Disease-associated Mortality Research Articles

Single-cell transcriptome analysis identifies subclusters and signature with N-glycosylation in endometrial cancer.

Endometrial cancer (EC) is a prevalent gynecologic cancer, with worldwide increasing incidence and disease-associated mortality. N-glycosylation, a critical post-translational modification, has been implicated in cancer progression and immune response modulation. We aimed to elucidate the role of N-glycosylation-related genes on EC cell heterogeneity, prognosis, and immunotherapy response. Data from single-cell RNA sequencing (scRNA) of five patients with EC were acquired from the Gene Expression Omnibus (GEO) database. Nonnegative matrix factorization (NMF) was used to identify cell subtypes related to N-glycosylation from a scRNA matrix. Subsequently, a consensus prognostic signature by integrating 101 combinations of 10 machine learning algorithms. The response to immunotherapy in EC was further examined by multiple algorithms. Our findings identified 11,020 differentially expressed genes (DEGs), of which 34 N-glycosylation-related DEGs were remarkably associated with overall survival (OS) in EC. Single-cell RNA sequencing analysis revealed 30,233 cells divided into eight clusters, with T cells and epithelial cells showing distinct functional characteristics. NMF clustering further classified malignant cells into four subtypes: N-glycosylation-C0, Glycosphingolipid-C1, O-GalNAc-C2, and Elongation-C3. The O-GalNAc-C2 subtype exhibited the highest metabolic pathway activity and activation of transcription factors SOX4, JUND, and FOS. Additionally, cell-cell interaction networks highlighted the MK signaling pathway as a critical mediator of intercellular communication. An integrated machine learning framework generated a prognostic model comprising eight DEGs (LAMC2, KRT7, IL32, KRT18, SERPINA1, PGR, AKAP12, EDN2), achieving an average C-index of 0.712 in training and validation cohorts. A low-risk score implies more significant immune cell infiltration and better response to immunotherapy. Our study underscores the role of N-glycosylation-related genes in EC prognosis and immunotherapy response prediction, and may provide a basis for the development of targeted therapies and personalized treatment strategies.

Cytokine priming enhances the antifibrotic effects of human adipose derived mesenchymal stromal cells conditioned medium

BackgroundFibrosis is a pathological scarring process characterized by persistent myofibroblast activation with excessive accumulation of extracellular matrix (ECM). Fibrotic disorders represent an increasing burden of disease-associated morbidity and mortality worldwide for which there are limited therapeutic options. Reversing fibrosis requires the elimination of myofibroblasts, remodeling of the ECM, and regeneration of functional tissue. Multipotent mesenchymal stromal cells (MSC) have antifibrotic properties mediated by secreted factors present in their conditioned medium (MSC-CM). However, there are no standardized in vitro assays to predict the antifibrotic effects of human MSC. As a result, we lack evidence on the effect of cytokine priming on MSC’s antifibrotic effects. We hypothesize that the MSC-CM promotes fibrosis resolution in vitro and that this effect is enhanced following MSC cytokine priming.MethodsWe compared the antifibrotic effects of resting versus interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α) primed MSC-CM in four in vitro assays: prevention of fibroblast activation, myofibroblasts deactivation, ECM degradation and fibrosis resolution in lung explant cultures. Furthermore, we performed transcriptomic analysis of myofibroblasts treated or not with resting or primed MSC-CM and proteomic characterization of resting and primed MSC-CM.ResultsWe isolated MSC from adipose tissue of 8 donors, generated MSC-CM and tested each MSC-CM independently. We report that MSC-CM treatment prevented TGF-β induced fibroblast activation to a similar extent as nintedanib but, in contrast to nintedanib, MSC-CM reduced fibrogenic myofibroblasts (i.e. transcriptomic upregulation of apoptosis, senescence, and inflammatory pathways). These effects were larger when primed rather than resting MSC-CM were used. Priming increased the ability of MSC-CM to remodel the ECM, reducing its content of collagen I and fibronectin, and reduced the fibrotic load in TGF-β treated lung explant cultures. Priming increased the following antifibrotic proteins in MSC-CM: DKK1, MMP-1, MMP-3, follistatin and cathepsin S. Inhibition of DKK1 reduced the antifibrotic effects of MSC-CM.ConclusionsIn vitro, MSC-CM promote fibrosis resolution, an effect enhanced following MSC cytokine priming. Specifically, MSC-CM reduces fibrogenic myofibroblasts through apoptosis, senescence, and by enhancing ECM degradation. Future studies will establish the in vivo relevance of MSC priming to fibrosis resolution.

Selective Activation of G Protein-coupled Estrogen Receptor 1 Attenuates Atherosclerosis.

Atherosclerosis remains a leading contributor to cardiovascular disease-associated morbidity and mortality. Interestingly, atherosclerosis-associated mortality rate is higher in men than women. This suggested a protective role for estrogen in the cardiovasculature. These effects of estrogen were initially thought to be mediated by the classic estrogen receptors, ER alpha, and beta. However, genetic knockdown of these receptors did not abolish estrogen's vasculoprotective effects suggesting that the other membranous Gprotein coupled estrogen receptor, GPER1, maybe the actual mediator. Indeed, in addition to its role in vasotone regulation, this GPER1 appears to play important roles in regulating vascular smooth cell phenotype, a critical player in the onset of atherosclerosis. Moreover, GPER1-selective agonists appear to reduce LDL levels by promoting the expression of LDL receptors as well as potentiating LDL re-uptake in liver cells. Further evidence also show that GPER1 can downregulate Proprotein Convertase Subtilisin/ Kexin type 9, leading to suppression of LDL receptor breakdown. Here, we review how selective activation of GPER1 might prevent or suppress atherosclerosis, with less side effects than those of the non-selective estrogen.

Primary Cutaneous NUT Carcinoma: Clinicopathologic and Genetic Study of 4 Cases.

WHO Classification of Skin Tumors, fifth edition (2023) has newly described primary cutaneous NUT carcinoma; however, information on this cancer type remains scarce. Herein, we performed clinicopathologic and genetic analyses of 4 cases. Four elderly women (median age 77y, range: 68 to 82y) were included. The median tumor size was 12.5 (10 to 40mm). Tumors were located on the scalp, temple, thigh, and palm. Two (50%) patients presented with regional lymph node metastases. Neither distant metastasis nor mortality was observed during patient follow-up of 10.5 (3 to 15) months. Sanger, panel DNA and whole-exome RNA sequencing revealed BRD3::NUTM1 (n=2) and BRD4::NUTM1 (n=2) fusions. Histology of BRD3 -rearranged tumors revealed an epidermal connection, relatively small tumor nests, and ductal or intracytoplasmic luminal formation, whereas that of BRD4 -rearranged tumors revealed large solid nests comprising discohesive tumor cells. NUT, cytokeratins, p63, EMA, TRPS1, c-MYB, CD56, and INSM1 were immunoexpressed to varying degrees in all (100%) tumors. Furthermore, diffuse SOX10 expression was common (3/4, 75%). The literature review of five previously described cases revealed women predominance, no recurrence, frequent BRD3::NUTM1 fusions, and histology of ductoglandular structures. Our study findings and literature suggest elderly women predominance, relatively frequent BRD3::NUTM1 fusions, histopathologic ductoglandular differentiation, absence of abrupt keratinisation, and a characteristic immunoprofile in primary cutaneous NUT carcinoma, unlike in that of other organ. No distant metastasis or disease-associated mortality was seen in all cases with limited follow-up.

Long-term exposure to air pollution and chronic kidney disease-associated mortality–Results from the pooled cohort of the European multicentre ELAPSE-study

Despite the known link between air pollution and cause-specific mortality, its relation to chronic kidney disease (CKD)-associated mortality is understudied. Therefore, we investigated the association between long-term exposure to air pollution and CKD-related mortality in a large multicentre population-based European cohort.Cohort data were linked to local mortality registry data. CKD-death was defined as ICD10 codes N18–N19 or corresponding ICD9 codes. Mean annual exposure at participant's home address was determined with fine spatial resolution exposure models for nitrogen dioxide (NO2), black carbon (BC), ozone (O3), particulate matter ≤2.5 μm (PM2.5) and several elemental constituents of PM2.5. Cox regression models were adjusted for age, sex, cohort, calendar year of recruitment, smoking status, marital status, employment status and neighbourhood mean income.Over a mean follow-up time of 20.4 years, 313 of 289,564 persons died from CKD. Associations were positive for PM2.5 (hazard ratio (HR) with 95% confidence interval (CI) of 1.31 (1.03–1.66) per 5 μg/m3, BC (1.26 (1.03–1.53) per 0.5 × 10− 5/m), NO2 (1.13 (0.93–1.38) per 10 μg/m3) and inverse for O3 (0.71 (0.54–0.93) per 10 μg/m3). Results were robust to further covariate adjustment. Exclusion of the largest sub-cohort contributing 226 cases, led to null associations. Among the elemental constituents, Cu, Fe, K, Ni, S and Zn, representing different sources including traffic, biomass and oil burning and secondary pollutants, were associated with CKD-related mortality.In conclusion, our results suggest an association between air pollution from different sources and CKD-related mortality.

A Psychometric Study of the Arabic Version of the "Searching for Hardships and Obstacles to Shots (SHOT)" Instrument for Use in Saudi Arabia.

Vaccines are considered one of the top 10 public health achievements of the 20th century and the most cost-effective public health intervention to overcome diseases and disease-associated mortality. This study translated the "Searching for Hardships and Obstacles to Shots" (SHOT) instrument from English to Arabic and conducted a psychometric evaluation of the Arabic version to measure parental barriers to childhood immunization. The cross-sectional study utilized multistage cluster random sampling to recruit parents visiting 70 primary health centers in Jizan. Scale translation and cultural adaptation were used to translate the SHOT survey into Arabic. The survey revealed that the best-factor model was a one-factor solution for "barriers to child immunization." The first principal component explained the highest variance (56.22%), and subsequent components explained decreasing percentages of variance. The third principal component explained the decreased variance (4.61%), and subsequent components explained the decreasing percentages of variance. The overall reliability (determined by Cronbach's alpha) was 0.96. The strong internal consistency of the Arabic version of the SHOT instrument (as indicated by the high Cronbach's alpha coefficients) indicates that researchers and practitioners can confidently use this scale to measure parents' attitudes toward and perceptions of vaccinations. Furthermore, the study results will help policymakers develop programs or interventional initiatives to overcome these barriers.

The experience of traumatic events, psychological distress, and social support: links to COVID-19 vaccine hesitancy and trends with age in a group of older Australians

BackgroundVaccination is important to reduce disease-associated morbidity and mortality in an ageing global population. While older adults are more likely than younger adults to accept vaccines, some remain hesitant. We sought to understand how traumatic events, psychological distress and social support contribute to older adults’ intention to receive a COVID-19 vaccine and whether these experiences change with age.MethodsWe analysed survey data collected as part of the Sax Institute’s 45 and Up Study in a population of Australian adults aged 60 years and over. Data were derived from the COVID Insights study; a series of supplementary surveys about how participants experienced the COVID-19 pandemic.ResultsHigher intention to receive a COVID-19 vaccine was associated with greater social support (adjusted odds ratio (aOR):1.08; 95%CI:1.06–1.11; p <.001) while lower intention was associated with personally experiencing a serious illness, injury or assault in the last 12 months (aOR:0.79; 95% CI:0.64–0.98; p =.03). Social support and the experience of traumatic events increased significantly with age, while psychological distress decreased.ConclusionsThere may be factors beyond disease-associated risks that play a role in vaccine acceptance with age. Older Australians on the younger end of the age spectrum may have specific needs to address their hesitancy that may be overlooked.

Chronic Obstructive Pulmonary Disease-Associated Mortality - China, 2014-2021.

China faces a growing burden of chronic obstructive pulmonary disease (COPD). Previous mortality estimations were primarily based on the underlying cause of death. This study analyzed COPD-associated death and its comorbidities using all COPD cases listed on the chain of events on death certificates. A retrospective analysis of the National Mortality Surveillance System (NMSS) was conducted to estimate COPD-associated mortality from 2014 to 2021. Age-standardized mortality rates (ASMRs) were calculated stratified by sex, region, and residence. Joinpoint regression was used to estimate the average annual percentage change (AAPC) during the study period. From 2014 to 2021, the ASMR of COPD decreased from 91.85 to 45.90 per 100,000 population. Significant but uneven decreases in COPD mortality were observed across gender [females: AAPC: -11.2%, 95% confidence interval (CI): -11.9 to -10.4%; males: AAPC: -8.0%, 95% CI: -9.2 to -6.8%], regions (eastern: AAPC: -10.7%, 95% CI: -11.5 to -9.9%; central: AAPC: -9.9%, 95% CI: -10.9 to -8.9%; western: AAPC: -7.7%, 95% CI: -10.6 to -4.7%), and residential areas (urban: AAPC: -10.9%, 95% CI: -12.3 to -9.5%; rural: AAPC: -8.3%, 95% CI: -9.1 to -7.4%). Other than COPD, cardiovascular diseases and respiratory conditions were the major underlying causes of death in COPD-associated mortality. COPD is a significant comorbidity of other disorders in China. Although COPD-associated mortality substantially decreased from 2014 to 2021, the burden remained high in underdeveloped regions.

Diversity and disparity in the treatment and care of sarcoidosis.

Clinical presentation and outcomes in patients with sarcoidosis vary by race, gender, ethnicity, and geolocation. African Americans and female individuals have the highest incidence of disease. They are also more likely to present with advanced and more severe forms of disease, and to die from sarcoidosis. African American female individuals have the highest disease-associated mortality, yet this varies by geolocation. The diverse presentation and outcomes in sarcoidosis have often been attributed to genetics and biology, yet this may not be entirely so. Several studies have shown that African Americans and female individuals are more likely to earn less and be more socioeconomically disadvantaged in society. Patients with sarcoidosis earning in the lowest income strata presented with the most severe disease and reported more barriers to care. It is plausible that the racial, gender, and geospatial differences in sarcoidosis are more reflective of healthcare disparities than genetics or biology alone. Preventable differences in the burden of disease and in the opportunities to achieve optimal health outcomes that are differentially experienced by groups of people disadvantaged by race, gender, ethnicity, or socioeconomic background should be identified and addressed.

Assessing hypertension and diabetes knowledge, attitudes and practices among residents in Akatsi South District, Ghana using the KAP questionnaire.

Low awareness of hypertension and diabetes is a public health concern in Ghana. Assessing the general population's behaviour via knowledge, attitude, and practice (KAP) will be invaluable in these diseases, where prevention and control need a lifelong commitment to a healthy lifestyle. Hence, our goal was to assess the behaviour of Akatsi South residents towards the diseases to assist health providers in implementing tailored intervention programs. This was a population-based cross-sectional study with 150 adults (18-70 years) from November to December 2021. A semi-structured questionnaire with face-to-face interviews was used to obtain data. All variables in the model had descriptive statistics. The Chi-square (χ2) test was used to examine correlations between variables, and a value of p < 0.05 was considered statistically significant. The factors associated with checking blood sugar levels and blood pressure were determined using binary logistic regression. The respondents' mean age and BMI were 32.40 years (± 12.07) and 24.98 kg/m2 (± 2.36), respectively. Only 46.67% of the respondents frequently monitor their blood pressure and 17.33% their blood glucose (at least once a year). Less than half of those surveyed had a good knowledge of hypertension (42.7%) and diabetes (32.0%), whereas nearly 3/4 had poor attitudes regarding both conditions. A binary logistic regression analysis revealed that having a good attitude toward hypertension (exp B = 2.479, p = 0.036) and diabetes (exp B = 4.547, p = 0.009) were the participants' strongest predictor of blood pressure and sugar level checks. However, being overweight (exp B = 0.046, p = 0.002,) or obese (exp B = 0.144, p = 0.034) negatively influenced the frequency with which our respondents checked their blood glucose levels. In the study, we found that the population generally has poor knowledge, which affects their behaviour (attitudes and practices) towards the diseases. To enable healthcare practitioners to reduce disease-associated mortality and morbidity in the future, frequent public health education and promotion about the conditions is critical to closing the knowledge gap.

Targeting Liver X Receptors for the Treatment of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) refers to a range of conditions in which excess lipids accumulate in the liver, possibly leading to serious hepatic manifestations such as steatohepatitis, fibrosis/cirrhosis and cancer. Despite its increasing prevalence and significant impact on liver disease-associated mortality worldwide, no medication has been approved for the treatment of NAFLD yet. Liver X receptors α/β (LXRα and LXRβ) are lipid-activated nuclear receptors that serve as master regulators of lipid homeostasis and play pivotal roles in controlling various metabolic processes, including lipid metabolism, inflammation and immune response. Of note, NAFLD progression is characterized by increased accumulation of triglycerides and cholesterol, hepatic de novo lipogenesis, mitochondrial dysfunction and augmented inflammation, all of which are highly attributed to dysregulated LXR signaling. Thus, targeting LXRs may provide promising strategies for the treatment of NAFLD. However, emerging evidence has revealed that modulating the activity of LXRs has various metabolic consequences, as the main functions of LXRs can distinctively vary in a cell type-dependent manner. Therefore, understanding how LXRs in the liver integrate various signaling pathways and regulate metabolic homeostasis from a cellular perspective using recent advances in research may provide new insights into therapeutic strategies for NAFLD and associated metabolic diseases.

5579775 OVERVIEW OF THE VOXELOTOR POST-APPROVAL CLINICAL RESEARCH PROGRAM

Background: Voxelotor, a sickle hemoglobin polymerization inhibitor, is approved in the United States for the treatment of sickle cell disease (SCD) in adults and pediatric patients 4 years of age and older, and in the European Union, United Arab Emirates, Oman, and Great Britain for adult and pediatric patients 12 years of age and older. Efficacy and safety data from the randomized, placebo-controlled HOPE trial demonstrated the effectiveness and durability of voxelotor in increasing hemoglobin (Hb) levels and reducing markers of hemolysis in adults and adolescents. Support for the use of voxelotor in children aged 4 to <12 years was provided by the open-label HOPE-KIDS 1 trial. Due to its mechanism of action, voxelotor has the potential to alter disease pathogenesis and mitigate disease-associated morbidity and mortality. Further research is needed to more clearly understand the role of voxelotor in preventing complications of SCD, reducing healthcare utilization, and improving quality of life. Aims: To establish a more thorough understanding of the impact of voxelotor on SCD, a wide-ranging post-approval clinical research program is underway and described herein. Methods: Eight GBT-sponsored post-approval studies of voxelotor are either currently active or have completed, with results pending. Two observational studies, 1 retrospective (RETRO) and 1 prospective (PROSPECT), are evaluating the effect of voxelotor in real-world settings. ActIVe is an interventional, open-label, single-group study evaluating the effect of voxelotor on daily physical activity and sleep quality, as measured by a wrist-worn device, in patients with SCD and chronic, moderate anemia. HOPE-KIDS 1 Part D is an open-label, multiple-dose trial evaluating the safety, tolerability, and pharmacokinetics of voxelotor in infants and young children with SCD. The 4 remaining studies are randomized, placebo-controlled studies: RESOLVE is evaluating the effects of voxelotor on the resolution of leg ulcers in patients with SCD; the Neurocognitive Function study is assessing the treatment effects of voxelotor on neurocognitive function, as assessed by the National Institutes of Health Toolbox Cognition Module of executive abilities in children and adolescents with SCD; the Cerebral Hemodynamics study is evaluating the impact of voxelotor treatment on cerebral blood flow in adults and adolescents with SCD; and HOPE-KIDS 2 is a post-approval confirmatory study evaluating the effect of voxelotor on transcranial Doppler flow velocity in pediatric patients with SCD. An overview of patient populations, study arms, and key endpoints for each of the voxelotor post-approval studies is provided in the Table. Results: RETRO recently completed data collection, and analyses are currently underway. All other trials are ongoing, with results expected to be released in late 2022 through 2029. Summary/Conclusion: The current post-approval clinical research plan for voxelotor represents a methodologically diverse set of studies, mixing real-world evidence with randomized, controlled trials. The data generated from these studies are expected to further guide clinicians and patients regarding the clinical use of voxelotor for people with SCD.

An update on the molecular mechanism and pharmacological interventions for Ischemia-reperfusion injury by regulating AMPK/mTOR signaling pathway in autophagy

AMP-activated protein kinase (5’-adenosine monophosphate-activated protein kinase, AMPK)/mammalian target of rapamycin (mTOR) is an important signaling pathway maintaining normal cell function and homeostasis in vivo. The AMPK/mTOR pathway regulates cellular proliferation, autophagy, and apoptosis. Ischemia-reperfusion injury (IRI) is secondary damage that frequently occurs clinically in various disease processes and treatments, and the exacerbated injury during tissue reperfusion increases disease-associated morbidity and mortality. IRI arises from multiple complex pathological mechanisms, among which cell autophagy is a focus of recent research and a new therapeutic target. The activation of AMPK/mTOR signaling in IRI can modulate cellular metabolism and regulate cell proliferation and immune cell differentiation by adjusting gene transcription and protein synthesis. Thus, the AMPK/mTOR signaling pathway has been intensively investigated in studies focused on IRI prevention and treatment. In recent years, AMPK/mTOR pathway-mediated autophagy has been found to play a crucial role in IRI treatment. This article aims to elaborate the action mechanisms of AMPK/mTOR signaling pathway activation in IRI and summarize the progress of AMPK/mTOR-mediated autophagy research in the field of IRI therapy.

Associations of serum uric acid levels with liver disease-related morbidity and mortality: A prospective cohort study of the UK Biobank.

The association of serum uric acid (SUA) levels with liver-related morbidity and mortality remains undetermined. Therefore, we aimed to explore the association of SUA levels with liver-related morbidity and mortality. The present cohort study included 459,619 adults from the UK Biobank. Multivariable Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of SUA levels with morbidity and mortality of overall liver disease. Mendelian randomization (MR) analyses were conducted to explore the underlying causality. A polygenic risk score was generated to assess whether there was a gene-exposure interaction. During a median follow-up of 12.6 years, 14,302 nonfatal and 609 fatal cases of overall liver disease were identified. Compared to individuals in the lowest quartile, the HRs (95% CI) of incident overall liver disease were 1.08 (1.02-1.14), 1.13 (1.07-1.20), and 1.44 (1.36-1.53) for individuals with SUA levels in quartiles 2, 3, and 4, respectively. Similarly, the HRs (95% CI) of liver disease-associated mortality were 1.09 (0.78-1.52), 1.55 (1.14-2.13), and 1.96 (1.42-2.69) for individuals with SUA levels in quartiles 2, 3, and 4, respectively. The MR results did not support the causal association of SUA levels with liver disease. In addition, there was a significant modification effect of the polygenic risk score on the association of SUA levels with incident overall liver disease (Pinteraction = 0.003). Higher SUA levels were significantly associated with an increased risk of overall liver disease morbidity and mortality.

Sex-biased infections scale to population impacts for an emerging wildlife disease.

Demographic factors are fundamental in shaping infectious disease dynamics. Aspects of populations that create structure, like age and sex, can affect patterns of transmission, infection intensity and population outcomes. However, studies rarely link these processes from individual to population-scale effects. Moreover, the mechanisms underlying demographic differences in disease are frequently unclear. Here, we explore sex-biased infections for a multi-host fungal disease of bats, white-nose syndrome, and link disease-associated mortality between sexes, the distortion of sex ratios and the potential mechanisms underlying sex differences in infection. We collected data on host traits, infection intensity and survival of five bat species at 42 sites across seven years. We found females were more infected than males for all five species. Females also had lower apparent survival over winter and accounted for a smaller proportion of populations over time. Notably, female-biased infections were evident by early hibernation and likely driven by sex-based differences in autumn mating behaviour. Male bats were more active during autumn which likely reduced replication of the cool-growing fungus. Higher disease impacts in female bats may have cascading effects on bat populations beyond the hibernation season by limiting recruitment and increasing the risk of Allee effects.

Genetics, Safety, Cost-Effectiveness, and Accessibility of Injectable Lipid-Lowering Agents: A Narrative Review.

Cardiovascular disease causes significant personal, financial, and societal burden and is a major cause of mortality and morbidity globally. Dyslipidemia has proven to be a major factor that contributes to its increased incidence; thus, since a long time, low-density lipoprotein cholesterol-lowering therapies have been employed to reduce coronary artery disease-associated mortality. The first-line therapy for hyperlipidemia and dyslipidemia is statins. Evidence showed that statins decrease the level of LDL-C resulting in a lower risk of CVD (20-25% for every decrease of 1 mmol/L). However, due to statin intolerance in some patients and despite using maximal doses, they have not been successful in lowering cardiovascular-associated mortality. Moreover, bococizumab was recently suspended due to its higher immunogenicity with time, resulting in less efficacy with long-term use. Alternatives to statins are PCSK9 inhibitors which are administered subcutaneously every two or four weeks. They are injectables with considerable lipid-lowering properties. This narrative review discusses their genetics, safety, tolerability, and cost-effectiveness. It also quantifies their benefit in certain subgroups by analyzing the findings from recent randomized clinical trials. Current data from phase 2 and 3 trials (ORION, ODYSSEY, and FOURIER) suggest a favorable profile for evolocumab, alirocumab, and inclisiran with minimal tolerable side effects and superior efficacy in statin-intolerant patients. Their cost-effectiveness has not yet been established clearly, but future outcomes seem promising.

Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension

BackgroundPulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension.MethodsWe conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro–B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension–Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive/Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit.ResultsA total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, −0.3 to 3.5) in the placebo group. The Hodges–Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive/Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure.ConclusionsIn patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.)

Preclinical or subclinical rheumatoid arthritis-associated interstitial lung disease: misleading terms with potentially deleterious consequences

Interstitial lung disease (ILD) is a leading cause of mortality in patients with rheumatic diseases, including rheumatoid arthritis. 1 Olson AL Swigris JJ Sprunger DB et al. Rheumatoid arthritis-interstitial lung disease-associated mortality. Am J Respir Crit Care Med. 2011; 183: 372-378 Crossref PubMed Scopus (299) Google Scholar The 5-year mortality rate is twice as high in patients with rheumatoid arthritis-associated ILD than in patients with rheumatoid arthritis without ILD. 2 Hyldgaard C Hilberg O Pedersen AB et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis. 2017; 76: 1700-1706 Crossref PubMed Scopus (159) Google Scholar Moreover, a report showed that mortality rates in patients with disease codes for rheumatoid arthritis-associated ILD remained unchanged from 2005–18, even though the overall rheumatoid arthritis mortality rate declined during this time period. 3 Jeganathan N Nguyen E Sathananthan M Rheumatoid arthritis and associated interstitial lung disease: mortality rates and trends. Ann Am Thorac Soc. 2021; 18: 1970-1977 Crossref PubMed Scopus (6) Google Scholar Despite the evidence that ILD contributes to premature death in rheumatoid arthritis, screening for ILD in patients with rheumatoid arthritis is not routinely performed in clinical practice and numerous questions remain regarding the management of rheumatoid arthritis-associated ILD. 4 Kelly C Emery P Dieudé P Current issues in rheumatoid arthritis-associated interstitial lung disease. Lancet Rheumatol. 2021; 3: e798-e807 Summary Full Text Full Text PDF Scopus (6) Google Scholar

Current Evidence-Based Systemic Therapy for Advanced and Recurrent Endometrial Cancer.

Endometrial cancer (EC) is the most common gynecologic malignancy, with worldwide increasing incidence and disease-associated mortality. Although most patients with EC are diagnosed with early-stage disease, systemic treatment options for patients with advanced or recurrent EC have historically been limited. EC-focused clinical trials and the ensuing therapeutic landscape have expanded since The Cancer Genome Atlas (TCGA) identified 4 distinct EC subgroups associated with differential survival. This endeavor revolutionized our understanding of the genomic characterization of EC as well as molecular drivers of this heterogeneous malignancy, leading to precision oncology approaches to therapeutics and advancement in treatment options. This review describes the current status of and recent advancements in therapeutic options for patients with advanced and recurrent EC. The NCCN Guidelines for Uterine Neoplasms provide detailed recommendations regarding the diagnosis, workup, and management of EC.

Worst pattern of invasion and other histopathological features in oral cancer as determinants of prognosis and survival rate: A retrospective cohort analysis.

Oral cavity squamous cell carcinoma (OCSCC) is a well-recognized malignancy of the head and neck. Studies on patients with early-stage oral cancer have shown that they develop locally recurring and/or regional lymph node metastasis, which results in disease-associated mortality. Thus, early-stage oral cancer does not always present good prognoses. The present study aimed to determine the efficacy of using worst pattern of invasion (WPOI) and other histopathological features, such as prognostic factors in OCSCC, and analyze the impact of resection margin status and histopathological prognostic indicators on local recurrence (LR) and overall survival (OS) in patients with OCSCC. A retrospective cohort study was conducted by reviewing the charts of 63 patients with OCSCC treated with primary surgery at King Abdulaziz University Hospital between 2012 and 2019. An author and an experienced pathologist reviewed pathology slides. Associations of histopathological factors, including differentiation, stage, lymphovascular invasion, extracapsular extension, perineural invasion (PNI), WPOI and surgical margins, with LR or disease-free survival (DFS) were evaluated. Univariate analysis identified WPOI and PNI, and multivariate analysis identified the WPOI as predictive factors for LR and DFS. Kaplan-Meier analysis identified the WPOI and PNI as predictive factors for OS and WPOI as a predictive factor for DFS. Therefore, it may be concluded that WPOI and PNI are significant independent prognostic factors for local tumor control and DFS in patients with OCSCC.