Role of Forkhead Box P3 in IFNγ-Mediated PD-L1 Expression and Bladder Cancer Epithelial-to-Mesenchymal Transition.

Antagonism of the PD-1/PD-L1 axis is a critical therapeutic strategy for patients with advanced bladder cancer. IFNγ functions as a key regulator of PD-L1 in both immune as well as cancer cells. Forkhead box P3 (FOXP3) is a transcription factor synonymous in T regulatory cell function but with increasingly described functions in cancer cells. Here, we investigated the relationship between FOXP3 and PD-L1 in bladder cancer. We showed that FOXP3 is critical in the ability for IFNγ to activate PD-L1 in bladder cancer cells. FOXP3 can bind to the PD-L1 promoter and induces a gene program that leads to regulation of multiple immune-related genes and genes involved in epithelial-to-mesenchymal transition (EMT). Using in vitro and in vivo human and murine models, we showed that FOXP3 can influence bladder cancer EMT as well as promote cancer metastases. Furthermore, FOXP3 may be a convergent factor for multiple activators of PD-L1, including the chemotherapeutic drug cisplatin. SIGNIFICANCE: Historically a key transcription factor driving T regulatory cell function, FOXP3 has an increasingly recognized role in cancer cells. In bladder cancer, we defined a novel mechanism whereby FOXP3 mediates the activation of the immune checkpoint PD-L1 by the cytokine IFNγ. We also showed that FOXP3 induces other immune checkpoints as well as genes involved in EMT, promoting immune resistance and cancer metastases.

Multidisciplinary Management Strategies for Long COVID: A Narrative Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of infections to date and has led to a worldwide pandemic. Most patients had a complete recovery from the acute infection, however, a large number of the affected individuals experienced symptoms that persisted more than 3 months after diagnosis. These symptoms most commonly include fatigue, memory difficulties, brain fog, dyspnea, cough, and other less common ones such as headache, chest pain, paresthesias, mood changes, muscle pain, and weakness, skin rashes, and cardiac, endocrine, renal and hepatic manifestations. The treatment of this syndrome remains challenging. A multidisciplinary approach to address combinations of symptoms affecting multiple organ systems has been widely adopted. This narrative review aims to bridge the gap surrounding the broad treatment approaches by providing an overview of multidisciplinary management strategies for the most common long COVID conditions.

Did the health care vaccine mandate work? An evaluation of the impact of the COVID-19 vaccine mandate on vaccine uptake and infection risk in a large cohort of Canadian health care workers.

BACKGROUND: We aimed to evaluate the impact of health care vaccine mandates on vaccine uptake and infection risk in a cohort of Canadian health care workers (HCWs). METHODS: We conduct interrupted time series analysis through a regression discontinuity in time approach to estimate the immediate and delayed impact of the mandate. Multilevel mixed effect modeling fitted with restricted maximum likelihood was used to estimate impact on infection risk. RESULTS: The immediate and sustained effects of the mandate was a 0.19% (P < .05) and a 0.012% (P < .05) increase in the daily proportion of unvaccinated HCWs getting their first dose, respectively. An additional 623 (95% confidence interval: 613-667) HCWs received first doses compared to the predicted uptake absent the mandate. Adjusted test positivity declined by 0.053% (95% confidence interval: 0.035%, 0.069) for every additional day the mandate was in effect. DISCUSSION: Our results indicate that the mandate was associated with significant increases in vaccine uptake and infection risk reduction in the cohort. CONCLUSIONS: Given the benefit that vaccination could bring to HCWs, understanding strategies to enhance uptake is crucial for bolstering health system resilience, but steps must be taken to avert approaches that sacrifice trust, foster animosity, or exacerbate staffing constraints for short-term results.

Amino Acid Uptake Limitations during Human Mesenchymal Stem Cell-Based Chondrogenesis.

A mino acids are the essential building blocks for collagen and proteoglycan, which are the main constituents for cartilage extracellular matrix (ECM). Synthesis of ECM proteins requires the uptake of various essential/nonessential amino acids. Analyzing amino acid metabolism during chondrogenesis can help to relate tissue quality to amino acid metabolism under different conditions. In our study, we studied amino acid uptake/secretion using human mesenchymal stem cell (hMSC)-based aggregate chondrogenesis in a serum-free induction medium with a defined chemical formulation. The initial glucose level and medium-change frequency were varied. Our results showed that essential amino acid uptake increased with time during hMSCs chondrogenesis for all initial glucose levels and medium-change frequencies. Essential amino acid uptake rates were initial glucose-level independent. The DNA-normalized glycosaminoglycans and hydroxyproline content of chondrogenic aggregates correlated with cumulative uptake of leucine, valine, and tryptophan regardless of initial glucose levels and medium-change frequencies. Collectively, our results show that amino acid uptake rates during in vitro chondrogenesis were insufficient to produce a tissue with an ECM content similar to that of human neonatal cartilage or adult cartilage. Furthermore, this deficiency was likely related to the downregulation of some key amino acid transporters in the cells. Such deficiency could be partially improved by increasing the amino acid availability in the chondrogenic medium by changing culture conditions.

UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, significantly delays tumor growth in pre-clinical settings. Our study reveals mechanisms of UCHL1 function in regulating the progression of neuroendocrine carcinomas and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosing and monitoring treatment responses in these malignancies.

Are COVID-19 vaccination mandates for healthcare workers effective? A systematic review of the impact of mandates on increasing vaccination, alleviating staff shortages and decreasing staff illness.

INTRODUCTION: The rapid development of COVID-19 vaccines is a cornerstone in the global effort to combat the pandemic. Healthcare workers (HCWs), being at the forefront of the pandemic response, have been the focus of vaccine mandate policies. This review aims to evaluate the impacts of COVID-19 vaccine mandates among HCWs, a critical step in understanding the broader implications of such policies in healthcare settings. OBJECTIVE: The review seeks to synthesize available literature to contribute to greater understanding of the outcomes associated with COVID-19 vaccine mandates for HCWs including vaccine uptake, infection rates, and staffing. METHODS: A systematic search of relevant literature published from March 2020 to September 2023 was conducted. The Newcastle-Ottawa scale was employed for quality assessment of the included articles. A total of 4,779 publications were identified, with 15 studies meeting the inclusion criteria for the review. A narrative synthesis approach was used to analyze these studies. RESULTS: COVID-19 vaccine mandates for HCWs were broadly successful in increasing vaccine uptake in most settings. Although the penalties imposed on unvaccinated HCWs did not lead to major disruption of health services, less well-resourced areas may have been more impacted. Furthermore, there is insufficient literature on the impact of the vaccine mandate on reducing SARS-CoV-2 infection among HCWs. CONCLUSION: COVID-19 vaccine mandates for HCWs have significant implications for public health policy and healthcare management. The findings underscore the need for tailored approaches in mandate policies, considering the specific contexts of healthcare settings and the diverse populations of HCWs. While mandates have shown potential in increasing vaccine uptake with minimal impacts to staffing, more work is needed to investigate the impacts of mandates across various contexts. In addition to these impacts, future research should focus on long-term effects and implications on broader public health strategies.

MSCs mediate long-term efficacy in a Crohn's disease model by sustained anti-inflammatory macrophage programming via efferocytosis.

Mesenchymal stem cells (MSCs) are novel therapeutics for the treatment of Crohn's disease. However, their mechanism of action is unclear, especially in disease-relevant chronic models of inflammation. Thus, we used SAMP-1/YitFc (SAMP), a chronic and spontaneous murine model of small intestinal inflammation, to study the therapeutic effects and mechanism of action of human bone marrow-derived MSCs (hMSC). hMSC dose-dependently inhibited naïve T lymphocyte proliferation via prostaglandin E2 (PGE2) secretion and reprogrammed macrophages to an anti-inflammatory phenotype. We found that the hMSCs promoted mucosal healing and immunologic response early after administration in SAMP when live hMSCs are present (until day 9) and resulted in a complete response characterized by mucosal, histological, immunologic, and radiological healing by day 28 when no live hMSCs are present. hMSCs mediate their effect via modulation of T cells and macrophages in the mesentery and mesenteric lymph nodes (mLN). Sc-RNAseq confirmed the anti-inflammatory phenotype of macrophages and identified macrophage efferocytosis of apoptotic hMSCs as a mechanism that explains their long-term efficacy. Taken together, our findings show that hMSCs result in healing and tissue regeneration in a chronic model of small intestinal inflammation and despite being short-lived, exert long-term effects via sustained anti-inflammatory programming of macrophages via efferocytosis.

Both acuity and long term prognosis are important Emergency Department metrics: comparison of mobility assessment with the Emergency Severity Index.

OBJECTIVE: To compare the SUHB mobility scale (i.e., stable(S), unstable gait(U), needing help to walk(H), or bedridden(B)) and the Emergency Severity Index (ESI) associations with admission and mortality outcomes. DESIGN: Post-hoc analysis of a prospective observational study including all consenting presenting to the ED over a period of 3 weeks. Odd ratios and AUCs were calculated to assess predictive performance of SUHB and compared with ESI. RESULTS: Out of 2422 patients, 65% presented with a stable gait, 45% with an ESI level 3. With increasing mobility impairment on the SUHB scale, the probability for admission and mortality increased. SUHB had a higher AUC than ESI for 1-year mortality. CONCLUSION: SUHB was a better predictor than ESI of long-term mortality. The scale, which is rapid, requires little additional training, and no extra costs, could be used as a useful supplement to the triage process.

The U.S. Food and Drug Administration, the mechanism of action, and other considerations for cell-based therapy candidates.

The focus of this Commentary is to introduce cell-based therapy in the context of how I believe the U.S. Food and Drug Administration (FDA) might establish criteria for the approval of clinical trials that could eventually lead to the final marketplace approval of these medically relevant, cell-based therapeutic products. It is important to emphasize that regulatory agencies have set up practices and procedures that are based on many years of evaluating pharmaceutically provided drugs. To consider cell-based therapies as single action drugs is inappropriate given the complexity of this technology. The regulatory agencies have been slowly reevaluating the criteria by which they allow clinical trials using cell-based therapies to proceed. This commentary focuses on a few key aspects of such considerations and provides suggestions for modifying the standard criteria.

Vaccination, time lost from work, and COVID-19 infections: a Canadian healthcare worker retrospective cohort study.

The COVID-19 pandemic highlighted hurdles for healthcare delivery and personnel globally. Vaccination has been an important tool for preventing severe illness and death in healthcare workers (HCWs) as well as the public at large. However, vaccination has resulted in some HCWs requiring time off work post-vaccination to recover from adverse events. We aimed to understand which HCWs needed to take time off work post-vaccination, for which vaccine types and sequence, and how post-vaccination absence impacted uptake of booster doses in a cohort of 26,267 Canadian HCWs. By March 31, 2022, more than 98% had received at least two doses of the approved COVID-19 vaccines, following a two-dose mandate. We found that recent vaccination and longer intervals between doses were associated with significantly higher odds of time-loss, whereas being a medical resident and receiving the BNT162b2 vaccine were associated with lower odds. A history of lab-confirmed SARS-CoV-2 infection was associated with lower odds of receiving a booster dose compared with no documented infection, aOR 0.61 (95% CI: 0.55, 0.68). Similarly, taking sick time following the first or second dose was associated with lower odds of receiving a booster dose, aOR 0.83 (95% CI: 0.75, 0.90). As SARS-CoV-2 becomes endemic, the number and timing of additional doses for HCWs requires consideration of prevention of illness as well as service disruption from post-vaccination time-loss. Care should be taken to ensure adequate staffing if many HCWs are being vaccinated, especially for coverage for those who are more likely to need time off to recover.

Mesenchymal stem cells ameliorate inflammation in an experimental model of Crohn's disease via the mesentery.

Objective: Mesenchymal stem cells (MSCs) are novel therapeutics for treatment of Crohn's disease. However, their mechanism of action is unclear, especially in disease-relevant chronic models of inflammation. Thus, we used SAMP-1/YitFc, a chronic and spontaneous murine model of small intestinal inflammation, to study the therapeutic effect and mechanism of human bone marrow-derived MSCs (hMSC). Design: hMSC immunosuppressive potential was evaluated through in vitro mixed lymphocyte reaction, ELISA, macrophage co-culture, and RT-qPCR. Therapeutic efficacy and mechanism in SAMP were studied by stereomicroscopy, histopathology, MRI radiomics, flow cytometry, RT-qPCR, small animal imaging, and single-cell RNA sequencing (Sc-RNAseq). Results: hMSC dose-dependently inhibited naïve T lymphocyte proliferation in MLR via PGE 2 secretion and reprogrammed macrophages to an anti-inflammatory phenotype. hMSC promoted mucosal healing and immunologic response early after administration in SAMP model of chronic small intestinal inflammation when live hMSCs are present (until day 9) and resulted in complete response characterized by mucosal, histological, immunologic, and radiological healing by day 28 when no live hMSCs are present. hMSC mediate their effect via modulation of T cells and macrophages in the mesentery and mesenteric lymph nodes (mLN). Sc-RNAseq confirmed the anti-inflammatory phenotype of macrophages and identified macrophage efferocytosis of apoptotic hMSCs as a mechanism of action that explains their long-term efficacy. Conclusion: hMSCs result in healing and tissue regeneration in a chronic model of small intestinal inflammation. Despite being short-lived, exert long-term effects via macrophage reprogramming to an anti-inflammatory phenotype. Data Transparency Statement: Single-cell RNA transcriptome datasets are deposited in an online open access repository 'Figshare' (DOI: https://doi.org/10.6084/m9.figshare.21453936.v1 ).

Human Mesenchymal Stem Cell (hMSC) Donor Potency Selection for the "First in Cystic Fibrosis" Phase I Clinical Trial (CEASE-CF).

Human Mesenchymal Stem Cell (hMSC) immunotherapy has been shown to provide both anti-inflammatory and anti-microbial effectiveness in a variety of diseases. The clinical potency of hMSCs is based upon an initial direct hMSC effect on the pro-inflammatory and anti-microbial pathophysiology as well as sustained potency through orchestrating the host immunity to optimize the resolution of infection and tissue damage. Cystic fibrosis (CF) patients suffer from a lung disease characterized by excessive inflammation and chronic infection as well as a variety of other systemic anomalies associated with the consequences of abnormal cystic fibrosis transmembrane conductance regulator (CFTR) function. The application of hMSC immunotherapy to the CF clinical armamentarium is important even in the era of modulators when patients with an established disease still need anti-inflammatory and anti-microbial therapies. Additionally, people with CF mutations not addressed by current modulator resources need anti-inflammation and anti-infection management. Furthermore, hMSCs possess dynamic therapeutic properties, but the potency of their products is highly variable with respect to their anti-inflammatory and anti-microbial effects. Due to the variability of hMSC products, we utilized standardized in vitro and in vivo models to select hMSC donor preparations with the greatest potential for clinical efficacy. The models that were used recapitulate many of the pathophysiologic outcomes associated with CF. We applied this strategy in pursuit of identifying the optimal donor to utilize for the "First in CF" Phase I clinical trial of hMSCs as an immunotherapy and anti-microbial therapy for people with cystic fibrosis. The hMSCs screened in this study demonstrated significant diversity in antimicrobial and anti-inflammatory function using models which mimic some aspects of CF infection and inflammation. However, the variability in activity between in vitro potency and in vivo effectiveness continues to be refined. Future studies require and in-depth pursuit of hMSC molecular signatures that ultimately predict the capacity of hMSCs to function in the clinical setting.

Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma.

Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL+) cells. Renal tumors with either VHL+ or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL+ cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL-) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.

Protecting healthcare workers during a pandemic: what can a WHO collaborating centre research partnership contribute?

Objectives: To ascertain whether and how working as a partnership of two World Health Organization collaborating centres (WHOCCs), based respectively in the Global North and Global South, can add insights on "what works to protect healthcare workers (HCWs) during a pandemic, in what contexts, using what mechanism, to achieve what outcome". Methods: A realist synthesis of seven projects in this research program was carried out to characterize context (C) (including researcher positionality), mechanism (M) (including service relationships) and outcome (O) in each project. An assessment was then conducted of the role of the WHOCC partnership in each study and overall. Results: The research found that lower-resourced countries with higher economic disparity, including South Africa, incurred greater occupational health risk and had less acceptable measures to protect HCWs at the onset of the COVID-19 pandemic than higher-income more-equal counterpart countries. It showed that rigorously adopting occupational health measures can indeed protect the healthcare workforce; training and preventive initiatives can reduce workplace stress; information systems are valued; and HCWs most at-risk (including care aides in the Canadian setting) can be readily identified to trigger adoption of protective actions. The C-M-O analysis showed that various ways of working through a WHOCC partnership not only enabled knowledge sharing, but allowed for triangulating results and, ultimately, initiatives for worker protection. Conclusions: The value of an international partnership on a North-South axis especially lies in providing contextualized global evidence regarding protecting HCWs as a pandemic emerges, particularly with bi-directional cross-jurisdiction participation by researchers working with practitioners.

Beyond Compliance: Growth as the Guiding Value in Undergraduate Medical Education.

Adhering to the paradigm of the natural sciences, much of undergraduate medical education (UME) in the United States remains committed to objectivity, compliance, and standardization in its approach to teaching, evaluation, student affairs, and accreditation practices. The authors argue that, while these simple and complicated problem solving (SCPS) approaches may be valid for some highly controlled environments of UME, they lack rigor in complex, real-world environments where optimal care and education is not standardized but is tailored to context and individual needs. This argument is supported by evidence that "systems" approaches, characterized by complex problem solving (CPS, differentiated from complicated problem solving), lead to better outcomes in patient care and student academic performance. Examples of interventions implemented at the University of Chicago Pritzker School of Medicine from 2011 to 2021 further illustrate this point. Interventions in student well-being that emphasize personal and professional growth have led to student satisfaction that is 20% higher than the national average on the Association of American Medical Colleges Graduation Questionnaire (GQ). Career advising interventions that augment the use of adaptive behaviors in place of rules and guidelines have yielded 30% fewer residency applications per student than the national average while simultaneously yielding residency "unmatched" rates that are one-third of the national average. Regarding diversity, equity, and inclusion, an emphasis on civil discourse around real-world problems has been associated with student attitudes toward diversity that are 40% more favorable than the national average on the GQ. In addition, there has been an increase in the number of matriculating students who are underrepresented in medicine to 35% of the incoming class. The article concludes with a review of philosophic barriers to incorporating the CPS paradigm into UME and of notable pedagogic differences between CPS and SCPS approaches.

A phase I study assessing the safety and tolerability of allogeneic mesenchymal stem cell infusion in adults with cystic fibrosis.

BACKGROUND: Mesenchymal stem cells are of particular interest in cystic fibrosis (CF) as a potential therapeutic. Data from pre-clinical studies suggest that allogeneic bone marrow-derived human mesenchymal stem cells (hMSCs) may provide a new therapeutic treatment for CF lung disease by attenuating pulmonary inflammation while decreasing bacterial growth and enhancing antibiotic efficacy. METHODS: Fifteen adults with CF were enrolled in a phase 1 dose-escalation trial of a single intravenous infusion of hMSCs derived from bone marrow aspirates obtained from a single pre-clinically validated healthy volunteer donor. The study employed a 3+3 dose escalation design with subjects receiving a single, intravenous dose of either 1×106, 3×106, or 5×106 hMSCs/kg. Subjects were monitored inpatient for 24 hours and by outpatient visits and telephone calls for 12 months after the infusion. Safety and tolerability were evaluated by monitoring symptoms, patient reported outcome questionnaires, adverse events (AEs), physical exam findings, spirometry, and analyses of safety laboratories. Preliminary evidence for potential efficacy using inflammatory markers in the blood and sputum were also evaluated. RESULTS: No dose-limiting toxicities, deaths or life-threatening adverse events were observed. Most AEs and serious adverse events (SAEs) were consistent with underlying CF. Vital signs, physical exam findings, spirometry and safety laboratory results showed no significant change from baseline. No trends over time were seen in serum or sputum inflammatory markers nor with clinical spirometry. CONCLUSION: Allogeneic hMSC intravenous infusions were safe and well-tolerated in this phase 1 study and warrant additional clinical testing as a potential therapeutic for CF lung disease.

Protecting healthcare workers during a pandemic: what can a WHO collaborating centre research partnership contribute? / Protección de los trabajadores de salud durante una pandemia: ¿qué puede aportar una alianza para la investigación entre centros colaboradores de la OMS? / Proteção dos trabalhadores da saúde em uma pandemia: qual seria a contribuição de uma parceria de pesquisa entre centros colaboradores da OMS?

ABSTRACT Objectives. To ascertain whether and how working as a partnership of two World Health Organization collaborating centres (WHOCCs), based respectively in the Global North and Global South, can add insights on "what works to protect healthcare workers (HCWs) during a pandemic, in what contexts, using what mechanism, to achieve what outcome". Methods. A realist synthesis of seven projects in this research program was carried out to characterize context (C) (including researcher positionality), mechanism (M) (including service relationships) and outcome (O) in each project. An assessment was then conducted of the role of the WHOCC partnership in each study and overall. Results. The research found that lower-resourced countries with higher economic disparity, including South Africa, incurred greater occupational health risk and had less acceptable measures to protect HCWs at the onset of the COVID-19 pandemic than higher-income more-equal counterpart countries. It showed that rigorously adopting occupational health measures can indeed protect the healthcare workforce; training and preventive initiatives can reduce workplace stress; information systems are valued; and HCWs most at-risk (including care aides in the Canadian setting) can be readily identified to trigger adoption of protective actions. The C-M-O analysis showed that various ways of working through a WHOCC partnership not only enabled knowledge sharing, but allowed for triangulating results and, ultimately, initiatives for worker protection. Conclusions. The value of an international partnership on a North-South axis especially lies in providing contextualized global evidence regarding protecting HCWs as a pandemic emerges, particularly with bi-directional cross-jurisdiction participation by researchers working with practitioners.

RESUMEN Objetivos. Determinar si la asociación de dos centros colaboradores de la Organización Mundial de la Salud, ubicados uno en el hemisferio norte y el otro en el hemisferio sur, puede aportar información sobre "qué es necesario para proteger a los trabajadores de salud durante una pandemia, en qué contextos, con qué mecanismos, con el objetivo de lograr qué resultados". Métodos. Se realizó una síntesis realista de siete proyectos en este programa de investigación para caracterizar el contexto (C) (incluida la posición del investigador), el mecanismo (M) (incluidas las relaciones de servicio) y el resultado (R) en cada proyecto. A continuación, se realizó una evaluación del papel que desempeñó la alianza de centros colaboradores de la OMS en términos generales y en cada estudio. Resultados. En la investigación se encontró que los países de escasos recursos con mayor disparidad económica, como Sudáfrica, incurrieron en un mayor riesgo para la salud ocupacional y tenían medidas menos aceptables para proteger a los trabajadores de salud al inicio de la pandemia de COVID-19 que los países homólogos de mayores ingresos y mayor equidad. Se de mostró que la adopción rigurosa de medidas de salud ocupacional puede proteger al personal de salud; la capacitación y las iniciativas preventivas pueden reducir el estrés en el lugar de trabajo; los sistemas de información se consideran valiosos; y los trabajadores de salud de mayor riesgo (como los asistentes de atención en el entorno canadiense) pueden identificarse con facilidad para la adopción de medidas de protección. El análisis de C-M-R mostró que las diferentes formas de trabajar por medio de una alianza de centros colaboradores de la OMS no solo facilitaron el intercambio de conocimientos, sino que además permitieron triangular los resultados y, en última instancia, las iniciativas para la protección de los trabajadores. Conclusiones. El valor de una alianza internacional radica especialmente en proporcionar evidencia mundial contextualizada sobre la protección de los trabajadores de salud cuando surge una situación de pandemia, particularmente con la participación bidireccional entre distintas jurisdicciones de investigadores que trabajan con el personal de salud.

RESUMO Objetivo. Determinar se, e como, o trabalho em parceria entre dois centros colaboradores da Organização Mundial da Saúde (OMS), localizados no Norte e no Sul global, pode contribuir com conhecimento sobre "o que é eficaz para proteger os trabalhadores da saúde em uma pandemia, em que contextos, com que mecanismos e para obter quais resultados". Métodos. Foi realizada uma síntese realista de sete projetos de pesquisa do programa da OMS para determinar o contexto (C) (incluindo a posicionalidade dos pesquisadores), o mecanismo (M) (incluindo as relações entre os serviços) e o resultado (O, do inglês outcome) de cada projeto e avaliar o papel da parceria entre os centros colaboradores em cada estudo e em geral. Resultados. Este estudo demonstrou que, nos países de baixa renda com maior desigualdade econômica (por exemplo, na África do Sul), o risco à saúde ocupacional foi maior e as medidas adotadas para proteger os trabalhadores da saúde na pandemia de COVID-19 foram menos adequadas em comparação ao observado em países comparáveis de alta renda com menor desigualdade. Verificou-se que a adoção rigorosa de medidas de saúde ocupacional efetivamente protege os trabalhadores da saúde, e que iniciativas de prevenção e capacitação dos profissionais reduzem o estresse no trabalho. Também se reconhece a importância dos sistemas de informação e que o pessoal com maior risco de exposição ao vírus (incluindo os cuidadores auxiliares, no caso do Canadá) pode ser prontamente identificado para que sejam adotadas medidas de proteção. A análise do tipo C-M-O indicou que as diferentes formas de trabalho em parceria entre os centros colaboradores possibilitaram não apenas dividir conhecimentos, mas também compartilhar resultados e, sobretudo, iniciativas para a proteção dos trabalhadores da saúde. Conclusões. A parceria internacional no eixo Norte-Sul é particularmente importante para obter evidências globais contextualizadas relativas à proteção dos trabalhadores da saúde em uma situação de pandemia, com a participação bidirecional entre foros de pesquisadores que trabalham com o pessoal da saúde.

Heparan Sulfate: A Regulator of White Adipocyte Differentiation and of Vascular/Adipocyte Interactions.

White adipose tissues are major endocrine organs that release factors, termed adipokines, which affect other major organ systems. The development and functions of adipose tissues depend largely upon the glycosaminoglycan heparan sulfate. Heparan sulfate proteoglycans (HSPGs) surround both adipocytes and vascular structures and facilitate the communication between these two components. This communication mediates the continued export of adipokines from adipose tissues. Heparan sulfates regulate cellular physiology and communication through a sulfation code that ionically interacts with heparan-binding regions on a select set of proteins. Many of these proteins are growth factors and chemokines that regulate tissue function and inflammation. Cells regulate heparan sulfate sulfation through the release of heparanases and sulfatases. It is now possible to tissue engineer vascularized adipose tissues that express heparan sulfate proteoglycans. This makes it possible to use these tissue constructs to study the role of heparan sulfates in the regulation of adipokine production and release. It is possible to regulate the production of heparanases and sulfatases in order to fine-tune experimental studies.

Efficacy and Safety of MSC Cell Therapies for Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis.

MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies show promise in decreasing mortality in acute respiratory distress syndrome (ARDS) and suggest benefits in treatment of COVID-19-related ARDS. We performed a meta-analysis of published trials assessing the efficacy and adverse events (AE) rates of MSC cell therapy in individuals hospitalized for COVID-19. Systematic searches were performed in multiple databases through November 3, 2021. Reports in all languages, including randomized clinical trials (RCTs), non-randomized interventional trials, and uncontrolled trials, were included. Random effects model was used to pool outcomes from RCTs and non-randomized interventional trials. Outcome measures included all-cause mortality, serious adverse events (SAEs), AEs, pulmonary function, laboratory, and imaging findings. A total of 736 patients were identified from 34 studies, which included 5 RCTs (n = 235), 7 non-randomized interventional trials (n = 370), and 22 uncontrolled comparative trials (n = 131). Patients aged on average 59.4 years and 32.2% were women. When compared with the control group, MSC cell therapy was associated with a reduction in all-cause mortality (RR = 0.54, 95% CI: 0.35-0.85, I  2 = 0.0%), reduction in SAEs (IRR = 0.36, 95% CI: 0.14-0.90, I  2 = 0.0%) and no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC. These findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function compared with conventional care. Large-scale double-blinded, well-powered RCTs should be conducted to further explore these results.

Low correlation between serum thyroglobulin and 131I radioiodine whole body scintigraphy: implication for postoperative disease surveillance in differentiated thyroid cancer.

PURPOSE: To evaluate postoperative serum thyroglobulin (Tg) as a reliable tumor marker in low-risk differentiated thyroid cancer (DTC). METHODS: Two hundred and three patients met the selection criteria of >18 years old; who had undergone total or near total thyroidectomy; had a postoperative Tg, and had undergone 131I pre ablation whole body scan (PA-WBS). The primary endpoint was the correlation between Tg level and functional remnant thyroid tissues. Outcomes were categorized as concordant and discordant. Concordant results were positive Tg (>1 ng/ml) with positive PA-WBS or negative Tg (<1 ng/ml) with negative PA-WBS. Discordant results were negative Tg with a positive PA-WBS or positive Tg with a negative PA-WBS. To increase the sensitivity of Tg detection, we evaluated Tg in patients with high thyroid stimulating hormone (TSH) with serum level >30 mU/l on thyroxine withdrawal protocol. RESULTS: One hundred ten patients (54.1%) had discordant results (p < 0.05) with positive PA-WBS and Tg <1 ng/ml, while 93 patients (45.9%) had concordant results. For concordant results, 88 patients had positive PA-WBS and Tg >1 ng/ml, and 5 patients had negative PA-WBS and Tg <1 ng/ml. There was no patient with Tg >1 ng/ml and negative PA-WBS. There were 74 patients with high TSH (>30 mU/l) on abstention (thyroxine withdrawal protocol). Twenty-four (32.5%) had discordant results (p < 0.001) and 50 (67.5%) had concordant results. CONCLUSION: There is low correlation between postoperative Tg and PA-WBS. The sole use of Tg as a serum biomarker for postoperative disease status may not be reliable.