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Tandem mass spectrometry is an important analytical tool for clinical laboratories, but tests developed and validated in-house (laboratory developed tests, or LDTs) require special consideration. In late 2022, the forecast for United States (U.S.) federal regulation of LDTs changed unexpectedly when the VALID Act was not passed by the U.S. Congress. This Act would have modified the Food and Drug Administration's (FDA's) role to increase regulatory oversight for LDT providers. In this revised context, we review optimization of quantitative mass spectrometry LDT validation and suggest avenues other than an additional FDA mandate to achieve uniform best practice. Common challenges, logistical barriers, and recommendations for easing the burden of best-quality quantitative mass spectrometry LDT method validation are discussed.

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All parties involved in health care, including patients and their families/caregivers play a significant role to achieve patient safety. Furthermore, patient engagement (PE) has not been adequately implemented to achieve safe healthcare in Indonesia, despite the introduction of the patient-centered care paradigm. This study aims to explore healthcare professionals' (HCPs) perspectives on PE and its application technique. A qualitative study was conducted in the chronic wards of a faith-based private hospital in Yogyakarta Province, Indonesia. Four focus group discussions among 46 HCPs, followed by 16 in-depth interviews, were carried out. Furthermore, the verbatim transcripts were subjected to thematic analysis. The result showed four main themes, including PE as a strategy for achieving safe healthcare, factors affecting its implementation, the need for comprehensive strategies to engage the patients, and their roles in safety efforts. Furthermore, the implementation of PE can be enhanced by encouraging healthcare professionals (HCPs) to play proactive roles in empowering recipients. To achieve PE, "partnership culture" and the removal of potential barriers as well as determining factors, must be established. This requires a high-level commitment, organizational support with a top-down approach, and integration into healthcare systems. In conclusion, PE is essential for patient safety and can be enhanced by strengthening organization support, integrating into the healthcare system, improving HCPs' roles, and empowering patients and caregivers to overcome potential barriers.

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The EU In-Vitro Diagnostic Device Regulation (IVDR) aims for transparent risk-and purpose-based validation of diagnostic devices, traceability of results to uniquely identified devices, and post-market surveillance. The IVDR regulates design, manufacture and putting into use of devices, but not medical services using these devices. In the absence of suitable commercial devices, the laboratory can resort to laboratory-developed tests (LDT) for in-house use. Documentary obligations (IVDR Art 5.5), the performance and safety specifications of ANNEX I, and development and manufacture under an ISO 15189-equivalent quality system apply. LDTs serve specific clinical needs, often for low volume niche applications, or correspond to the translational phase of new tests and treatments, often extremely relevant for patient care. As some commercial tests may disappear with the IVDR roll-out, many will require urgent LDT replacement. The workload will also depend on which modifications to commercial tests turns them into an LDT, and on how national legislators and competent authorities (CA) will handle new competences and responsibilities. We discuss appropriate interpretation of ISO 15189 to cover IVDR requirements. Selected cases illustrate LDT implementation covering medical needs with commensurate management of risk emanating from intended use and/or design of devices. Unintended collateral damage of the IVDR comprises loss of non-profitable niche applications, increases of costs and wasted resources, and migration of innovative research to more cost-efficient environments. Taking into account local specifics, the legislative framework should reduce the burden on and associated opportunity costs for the health care system, by making diligent use of existing frameworks.

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Introduction: Adherence to medication is an important determinant of outcomes in chronic diseases like heart failure. Drug assays provide objective adherence biomarkers. Dried blood spots (DBS) are appealing samples for drug assays due to less demanding transportation and storage requirements. Objectives: To analytically validate a LC-MS/MS method for the simultaneous quantification of carvedilol, enalaprilat, and perindoprilat in DBS and evaluate the feasibility of using the method as an adherence determining assay. To validate the assay further clinically by establishing correlation and agreement between plasma and DBS samples from a pharmacokinetic pilot study. Methods: The method was validated over a concentration range of 1.00-200 ng/mL according to FDA guidelines. Adherence tracking ability of the assay was evaluated using a pharmacokinetic pilot study. Correlation and agreement were evaluated through Deming regression and Bland-Altman analysis, respectively. Results: Accuracy, precision, selectivity, and sensitivity were proven with complete and reproducible extraction recovery at all concentrations tested. Stability of the analytes in the matrix and throughout sample processing was proven. The full range of concentrations of the pharmacokinetic pilot study could be quantified for enalaprilat, but not for carvedilol and perindoprilat. The difference between the observed and calculated plasma concentrations was less than 20 % of their mean for >67 % of samples for all analytes. Conclusions: The assay is suitable as a screening tool for carvedilol and perindoprilat, while suitable as an adherence determining assay for enalaprilat. Equivalence between observed and predicted plasma concentrations proves DBS and plasma concentrations can be used interchangeably.

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Introduction: Since the start of the Syrian conflict in 2011, Jordan and Lebanon have hosted large refugee populations, with a high pre-conflict burden of non-communicable diseases (NCDs). We aimed to explore NCD service provision to Syrian refugees in these two host countries and to identify lessons learned that may inform the global response to the changing health needs of refugees. Methods: Between January 2017 and June 2018, we conducted 36 in-depth interviews with stakeholders from Jordan and Lebanon, as well as global stakeholders, to understand the context, the achievements, gaps and priorities in the provision and uptake of NCD prevention, testing and treatment services to Syrian refugees. Findings: Both countries succeeded in embedding refugee health care within national health systems, yet coverage and quality of NCD health services offered to Syrian refugees in both contexts were affected by under-funding and consequent policy constraints. Changes in policies relating to cost sharing, eligibility and vulnerability criteria led to difficulties navigating the system and increased out-of-pocket payments for Syrians. Funding shortages were reported as a key barrier to NCD screening, diagnosis and management, including at the primary care level and referral from primary to secondary healthcare, particularly in Lebanon. These barriers were compounded by suboptimal implementation of NCD guidelines and high workloads for healthcare providers resulting from the large numbers of refugees. Conclusions: Despite the extraordinary efforts made by host countries, provision and continuity of high quality NCD services at scale remains a tremendous challenge given ongoing funding shortfalls and lack of prioritization of NCD care for refugees. The development of innovative, effective and sustainable solutions is necessary to counter the threat of NCDs.

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Biofilm at water-oil interface of hypoxic water columns of microcosms, prepared from a lacustrine sample, that used diesel as a carbon source was found to show electrogenic properties. These microcosms named, Liquid Microbial Fuel Cells (L-MFCs) were electrically characterized using a custom electronic analyzer; accurate determination of voltage (V), power density (W/m 2), and current density (A/m2) for both charge and discharge phases was carried out. The instrument made it possible to carry out cell characterizations using resistive loads between 0 Ω (Ohm) and 10 kΩ. During the hypoxic and electrogenic phase, the synthesis of a system of "bacterial piping induction", produced filaments of hundreds of micrometers in which the microbial cells are hosted. Ultrastructural microscopy collected by scanning (SEM), transmission (TEM), immunofluorescence, Thunder Imager 3D, confocal laser scanning (CLSM) microscopy revealed a "myelin like" structure during filamentation processes; this "myelin like" structure exhibited cross-reactivity towards different epitopes of the myelin basic protein (MBP) and Claudin 11 (O4) of human oligodendrocytes. The disclosure of these filamentation processes could be helpful to describe further unconventional microbial structures in aquatic ecosystems and of the animal world. The data that support the findings of this study are openly available in at https://data.mendeley.com/datasets/7d35tj3j96/1.

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Introduction and background: The COVID-19 pandemic has required rapid and repetitive adjustment of radiotherapy practice, hospital-level and department-level organization and hygiene measures. To prospectively monitor and manage stress levels and health concerns, employees of a radiation oncology department were invited to participate in weekly online surveys during the first year of the pandemic. Materials and methods: Starting March 31st, 2020, cross-sectional online surveys were distributed to all employees of the Department of Radiation Oncology, University Hospital Zurich. The survey included questions about the profession, the work setting, the global stress level as well as the health concerns during the past work week. Stress levels and health concerns were assessed on a 10-point scale. SurveyMonkey® was used to conduct the survey. Distribution was performed via email. Participation was anonymous and voluntary. Results: Between March 2020 and February 2021, 50 weekly surveys were distributed to 127 employees on average and resulted in 1,877 individual responses. The average response rate was 30%. The mean global stress level varied significantly by profession, ranging from 2.7 (±2.5) points for administrative staff to 6.9 (±2.3) points for radiation therapy technicians (p < 0.001). The mean global stress level was highest with 4.8 (±2.9) points for in-hospital work with direct patient contact. Health concerns were highest regarding family and friends with 4.0 (±3.1) points on average. Changes of the stress level varied in correlation with infection waves. Conclusion: Weekly online surveys for prospective assessment of stress levels and health concerns were successfully conducted during the first year of the COVID-19 pandemic, indicating their feasibility and value to monitor profession and workplace specific stress patterns and to allowed for tailored interventions. The physical and mental health of frontline healthcare workers in radiation oncology should remain a top priority for departmental leadership beyond the COVID-19 pandemic.

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Background: Workers are exposed to several risks in academic laboratories due to the presence of potentially hazardous substances. The main objective of this study was to assess the prevalence of accident occurrence and associated risk factors among laboratory workers at the scientific laboratories of the public university in Lebanon and the impact of safety measures training and availability. Methods: In this observational study, a survey was conducted for one year in scientific laboratories at faculties of the public university. Results: Among the participants (N = 220), 45.0% have had accidents; the main cause was exposure to chemicals (73.7%) and more specifically by inhalation (45.4%). Females (85.9%) were more exposed to accidents than males. Laboratory workers with a master's degree, a full-time schedule, and more than ten years of experience were significantly more exposed to accidents (p < 0.05). A significant association was found between accident occurrence and training on management of hazardous products (p = 0.044), risks related to workplace (p = 0.030), eyewash and emergency shower (p < 0.001), first aid (p = 0.012), and facial protection availability (p = 0.019). In spite of the lack of safety culture and efficient training on laboratory safety, participants have shown a very good perception regarding safety measures to be applied in case of work accidents. Conclusion: Based on our findings, the prevalence of accident occurrence is elevated among lab workers at the public university. The impact of regular training on laboratory safety preventive measures is of great importance to ensure the efficiency of occupational health and safety in scientific laboratories.

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This article aims to develop management solutions to accompany the processes of acquiring and distributing equipment and/or materials needed for the restructuring of associated laboratories to the sentinel services (Sentinel Laboratories) for syphilis and other sexually transmitted infection in the scope of the "Syphilis No!" Project. To this end, we have taken steps to create an overview of the restructuring project for the sentinel laboratories, define the stages of project execution, monitor the implementation of the project, and elaborate a standard operating procedure for the delivery of equipment and/or materials to the sentinel laboratories. Among the results, we highlight: the detailed workflow for the process of public procurement through direct purchases or bidding; the workflow for storage of the equipment and materials; the standard operating procedures (SOP) for contact with the laboratories; and the SOP for delivery of items acquired for the sentinel laboratories.

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BACKGROUND: Haematopoietic stem cell (HSC) infusion has demonstrated short-term improvement in liver functions in patients with chronic liver disease. The combination of HSC with mesenchymal stem cells (MSCs), which has an immunomodulatory effect, may augment the effects and enhance the duration of improvements on liver functions. The aim of the present study was to assess the safety of infusing the combination of autologous HSCs and MSCs in decompensated liver cirrhosis. METHODS: In phase I of the study, in vitro assessment was performed to observe the effect of coculturing MSCs with HSCs on their viability and cytokine profiles. Phase II of the study was to assess the safety of combination of stem cell infusions. Bone marrow (50 ml) was aspirated for MSC isolation and expansion using standard protocol. Patients received subcutaneous doses (n = 5) of granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization followed by leukapheresis for harvesting HSCs using CliniMacs. HSCs and MSCs were infused through the hepatic artery under fluoroscopic guidance and were monitored for any adverse effects. RESULTS: In vitro studies revealed 94% viable HSCs in coculture similar to monoculture. HSCs released only interleukin (IL)-8, whereas MSCs secreted IL-8 and IL-6 in monocultures, and both IL-8 and IL-6 were secreted in coculture. G-CSF administration- and bone marrow aspiration-related complications were not observed. Infusion of the cells through the hepatic artery was safe, and no postprocedural complications were noted. CONCLUSION: The combination of autologous HSC and MSC infusion is a safe procedure in patients with decompensated liver cirrhosis, and the outcomes needed to be assessed in larger studies. TRIAL NUMBER: NCT04243681.

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AIM AND BACKGROUND: To assess the use of hypofractionated (HG-RT) versus normofractionated radiation therapy (NF-RT) in Breast Cancer in German speaking countries. MATERIALS AND METHODS: Between July 2017 and August 2017, an email-based survey was sent to all 1408 physicians that are members of the German Society of Radiation Oncology (DEGRO). The survey was completed by 180 physicians including 10 private practice owners and 52 heads of departments. The majority (82.1%) of the participants had >15 years of experience in radiation therapy (RT). RESULTS: The majority (83.9%) of the heads of the departments agreed on using the normofractionated regimen of RT as standard treatment for breast cancer. Several physicians were skeptical about HF-RT with 6.5% of the heads refusing to use HF-RT. 40.3% of the departments had not seen the new German guidelines suggesting HF-RT as the standard treatment for all patients as positive or merely adopted a neutral position toward the guidelines (33.9%). The main points of criticism were increased side effects, an impaired toxicity profile and insufficient data. Most departments (46.8%) that perform HF-RT do so in an individual based manner. CONCLUSIONS: HF-RT remains controversial in German speaking countries. Our data shows that NF-RT remains the predominant method of treatment. HF-RT is only used in a defined group of patients as most German physicians agree that particular patients, especially those at higher risk of RT late effects, may benefit from a less intense, extended fractionation schedule.

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Humic substances are ubiquitous in soils and waters. These complex superstructures are derived from the decomposition of dead plant and animal matter and are vital to soil health. Their heterogenous composition is specific to their site of origin and is comprised of weakly bound aggregates of small organic compounds that can sequester minerals and make them available to plants. As such, they may possess potential nutritional value for humans, and extractions of fulvic and humic acids can be produced that could be suitable for such purposes. For this reason, we evaluated the toxicological profile of a specific preparation (blk. 333) of fulvic and humic acids derived from a lignite deposit in Alberta, Canada and found it to lack genotoxic potential in a bacterial reverse mutation test, in vitro mammalian chromosomal aberration test, and in vivo mammalian micronucleus test. No general or organ toxicity was observed in Wistar rats following 90 days of continuous exposure, and a no observed adverse effect level (NOEAL) was determined at 2000 mg/kg bw/day, the highest tested dose. Our results suggest the feasibility of further evaluation for development of the preparation as a nutritional supplement in food.

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The Clinical Trials Transformation Initiative (CTTI) Strengthening the Investigator Community Project was prompted by the need to understand the reasons for high rates of turnover among investigators who lead US Food and Administration-regulated clinical trials at research sites. Because investigator knowledge and experience directly affect the quality and ultimate success of clinical trials, investigator turnover has important implications for the research enterprise, as well as the patients and other stakeholders who depend on the outcomes of clinical research. The CTTI project team used findings from both quantitative and qualitative research activities, as well as input from an expert meeting with multiple stakeholders, to delineate key concerns faced by investigators and recommend practical, action-based solutions. The recommendations focus on strengthening four key categories of site-based research activity: developing site-based research infrastructure and staff, optimizing trial execution and conduct, improving site budget development and contract negotiations, and discovering opportunities for conducting additional trials.

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OBJECTIVE: To reliably improve diagnostic fidelity and identify delays using a standardized approach applied to the electronic medical records of patients with emerging critical illness. PATIENTS AND METHODS: This retrospective observational study at Mayo Clinic, Rochester, Minnesota, conducted June 1, 2016, to June 30, 2017, used a standard operating procedure applied to electronic medical records to identify variations in diagnostic fidelity and/or delay in adult patients with a rapid response team evaluation, at risk for critical illness. Multivariate logistic regression analysis identified predictors and compared outcomes for those with and without varying diagnostic fidelity and/or delay. RESULTS: The sample included 130 patients. Median age was 65 years (interquartile range, 56-76 years), and 47.0% (52 of 130) were women. Clinically significant diagnostic error or delay was agreed in 23 (17.7%) patients (κ=0.57; 95% CI, 0.40-0.74). Median age was 65.4 years (interquartile range, 60.3-74.8) and 9 of the 23 (30.1%) were female. Of those with diagnostic error or delay, 60.9% (14 of 23) died in the hospital compared with 19.6% (21 of 107) without; P<.001. Diagnostic error or delay was associated with higher Charlson comorbidity index score, cardiac arrest triage score, and do not intubate/do not resuscitate status. Adjusting for age, do not intubate/do not resuscitate status, and Charlson comorbidity index score, diagnostic error or delay was associated with increased mortality; odds ratio, 5.7; 95% CI, 2.0-17.8. CONCLUSION: Diagnostic errors or delays can be reliably identified and are associated with higher comorbidity burden and increased mortality.

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Parents are often uncertain about the vaccination status of their children. In times of vaccine hesitancy, vaccination programs could benefit from active patient participation. The Vaccination App (VAccApp) was developed by the Vienna Vaccine Safety Initiative, enabling parents to learn about the vaccination status of their children, including 25 different routine, special indication and travel vaccines listed in the WHO Immunization Certificate of Vaccination (WHO-ICV). Between 2012 and 2014, the VAccApp was validated in a hospital-based quality management program in Berlin, Germany, in collaboration with the Robert Koch Institute. Parents of 178 children were asked to transfer the immunization data of their children from the WHO-ICV into the VAccApp. The respective WHO-ICV was photocopied for independent, professional data entry (gold standard). Demonstrating the status quo in vaccine information reporting, a Recall Group of 278 parents underwent structured interviews for verbal immunization histories, without the respective WHO-ICV. Only 9% of the Recall Group were able to provide a complete vaccination status; on average 39% of the questions were answered correctly. Using the WHO-ICV with the help of the VAccApp resulted in 62% of parents providing a complete vaccination status; on average 95% of the questions were answered correctly. After using the VAccApp, parents were more likely to remember key aspects of the vaccination history. User-friendly mobile applications empower parents to take a closer look at the vaccination record, thereby taking an active role in providing accurate vaccination histories. Parents may become motivated to ask informed questions and to keep vaccinations up-to-date.

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Introduction There have been numerous initiatives by government and private organizations to help hospitals become better prepared for major disasters and public health emergencies. This study reports on efforts by the US Department of Veterans Affairs (VA), Veterans Health Administration, Office of Emergency Management's (OEM) Comprehensive Emergency Management Program (CEMP) to assess the readiness of VA Medical Centers (VAMCs) across the nation. Hypothesis/Problem This study conducts descriptive analyses of preparedness assessments of VAMCs and examines change in hospital readiness over time. METHODS: To assess change, quantitative analyses of data from two phases of preparedness assessments (Phase I: 2008-2010; Phase II: 2011-2013) at 137 VAMCs were conducted using 61 unique capabilities assessed during the two phases. The initial five-point Likert-like scale used to rate each capability was collapsed into a dichotomous variable: "not-developed=0" versus "developed=1." To describe changes in preparedness over time, four new categories were created from the Phase I and Phase II dichotomous variables: (1) rated developed in both phases; (2) rated not-developed in Phase I but rated developed in Phase II; (3) rated not-developed in both phases; and (4) rated developed in Phase I but rated not- developed in Phase II. RESULTS: From a total of 61 unique emergency preparedness capabilities, 33 items achieved the desired outcome - they were rated either "developed in both phases" or "became developed" in Phase II for at least 80% of VAMCs. For 14 items, 70%-80% of VAMCs achieved the desired outcome. The remaining 14 items were identified as "low-performing" capabilities, defined as less than 70% of VAMCs achieved the desired outcome. CONCLUSION: Measuring emergency management capabilities is a necessary first step to improving those capabilities. Furthermore, assessing hospital readiness over time and creating robust hospital readiness assessment tools can help hospitals make informed decisions regarding allocation of resources to ensure patient safety, provide timely access to high-quality patient care, and identify best practices in emergency management during and after disasters. Moreover, with some minor modifications, this comprehensive, all-hazards-based, hospital preparedness assessment tool could be adapted for use beyond the VA. Der-Martirosian C , Radcliff TA , Gable AR , Riopelle D , Hagigi FA , Brewster P , Dobalian A . Assessing hospital disaster readiness over time at the US Department of Veterans Affairs. Prehsop Disaster Med. 2017;32(1):46-57.

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DNA sequencing continues to evolve quickly even after > 30 years. Many new platforms suddenly appeared and former established systems have vanished in almost the same manner. Since establishment of next-generation sequencing devices, this progress gains momentum due to the continually growing demand for higher throughput, lower costs and better quality of data. In consequence of this rapid development, standardized procedures and data formats as well as comprehensive quality management considerations are still scarce. Here, we listed and summarized current standardization efforts and quality management initiatives from companies, organizations and societies in form of published studies and ongoing projects. These comprise on the one hand quality documentation issues like technical notes, accreditation checklists and guidelines for validation of sequencing workflows. On the other hand, general standard proposals and quality metrics are developed and applied to the sequencing workflow steps with the main focus on upstream processes. Finally, certain standard developments for downstream pipeline data handling, processing and storage are discussed in brief. These standardization approaches represent a first basis for continuing work in order to prospectively implement next-generation sequencing in important areas such as clinical diagnostics, where reliable results and fast processing is crucial. Additionally, these efforts will exert a decisive influence on traceability and reproducibility of sequence data.

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Germ-free mice are used to examine questions about the role of the gut microbiota in development of diseases. Generally these animals are maintained in semi-rigid or flexible-film isolators to ensure their continued sterility or, if colonized with specific microbiota, to ensure that no new species are introduced. Here, we describe the use of a caging system in which individual cages are hermetically sealed and have their own filtered positive airflow. This isopositive caging system requires less space and reduces animal housing costs. By using strict sterile techniques, we kept mice germ-free in this caging system for 12 weeks. We also used this caging system and approach to conduct studies evaluating a) the stability of the microbiome in germ-free mice receiving a fecal transplant and b) the stability of dietary-induced microbiota changes in fecal-transplanted mice. As has been shown in fecal transfer studies in isolators, we found that the transferred microbiota stabilizes as early as 2 weeks post transfer although recipient microbiota did not completely recapitulate those of the donors. Interestingly, we also noted some sex effects in these studies indicating that the sex of recipients or donors may play a role in colonization of microbiota. However, a larger study will be needed to determine what role, if any, sex plays in colonization of microbiota. Based on our studies, an isopositive caging system may be utilized to test multiple donor samples for their effects on phenotypes of mice in both normal and disease states even with limited available space for housing.

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