Search

Introduction: Growing interest centers on the association between circulating ketone bodies (KB) and cognitive function, notably in aging and neurodegenerative diseases. Methods: Associations of plasma KB with incident dementia and cognitive performances were examined among Multi‐Ethnic Study of Atherosclerosis (MESA) participants. KB were measured using plasma samples collected following an overnight fasting at Exam 1 (2000–02) and detailed cognitive testing at Exam 5 (2010–2012, N = 4392), Exam 6 (2016–2018, N = 1838), and in MESA‐MIND (2019–2021, N = 2060). Results: Over 16.7 years, a doubling of total KB was associated with a greater risk of incident dementia (hazard ratio [HR]: 1.14 [1.04–1.29]). Higher total KB was associated with worse cognitive performance in the Digit Span test at exam 5 [β: −0.30 (−0.47, −0.14)]. We also found that a higher KB was associated with greater functional impairment and a higher Quick Dementia Rating Scale (QDRS) score. Discussion: In a diverse, cardiovascular disease‐free population, elevated KB levels were associated with incident dementia and impaired cognitive performance in specific domains. Highlights: A study of ketone bodies (KB) and cognitive performance and incident dementia.Nuclear magnetic resonance (NMR) spectroscopy was used to measure plasma KB at baseline.Doubling of baseline total KB was associated with higher incident dementia.Higher KB was also associated with worse performance on a test of working memory. [ABSTRACT FROM AUTHOR]

Introduction: Undifferentiated round cell tumours (URCTs) are rare and less researched Ewing-like mesenchymal tumours that primarily affect bones and soft tissues. Therapeutic options for advanced URCT are limited. Pazopanib, a multi-tyrosine kinase and angiogenesis inhibitor, is currently used for managing advanced soft-tissue sarcoma. However, its efficacy in the treatment of URCT remains uncertain and has not been established. In this study, we have cultured and characterised a patient-derived URCT cell line to understand the in vitro growth properties and anti-cancer agent sensitivity. Materials and Methods: Primary cell culture was performed by mechanical and enzymatic dissociation of URCT tissue specimens to derive a cell line. Morphology, growth properties and immunological features characterised the cells. Further, the in vitro sensitivity for clinically used anti-cancer drugs was evaluated. Results: The URCT cell line was established from a high-grade round-cell tumour patient. The cells had mesenchymal morphology and showed cyclin B3 (CCNB3) positivity, which was confirmed in the tissue from the patient. The cells exhibited an anchorage-independent growth property and aggregated to form spheroids in a non-adherent in vitro system. Anti-cancer agents vincristine, doxorubicin, etoposide and pazopanib inhibited URCT cell proliferation. Pazopanib exhibited cytotoxic action in URCT cells, leading to cell death. Conclusions: This is an early report of cultured URCT cells expressing CCNB3, studied in vitro. The patient-derived model suggests the efficacy of pazopanib in URCT cells. The characterised line will be helpful to advance sarcoma studies. [ABSTRACT FROM AUTHOR]

Obesity continues to be a significant global health challenge, affecting over 800 million individuals worldwide. Traditional management strategies, including dietary, exercise, and behavioral interventions, often result in insufficient and unsustainable weight loss. Lifestyle modification remains the cornerstone of obesity management, providing the foundation for other strategies. While options such as bariatric surgery remain an effective intervention for severe obesity, it is associated with its own set of risks and is typically reserved for patients who have not achieved the desired results with pharmacotherapy and lifestyle interventions. Incretin hormone agonists represent a significant advancement in the pharmacotherapy of obesity, offering substantial weight reduction and cardiometabolic benefits. Agents like liraglutide, semaglutide, and tirzepatide supported by key clinical trials such as Satiety and Clinical Adipose Liraglutide Evidence (SCALE), Semaglutide Treatment Effect in People with Obesity (STEP) program trials, and Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT‐1) have demonstrated remarkable efficacy in promoting weight loss and improving metabolic outcomes. Additionally, novel therapies, including dual and triple incretin agonists, are under investigation and hold the potential for further advancements in obesity treatment. These novel therapies can be categorized by their mechanisms of action and route of administration into oral glucagon‐like peptide‐1 (GLP‐1) receptor agonists, triple agonists (targeting GLP‐1, glucose‐dependent insulinotropic polypeptide [GIP], and glucagon receptors), and glucagon receptor‐GLP‐1 receptor co‐agonists. Other innovative approaches include oral GIP‐GLP‐1 receptor co‐agonists, and the combination of long‐acting amylin receptor agonists with GLP‐1 receptor agonists. The ongoing development of incretin‐based therapies and the expanding availability of currently available agents are expected to enhance clinical outcomes further and reduce the burden of obesity‐related health complications. This review aims to discuss the mechanisms and efficacy of current and emerging incretin hormone agonists for obesity management. [ABSTRACT FROM AUTHOR]

The present work focuses on comparing the performance of novel cationic graft copolymer polyvinylpyrrolidone-graft-poly(acrylamide-co-diallyldimethylammonium chloride) (PVP-g-p(AM-co-DADMAC)) synthesized via microwave-assisted technique, with varying amounts of monomers acrylamide (AM) and diallyldimethylammonium chloride (DADMAC) as a flocculant for sugarcane juice. The intended grafting was supported by extensive characterization of the material by various physicochemical methods. As compared to only AM or DADMAC grafted onto PVP, grafted copolymer with highest DADMAC-to-AM ratio was found to be more effective in removing colloids from fresh unaltered cane juice. The mode of action of the synthesized flocculant was explained by synergistic bridging and charge neutralization mechanism. The best grade of PVP-g-p(AM-co-DADMAC) at an optimum dose of only four ppm (within US FDA approved limit) showed a good reduction in the zeta potential (− 7.8 to − 2.9 mV) of the juice along with the formation of large-size floc (618 nm) without affecting the percentage of natural sugar content (degree brix- °bx). [ABSTRACT FROM AUTHOR]

Advanced Non-Small Cell Lung Carcinoma (NSCLC) patients with ROS1 gene rearrangement have shown significant therapeutic responses to tyrosine kinase inhibitors approved by the US Food and Drug Administration, with approximately 40 fusion partners documented in the existing literature. Our report highlights a novel fusion partner of ROS1 that has demonstrated a conclusive response to the current standard of treatment. [ABSTRACT FROM AUTHOR]

Spindle epithelial tumor with thymus-like elements (SETTLE) is a rare malignant neoplasm of the thyroid gland which is believed to arise from intrathyroidal thymic tissue. It predominantly affects young adults and children presenting with a thyroid mass of variable duration and rarely occurs in adults. It has a high overall survival with a tendency for delayed metastasis. SETTLE is a biphasic lobulated tumor composed of spindle shaped cells along with glandular formations seen on histopathological examination. Despite its typical morphology it is commonly misdiagnosed on histopathology due to its rarity and overlapping morphology with other close mimics such as a carcinoma, synovial sarcoma and thymoma. Herein we report such a case occurring in a middle aged female presenting with a neck mass. She had an initial diagnosis of metastatic poorly differentiated squamous cell carcinoma possibly with an orophayngeal primary in view of co expression of CK, p40 and p16 on immunohistochemistry. The patient underwent surgical resection with modified neck dissection. On review at our hospital it was diagnosed as SETTLE and she remains disease free after a follow-up period of 1 year. Diligent histopathological examination espoused with a judicious panel of IHC markers in conjunction with clinicoradiological findings forms the mainstay of diagnosis. Diffuse and strong p16 immunoexpression has not been documented or evaluated in literature so far, and needs to be explored for its diagnostic utility in this rare entity. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) accounts for 2% of all cancer cases worldwide, and majority are sporadic. The latest World Health Organization (WHO) classification of renal cell tumors (fifth edition, 2022) has molecularly defined renal tumor entities, which includes fumarate hydratase (FH)–deficient RCC. FH‐deficient RCC is an aggressive carcinoma caused by pathogenic alterations in FH gene, seen in 15% of patients with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) syndrome. These tumors occur more frequently at a younger age and present at an advanced stage, carrying a dismal prognosis. We report a series of 10 cases of FH‐deficient RCC. The mean age was 49.8 years, and all cases presented in advanced stages (III and IV). Morphologically, the cases had varied architectural patterns with characteristic eosinophilic macronucleoli and perinucleolar halo. On immunohistochemistry (IHC), all showed diffuse nucleo‐cytoplasmic expression of S‐(2‐succino)‐cysteine (2‐SC), with loss of FH in seven cases. FH‐deficient RCCs are aggressive neoplasms and can be diagnosed using specific IHC markers (FH and 2‐SC). These patients should undergo germline testing for FH gene mutation, genetic counseling, and surveillance of family members. [ABSTRACT FROM AUTHOR]

Aim: Patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) are at increased risk of incident cardiovascular disease. However, the clinical characteristics and prognostic importance of MASLD in patients presenting with acute myocardial infarction (AMI) have yet to be examined. Methods: This study compared the characteristics and outcomes of patients with and without MASLD presenting with AMI at a tertiary centre in Singapore. MASLD was defined as hepatic steatosis, with at least one of five metabolic criteria. Hepatic steatosis was determined using the Hepatic Steatosis Index. Propensity score matching was performed to adjust for age and sex. The Kaplan‐Meier curve was constructed for long‐term all‐cause mortality. Cox regression analysis was used to investigate independent predictors of long‐term all‐cause mortality. Results: In this study of 4446 patients with AMI, 2223 patients with MASLD were matched with patients without MASLD using propensity scores. The mean follow‐up duration was 3.4 ± 2.4 years. The MASLD group had higher rates of obesity, diabetes and chronic kidney disease than their counterparts. Patients with MASLD had early excess all‐cause mortality (6.8% vs. 3.6%, p <.001) at 30 days, with unfavourable mortality rates sustained in the long‐term (18.3% vs. 14.5%, p =.001) compared with those without MASLD. After adjustment, MASLD remained independently associated with higher long‐term all‐cause mortality (hazard ratio 1.330, 95% confidence interval 1.106‐1.598, p =.002). Conclusion: MASLD embodies a higher burden of metabolic dysfunction and is an independent predictor of long‐term mortality in the AMI population. Its early identification may be beneficial for risk stratification and provide therapeutic targets for secondary preventive strategies in AMI. [ABSTRACT FROM AUTHOR]

Extrarenal rhabdoid tumors (ERRTs) are highly aggressive pediatric tumors with very few cases reported in the literature. These tumors, similar to their renal counterparts, are characterized by inactivating mutations of the SMARCB1/INI-1 gene, a member of the SWI/SNF chromatin remodeling pathway. Diagnosis of ERRTs appears challenging owing to its rarity, varied morphological profile with a higher tendency for rhabdoid differentiation, and overlapping features with other SMARCB-1 deficient tumors. Here, we report a case of ERRT in the pelvis of a three-year-old child with an unusual expression of SALL4 and C-kit on immunohistochemistry. A complete immunohistochemical workup might help in differentiating ERRTs from other SMARCB1/INI1-deficient soft tissue tumors. The expression of stem cell markers in the presented case also suggests that these tumors might originate from or share similarities with embryonic stem cells or germ cells. [ABSTRACT FROM AUTHOR]

Objective: This network meta‐analysis evaluates the efficacy and safety of tirzepatide compared to glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) and other weight loss drugs in the treatment of overweight and obesity. Methods: MEDLINE, Embase, and Cochrane CENTRAL were searched for randomized controlled trials on tirzepatide, GLP‐1 RA, and weight loss drugs approved by the US Food and Drug Administration. A network meta‐analysis was performed, drawing direct and indirect comparisons between treatment groups. Network diagrams and surface under the cumulative ranking curve analysis were performed for primary (≥5%, ≥10%, ≥15%, absolute weight loss) and secondary outcomes and adverse effects. Results: Thirty‐one randomized controlled trials, involving more than 35,000 patients, were included in this study. Tirzepatide 15 mg ranked in the top three across weight‐related parameters, glycemic profile (glycated hemoglobin), lipid parameters (total cholesterol, high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, triglycerides), and blood pressure. Tirzepatide 15 mg had the highest efficacy compared with placebo for achieving ≥15% weight loss (risk ratio 10.24, 95% CI: 6.42–16.34). As compared to placebo, tirzepatide and GLP‐1 RA across all doses had significant increases in gastrointestinal adverse effects. Conclusions: The superiority of tirzepatide and GLP‐1 RA in inducing weight loss and their ability to target multiple metabolic parameters render them promising candidates in the treatment of patients with overweight and obesity. [ABSTRACT FROM AUTHOR]

Purpose of Review: The objective of this manuscript is to examine the current literature on the epidemiology of metabolic dysfunction-associated steatotic liver disease (MASLD), its correlation with cardiovascular disease (CVD) outcomes, as well as to evaluate the update in nomenclature from non-alcoholic liver disease (NAFLD). Recent Findings: The update of diagnostic criteria from NAFLD to MASLD reduces the stigma associated with alcohol consumption and poor health choices. It also shines a light on the crucial role of cardiometabolic risk factors in disease pathophysiology. The incidence and prevalence of MASLD are projected to increase significantly in the future as the population burden of cardiometabolic risk factors rises. MASLD is also a potent risk factor for developing CVD that should be tackled by using a multi-disciplinary team with a holistic approach. Summary: As the new nomenclature for metabolic liver disease is adopted on a global scale, more research is needed to investigate the applicability of findings from previous trials focusing on NAFLD. It is anticipated that the epidemic of MASLD will continue to increase globally, hence the urgent need for therapeutic approaches to reverse this trend. [ABSTRACT FROM AUTHOR]

This document provides a comprehensive overview of PD-L1 testing and assessment for oncologists and pathologists. It explains the importance of PD-L1 immunohistochemistry (IHC) testing as a predictive biomarker for immune checkpoint inhibitors. The article discusses the three most commonly used PD-L1 IHC assays and their platforms, as well as the different scoring methods used to assess PD-L1 immunoexpression. It also outlines the clinical settings for PD-L1 testing, including companion diagnostic tests and complementary diagnostic tests. The document emphasizes the need for further research to fully understand the limitations and precise role of PD-L1 testing in predicting response to immune checkpoint inhibitor therapy. [Extracted from the article]

Melanocytic lesions involving the central nervous system are extremely rare and pose a diagnostic challenge owing melanoma being the third most common malignancy metastasizing to the spine. Morphology and immunohistochemistry are identical in both primary and secondary cases, and hence may not help in rendering a final diagnosis. Molecular alterations involving melanomas of the spine and melanomas elsewhere are distinct and help establish the appropriate diagnosis. We report an interesting case where molecular profiling of the tumor tissue helped render the final diagnosis. [ABSTRACT FROM AUTHOR]

With the advent of molecular immunohistochemistry and next generation sequencing, Switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex altered tumors have gained recognition recently. SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily B member 1 (SMARCB1) and SMARCA4 are the primary SWI/SNF components altered in several recently described undifferentiated malignancies in head and neck region with predilection for paranasal sinuses in SMARCB1-deficient tumors and nasal cavity in SMARCA4-deficient tumors. However, to the best of our knowledge, SMARCA4-deficient tumors of the oropharynx have not been described. We present an unusual case of SMARCA4-deficient carcinoma of the oropharynx (palatine tonsil) which is the first case in the literature, expanding the topographic distribution of SMARCA4-deficient tumors in the head and neck region and emphasizing the importance of BRG1 as an essential immunohistochemical marker for the diagnosis of this distinct entity. [ABSTRACT FROM AUTHOR]

Background: N6-methyladenosine (m6A) is a prevalent and crucial RNA methylation modification that plays a significant role in various biological and pathological processes. The dysregulation of m6A has been linked to the initiation, progression, and metastasis of several cancer types, including colon cancer. The transcriptome of colon cancer indeed provides insight into dysregulated coding and non-coding RNAs, but it does not reveal the mechanisms, such as m6A modifications, that determine post-transcriptional and pre-translational regulations. This study using MeRIP sequencing aims to explain the distribution of m6A modification across altered gene expression and its association with colon cancer. Methods and results: The levels of m6A in different colon cancer cell lines were quantified and correlated with the expression of m6A modifiers such as writers, readers, and erasers. Our results showed that global m6A levels in colon cancer were associated with METTL14, YTHDF2, and YTHDC1. We performed Epi-transcriptome profiling of m6A in colon cancer cell lines using Methylated RNA Immunoprecipitation (MeRIP) sequencing. The differential methylation analysis revealed 7312 m6A regions among the colon cancer cell lines. Our findings indicated that the m6A RNA methylation modifications were mainly distributed in the last exonic and 3′ untranslated regions. We also discovered that non-coding RNAs such as miRNA, lncRNA, and circRNA carry m6A marks. Gene set enrichment and motif analysis suggested a strong association of m6A with post-transcriptional events, particularly splicing control. Overall, our study sheds light on the potential role of m6A in colon cancer and highlights the importance of further investigation in this area. Conclusion: This study reports m6A enrichment in the last exonic regions and 3′ UTRs of mRNA transcripts in colon cancer. METTL14, YTHDF2, and YTHDC1 were the most significant modifiers in colon cancer cells. The functions of m6A-modified genes were found to be RNA methylation and RNA capping. Overall, the study illustrates the transcriptome-wide distribution of m6A and its eminent role in mRNA splicing and translation control of colon cancer. [ABSTRACT FROM AUTHOR]

High-density lipoprotein (HDL) contributes to reverse cholesterol transport, which is 1 of the main explanations for the described inverse association between HDL-cholesterol (HDL-C) and atherosclerotic cardiovascular disease (ASCVD) risk. However, efforts to therapeutically raise HDL-C levels with niacin, fibrates, or cholesteryl ester transfer protein inhibitors have not demonstrated a reduction in ASCVD events when compared with placebo among individuals treated with statins. Furthermore, mendelian randomization studies suggest that HDL-C is unlikely to be a direct biologic variable impacting ASCVD risk. More recently, observations from well-conducted epidemiologic studies have indicated a nonlinear U-shaped relationship between HDL-C and subclinical atherosclerosis, and that very high HDL-C (≥80 mg/dL in men, ≥100 mg/dL in women) is paradoxically associated with higher all-cause and ASCVD-related mortality. These observations suggest that HDL-C is not a universal protective factor for atherosclerosis. Thus, there are several opportunities for reframing the contribution of HDL-C to ASCVD risk and related clinical calculators. Here, we examine our growing understanding of HDL-C and its role in ASCVD risk assessment, treatment, and prevention. We discuss the biological functions of HDL-C and its normative values in relation to demographics and lifestyle markers. We then summarize original studies that observed a protective association between HDL-C and ASCVD risk and more recent evidence indicating an elevated ASCVD risk at very high HDL-C levels. Through this process, we advance the discussion regarding the future role of HDL-C in ASCVD risk assessment and identify knowledge gaps pertaining to the precise role of HDL-C in atherosclerosis and clinical ASCVD. [ABSTRACT FROM AUTHOR]

This article describes a case of myeloid sarcoma with RAM immunophenotype in an adult male who had a relapse of a primary mediastinal mass lesion with involvement in the central nervous system (CNS) and bone marrow. The patient had previously been diagnosed with myeloid sarcoma in the pediatric population. The article discusses the unique characteristics of AML-RAM, including its association with CBFA2T3::GLIS2 fusion and its predominantly pediatric occurrence. The prognosis for AML-RAM is generally poor, and further research is needed to improve outcomes and explore targeted therapies. [Extracted from the article]

Plasma metabolomics profiling is an emerging methodology to identify metabolic pathways underlying cardiovascular health (CVH). The objective of this study was to define metabolomic profiles underlying CVH in a cohort of Black adults, a population that is understudied but suffers from disparate levels of CVD risk factors. The Morehouse-Emory Cardiovascular (MECA) Center for Health Equity study cohort consisted of 375 Black adults (age 53 ± 10, 39% male) without known CVD. CVH was determined by the AHA Life's Simple 7 (LS7) score, calculated from measured blood pressure, body mass index (BMI), fasting blood glucose and total cholesterol, and self-reported physical activity, diet, and smoking. Plasma metabolites were assessed using untargeted high-resolution metabolomics profiling. A metabolome wide association study (MWAS) identified metabolites associated with LS7 score after adjusting for age and sex. Using Mummichog software, metabolic pathways that were significantly enriched in metabolites associated with LS7 score were identified. Metabolites representative of these pathways were compared across clinical domains of LS7 score and then developed into a metabolomics risk score for prediction of CVH. We identified novel metabolomic signatures and pathways associated with CVH in a cohort of Black adults without known CVD. Representative and highly prevalent metabolites from these pathways included glutamine, glutamate, urate, tyrosine and alanine, the concentrations of which varied with BMI, fasting glucose, and blood pressure levels. When assessed in conjunction, these metabolites were independent predictors of CVH. One SD increase in the novel metabolomics risk score was associated with a 0.88 higher LS7 score, which translates to a 10.4% lower incident CVD risk. We identified novel metabolomic signatures of ideal CVH in a cohort of Black Americans, showing that a core group of metabolites central to nitrogen balance, bioenergetics, gluconeogenesis, and nucleotide synthesis were associated with CVH in this population. [ABSTRACT FROM AUTHOR]

Background: The Ring Finger 43 (RNF43) is a tumor suppressor gene that negatively regulates the Wnt/β-catenin signaling. The p.G659fs is a recurrent RNF43 C-terminal truncating variant frequent in colorectal cancer (CRC) patients. We aimed to identify this hotspot variant in CRC patients and assessed the relationship between the mutation, clinical characteristics, and tumor β-catenin localization. Materials and Methods: Formalin-fixed, paraffin-embedded tissue samples of upfront, surgically resected, sporadic colorectal adenocarcinoma cases were selected. The p.G659fs mutation was determined by capillary sequencing with sequence-specific primers. Tissue microarray and immunohistochemistry were employed to analyze nuclear β-catenin expression and the expression of mismatch repair (MMR) proteins, respectively. In addition, clinical details were retrieved from the hospital medical records and data were analyzed. Results: The RNF43 p.G659fs mutation was observed in 8% of CRC patients. In total, 25% of tumors showed a loss of immunostaining for one or more MMR proteins and 14.6% of tumors showed positive nuclear β-catenin staining. The p.G659fs variant was significantly enriched in MMR-deficient tumors (P = 0.04). Importantly, no correlation was observed between the variant and nuclear β-catenin localization (P = 0.48), indicating a Wnt-independent role of this variant in CRC tumors. Conclusions: To the best of our knowledge, this is the first study from North India to show the involvement of RNF43 p.G659fs variant in CRC patients. The mutation correlated with MMR protein deficiency and seems to be conferring tumorigenicity independent of the Wnt pathway. [ABSTRACT FROM AUTHOR]

Folliclular dendritic cell sarcoma (FDCS) is an extremely rare neoplasm originating from folliclular dendritic cells, both nodally and extranodally. Its primary presentation as a large colonic mass is rare and can be misdiagnosed as epithelial tumor/soft tissue tumor both clinically and through histomorphology. Due to its rarity and limited consensus guidelines about its management, it presents as a diagnostic and therapeutic challenge for pathologists and oncologists. However, accurate diagnosis is imperative due to its distinct prognostic and therapeutic implications. Herein we report, two cases of extranodal FDCS of colon with the aim of contributing to the management of this uncommon entity. [ABSTRACT FROM AUTHOR]

Purpose of Review: The objective of this manuscript is to examine the current literature on non-alcoholic fatty liver disease (NAFLD) biomarkers and their correlation with cardiovascular disease (CVD) outcomes and cardiovascular risk scores. Recent Findings: There has been a growing appreciation for an independent link between NAFLD and CVD, culminating in a scientific statement by the American Heart Association in 2022. More recently, studies have begun to identify biomarkers of the three NAFLD phases as potent predictors of cardiovascular risk. Summary: Despite the body of evidence supporting a connection between hepatic biomarkers and CVD, more research is certainly needed, as some studies find no significant relationship. If this relationship continues to be robust and readily reproducible, NAFLD and its biomarkers may have an exciting role in the future of cardiovascular risk prediction, possibly as risk-enhancing factors or as components of novel cardiovascular risk prediction models. [ABSTRACT FROM AUTHOR]

Purpose of Review: Review updates for the association of HDL-cholesterol with atherosclerotic cardiovascular disease (ASCVD) and discuss the approach to incorporating HDL-cholesterol within risk assessment. Recent Findings: There is a U-shaped relationship between HDL-cholesterol and ASCVD. Both low HDL-cholesterol (< 40 mg/dL in men, < 50 mg/dL in women) and very-high HDL-cholesterol (≥ 80 mg/dL in men) are associated with a higher risk of all-cause and ASCVD mortality, independent from traditional risk factors. There has been inconsistency for the association between very-high HDL-cholesterol and mortality outcomes in women. It is uncertain whether HDL-cholesterol is a causal ASCVD risk factor, especially due to mixed results from Mendelian randomization studies and the collinearity of HDL-cholesterol with established risk factors, lifestyle behaviors, and socioeconomic status. Summary: HDL-cholesterol is a risk factor or risk enhancer in primary prevention and high-risk condition in secondary prevention when either low (men and women) or very-high (men). The contribution of HDL-cholesterol to ASCVD risk calculators should reflect its observed U-shaped association with all-cause and ASCVD mortality. [ABSTRACT FROM AUTHOR]

Lipoprotein(a), or Lp(a), is structurally like low‐density lipoprotein (LDL) but differs in that it contains glycoprotein apolipoprotein(a) [apo(a)]. Due to its prothrombotic and proinflammatory properties, Lp(a) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis. Lp(a) levels are genetically determined, and it is estimated that 20%–25% of the global population has an Lp(a) level ≥50 mg/dL (or ≥125 nmol/L). Diet and lifestyle interventions have little to no effect on Lp(a) levels. Lipoprotein apheresis is the only approved treatment for elevated Lp(a) but is time‐intensive for the patient and only modestly effective. Pharmacological approaches to reduce Lp(a) levels and its associated risks are of significant interest; however, currently available lipid‐lowering therapies have limited effectiveness in reducing Lp(a) levels. Although statins are first‐line agents to reduce LDL cholesterol levels, they modestly increase Lp(a) levels and have not been shown to change Lp(a)‐mediated ASCVD risk. Alirocumab, evolocumab, and inclisiran reduce Lp(a) levels by 20‐25%, yet the clinical implications of this reduction for Lp(a)‐mediated ASCVD risk are uncertain. Niacin also lowers Lp(a) levels; however, its effectiveness in mitigating Lp(a)‐mediated ASCVD risk remains unclear, and its side effects have limited its utilization. Recommendations for when to screen and how to manage individuals with elevated Lp(a) vary widely between national and international guidelines and scientific statements. Three investigational compounds targeting Lp(a), including small interfering RNA (siRNA) agents (olpasiran, SLN360) and an antisense oligonucleotide (pelacarsen), are in various stages of development. These compounds block the translation of messenger RNA (mRNA) into apo(a), a key structural component of Lp(a), thereby substantially reducing Lp(a) synthesis in the liver. The purpose of this review is to describe current recommendations for screening and managing elevated Lp(a), describe the effects of currently available lipid‐lowering therapies on Lp(a) levels, and provide insight into emerging therapies targeting Lp(a). [ABSTRACT FROM AUTHOR]

Purpose of Review: This review describes the discovery and development of ACE inhibitors as antihypertensive agents, compares their efficacy, tolerability, and safety to ARBs, and highlights the contemporary issues surrounding ACE inhibitor use for HTN. Recent Findings: Angiotensin-converting enzyme (ACE) inhibitors are commonly prescribed medications for the management of hypertension (HTN) and other chronic conditions including heart failure and chronic kidney disease. These agents inhibit ACE, the enzyme that is responsible for converting angiotensin (AT) I to AT II. Inhibiting the synthesis of AT II causes arterial and venous vasodilation, natriuresis, and a decrease in sympathetic activity, resulting in the reduction of blood pressure. ACE inhibitors are first-line therapy in HTN management along with thiazide diuretics, calcium channel blockers, and angiotensin receptor blockers (ARB). Along with inhibiting AT II synthesis, inhibition of ACE causes accumulation of bradykinin, increasing the risk of bradykinin-mediated side effects like angioedema and cough. Since ARBs do not work on ACE in the renin-angiotensin system, the risk of angioedema and cough are lower with ARBs. Recent evidence has also suggested ARBs may have neuroprotective effects compared to other antihypertensives, including ACE inhibitors; however, this warrants further study. Summary : Currently, ACE inhibitors and ARBs have an equal class of recommendation for first-line treatment for the management of HTN. Recent evidence has shown ARBs to be just as effective as ACE inhibitors for HTN but with improved tolerability. [ABSTRACT FROM AUTHOR]

Nucleic acid testing (NAT) is used to screen transfusiontransmittable infections (TTIs) in donated blood samples and provide an additional layer of blood safety. In this study, we describe our experience in screening viral TTIs using two formats of NAT: cobas® MPX2 polymerase chain reaction- based minipool NAT (PCR MP-NAT) and Procleix Utrio Plus transcription-mediated amplificationbased individual donor-NAT (TMA ID-NAT). Data routinely collected as a part of blood bank operations were retrospectively analysed over a period of 70 months for TTIs. Blood samples were initially screened for HIV, HBV, HCV, syphillis by chemiluminescence and malaria by Rapid card test. In addition to serological testing, all samples were further screened by TMA-based ID-NAT (ProcleixUltrio Plus Assay) during Jan 2015–Dec 2016, and by PCR-based MP-NAT (Cobas® TaqScreen MPX2) during Jan 2017–Oct 2020. RESULTS: A total of 48,151 donations were processed over 70 months, of which 16,212 donations were screened by ProcleixUtrio Plus TMA ID-NAT and 31,939 donations by cobas® MPX2 PCR MP-NAT. Replacement donors and male donors outnumbered voluntary donors and female donors respectively. The overall NAT yield rate of MP-NAT was 1:2281 compared to 1:3242 with ID-NAT, during the respective time period. ID-NAT detected 5 HBV infections missed by serology, whereas MP-NAT detected 13 HBV infections and 1 HCV infection missed by serology. The proportion of donations that were both seroreactive and NAT reactive was higher with MP-NAT (59.8%) compared to ID-NAT (34.6%). Cobas® MPX2MP-NAT had higher overall NAT yield rate compared to ProcleixUtrio Plus ID-NAT and confirmed a higher proportion of seroreactive donations. Due to the ease of operation, simple algorithm, cobas® MPX2 PCR based MP-NAT can be an effective solution for blood screening in India. [ABSTRACT FROM AUTHOR]

BACKGROUND: Multiple reports are available from different parts of the globe indicating the incidences of alloimmunization and blood transfusion-related reactions, which emphasizes the need for phenotyping and providing antigen-matched safe blood. AIMS AND OBJECTIVES: This study aims to determine the frequency of Rh and Kell antigens and phenotype for both donors and patients to propose the importance of providing Rh Kell phenotype cross-matched packed red blood cell (RBC) units to minimize the alloimmunization and transfusion reactions. MATERIALS AND METHODS: Ten thousand blood donors and four thousand patients were investigated between October 2017 and July 2019. Each donor unit was tested for blood grouping, antibody screening, and Rh Kell antigen Phenotyping, and the blood unit was issued after the patient's blood grouping, antibody screening by 3 cell panels, and Rh Kell antigen phenotyping followed by cross-matching with an Rh Kell-matched phenotype RBC unit. RESULTS: Nine thousand four hundred and fifty-two donors were D positive (94.5%) while 548 tested D negative (5.5%). Overall Rh and K antigens frequencies in donors were: "e" (98%) >"D" (94.5%) >"C" (86.6%) > "c" (57.5%) >"E" (18.8%) >K (0.98%). Among patients, 3762 tested D positive (94.05%), and 238 tested D negative (5.95%). Overall Rh and K antigens frequencies in patients were: "e" (98.5%) >"D" (94.05%) >"C" (90.2%) >"c" (51%) >"E" (18.2%) >K (1.8%). CONCLUSION: Our study has given us more clarity on the prevalence of major Rh and K antigens in our donor as well as patient populations, highlighting the similarities as well as differences. This variance holds a great significance, since such donor units when transfused into patients may lead to alloimmunization and adverse transfusion reactions. Hence, the determination of Rh and Kell phenotypes and providing phenotype-matched blood will help prevent such events. [ABSTRACT FROM AUTHOR]

Erdheim Chester Disease (ECD) is a rare histiocytic neoplasm with heterogeneous features. It can frequently be misdiagnosed if proper clinical and radiological details are not available. Biopsy with confirmatory immunohistochemistry (IHC) for BRAFV600E or molecular analysis for the gene forms the mainstay of diagnosis. Most ECD patients require treatment and the choice of therapy must be individualized based on clinical characteristics. Herein is reported one such case of ECD in a 45-year-old male who remains disease-free after six months of follow-up. [ABSTRACT FROM AUTHOR]

Purpose of Review: Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the liver and reduce atherosclerotic cardiovascular disease (ASCVD) risk by enhancing low-density lipoprotein (LDL) clearance from the circulation. In this review, we discuss their efficacy, safety, and real-world utilization to make a case for reclassifying statins as nonprescription over-the-counter drugs to improve access and availability with the overarching goal of increasing statin utilization in patients most likely to benefit from this class of therapy. Recent Findings: Statin efficacy for reducing risk in primary and secondary ASCVD prevention populations as well as their safety and tolerability has been thoroughly investigated in large-scale clinical trials over the past 3 decades. Despite the overwhelming scientific evidence, statins are underutilized even among those at the highest ASCVD risk. Summary: We propose a nuanced approach to use statins as nonprescription drugs that leverages a multi-disciplinary clinical model. It integrates lessons learned from experiences outside the USA with a proposed Food and Drug Administration rule change that allows nonprescription drug products with an additional condition for nonprescription use. [ABSTRACT FROM AUTHOR]

Aim: To examine the prevalence and prognosis of hepatic steatosis and fibrosis in post‐acute myocardial infarction (AMI) patients. Methods: Patients presenting with AMI to a tertiary hospital were examined from 2014 to 2021. Hepatic steatosis and advanced hepatic fibrosis were determined using the Hepatic Steatosis Index and fibrosis‐4 index, respectively. The primary outcome was all‐cause mortality. Cox regression models identified determinants of mortality after adjustments and Kaplan–Meier curves were constructed for all‐cause mortality, stratified by hepatic steatosis and advanced fibrosis. Results: Of 5765 patients included, 24.8% had hepatic steatosis, of whom 41.7% were diagnosed with advanced fibrosis. The median follow‐up duration was 2.7 years. Patients with hepatic steatosis tended to be younger, female, with elevated body mass index and an increased metabolic burden of diabetes, hypertension and hyperlipidaemia. Patients with hepatic steatosis (24.6% vs. 20.9% mortality, P <.001) and advanced fibrosis (45.6% vs. 32.9% mortality, P <.001) had higher all‐cause mortality rates compared with their respective counterparts. Hepatic steatosis (adjusted hazard ratio 1.364, 95% CI 1.145‐1.625, P =.001) was associated with all‐cause mortality after adjustment for confounders. Survival curves showed excess mortality in patients with hepatic steatosis compared with those without (P =.002). Conclusions: Hepatic steatosis and advanced fibrosis have a substantial prevalence among patients with AMI. Both are associated with mortality, with an incrementally higher risk when advanced fibrosis ensues. Hepatic steatosis and fibrosis could help risk stratification of AMI patients beyond conventional risk factors. [ABSTRACT FROM AUTHOR]

Due to the COVID-19 pandemic's rapid expansion, the creation of vaccines is crucial for lowering disease transmission. Therefore, to determine the safety and efficacy of the vaccine against symptomatic illness and to evaluate breakthrough infections, those who received single or both the doses of vaccine against COVID-19 infection. A retrospective observational study was carried out on vaccine efficacy and the incidence of the breakthrough infections among the heath care workers, support staff and administrative staff. Out of 599 fully vaccinated health care workers, those who tested COVID-19 positive post-vaccination only 1.16% developed a severe illness that necessitates hospitalization. This study reflects a significant vaccine efficacy of 81.3% after a complete dose of vaccination and protection of 76.9% after one standard dose against symptomatic disease. The frequency of COVID-19 vaccine breakthrough is very low, which means that COVID-19 vaccines are highly effective at preventing COVID-19, particularly when it comes to severity. [ABSTRACT FROM AUTHOR]

Background: KRAS, although a common variant of occurrence (~20% of non‐small‐cell lung carcinoma [NSCLC]) has been untargetable, owing to the molecular structure which inherently prevents drug binding. KRAS mutations in NSCLC are associated with distinct clinical profiles including smokers and mucinous histology. KRAS G12C mutations account for ~40% KRAS altered NSCLC, but NSCLC being a geographically diverse disease, the features may be distinct in this part of the world. This is a single‐center experience of KRAS‐mutated NSCLC including clinical, imaging, pathologic features, and treatment patterns and outcomes. Methods: This is a single‐center retrospective study of KRAS‐mutated NSCLC. The clinicopathological features and outcomes were retrieved and collated from the medical record archives of the hospital. Results: Fifty (30.6%) patients with advanced‐stage NSCLC with alterations in the KRAS gene were enrolled in the 163 patients who were tested for KRAS alterations. The median age was 61 years. Molecular detection revealed three main types of KRAS mutations viz‐a‐vis: G12C in 17 (34%), G12V in 9 (18%), and G12D in 6 (12%) patients. Comparing G12C versus the non‐G12C mutated cases, co‐mutations were common in the non‐G12C subgroup (p < 0.05). Among the 36, who were treated at our center, all received chemotherapy as the first line with a median progression‐free survival (PFS)of 5.4 months. The PFS of G12C was higher than the non‐G12C subgroup (6.4 vs 3.8 months). Conclusion: This is the largest single‐center experience from the Indian subcontinent for KRAS‐mutated NSCLC with distinct clinical features. It highlights the unmet need for G12C inhibitors in our country, where prevalence is equivalent to the West. [ABSTRACT FROM AUTHOR]

In-frame fusions in NTRK genes, with intact kinase domain, have been reported to occur at higher frequencies in rare tumors like infantile fibrosarcoma, congenital mesoblastic nephroma, and secretory carcinoma, whereas they occur at very low frequencies in common malignancies like NSCLC and colon cancers (0.1%–1%). Despite the rare occurrence, these alterations have gained importance owing to approval of drugs like entrectinib and larotrectinib targeting the kinase domain of the gene. More than 50 fusion partners have been described, and only in-frame fusions result in constitutive ligand-independent kinase activity leading to oncogenesis. The commonly reported NTRK fusions in the lung include SQSTM1–NTRK1, ETV6–NTRK3, and SQSTM1–NTRK3. Detection of these rests on the use of conventional modalities like Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH); however, accurate characterization requires direct sequencing methods. We report an interesting case of an NTRK fusion-positive NSCLC, exhibiting good response to entrectinib. [ABSTRACT FROM AUTHOR]

Socioeconomic status is an overlooked risk factor for cardiovascular disease (CVD). Low family income is a measure of socioeconomic status and may portend greater CVD risk. Therefore, we assessed the association of family income with cardiovascular risk factor and disease burden in American adults. This retrospective analysis included data from participants aged ≥ 20 years from the National Health and Nutrition Examination Survey (NHANES) cycles between 2005 and 2018. Family income to poverty ratio (PIR) was calculated by dividing family (or individual) income by poverty guidelines specific to the survey year and used as a measure of socioeconomic status. The association of PIR with the presence of cardiovascular risk factors and CVD as well as cardiac mortality and all-cause mortality was examined. We included 35,932 unweighted participants corresponding to 207,073,472 weighted, nationally representative participants. Participants with lower PIR were often female and more likely to belong to race/ethnic minorities (non-Hispanic Black, Mexican American, other Hispanic). In addition, they were less likely to be married/living with a partner, to attain college graduation or higher, or to have health insurance. In adjusted analyses, the prevalence odds of diabetes mellitus, hypertension, coronary artery disease (CAD), congestive heart failure (CHF), and stroke largely decreased in a step-wise manner from highest (≥ 5) to lowest PIR (< 1). In adjusted analysis, we also noted a mostly dose-dependent association of PIR with the risk of all-cause and cardiac mortality during a mean 5.7 and 5.8 years of follow up, respectively. Our study demonstrates a largely dose-dependent association of PIR with hypertension, diabetes mellitus, CHF, CAD and stroke prevalence as well as incident all-cause mortality and cardiac mortality in a nationally representative sample of American adults. Public policy efforts should be directed to alleviate these disparities to help improve cardiovascular outcomes in vulnerable groups with low family income. [ABSTRACT FROM AUTHOR]

There are so many changes taking place within the organization and outside the organization. Situations outside the business organization are not within the control of any individual or management but it has can be cope up skillfully provided the necessary changes are introduced well in time. It has been observed that every institution wish to incorporate the required changes but they face reluctance from the employees working in the organization. Employees feel comfort in the current situation or they are apprehensive about the outcome of changes going to be introduced. There is also fear of discomfort or loss associated with the changes. This research work has been executed to identify the appropriate and significant methods to overcome the resistance towards change. Employees in small cities have different approach towards work. Three methods have been critically studied namely standard operating procedure (SOP), dynamic environment and financial incentives. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) is one of the leading causes of cancer deaths worldwide. In India, the incidence of LC is increasing rapidly, and a majority of the patients are diagnosed at advanced stages of the disease when treatment is less likely to be effective. Recent therapeutic developments have significantly improved survival outcomes in patients with LC. Prompt specialist referral remains critical for early diagnosis for improved patient survival. In the Indian scenario, distinguishing LC from benign and endemic medical conditions such as tuberculosis can pose a challenge. Hence, awareness regarding the red flags—signs and symptoms that warrant further investigations and referral—is vital. This review is an effort toward encouraging general physicians to maintain a high index of clinical suspicion for those at risk of developing LC and assisting them in refering patients with concerning symptoms to specialists or multidisciplinary teams as early as possible. [ABSTRACT FROM AUTHOR]

Background: Plasmacytoma involving thyroid gland is infrequent and can present as either primary extramedullary plasmacytoma or secondary to multiple myeloma. Methods and Results: We present a case of 71 years old male who complained of a huge anterior neck swelling accompanied by dysphagia and dyspnoea. Fine needle aspiration cytology was suggestive of anaplastic carcinoma of thyroid (ATC), however, the subsequent histomorphology supported by immunohistochemistry (IHC) astoundingly favoured the diagnosis of plasmacytoma. Further evaluation revealed the presence of lymphadenopathy and single bone lesion in the present case which was rather suggestive of secondary involvement of thyroid to multiple myeloma. However, the case was unique in view of its presentation as a rapidly enlarging thyroid mass associated with stridor and cytomorphological findings which were of an undifferentiated malignancy favouring ATC. The use of a broad and judicious IHC panel clinched the final diagnosis of plasmacytoma. Conclusion: The present case emphasizes the diligent use of IHC in such cases given different therapeutic and prognostic implications. [ABSTRACT FROM AUTHOR]