Relative Risk Of Death Research Articles

Novel immunogenic cell death-related risk signature to predict prognosis and immune microenvironment in lung adenocarcinoma.

Immunogenic cell death (ICD) is a type of regulated cell death (RCD) which was discovered to activate adaptive immunity. To date, the effect of ICD on lung adenocarcinoma (LUAD) remains unclear. In this research, we will study the role of ICD-related genes (ICDG) in LUAD. RNA sequencing and clinical data were gathered from TCGA-LUAD cohorts and GEO database. Using unsupervised cluster analysis, three clusters were identified with distinctive immune characteristics and significant overall survival based on 18 ICDG. Using LASSO Cox regression, three genes were identified and used to construct the prognosis signature. The association between the 3-ICDG risk signature and immune microenvironment analysis, somatic mutation, and enriched molecular pathways was investigated. Consensus clustering separated the LUAD samples into three clusters (ICDcluster A, B and C), and ICDcluster B had the best prognosis. Different TME cell infiltration characteristics and biological behavior were found in three ICD clusters. Prognostic risk model was contrasted based on the 3 best prognostic ICD-related genes. Subsequently, vitro experiments verified the above analysis results. The high-risk group showed a poor prognosis and enrichment of cancer promoting signal pathway. Multivariate analysis indicated that this 3-ICDG prognostic model might be an accurate prediction parameter for LUAD. Moreover, conducting immune related analysis, we found that the 3-ICDG risk signature was characterized by an immune-active subtype on account of the high infiltration of immune-active cells. This study expands our cognition of ICD in LUAD microenvironment, excavated prognostic biomarkers, and provided potential value for guiding immunotherapy and chemotherapy.

Effectiveness of COVID-19 Vaccination with mRNA Vaccines for Patients with Cirrhosis in Hungary: Multicentre Matched Cohort Study

Patients with cirrhosis are vulnerable to hepatic decompensation events and death following COVID-19 infection. Therefore, primary vaccination with COVID-19 vaccines is fundamental to reducing the risk of COVID-19 related deaths in patients with cirrhosis. However, limited data are available about the effectiveness of mRNA vaccines compared to other vaccines. The aim of our study was to investigate the efficacy of mRNA vaccines versus other vaccines in cirrhosis. In this retrospective study, we compared clinical characteristics and vaccine effectiveness of 399 COVID-19 patients without cirrhosis (GROUP A) to 52 COVID-19 patients with cirrhosis (GROUP B). 54 hospitalised cirrhosis controls without COVID-19 (GROUP C) were randomly sampled 1:1 and matched by gender and age. Of the cirrhosis cases, we found no difference (p = 0.76) in mortality rates in controls without COVID-19 (11.8%) compared to those with COVID-19 (9.6%). However, COVID-19 patients with cirrhosis were associated with higher rates of worsening hepatic encephalopathy, ascites and esophageal varices. Patients with cirrhosis receiving mRNA vaccines had significantly better survival rates compared to viral vector or inactivated vaccines. Primary vaccination with the BNT162b2 vaccine was the most effective in preventing acute hepatic decompensating events, COVID-19 infection requiring hospital admission and in-hospital mortality.

THE CAUSES OF POVERTY AND INFANT MORTALITY IN THE DISTRICT KECH, TURBAT, BALOCHISTAN

This study investigated the theoretical and empirical relationship among the income, poverty and infant mortality differences in district Kech, Turbat Balochistan. The study analyses the relative influence of a number of biological, social, and economic factors on the risk of infant mortality on the basis of national data collected since 2000 to 2016 in the concerned departments. The analytical methods used on multidimensional contingency tables offer an assessment of the relative risks of infant deaths in various sub-populations, with the documented combination of the birth and death data, with the coefficient estimates of these models being used. The Hospital care during the neonatal period, however, seems to reduce this increased risk for some high-risk infants. The continued poverty and unequal access to health care for expectant mothers and young moms in Turbat city and its environs show that these disparities have persisted into the present. To reduce these disparities, it is advised to increase access to and support for family health services through income subsidies and employment programming.

Associations between 24-hour urinary sodium excretion and all-cause mortality in adults living in north China

Objective: To investigate the associations between 24-hour urinary sodium excretion (24hUNaE) and all-cause mortality in adult Northern Chinese population. Methods: Data from this study were derived from the prospective urban and rural epidemiology (PURE) study in north China. Baseline information of all participants were obtained by face to face interview through trained research staffs based on questionnaires, and morning fasting urine samples of participants were collected to estimate 24hUNaE and 24-hour potassium excretion (24hUKE). Multivariable frailty Cox regression models were used to explore the association between 24hUNaE (<3.00, 3.00-3.99, 4.00-4.99, 5.00-5.99 and ≥6 g/d) and all-cause death. Results: A total of 27 310 participants were included in this study. The mean 24hUNaE was (5.84±1.73) g/d. After a median follow-up of 8.8 years, 1 024 participants died (3.7%), including 390 cardiovascular related deaths and 591 non-cardiovascular related deaths. The cause of death of the remaining patients could not be determined. Using 24hUNaE level of 4.00-4.99 g/d as the reference group, after fully adjustment, 24hUNaE ≥6.00 g/d was associated with an increased risk of all-cause death (HR=1.24, 95%CI: 1.02-1.49) and cardiovascular related death (HR=1.39, 95%CI: 1.02-1.88). 24hUNaE<3.00 g/d was associated with increased risk of all-cause mortality (HR=1.38, 95%CI: 0.96-1.99). There was no significant association between 24hUNaE and non-cardiovascular related death. Furthermore, using the combination of 24hUNaE 4.00-4.99 g/d and 24hUKE≥2.11 g/d as the reference group, the highest risk occurred in participants with the combination of low sodium (<3.00 g/d) and low potassium (<2.11 g/d). Conclusion: 24hUNaE equal or higher than 6 g/d or lower than 3 g/d is associated with increased risk of all-cause mortality and cardiovascular related death in Northern Chinese population. Besides, moderate sodium intake in combination with increased potassium intake might reduce the risk of all-cause death.

Comparing Risks of Firearm-Related Death and Injury Among Young Adult Males in Selected US Cities With Wartime Service in Iraq and Afghanistan

In 2020, homicides in the United States saw a record single-year increase, with firearm injuries becoming the leading cause of death for children, adolescents, and young adults. It is critical to understand the magnitude of this crisis to formulate an effective response. To evaluate whether young adult males living in parts of 4 major US cities faced a firearm-related death and injury risk comparable with risks encountered during recent wartime service in Iraq and Afghanistan. In this cross-sectional study of young adult males aged 18 to 29 years living in the top 10% most violent zip codes in each domestic setting (as measured by fatal shooting rates), fatal and nonfatal shooting data for 2020 and 2021 were aggregated at the zip code level for 4 of the largest US cities (Chicago, Illinois; Los Angeles, California; New York, New York; and Philadelphia, Pennsylvania). Wartime mortality and combat injury rates for the conflicts in Iraq and Afghanistan were used to assess relative risk. The relative risk of firearm-related death and nonfatal shootings in each setting as compared with combat death and injury in the comparator setting. Of 129 826 young adult males aged 18 to 29 years living in the top 10% most violent zip codes in the 4 cities studied, 45 725 (35.2%) were Black, 71 005 (54.7%) were Hispanic, and 40 355 (31.1%) were White. Among this population, there were 470 homicides and 1684 firearm-related injuries. Young adult males living in the most violent zip code of Chicago (2585 individuals aged 20-29 y) and Philadelphia (2448 individuals aged 18-29 y) faced a higher risk of firearm-related homicide than US soldiers who were deployed to Afghanistan, with risk ratios of 3.23 (95% CI, 2.47-4.68) and 1.91 (95% CI, 1.32-3.46), respectively. In expanding the analysis to the top 10% of the cities' most violent zip codes, the risks in Chicago likewise exceeded those of combat death faced by military service members, with a risk ratio of 2.10 (95% CI, 1.82-2.46), and the risks in Philadelphia were comparable with those of deployment to war 1.15 (95% CI, 0.98-1.39). Nonfatal shooting risks were comparable with, or exceeded, the injury risk of combat in Iraq, producing a combined annual firearm risk of 5.8% in Chicago and 3.2% in Philadelphia. However, these findings were not observed in the most violent zip codes of Los Angeles and New York City, where young men faced a 70% to 91% lower risk than soldiers in the Afghanistan war across fatal and nonfatal categories (eg, fatal shooting in most violent zip code in Los Angeles: risk ratio, 0.30; 95% CI, 0.26-0.34; nonfatal shooting in top 10% most violent zip codes in New York: risk ratio, 0.09; 95% CI, 0.08-0.10). The risk of violent death and injury observed in the zip codes studied was almost entirely borne by individuals from minoritized racial and ethnic groups: Black and Hispanic males represented 96.2% of those who were fatally shot (452 individuals) and 97.3% of those who experienced nonfatal injury (1636 individuals) across the 4 settings studied. In this cross-sectional study, for young adult men in several of the communities studied, firearm violence carried morbidity and mortality risks that exceeded those of war. Health equity requires prioritizing effective responses.

Sodium-glucose co-transporter 2 inhibitors and erythrocytosis: a review

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a class of anti-hyperglycaemic agents widely used in the treatment of type 2 diabetes mellitus (T2DM). They function by reducing renal glucose reabsorption and thereby promote urinary glucose excretion, resulting in improvement in glycaemic control. In large-scale clinical trials, SGLT2i have been shown to reduce cardiovascular mortality, non-fatal myocardial infarction and stroke significantly. In addition, clinical evidence suggests that they are renal protective as their use reduces the relative risk of end-stage renal disease and death from renal causes. These positive results have led to a rapid uptake of SGLT2i in clinical practice. Recently, clinical studies and case reports have suggested a link between SGLT2i therapy and erythrocytosis. The authors discuss possible mechanisms at cellular level that may cause erythrocytosis and explore its clinical relevance in people living with T2DM who are taking SGLT2i therapy.

Impact of Severe Acute Respiratory Syndrome Coronavirus 2 Variants on Inpatient Clinical Outcome.

Prior observation has shown differences in COVID-19 hospitalization risk between SARS-CoV-2 variants, but limited information describes hospitalization outcomes. Inpatients with COVID-19 at 5 hospitals in the eastern United States were included if they had hypoxia, tachypnea, tachycardia, or fever, and SARS-CoV-2 variant data, determined from whole-genome sequencing or local surveillance inference. Analyses were stratified by history of SARS-CoV-2 vaccination or infection. The average effect of SARS-CoV-2 variant on 28-day risk of severe disease, defined by advanced respiratory support needs, or death was evaluated using models weighted on propensity scores derived from baseline clinical features. Severe disease or death within 28 days occurred for 977 (29%) of 3369 unvaccinated patients and 269 (22%) of 1230 patients with history of vaccination or prior SARS-CoV-2 infection. Among unvaccinated patients, the relative risk of severe disease or death for Delta variant compared with ancestral lineages was 1.30 (95% confidence interval [CI]: 1.11-1.49). Compared with Delta, the risk for Omicron patients was .72 (95% CI: .59-.88) and compared with ancestral lineages was .94 (.78-1.1). Among Omicron and Delta infections, patients with history of vaccination or prior SARS-CoV-2 infection had half the risk of severe disease or death (adjusted hazard ratio: .40; 95% CI: .30-.54), but no significant outcome difference by variant. Although risk of severe disease or death for unvaccinated inpatients with Omicron was lower than with Delta, it was similar to ancestral lineages. Severe outcomes were less common in vaccinated inpatients, with no difference between Delta and Omicron infections.

1035: GEOSPATIAL FACTORS INTERACT WITH BASELINE HEALTH TO IMPACT COVID-19 MORTALITY (COMMUNITY HOSPITAL)

Introduction: Social determinants of health have been under-reported in critically ill patients during the pandemic. We hypothesized that geospatial factors and baseline health status in our community would significantly impact outcomes from Covid-19 infection. Methods: We conducted an urban, single-center, observational study of patients with Covid-19 infection admitted to our adult ICU over ten months (March 23, 2020 to January 21, 2021, after approval by our hospital’s Institutional Review Board. Weekly prospective data on the Covid-19 study population were entered in our ICU’s quality assurance database. Data specific to test our hypothesis—zip code of residence, functional status, and Canadian Frailty Score (1-7)—were collected from retrospective chart review. The studied population was dichotomized to access patients who resided in long-term care facilities or home residence. Five zip code regions based on sample size and the distance from the patient’s residence to the hospital allowed random sampling. Statistical significance was determined using ANOVA and T-test as indicated. Results: A total of 300 patients were enrolled. Across the designated cohort-based zip code regions, the mean frailty score of patients who resided at home differed significantly (2.9± SE.98 vs. 3.8± SE. 1.28, p< 0.01). Favorable frailty scores of 1-2 had a combined death and hospice rate of 23%. Of the survivors, 30% were transferred to skilled nursing facilities (SNF) and 26% were discharged to home. Patients with frailty scores of 6-7 had a final mortality rate of 83%. Of the survivors, only 2% were transferred to a SNF and 6% were discharged to home. Compared to admitting frailty scores between 1-3, a frailty score of 4 or greater (which represented 35% of all Covid ICU patients admitted from home) had a 1.8 relative risk of death (p< 0.0001). Conclusions: In our adult Covid-19 population, geospatial factors were associated with significant variances in frailty determined on ICU admission. Worsening frailty scores were associated with marked differences in both survival and final disposition, with combined death and hospice rates as high as 80%. We recommend that these metrics be added to routine data reporting to help better characterize ICU populations and stimulate efforts to improve frailty in vulnerable populations.

Regional variation in sudden unexpected death in infancy in New Zealand.

To estimate the relative risk of sudden unexpected death in infancy (SUDI) by district health board (DHB) in New Zealand after adjustment for socio-economic deprivation, ethnicity and other demographic factors. We conducted a population-based cohort study using data from the Integrated Data Infrastructure, a large research database containing linked data from a range of government agencies. The study population was all live births and their mothers in New Zealand from 2012 to 2018. The exposure of interest was DHB. The outcome was SUDI. There were 418 068 live births in New Zealand from 2012 to 2018, and of these 415 401 (99.4%) had valid DHB data. There was considerable variation in the proportion of infants in each DHB living in the most deprived decile varying from 4.5% in Nelson, West Coast and Canterbury to 29.7% in Counties Manukau. There were 267 SUDI cases, giving an overall rate of 0.64/1000 live births during the study period (2012-2018). The SUDI rate varied from 1.11/1000 in Northland to 0.30/1000 in Waitemata and Auckland. Counties Manukau had the largest number of deaths (n=54; rate=1.08/1000). Five DHB regions had increased risk of SUDI compared to the reference group but, after adjustment, no DHB was significantly increased. This study found that there is marked variation in SUDI risk by DHB, but this is explained by socio-economic and demographic variation within DHBs. This study emphasises the importance of the contribution of social determinants of health to SUDI.

Depressive symptoms and mortality in older people in Latin America: systematic review and meta-analysisSíntomas de depresión y mortalidad en personas mayores en América Latina: revisión sistemática con metanálisis

To determine the existence of association between depressive symptoms and mortality in older individuals in Latin America. A systematic review with meta-analysis was performed based on published studies indexed in PubMed, Scientific Electronic Library Online (SciELO), Web of Science, Cochrane Library, Scopus, and LILACS (Literatura Latino-Americana e do Caribe em Ciências da Saúde). The review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO), and structured according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Meta-analysis was performed using random effects models, and the data analyzed included crude relative risk (RR) and heterogeneity, with poin estimates and 95% confidence intervals (95%CI). Five studies, performed in Brazil and Mexico, were included in the meta-analysis, for a total of 8 954 older individuals. RR for mortality in the presence of depressive symptoms was 1.44 (95%CI: 1.16; 1.78). Heterogeneity was 80.87%. Meta-regression showed that the higher the proportion of women in the sample, the higher the mortality risk associated with depressive symptoms; and that the longer the study follow-up, the lower the risk of mortality associated with depressive symptoms. The presence of depressive symptoms was positively associated with mortality in older Latin American individuals. The RR for death was 44.0% higher in individuals with depressive symptoms as compared to those without depressive symptoms. The main study limitations were the lower number of studies retrieved through systematic review and the variety of scales used to determine the presence of depressive symptoms.

Cardiovascular safety of hormone therapy for prostate cancer

Background. As of 2019, prostate cancer (PCa) is the second most common malignancy in men living in Russia (15.7 % of all cancer cases detected in 2019). Cardiovascular diseases, in particular atherosclerosis, are believed to be the second most frequent cause of death in PCa patients.Aim. To evaluate cardiovascular safety of hormone therapy for PCa on the example of gonadotropin releasing hormone (GnRH) agonists and antagonists (leuprolide and degarelix), second-generation antiandrogens (enzalutamide), and steroidogenesis inhibitors (abiraterone).Materials and methods. We analyzed the results of original studies assessing cardiovascular safety of hormone therapy in PCa patients published in 2020–2021 and indexed in PubMed. The results of other meta-analyses and systematic reviews were not included.The search for publications was performed using the PubMed database and the Google system. The following key words were used for searching: prostate cancer, cardiovascular risks, cardiovascular safety, outcomes, atherosclerosis, etc. We analyzed studies published between January 2020 and January 2022. Articles in English and Russian were selected manually; no filters were applied.Results. We examined the results of the latest and most relevant original studies assessing cardiovascular safety of key innovative hormone therapies for PCa. The majority of recent studies were based on routine clinical practice; they were registered in highly specialized cancer registers.Hormone therapy is associated with cardiotoxicity, which increases the risk of non-cancer related death in PCa patients. New, sometimes conflicting evidence is being constantly accumulated. This evidence suggests that the GnRH antagonist (degarelix) has a better cardiovascular safety profile than the GnRH agonist (leuprolide); enzalutamide is safer than abiraterone. Further search for prognostic biomarkers in PCa patients is needed.Conclusion. More high-quality studies analyzing adverse cardiovascular events in PCa patients conducted in routine clinical practice and registered in the online databases are the next stage to identify benefits of one antitumor drug over another. This will help to choose optimal hormone therapy algorithms for PCa patients and, therefore, increase their overall survival.

Incidence of and Neurodevelopmental Outcomes After Late-Onset Meningitis Among Children Born Extremely Preterm

Late-onset meningitis (LOM) has been associated with adverse neurodevelopmental outcomes in children born extremely preterm. To report the incidence of LOM during birth hospitalization and neurodevelopmental outcomes at 18 to 26 months' corrected age. This cohort study is a secondary analysis of a multicenter prospective cohort of children born at 22 to 26 weeks' gestation between 2003 and 2017 with follow-up from 2004 to 2021. The study was conducted at 25 Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network centers. Culture-confirmed LOM. Incidence and microbiology of LOM (2003-2017); lumbar puncture (LP) performance in late-onset sepsis (LOS) evaluations (2011-2017); composite outcome of death or neurodevelopmental impairment (NDI; 2004-2021). Among 13 372 infants (median [IQR] gestational age, 25.4 [24.4-26.1] weeks; 6864 [51%] boys), LOM was diagnosed in 167 (1%); LOS without LOM in 4564 (34%); and neither LOS nor LOM in 8641 (65%). The observed incidence of LOM decreased from 2% (95% CI, 1%-3%) in 2003 to 0.4% (95% CI, 0.7%-1.0%) in 2017 (P < .001). LP performance in LOS evaluations decreased from 36% (95% CI, 33%-40%) in 2011 to 24% (95% CI, 21%-27%) in 2017 (P < .001). Among infants with culture-confirmed LOS, LP performance decreased from 58% (95% CI, 51%-65%) to 45% (95% CI, 38%-51%; P = .008). LP performance varied by center among all LOS evaluations (10%-59%, P < .001) and among those with culture-confirmed LOS (23%-79%, P < .001). LOM occurred in the absence of concurrent LOS in 27 of 167 cases (16%). The most common LOM isolates were coagulase-negative Staphylococcus (98 [59%]), Candida albicans (38 [23%]), and Escherichia coli (27 [16%]). Death or NDI occurred in 22 of 46 children (48%) with LOM due to coagulase-negative Staphylococcus, 43 of 67 (64%) due to all other bacterial pathogens, and 26 of 33 (79%) due to fungal pathogens. The adjusted relative risk of death or NDI was increased among children with LOM (aOR, 1.53; 95% CI, 1.04-2.25) and among those with LOS without LOM (aOR, 1.41; 95% CI, 1.29-1.54) compared with children with neither infection. In this cohort study, LP was performed with decreasing frequency, and the observed incidence of LOM also decreased. Both LOM and LOS were associated with increased risk of death or NDI; risk varied by LOM pathogen. The full association of LOM with outcomes of children born extremely preterm may be underestimated by current diagnostic practices.

Impact of treatment-duration-ratio of traditional Chinese medicine on survival period of primary liver cancer —A real-world study

IntroductionIn China, traditional Chinese medicine (TCM) is regarded as an effective treatment for primary liver cancer (PLC). The present study analyzed the effect of TCM on the survival period of patients with PLC by analyzing the relationship between the treatment-duration-ratio of traditional Chinese medicine (C-TDR, (traditional Chinese medicine treatment duration)/(Overall treatment duration) × 100%) and the survival time of 1002 patients with PLC. MethodsIn this study, 1002 patients with PLC admitted to TCM Oncology Department of Changhai Hospital from January, 2015 to December, 2019 were enrolled. The univariate and multivariate Cox regression equation, propensity score matching (PSM) were performed to identify independent prognostic factors for survival outcomes of PLC patients at different stages and estimate the influence of C-TDR on survival time. ResultsCox regression analysis indicated that C-TDR was an independent prognostic factor for survival outcome (P＜0.05) and a corresponding reduction of relative risk of death of 75.67% (relative risk (RR) = 0.2433; 95%Confedential Interval (CI) = 0.1747–0.3388). Similarly, it is also an independent prognostic factor for patients outcome of each stage (P＜0.05). The 251 patients of BCLC-A reduced 96.09% risk of mortality (RR = 0.0391; 95%CI = 0.0151–0.1012). The 396 BCLC-B patients decreased risk of death of 81.24% (RR = 0.1876, 95%CI = 0.1112–0.3163). Moreover, 355 patients of stage C demonstrated a 51.36% lower risk of death (RR = 1.0016, 95%CI = 0.9885–1.0149). Significant differences were found in the median overall survival (OS) both higher and lower C-TDR of all patients. Even after PSM, the overall survival of two groups were significantly improved following each stage. ConclusionEarlier administration of traditional Chinese medicine can reduce the risk of mortality and prolong survival in patients with liver cancer.

Influence of type 2 sodium-glucose co-transporter inhibitors (dapagliflozin) on the indicators of total mortality in patients with type 2 diabetes (CARDIA-MOS study, Moscow)

BACKGROUND: The widespread use in clinical practice of drugs with cardio- and nephroprotective properties, in particular, sodium-glucose cotransporter type 2 inhibitors (SGLT2i), is based on the results of large-scale international randomized trials. Meanwhile, there are no data demonstrating the possibility of the influence of these drugs on mortality rates in real clinical practice in Russian patients. To study this issue, a CARDIA-MOS study was conducted on a population of patients with type 2 diabetes (T2DM) in Moscow.AIM: To study the effect of SGLT2i on the total mortality of patients with T2DM in Moscow.MATERIALS AND METHODS: To assess the frequency of different outcomes, two samples of patients were formed according to predetermined criteria: 1) patients who started therapy with SGLT2i (dapagliflozin) in 2017; 2) a control group of patients corresponding to the main group in terms of key indicators: age, duration of T2DM, presence of cardiovascular diseases, use of insulin therapy, HbA1c level.RESULTS: Firstly, an analysis of the data of 499 patients who started treatment with dapagliflozin in 2017, as well as 499 patients in the control group (n = 998) was made. The baseline characteristics of the patients were generally comparable. Pre-study SBP and HbA1c were worse in the dapagliflozin group. The use of dapagliflozin was associated with a 39% reduction in the relative risk of death from all causes (RR 0.614, 95% CI 0.417–0.903, p = 0.013), led to a decrease in HbA1c levels by 0.8% (from 8.5 to 7.7%, p&lt;0.001) for 48 months. observations. The safety profile of dapagliflozin was comparable to that of the control groupCONCLUSION: The use of dapagliflozin in the treatment of patients with T2DM can reduce overall mortality and improve glycemic control.

Impact of fluvoxamine on outpatient treatment of COVID-19 in Honduras in a prospective observational real-world study.

Background: The COVID-19 pandemic has impacted millions of lives globally. While COVID-19 did not discriminate against developed or developing nations, it has been a significant challenge for third world countries like Honduras to have widespread availability of advanced therapies. The concept of early treatment was almost unheard of when early outpatient treatments utilizing repurposed drugs in Latin American countries began showing promising results. One such drug is fluvoxamine, which has shown tremendous potential in two major studies. As a direct result, fluvoxamine was added to the standard of care in a major medical center outpatient COVID-19 clinic. Methods: This is a prospective observational study performed at the Hospital Centro Médico Sampedrano (CEMESA) in San Pedro Sula, Cortes, Honduras in the COVID-19 outpatient clinic. All patients were at least 15years of age who had presented with mild or moderate signs and symptoms of COVID-19, and who also had a documented positive SARS-CoV-2 antigen or Reverse Transcription Polymerase Chain Reaction (RT-PCR) were included in the study. These patients then were all prescribed fluvoxamine. The cohort of patients who decided to take fluvoxamine were compared for primary endpoints of mortality and hospitalization risk to the cohort who did not take fluvoxamine. Patients were then monitored for 30days with the first follow up at 7days and the second follow up at 10-14days of symptom onset. Categorical variables were compared by Pearson Chi-square test. The Relative risk was calculated using regression models. Continuous variables were compared by t-test and Wilcoxon rank-sum tests. Results: Out of total 657 COVID-19 cases, 594 patients took fluvoxamine and 63 did not take fluvoxamine. A total of five patients (0.76 percent) died, with only one death occurring in the fluvoxamine group. Patients who received fluvoxamine had a significantly lower relative risk of mortality (RR 0.06, p 0.011, 95% CI 0.007-0.516). There was a lower relative risk of hospitalization in the patients who in the fluvoxamine group. (-10 vs. 30 hospitalizations, RR 0.49, p = 0.035, 95% CI 0.26-0.95). There was 73 percent reduction in relative risk of requiring oxygen in the fluvoxamine group (RR 0.27, p < 0.001, 95% CI 0.14-0.54 Mean lymphocytes count on the first follow-up visit was significantly higher in the fluvoxamine group (1.72 vs. 1.38, Δ 0.33, p 0.007, CI 0.09-0.58). Conclusion: The results of our study suggest that fluvoxamine lowers the relative risk of death, hospitalization, and oxygen requirement in COVID 19 patients.

A joint Bayesian spatiotemporal risk prediction model of COVID-19 incidence, IC admission, and death with application to Sweden

The three closely related COVID-19 outcomes of incidence, intensive care (IC) admission and death, are commonly modelled separately leading to biased estimation of the parameters and relatively poor forecasts. This paper presents a joint spatiotemporal model of the three outcomes based on weekly data that is used for risk prediction and identification of hotspots. The paper applies a pure spatiotemporal model consisting of structured and unstructured spatial and temporal effects and their interaction capturing the effects of the unobserved covariates. The pure spatiotemporal model limits the data requirements to the three outcomes and the population at risk per spatiotemporal unit. The empirical study for the 21 Swedish regions for the period 1 January 2020–4 May 2021 confirms that the joint model predictions outperform the separate model predictions. The fifteen-week-ahead spatiotemporal forecasts (5 May–11 August 2021) show a significant decline in the relative risk of COVID-19 incidence, IC admission, death and number of hotspots.

Expression of c-MET in Estrogen Receptor Positive and HER2 Negative Resected Breast Cancer Correlated with a Poor Prognosis.

Introduction: The mesenchymal-epithelial transition factor (c-MET) receptor is overexpressed in about 14−54% of invasive breast cancers, but its prognostic value in clinical practice is still unclear. Methods: In order to investigate the relationship between c-MET expression levels and prognosis, we retrospectively reviewed the clinical features and outcomes of 105 women with estrogen receptor positive HER2 negative (ER+/HER2-) resected breast cancer. We used the Kaplan Meier method to estimate Disease Free Survival (DFS) and Breast Cancer Specific Survival (BCSS) in the subgroups of patients with high (≥50%) and low (<50%) c-MET expression. Univariate and multivariate Cox proportional regression models were performed to assess the prognostic impact of clinicopathological parameters for DFS an BCSS. Results: High c-MET values significantly correlated with tumor size, high Ki67 and low (<20%) progesterone receptor expression. At a median follow up of 60 months, patients with high c-MET tumor had significantly worse (p = 0.00026) and BCSS (p = 0.0013). Univariate analysis showed a significant association between large tumor size, elevated Ki67, c-MET values and increased risk of recurrence or death. The multivariate COX regression model showed that tumor size and high c-MET expression were independent predictors of DFS (p = 0.019 and p = 0.022). Moreover, large tumor size was associated with significantly higher risk of cancer related death at multivariate analysis (p = 0.017), while a trend towards a poorer survival was registered in the high c-MET levels cohort (p = 0.084). Conclusions: In our series, high c-MET expression correlated with poor survival outcomes. Further studies are warranted to validate the clinical relevance and applicability of c-MET as a prognostic factor in ER+/HER2- early BC.

Telomeres in clinical diabetes research – Moving towards precision medicine in diabetes care?

The early prediction of health outcomes for people with diabetes mellitus is desirable, as are adjunct therapies to reduce the related chronic complications and risk of premature death. The length of telomeres, protective caps on chromosome ends, is influenced by genetic and acquired factors, and shorter telomeres have been associated with and predictive of adverse cardiometabolic outcomes. Many studies have shown associations between telomere length in white blood cells (WBC) and diabetes per se and its chronic complications, and some studies show that telomeres do not always progressively shorten in people with diabetes. With the pandemic of diabetes and taking into consideration the calculations of residual risk using existent risk equations, additional tests to stratify subject risk are desirable. In this evolving era of precision medicine for people with diabetes, this ‘global biomarker’ of WBC telomere length may be useful to help predict health outcomes, to monitor health status, and may be a therapeutic target. We comment on the field of telomere investigations in diabetes, including recommending areas for further clinical research.

Comparative Efficacy of Targeted Therapies in Old Unfit Intermediate to High-Risk Patients with Acute Myeloid Leukemia: A Meta-Analysis of Comparative Studies

Introduction: Acute myeloid leukemia (AML) commonly affects the elderly with a median age of 67 years at diagnosis. Elderly AML is associated with high risk factors and adverse cytogenetics contributing to its worse outcomes. Moreover, older patients with AML respond poorly to intensive induction chemotherapy due pre-existing comorbidities. Novel therapies that include Bcl-2 inhibitors (Bcl-2i) and hypomethylating agents (HMA) have been used to treat AML in this patient population with varying degrees of response and success. Often, combination therapy with Bcl-2i and HMA has been used as frontline therapy for older patients or younger unfit patients who are not candidates for intensive chemotherapy. Currently, there are no randomized studies comparing various HMA, Bcl-2i, IDH-targeting agents, and their combinations. We performed a set of meta-analyses to evaluate relative efficacy of these various regimens in the treatment of AML in an old unfit intermediate to high-risk patient population. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of English language; newly diagnosed or relapsed/refractory (R/R) AML; AML in elderly, unfit, intermediate to high-risk patients; comparative studies involving Azacitidine (A), Decitabine (D), Venetoclax (V), Enasidenib (E), and intensive chemotherapy (IC); and comparative studies reporting death rates over 2 year-period. Relative risk (RR) of death was calculated for each regimen. For comparative efficacy of different therapeutic regimens, a frequentists network meta-analysis was conducted using netmeta package and random effects model. For molecular alteration % response across various studies, a proportional meta-analysis was conducted. The pooled proportion with 95% CI was given both for the fixed effects model and the random effects model. Results: Five studies comprising 1,109 participants were included. The RR of death was lowest in A+V<D+V<E+A<A<IC in increasing order. This pattern persisted when the data was analyzed by RR of death at 1, 1.5, and 2 years. While A+V RR of death was the lowest at 1.5 years compared to the rest of the treatment regimens, theirs did not seem to vary much at the different time points. A+V and D+V had a significantly superior RR of death compared to IC, whereas A+V demonstrated also superior RR of death over A. The network meta-analysis ranked A+V as the most favorable regimen for newly diagnosed or R/R AML in an unfit, intermediate to high-risk patients followed by D+V, E+A, A, and IC in a decreasing order. We then analyzed the % CR/CRi rates of A+V across different AML molecular alternations. Those with CR/CRi rates <30%: KRAS, CBL, U2AF1. Alterations with CR/CRi rates 30-49%: JAK2, ETV6, GATA2, ZRSR2, ASXL1, CEBPA, SRSF2, STAG2, WT1. Those with CR/CRi rates of 50-70%: BCOR, BCORL, NF1, TP53, FLT3ITD, TET2, NRAS, DNMT3A, FLT3TKD, PTPN11, RUNX1, SF3B1, IDH2, EZH2. Lastly alterations with CR/CRi rates > 70%: IDH1, NPM1. Conclusions: This network meta-analysis is the first to compare and rank AML targeted therapies in patients with newly diagnosed or R/R AML who are intermediate to high-risk and unfit. It indicates that A+V has better RR of death than A or IC and was ranked as the preferred combination. It also demonstrates that A+V has wide range of activity with demonstrable CR/CRi across various AML molecular alterations.

Chronic-Phase Chronic Myeloid Leukemia Times to Death By Disease Support Tyrosine Kinase Inhibitor Dose Reductions When BCR::ABL1 Level Is

Tyrosine kinase inhibitors (TKIs) are commonly believed to provide almost-normal lifespans to patients with chronic-phase (CP) chronic myeloid leukemia (CML). This is, however, not supported by Surveillance, Epidemiology, and End Results (SEER) mortalities >10 years after diagnoses that reveal a CP-CML relative risk (RR) of death of 2.14 (95% confidence interval [CI], 1.97-2.32); normal lifespans yield RR = 1.00, and by 10 years after diagnoses, most CML patients still alive were in CP at diagnosis, dates of which were between 2001 and 2009. This CP-CML RR estimate of 2.14 is comparable to those of Hodgkin's lymphoma (2.08; 95% CI, 1.95-2.22) and acute myeloid leukemia (2.22; 95% CI, 1.99-2.47) and higher than those of non-Hodgkin's lymphoma (1.62; 95% CI, 1.59-1.65) and chronic lymphocytic leukemia (1.84; 95% CI, 1.79-1.9). Thus, CP-CML is not functionally cured. In contrast, the RRs of hairy cell leukemia (1.14; 95% CI, 0.98-1.31) and acute promyelocytic leukemia (1.15; 95% CI, 0.87-1.49) are consistent with these leukemias being functionally cured. Of excess CP-CML deaths, roughly two thirds were by disease. These excess deaths by disease may be due in part to prolonged dose interruptions in response to treatment-related toxicities or to reduce financial burdens (ie, absence of TKI therapy). Frequencies of such events, and thus deaths by disease, could be decreased by reducing TKI doses moderately as cancer loads fall low enough to pose negligible progression risks. We present CML-intrinsic, TKI-agnostic support for reducing TKI doses when BCR::ABL1IS is <1% and decreasing. Times from diagnosis to death for 2732 SEER patients with CML diagnosed between 1975 and 1985 (before the availability of TKIs) informed a Markov model of CP → accelerated phase → blast crisis → death that assumed CML-saturated marrows in the absence of disease-modifying therapies during this time. The probabilities of transitioning from each phase to the next were fitted to the excess absolute risk of death (compared with the general US population) as a function of years after diagnosis (Panel A). To predict TKI effects on the probability of death by disease, the chronic-to-accelerated phase transition rate was assumed to be proportional to TKI-induced reductions in CML load fraction L, due to the reduced number of leukemic cells susceptible to a transforming mutation. Reducing L by a factor of 10 (from 1 to 0.1) increased the amount of time needed to reach a 5% probability of death by disease from 1 to 3 years. Lowering L by an additional factor of 10 (to 0.01 [1%]) increased the expected number of years to 16 (ie, ~5-fold). Finally, a third reduction of L by a factor of 10 (to 0.001 [0.1%]) yielded nearly an additional 10-fold increase in the time needed to reach a 5% probability of death by disease, from 16 to 145 years (Panel B). Gains in relative delay in 5% probability of death by disease divided by relative decrease in L were maximal at L = 0.015, which can be argued to correspond to BCR::ABLIS = 0.75% = ~1%, which appears to be a point of departure in Panel B. Based on data that predates TKIs, our analysis suggests that there is a strong need to lower disease burdens (BCR::ABLIS) below 1% and essentially no need to lower them below 0.1%. Thus, while it is important to use drug dosing that maintains responses at 1% or lower, if BCR::ABLIS is <1% and decreasing, dose reductions should be considered. Such reductions may prevent deaths associated with mismanagement of drug directly and deaths by disease indirectly, as reducing doses prospectively may avoid toxicities that may otherwise result in prolonged interruptions that cause to rise enough to cause death by disease. These dose reduction benefits should be included in patient-physician discussions of pursuing lower BCR::ABLIS levels in hopes of achieving a treatment-free remission versus pursuing lower doses to mitigate toxicity risks. Envisioned here is a future in which personalized patient safety parameters are weighed against personalized predictions of BCR::ABLIS response dynamics that, through computer simulations incorporating our Markov model, project to risks of progression and death by disease. Decision support based on such models may help patients and physicians balance drug versus disease risks. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal