) a first-of-its-kind demonstration of the BO method used for the AHV iFEA; and (ii) the evaluation of a candidate AHV in-silico modeling approach wherein the chordae could be substituted with equivalent displacement boundary conditions, rendering the better iFEA convergence and a smoother objective surface.

A Critical Analysis of Possible Mechanisms for the Oxygen Effect in Radiation Therapy with FLASH.

The aim of this review is to stimulate readers to undertake appropriate investigations of the mechanism for a possible oxygen effect in FLASH. FLASH is a method of delivery of radiation that empirically, in animal models, appears to decrease the impact of radiation on normal tissues while retaining full effect on tumors. This has the potential for achieving a significantly increased effectiveness of radiation therapy. The mechanism is not known but, especially in view of the prominent role that oxygen has in the effects of radiation, investigations of mechanisms of FLASH have often focused on impacts of FLASH on oxygen levels. We and others have previously shown that simple differential depletion of oxygen directly changing the response to radiation is not a likely mechanism. In this review we consider how time-varying changes in oxygen levels could account for the FLASH effect by changing oxygen-dependent signaling in cells. While the methods of delivering FLASH are still evolving, current approaches for FLASH can differ from conventional irradiation in several ways that can impact the pattern of oxygen consumption: the rate of delivery of the radiation (40 Gy/s vs. 0.1 Gy/s), the time over which each fraction is delivered (e.g., <0.5 s. vs. 300 s), the delivery in pulses, the number of fractions, the size of the fractions, and the total duration of treatment. Taking these differences into account and recognizing that cell signaling is an intrinsic component of the need for cells to maintain steady-state conditions and, therefore, is activated by small changes in the environment, we delineate the potential time dependent changes in oxygen consumption and overview the cell signaling pathways whose differential activation by FLASH could account for the observed biological effects of FLASH. We speculate that the most likely pathways are those involved in repair of damaged DNA.

An investigation of how specimen dimensions affect biaxial mechanical characterizations with CellScale BioTester and constitutive modeling of porcine tricuspid valve leaflets.

Biaxial mechanical characterizations are the accepted approach to determine the mechanical response of many biological soft tissues. Although several computational and experimental studies have examined how experimental factors (e.g., clamped vs. suture mounting) affect the acquired tissue mechanical behavior, little is known about the role of specimen dimensions in data acquisition and the subsequent modeling. In this study, we combined our established mechanical characterization framework with an iterative size-reduction protocol to test the hypothesis that specimen dimensions affect the observed mechanical behavior of biaxial characterizations. Our findings indicated that there were non-significant differences in the peak equibiaxial stretches of tricuspid valve leaflets across four specimen dimensions ranging from 4.5×4.5mm to 9 × 9mm. Further analyses revealed that there were significant differences in the low-tensile modulus of the circumferential tissue direction. These differences resulted in significantly different constitutive model parameters for the Tong-Fung model between different specimen dimensions of the posterior and septal leaflets. Overall, our findings demonstrate that specimen dimensions play an important role in experimental characterizations, but not necessarily in constitutive modeling of soft tissue mechanical behavior during biaxial testing with the commercial CellScale BioTester.

Implications of "flash" radiotherapy for biodosimetry.

Extremely high dose rate radiation delivery (FLASH) for cancer treatment has been shown to produce less damage to normal tissues while having the same radiotoxic effect on tumor tissue (referred to as the FLASH effect). Research on the FLASH effect has two very pertinent implications for the field of biodosimetry: (1) FLASH is a good model to simulate delivery of prompt radiation from the initial moments after detonating a nuclear weapon and (2) the FLASH effect elucidates how dose rate impacts the biological mechanisms that underlie most types of biological biodosimetry. The impact of dose rate will likely differ for different types of biodosimetry, depending on the specific underlying mechanisms. The greatest impact of FLASH effects is likely to occur for assays based on biological responses to radiation damage, but the consequences of differential effects of dose rates on the accuracy of dose estimates has not been taken into account.

EPR biodosimetry: challenges and opportunities.

This paper briefly examines electron paramagnetic resonance (EPR) techniques to measure dose from exposure to external radiation, assessing their current status, potential future uses and the challenges impacting their progress. We conclude the uses and potential value of different EPR techniques depend on the number of victims and whether they characterize short- or long-term risks from exposure. For large populations, EPR biodosimetry based on in vivo measurements or using co-located inanimate objects offer the greatest promise for assessing acute, life-threatening risk and the magnitude and extent of such risk. To assess long-term risk, ex vivo EPR methods using concentrated enamel from exfoliated teeth are most impactful. For small groups, ex vivo EPR biodosimetry based on available samples of teeth, nails and/or bones are most useful. The most important challenges are common to all approaches: improve the technique's technical capabilities and advance recognition by planning groups of the relative strengths EPR techniques offer for each population size. The most useful applications are likely to be for triage and medical guidance in large events and for radiation epidemiology to evaluate long-term risks.

Benefits and challenges of in vivo EPR nail biodosimetry in a second tier of medical triage in response to a large radiation event.

Following large-scale radiation events, an overwhelming number of people will potentially need mitigators or treatment for radiation-induced injuries. This necessitates having methods to triage people based on their dose and its likely distribution, so life-saving treatment is directed only to people who can benefit from such care. Using estimates of victims following an improvised nuclear device striking a major city, we illustrate a two-tier approach to triage. At the second tier, after first removing most who would not benefit from care, biodosimetry should provide accurate dose estimates and determine whether the dose was heterogeneous. We illustrate the value of using in vivo electron paramagnetic resonance nail biodosimetry to rapidly assess dose and determine its heterogeneity using independent measurements of nails from the hands and feet. Having previously established its feasibility, we review the benefits and challenges of potential improvements of this method that would make it particularly suitable for tier 2 triage. Improvements, guided by a user-centered approach to design and development, include expanding its capability to make simultaneous, independent measurements and improving its precision and universality.

Comparison of Tumor Control and Skin Damage in a Mouse Model after Ultra-High Dose Rate Irradiation and Conventional Irradiation.

Recent studies suggest ultra-high dose rate radiation treatment (UHDR-RT) reduces normal tissue damage compared to conventional radiation treatment (CONV-RT) at the same dose. In this study, we compared first, the kinetics and degree of skin damage in wild-type C57BL/6 mice, and second, tumor treatment efficacy in GL261 and B16F10 dermal tumor models, at the same UHDR-RT and CONV-RT doses. Flank skin of wild-type mice received UHDR-RT or CONV-RT at 25 Gy and 30 Gy. Normal skin damage was tracked by clinical observation to determine the time to moist desquamation, an endpoint which was verified by histopathology. Tumors were inoculated on the right flank of the mice, then received UHDR-RT or CONV-RT at 1 × 11 Gy, 1 × 15, 1 × 25, 3 × 6 and 3 × 8 Gy, and time to tumor tripling volume was determined. Tumors also received 1 × 11, 1 × 15, 3 × 6 and 3 × 8 Gy doses for assessment of CD8+/CD4+ tumor infiltrate and genetic expression 96 h postirradiation. All irradiations of the mouse tumor or flank skin were performed with megavoltage electron beams (10 MeV, 270 Gy/s for UHDR-RT and 9 MeV, 0.12 Gy/s for CONV-RT) delivered via a clinical linear accelerator. Tumor control was statistically equal for similar doses of UHDR-RT and CONV-RT in B16F10 and GL261 murine tumors. There were variable qualitative differences in genetic expression of immune and cell damage-associated pathways between UHDR and CONV irradiated B16F10 tumors. Compared to CONV-RT, UHDR-RT resulted in an increased latent period to skin desquamation after a single 25 Gy dose (7 days longer). Time to moist skin desquamation did not significantly differ between UHDR-RT and CONV-RT after a 30 Gy dose. The histomorphological characteristics of skin damage were similar for UHDR-RT and CONV-RT. These studies demonstrated similar tumor control responses for equivalent single and fractionated radiation doses, with variable difference in expression of tumor progression and immune related gene pathways. There was a modest UHDR-RT skin sparing effect after a 1 × 25 Gy dose but not after a 1 × 30 Gy dose.