Controversy on the CONVINCE study findings: the PRO take / Controvérsia sobre os achados do estudo CONVINCE: a perspectiva PRO

ABSTRACT The CONVINCE study, recently published in the New England Journal of Medicine, reveals a groundbreaking 23% reduction in the relative risk of all-cause mortality among end-stage kidney patients undergoing high convective volume hemodiafiltration. This significant finding challenges the conventional use of high-flux hemodialysis and offers hope for improving outcomes in chronic kidney disease patients. While some controversies surround the study's findings, including concerns about generalizability and the causes of death, it is essential to acknowledge the study's design and its main outcomes. The CONVINCE study, part of the HORIZON 2020 project, enrolled 1360 patients and demonstrated the superiority of hemodiafiltration in reducing all-cause mortality overall, as well as in specific patient subgroups (elderly, short vintage, non-diabetic, and those without cardiac issues). Interestingly, it was shown that hemodiafiltration had a protective effect against infection, including COVID-19. Future research will address sustainability, dose scaling effects, identification of subgroups especially likely to benefit and cost-effectiveness. However, for now, the findings strongly support a broader adoption of hemodiafiltration in renal replacement therapy, marking a significant advancement in the field.

RESUMO O estudo CONVINCE, publicado recentemente no New England Journal of Medicine, revela uma redução inovadora de 23% no risco relativo de mortalidade por todas as causas entre pacientes renais em estágio terminal submetidos à hemodiafiltração de alto volume de convecção. Esse achado significativo desafia o uso convencional da hemodiálise de alto fluxo e oferece esperança de melhoria dos desfechos em pacientes com doença renal crônica. Embora algumas controvérsias cerquem os achados do estudo, incluindo preocupações sobre a generalização e as causas de óbito, é essencial reconhecer o desenho do estudo e seus principais desfechos. O estudo CONVINCE, parte do projeto HORIZON 2020, inscreveu 1.360 pacientes e demonstrou a superioridade da hemodiafiltração na redução da mortalidade por todas as causas em geral, bem como em subgrupos específicos de pacientes (idosos, HD de curta duração, não diabéticos e aqueles sem problemas cardíacos). Curiosamente, demonstrou-se que a hemodiafiltração teve um efeito protetor contra infecções, incluindo a COVID-19. Pesquisas futuras abordarão sustentabilidade, efeitos de escalonamento da dose, identificação de subgrupos especialmente propensos a se beneficiar e a relação custo-benefício. No entanto, por ora, os achados apoiam fortemente uma adoção mais ampla da hemodiafiltração na terapia renal substitutiva, marcando um avanço significativo na área.

Risk factors for acute kidney injury in patients hospitalized with COVID-19 / Fatores de risco para lesão renal aguda em pacientes hospitalizados com COVID-19

Abstract Introduction: Acute kidney injury (AKI) occurs frequently in COVID-19 patients and is associated with greater morbidity and mortality. Knowing the risks of AKI allows for identification, prevention, and timely treatment. This study aimed to identify the risk factors associated with AKI in hospitalized patients. Methods: A descriptive, retrospective, cross-sectional, and analytical component study of adult patients hospitalized with COVID-19 from March 1 to December 31, 2020 was carried out. AKI was defined by the creatinine criteria of the KDIGO-AKI guidelines. Information, regarding risk factors, was obtained from electronic medical records. Results: Out of the 934 patients, 42.93% developed AKI, 60.59% KDIGO-1, and 9.9% required renal replacement therapy. Patients with AKI had longer hospital stay, higher mortality, and required more intensive care unit (ICU) admission, mechanical ventilation, and vasopressor support. Multivariate analysis showed that age (OR 1.03; 95% CI 1.02-1.04), male sex (OR 2.13; 95% CI 1.49-3.04), diabetes mellitus (DM) (OR 1.55; 95% CI 1.04-2.32), chronic kidney disease (CKD) (OR 2.07; 95% CI 1.06-4.04), C-reactive protein (CRP) (OR 1.02; 95% CI 1.00-1.03), ICU admission (OR 1.81; 95% CI 1.04-3.16), and vasopressor support (OR 7.46; 95% CI 3.34-16.64) were risk factors for AKI, and that bicarbonate (OR 0.89; 95% CI 0.84-0.94) and partial pressure arterial oxygen/inspired oxygen fraction index (OR 0.99; 95% CI 0.98-0.99) could be protective factors. Conclusions: A high frequency of AKI was documented in COVID-19 patients, with several predictors: age, male sex, DM, CKD, CRP, ICU admission, and vasopressor support. AKI occurred more frequently in patients with higher disease severity and was associated with higher mortality and worse outcomes.

RESUMO Introdução: Lesão renal aguda (LRA) ocorre frequentemente em pacientes com COVID-19 e associa-se a maior morbidade e mortalidade. Conhecer riscos da LRA permite a identificação, prevenção e tratamento oportuno. Este estudo teve como objetivo identificar fatores de risco associados à LRA em pacientes hospitalizados. Métodos: Realizou-se estudo descritivo, retrospectivo, transversal e de componente analítico de pacientes adultos hospitalizados com COVID-19 de 1º de março a 31 de dezembro, 2020. Definiu-se a LRA pelos critérios de creatinina das diretrizes KDIGO-LRA. Informações sobre fatores de risco foram obtidas de prontuários eletrônicos. Resultados: Dos 934 pacientes, 42,93% desenvolveram LRA, 60,59% KDIGO-1 e 9,9% necessitaram de terapia renal substitutiva. Pacientes com LRA apresentaram maior tempo de internação, maior mortalidade e necessitaram de mais internações em UTIs, ventilação mecânica e suporte vasopressor. A análise multivariada mostrou que idade (OR 1,03; IC 95% 1,02-1,04), sexo masculino (OR 2,13; IC 95% 1,49-3,04), diabetes mellitus (DM) (OR 1,55; IC 95% 1,04-2,32), doença renal crônica (DRC) (OR 2,07; IC 95% 1,06-4,04), proteína C reativa (PCR) (OR 1,02; IC 95% 1,00-1,03), admissão em UTI (OR 1,81; IC 95% 1,04-3,16) e suporte vasopressor (OR 7,46; IC 95% 3,34-16,64) foram fatores de risco para LRA, e que bicarbonato (OR 0,89; IC 95% 0,84-0,94) e índice de pressão parcial de oxigênio arterial/fração inspirada de oxigênio (OR 0,99; IC 95% 0,98-0,99) poderiam ser fatores de proteção. Conclusões: Documentou-se alta frequência de LRA em pacientes com COVID-19, com diversos preditores: idade, sexo masculino, DM, DRC, PCR, admissão em UTI e suporte vasopressor. LRA ocorreu mais frequentemente em pacientes com maior gravidade da doença e associou-se a maior mortalidade e piores desfechos.

Comprehensive analysis of immunogenic cell death-related gene and construction of prediction model based on WGCNA and multiple machine learning in severe COVID-19.

The death of coronavirus disease 2019 (COVID-19) is primarily due to from critically ill patients, especially from ARDS complications caused by SARS-CoV-2. Therefore, it is essential to contribute an in-depth understanding of the pathogenesis of the disease and to identify biomarkers for predicting critically ill patients at the molecular level. Immunogenic cell death (ICD), as a specific variant of regulatory cell death driven by stress, can induce adaptive immune responses against cell death antigens in the host. Studies have confirmed that both innate and adaptive immune pathways are involved in the pathogenesis of SARS-CoV-2 infection. However, the role of ICD in the pathogenesis of severe COVID-19 has rarely been explored. In this study, we systematically evaluated the role of ICD-related genes in COVID-19. We conducted consensus clustering, immune infiltration analysis, and functional enrichment analysis based on ICD differentially expressed genes. The results showed that immune infiltration characteristics were altered in severe and non-severe COVID-19. In addition, we used multiple machine learning methods to screen for five risk genes (KLF5, NSUN7, APH1B, GRB10 and CD4), which are used to predict COVID-19 severity. Finally, we constructed a nomogram to predict the risk of severe COVID-19 based on the classification and recognition model, and validated the model with external data sets. This study provides a valuable direction for the exploration of the pathogenesis and progress of COVID-19, and helps in the early identification of severe cases of COVID-19 to reduce mortality.

Diaphragmatic morphological post-mortem findings in critically ill COVID-19 patients: an observational study.

Our study investigates the post-mortem findings of the diaphragm's muscular structural changes in mechanically ventilated COVID-19 patients. Diaphragm samples of the right side from 42 COVID-19 critically ill patients were analyzed and correlated with the type and length of mechanical ventilation (MV), ventilatory parameters, prone positioning, and use of sedative drugs. The mean number of fibers was 550±626. The cross-sectional area was 4120±3280 µm2, while the muscular fraction was 0.607±0.126. The overall population was clustered into two distinct populations (clusters 1 and 2). Cluster 1 showed a lower percentage of slow myosin fiber and higher fast fiber content than cluster 2, 68% versus 82%, p<0.00001, and 29.8% versus 18.8%, p=0.00045 respectively. The median duration of MV was 180 (41-346) hours. In cluster 1, a relationship between assisted ventilation and fast myosin fiber percentage (R2=-0.355, p=0.014) was found. In cluster 2, fast fiber content increased with increasing the length of the controlled MV (R2=0.446, p=0.006). A high grade of fibrosis was reported. Cluster 1 was characterized by fibers' atrophy and cluster 2 by hypertrophy, supposing different effects of ventilation on the diaphragm but without excluding a possible direct viral effect on diaphragmatic fibers.

Oral administration of PEDV-dissolved Alg-CS gel induces high and sustained mucosal immunity in mice.

Porcine epidemic diarrhea (PED) is a serious disease in piglets that leads to high mortality. An effective measure that provides higher IgA levels in the intestine and milk is required to decrease losses. Porcine epidemic diarrhea virus (PEDV) was dissolved in calcium alginate (Alg) and combined with chitosan (CS) via electrostatic interactions between cationic chitosan and anionic alginate to create a porous gel (Alg-CS+PEDV). The gel was used to immunize mice orally or in combination with subcutaneous injections of inactivated PEDV vaccine. At 12 and 24 days after immunization, levels of IgA and IgG in Alg-CS+PEDV were higher than with normal PEDV oral administration. At 24 days after immunization, the concentration of IFN-γ in Alg-CS+PEDV was higher than with normal PEDV oral administration. Furthermore, oral administration combining subcutaneous immunization induced higher levels of IgG and IgA than oral administration alone. Our study provides a new method for the preparation and administration of oral vaccines to achieve enhanced mucosal immunity against PEDV.

Smoking cessation among tuberculosis patients during the coronavirus disease-2019 pandemic.

Smoking has been recognized as a significant risk factor for COVID-19 and mortality. The World Health Organization (WHO) has recommended smoking cessation to reduce the impact of COVID-19. This study aimed to evaluate the smoking cessation rate of patients starting tuberculosis (TB) treatment at six months using motivational interviewing based on the WHO "five steps to quit" model. In addition, we assessed the knowledge about smoking and the barriers to smoking cessation. We conducted a retrospective cohort study. Outpatients aged >18 years, smokers, and those who are starting TB treatment in two outpatient TB clinics were invited to participate. Patients received information about the importance of smoking cessation, especially in TB patients, and standardized advice based on guidelines. This information was repeated during phone calls during the second and fourth months of treatment. During the study period, 111 patients were included. The primary outcome was the smoking cessation rate at the end of the sixth month of treatment, which was 26.8% (19/71). The barriers to smoking cessation described by the patients were anxiety/depression (47.4%), seeing someone smoking (38.5%), drug use (19.2%), and alcohol abuse (2.6%). The assessment of knowledge about smoking showed that patients had some information gaps. In conclusion, TB smokers who tried to quit smoking during the COVID-19 pandemic faced many challenges. Despite this, we demonstrated a reasonable smoking cessation rate with a nurse-conducted motivational interview.

Vaccine Attitudes and Uptake Among Latino Residents of a Former COVID-19 Hotspot.

Early in the COVID-19 pandemic, the Centers for Disease Control and Prevention identified Prince William County (PWC), Va. as a hotspot with a high disease rate among Latinos. This study uses spatial, survey, and qualitative data to understand attitudes towards vaccine uptake among PWC Latinos. A quantitative analysis (n=266) estimates the association for vaccine acceptance among Latinos. Next, qualitative interviews with Latinos (n=37) examine vaccine attitudes. Finally, a spatial analysis identifies clusters of social vulnerability and low vaccine uptake in PWC and adjacent counties. Our findings show that a substantial proportion of PWC Latinos had low vaccination rates as of December 2022, two years after the vaccine's release. Side effects and safety and approval concerns were cited in both the quantitative and qualitative studies. Persistent vaccine disparities are concerning given the high hospitalization and mortality rates that prevailed among Latinos early in the pandemic.

[A Case of Interstitial Pneumonia Induced by Immune Checkpoint Inhibitors for Gastric Cancer During the COVID- 19 Pandemic].

BACKGROUND: The novel coronavirus disease(corona virus disease 2019: COVID-19)has calmed down worldwide, and the severity of the disease is decreasing. On the other hand, due to the emergence of strain mutations, the number of infected people shows a wavy course. I have experienced a case of gastric cancer that underwent chemotherapy including an immune checkpoint inhibitors(ICI) early after COVID-19, so I will report it including a discussion. CASE: A 71-year-old man. The patient visited our hospital with a chief complaint of stomach discomfort, and gastrointestinal endoscopy revealed advanced gastric cancer accompanied by narrowing of the gastric lumen. The histopathological examination showed a poorly differentiated adenocarcinoma. A CT scan of the chest and abdomen showed thickening of the entire gastric wall, indicating the presence of enlarged adjacent lymph nodes and infiltration into adjacent organs. No other obvious distant metastases were observed. Staging laparoscopy was performed, it revealed infiltration of the posterior wall of the stomach into the celiac artery and anterior surface of the pancreas. We determined that curative resection would be difficult. As a result of planning chemotherapy for locally advanced gastric cancer, the patient contracted COVID-19 due to a hospital- acquired infection. The patient's COVID-19 infection was managed with supportive care alone without severe complications, and they recovered within the course of treatment. Two weeks after the onset of the infection, chemotherapy(FOLFOX+ Nivo)was initiated. The patient completed up to 9 courses of chemotherapy, and the treatment response was determined to be stable disease(SD). Due to a tendency of stenosis in the gastric lumen, the possibility of future dilation procedures was considered. As a result, the patient underwent second-line chemotherapy with a combination of wPTX+RAM. After completing 1 course of treatment, the patient developed drug-induced interstitial pneumonia, which was managed with intensive care and steroid pulse therapy, resulting in improvement. There was progression of gastric lumen stenosis, and an endoscopic dilation procedure/stent placement was performed. Subsequently, there was a rapid increase in malignant ascites and a decline in activities of daily living(ADL), leading to palliative care. Unfortunately, the patient succumbed to cancer-related complications 10 months after the diagnosis. DISCUSSION: In this case, the serial antibody titers of COVID-19 also indicated the sustained effectiveness of the multi-drug combination chemotherapy. The treatment course suggests a suspicion of drug-induced interstitial pneumonia due to PTX/RAM, but the long-term imaging follow-up implies that ICI may be the cause. When using ICI, COVID-19 infection alone may pose a potential risk factor.

Maintaining essential health services during a pandemic: lessons from Costa Rica's COVID-19 response.

Studies on COVID-19 usually focus on health system responses to decrease the rate of COVID-19 infection and death, but patients with other diseases also require access to health services during the pandemic. This paper describes the structures and processes by which the Costa Rican Social Security Fund (CCSS) changed in response to the COVID-19 pandemic, which helped to sustain essential health services (EHSs). We conducted a desk review of the local literature and semistructured qualitative interviews with key informants from the CCSS. We found that the CCSS implemented changes in structure, such as creating a specialised COVID-19 centre and hiring additional interim health workers. The CCSS also implemented changes in processes, including leveraging its integrated network to optimise its resources and support alternative care modalities. These changes generated changes in outputs and outcomes that helped sustain EHSs for non-COVID-19 patients. These interventions were possible primarily due to Costa Rica's underlying health system, particularly its integrated nature with a single institution in charge of healthcare provision financed through mandatory health insurance, a unique digital medical record system and a contingency fund.

Severe acute myositis and myocarditis on initiation of 6-weekly pembrolizumab post-COVID-19 mRNA vaccination.

We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.

SARS-CoV-2 and its ORF3a, E and M viroporins activate inflammasome in human macrophages and induce of IL-1α in pulmonary epithelial and endothelial cells.

Inflammasome assembly is a potent mechanism responsible for the host protection against pathogens, including viruses. When compromised, it can allow viral replication, while when disrupted, it can perpetuate pathological responses by IL-1 signaling and pyroptotic cell death. SARS-CoV-2 infection was shown to activate inflammasome in the lungs of COVID-19 patients, however, potential mechanisms responsible for this response are not fully elucidated. In this study, we investigated the effects of ORF3a, E and M SARS-CoV-2 viroporins in the inflammasome activation in major populations of alveolar sentinel cells: macrophages, epithelial and endothelial cells. We demonstrated that each viroporin is capable of activation of the inflammasome in macrophages to trigger pyroptosis-like cell death and IL-1α release from epithelial and endothelial cells. Small molecule NLRP3 inflammasome inhibitors reduced IL-1 release but weakly affected the pyroptosis. Importantly, we discovered that while SARS-CoV-2 could not infect the pulmonary microvascular endothelial cells it induced IL-1α and IL-33 release. Together, these findings highlight the essential role of macrophages as the major inflammasome-activating cell population in the lungs and point to endothelial cell expressed IL-1α as a potential novel component driving the pulmonary immunothromobosis in COVID-19.

Loss of TRIM29 mitigates viral myocarditis by attenuating PERK-driven ER stress response in male mice.

Viral myocarditis, an inflammatory disease of the myocardium, is a significant cause of sudden death in children and young adults. The current coronavirus disease 19 pandemic emphasizes the need to understand the pathogenesis mechanisms and potential treatment strategies for viral myocarditis. Here, we found that TRIM29 was highly induced by cardiotropic viruses and promoted protein kinase RNA-like endoplasmic reticulum kinase (PERK)-mediated endoplasmic reticulum (ER) stress, apoptosis, and reactive oxygen species (ROS) responses that promote viral replication in cardiomyocytes in vitro. TRIM29 deficiency protected mice from viral myocarditis by promoting cardiac antiviral functions and reducing PERK-mediated inflammation and immunosuppressive monocytic myeloid-derived suppressor cells (mMDSC) in vivo. Mechanistically, TRIM29 interacted with PERK to promote SUMOylation of PERK to maintain its stability, thereby promoting PERK-mediated signaling pathways. Finally, we demonstrated that the PERK inhibitor GSK2656157 mitigated viral myocarditis by disrupting the TRIM29-PERK connection, thereby bolstering cardiac function, enhancing cardiac antiviral responses, and curbing inflammation and immunosuppressive mMDSC in vivo. Our findings offer insight into how cardiotropic viruses exploit TRIM29-regulated PERK signaling pathways to instigate viral myocarditis, suggesting that targeting the TRIM29-PERK axis could mitigate disease severity.

"Access to healthcare is a human right": a constructivist study exploring the impact and potential of a hospital-community partnered COVID-19 community response team for Toronto homeless services and congregate living settings.

BACKGROUND: Individuals experiencing homelessness face unique physical and mental health challenges, increased morbidity, and premature mortality. COVID -19 creates a significant heightened risk for those living in congregate sheltering spaces. In March 2020, the COVID-19 Community Response Team formed at Women's College Hospital, to support Toronto shelters and congregate living sites to manage and prevent outbreaks of SARS-CoV-2 using a collaborative model of onsite mobile testing and infection prevention. From this, the Women's College COVID-19 vaccine program emerged, where 14 shelters were identified to co-design and support the administration of vaccine clinics within each shelter. This research seeks to evaluate the impact of this partnership model and its future potential in community-centered integrated care through three areas of inquiry: (1) vaccine program evaluation and lessons learned; (2) perceptions on hospital/community partnership; (3) opportunities to advance hospital-community partnerships. METHODS: Constructivist grounded theory was used to explore perceptions and experiences of this partnership from the voices of shelter administrators. Semi-structured interviews were conducted with administrators from 10 shelters using maximum variation purposive sampling. A constructivist-interpretive paradigm was used to determine coding and formation of themes: initial, focused, and theoretical. RESULTS: Data analysis revealed five main categories, 16 subcategories, and one core category. The core category "access to healthcare is a human right; understand our communities" emphasizes access to healthcare is a consistent barrier for the homeless population. The main categories revealed during a time of confusion, the hospital was seen as credible and trustworthy. However, the primary focus of many shelters lies in housing, and attention is often not placed on health resourcing, solidifying partnerships, accountability, and governance structures therein. Health advocacy, information sharing tables, formalized partnerships and educating health professionals were identified by shelter administrators as avenues to advance intersectoral relationship building. CONCLUSION: Hospital-community programs can alleviate some of the ongoing health concerns faced by shelters - during a time of COVID-19 or not. In preparation for future pandemics, access to care and cohesion within the health system requires the continuous engagement in relationship-building between hospitals and communities to support co-creation of innovative models of care, to promote health for all.

Trust in public health policy in the time of the COVID-19 epidemic in Israel.

The government of Israel provides universal health care through four health care organizations ("sick funds") that enjoy general public trust. In hindsight, the response of the government to the COVID-19 epidemic seems reasonable. In the first year of the epidemic, tests and vaccines were developed and other measures were taken, including social distancing, focusing on risk factors for infection and disease severity, and improving treatment. The COVID-19 mortality rate between January 2000 and June 2021 was around 750 per million inhabitants, well below the OECD average of 1300. Still, although the control measures were largely well received, the media and an ad hoc non-governmental Emergency Council for the coronavirus crisis in Israel criticized the government's response to the epidemic thereby contributing to a decline in public trust in government policy. This commentary provides an overview of the importance of trust in medical institutions and the difficulties of evaluating healthcare decisions in an attempt to justify three conclusions. First, when physicians and self-appointed experts publicly disapprove of a government policy, they should consider the trade-off between improving care and undermining public trust. Second, when evaluating a medical decision, experts should not ask, "Would I have acted differently?" but rather, "Was the decision under review completely unreasonable?" Thirdly, criticism is certainly worth listening to. However, I believe that by calling for organized resistance against the government, the publicly announced establishment of the Emergency Council for the Corona crisis blatantly crossed the line between constructive criticism and destructive mistrust.

"It didn't hurt me": patients' and providers' perspectives on unsupervised take-home doses, drug diversion, and overdose risks in the provision of medication for opioid use disorder during COVID-19 in San Juan, Puerto Rico.

BACKGROUND: During the COVID-19 pandemic, clinics offering medication for opioid use disorder (MOUD) needed to rapidly introduce unsupervised take-home dosing, while relapsing patients and patients unable to enter treatment faced increased risks of fentanyl-related overdose deaths and other drug-related harms. Based on a qualitative study of people who inject drugs (PWID) receiving MOUD treatment and MOUD staff in Puerto Rico, this paper documents the lived experiences of patients and providers during this period and the risk perceptions and management strategies to address substance misuse and drug diversion attributable to unsupervised take-home-dose delivery. METHODS: In-depth qualitative interviews were conducted with patients (N = 25) and staff (N = 25) in two clinics providing MOUD in San Juan, Puerto Rico, during 2022. Patients and staff were receiving or providing treatment during the pandemic, and patients reported injection drug use during the past thirty days. RESULTS: Patients were overwhelmingly male (84%), unmarried (72%), and unemployed (52%), with almost half (44%) injecting one to three times a day. Mean time in treatment was 7 years. Staff had a mean age of 46 years with more than half of the sample (63%) female. The majority of patients believed that unsupervised take-home dosing had no significant effect on their treatment adherence or engagement. In contrast, providers expressed concerns over the potential for drug diversion and possible increased risks of patient attrition, overdose episodes, and poor treatment outcomes. CONCLUSION: This study underscores the importance of insider perspectives on harm-reduction changes in policy implemented during a health crisis. Of note is the finding that staff disagreed among themselves regarding the potential harms of diversion and changes in drug testing protocols. These different perspectives are important to address so that future pandemic policies are successfully designed and implemented. Our study also illuminates disagreement in risk assessments between patients and providers. This suggests that preparation for emergency treatment plans requires enhanced communication with patients to match treatments to the context of lived experience.

Prophylactic-dose direct oral anticoagulants for non-hospitalised people with COVID-19: A meta-analysis of randomised controlled trials.

Background: Several reviews have been conducted on thromboprophylaxis in non-hospitalised patients with coronavirus disease 2019 (COVID-19). In this systematic review and meta-analysis, we sought to investigate the impact of prophylactic-dose direct oral anticoagulants (DOACs) in this population. Methods: We searched PubMed, Web of Science, EMBASE and Cochrane Library for randomised controlled trials (RCTs) comparing prophylactic-dose DOACs with placebo or no treatment in non-hospitalised patients with COVID-19 until September 2023. The primary efficacy outcome was a composite of all-cause mortality and thromboembolic events, while major bleeding events were the primary safety outcome. We expressed continuous outcome data as mean differences (MDs) with 95% confidence intervals (CIs) and dichotomous outcome data as risk ratios (RRs) with 95% CIs. Results: We included six RCTs involving 4307 patients. Prophylactic-dose DOAC therapy compared with placebo or no treatment was associated with significantly decreased risks of the composite outcome of all-cause mortality and thromboembolic events (1.43% vs 2.67% (RR = 0.53; 95% CI = 0.34-0.82, P = 0.004, I2 = 3%)). Major bleeding events were infrequent, and we detected no significant differences between patients assigned to prophylactic-dose DOACs vs placebo or no treatment (0.19% vs 0.05% (RR = 2.50; 95% CI = 0.49-12.87, P = 0.27, I2 = 0%)). The use of prophylactic-dose DOACs was also associated with a reduction in venous thromboembolism, with no difference in all-cause mortality, arterial thromboembolism, hospitalisations, and clinically relevant nonmajor bleeding between two groups. Sensitivity analyses with the leave-one-out method for the primary efficacy and safety outcome did not change the effect estimate substantially. Conclusions: We found that prophylaxis-dose DOACs could significantly improve clinical outcomes and reduce venous thrombotic events without increasing the risk of major bleeding events compared with placebo or no treatment in non-hospitalised patients with COVID-19. Registration: PROSPERO: CRD42023466889.

Maximal Resistance Training in the Treatment of Anorexia Nervosa - A Case Report Series.

Objective: Anorexia Nervosa (AN) has one of the highest mortality rates of all mental health disorders, low recovery rate and is associated with widespread endocrine dysfunction. Resistance training (RT) has been consistently shown to provide beneficial effects on health outcomes that are often negatively affected by AN, however participation in exercise is controversial for individuals with AN. The objective of this study was to assess the effects of maximal RT as an add-on to standard of care in patients with AN. Methods: Originally, a controlled clinical trial was planned but due to COVID-19 pandemic, the study was prematurely ended and reported as a case series design. Three female inpatients with AN (Age 18-29 years, body mass index (BMI) 14.5-16.3 kg/m2, illness duration 1-7 years) underwent a supervised 6-week RT intervention as an add-on to standard of care. Primary outcome was muscular strength, as measured by a 1-repetition maximum. Secondary outcomes included BMI, eating disorder psychopathology and maladaptive exercise tendencies. Results: No adverse events were reported. All three participants improved lower body muscle strength, ranging from 32% to 134% in the leg press. Changes of 4% to 134% in the bench press and -3% to 38% in the pulldown were also observed. Conclusions: RT improved muscular strength in the participants. RT as part of standard of care may also provide additional benefits for individuals with AN, although further research is required to determine which subtype of patients would benefit from the addition of RT to their treatment protocol.

Proportion of cancer cases and deaths attributable to potentially modifiable risk factors in Peru.

BACKGROUND: Limited evidence exists on the population attributable fraction (PAF) of cancer cases and deaths in Latin America. In Peru several studies have been published regarding the PAF of various risk factors and their associated diseases. The objective of this study was to estimate the fraction of cancer cases and deaths attributable to potentially modifiable risk factors in Peru in 2018, before the COVID-19 pandemic in the population of 15 years old and older. METHODS: An ecological study was conducted using the prevalence of exposure of the Peruvian population to modifiable risk factors for cancer, the relative risk associated with each factor, and the number of cancer cases and deaths in 2018 as inputs. We used the Parkin formula with a Montecarlo statistical simulation model to calculate the PAF and confidence intervals. The number of new cancer cases and deaths attributed to each risk factor was determined by multiplying the number of cases and deaths in each gender by the PAF of each risk factor. FINDINGS: In Peru, 38.5% of new cases (34.5% in men and 42% in women) and 43.4% of cancer-related deaths (43.4% in men and 43.4% in women) were attributable to modifiable risk factors. The number of cancers attributable was 25,308 (10,439 in men and 14,869 in women) and the number of deaths attributable to cancer was 14,839 (6,953 in men and 7,886 in women). The predominant modifiable risk factors contributing to the highest number of cases and deaths were HPV infection (4,563 cases, 2,409 deaths), current tobacco use (3,348 cases, 2,180 deaths), and helicobacter pylori infection (2,677 cases, 1,873 deaths). Among the risk factors, oncogenic infections constituted the group with the highest PAF (16.6% for cases, 19.2% for deaths) followed by other unhealthy lifestyle factors (14.2% for cases, 16.7% for deaths), tobacco (7.2% for cases, 7.2% for deaths) and ultraviolet radiation (0.5% for cases, 0.3% for deaths). CONCLUSIONS: Prior to the COVID-19 pandemic, 38.5% of cancer cases and 43.4% of cancer-related deaths in Peru were linked to modifiable risk factors in the population of 15 years old and older. Most preventable cancer cases and deaths were related to oncogenic infections, primarily caused by HPV and helicobacter pylori, followed by tobacco and obesity.

The role of colchicine in the management of COVID-19: a Meta-analysis.

BACKGROUND: The Coronavirus disease 2019 (COVID-19) pandemic has robustly affected the global healthcare and economic systems and it was caused by coronavirus-2 (SARS-CoV-2). The clinical presentation of the disease ranges from a flu-like illness to severe pneumonia and death. Till September 2022, the cumulative number of cases exceeded 600 million worldwide and deaths were more than 6 million. Colchicine is an alkaloid drug that is used in many autoinflammatory conditions e.g., gout, familial Mediterranean fever, and Behçet's syndrome. Colchicine inhibits the production of superoxide and the release of interleukins that stimulate the inflammatory cascade. Colchicine decreases the differentiation of myofibroblast and the release of fibrotic mediators including transforming growth factor (TGF-ß1) that are related to the fibrosis. Moreover, colchicine has been used to traet viral myocarditis caused by CMV or EBV, interstitial pneumonia, and pericarditis resulting from influenza B infection. Additionally, colchicine is considered safe and affordable with wide availability. OBJECTIVE: The aim of the current study was to assess the evidence of colchicine effectiveness in COVID-19 treatment. METHODS: A comprehensive review of the literature was done till May 2022 and yielded 814 articles after ranking the articles according to authors and year of publication. Only 8 clinical trials and cohort studies fulfilling the inclusion criteria were included for further steps of data collection, analysis, and reporting. RESULTS: This meta-analysis involved 16,488 patients; 8146 patients in the treatment group and 8342 patients in the control group. The results showed that colchicine resulted in a significant reduction in the mortality rate among patients received colchicine in comparison with placebo or standard care (RR 0.35, 95%CI: 0.15-0.79). Colchicine resulted in a significant decrease in the need for O2 therapy in patients with COVID-19 (RR 0.07, 95%CI 0.02-0.27, P = 0.000024). However, colchicine had no significant effect on the following outcomes among COVID-19 patients: the need for hospitalization, ICU admission, artificial ventilation, and hospital discharge rate. Among the PCR confirmed COVID-19 patients, colchicine decreased the hospitalization rate (RR 0.75, 95%CI 0.57-0.99, P = 0.042). However, colchicine had no effect on mortality and the need for mechanical ventilation among this subgroup. CONCLUSION: Colchicine caused a significant clinical improvement among COVID-19 patients as compared with the standard care or placebo, in terms of the need for O2, and mortality. This beneficial effect could play a role in the management of COVID-19 especially severe cases to decrease need for oxygen and to decrease mortality among these patients.

Melatonin: a ferroptosis inhibitor with potential therapeutic efficacy for the post-COVID-19 trajectory of accelerated brain aging and neurodegeneration.

The unprecedented pandemic of COVID-19 swept millions of lives in a short period, yet its menace continues among its survivors in the form of post-COVID syndrome. An exponentially growing number of COVID-19 survivors suffer from cognitive impairment, with compelling evidence of a trajectory of accelerated aging and neurodegeneration. The novel and enigmatic nature of this yet-to-unfold pathology demands extensive research seeking answers for both the molecular underpinnings and potential therapeutic targets. Ferroptosis, an iron-dependent cell death, is a strongly proposed underlying mechanism in post-COVID-19 aging and neurodegeneration discourse. COVID-19 incites neuroinflammation, iron dysregulation, reactive oxygen species (ROS) accumulation, antioxidant system repression, renin-angiotensin system (RAS) disruption, and clock gene alteration. These events pave the way for ferroptosis, which shows its signature in COVID-19, premature aging, and neurodegenerative disorders. In the search for a treatment, melatonin shines as a promising ferroptosis inhibitor with its repeatedly reported safety and tolerability. According to various studies, melatonin has proven efficacy in attenuating the severity of certain COVID-19 manifestations, validating its reputation as an anti-viral compound. Melatonin has well-documented anti-aging properties and combating neurodegenerative-related pathologies. Melatonin can block the leading events of ferroptosis since it is an efficient anti-inflammatory, iron chelator, antioxidant, angiotensin II antagonist, and clock gene regulator. Therefore, we propose ferroptosis as the culprit behind the post-COVID-19 trajectory of aging and neurodegeneration and melatonin, a well-fitting ferroptosis inhibitor, as a potential treatment.