Search

This study reports a unique case of a 19-year-old male with Takayasu arteritis initially misdiagnosed as brucellosis due to persistently positive brucella serology. Despite multiple anti-brucellosis treatments, symptoms persisted until the correct diagnosis of Takayasu arteritis was made, Subsequent immunosuppressive therapy for Takayasu arteritis led to symptom improvement and normalization of serological markers. This highlights the challenge of distinguishing between these conditions and the potential for immunosuppression to impact brucella serology in such cases., Competing Interests: No conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Bariatric surgery is the most effective treatment for severe obesity. There can be variation in the degree of weight reduction following bariatric surgery. It is unknown whether single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor locus (GRL) affect postoperative weight loss and metabolic outcomes., Materials/methods: We studied the association between selected candidate SNPs and postoperative weight loss and metabolic outcomes in patients with severe obesity undergoing bariatric surgery. The polymorphisms rs41423247 (Bcl1), rs56149945 (N363S) and rs6189/rs6190 (ER22/23EK) were analysed., Results: The 139 participants included 95 women (68.3%) and had a median (interquartile range) age of 53.0 (46.0-60.0) years and mean (SD) weight of 140.8 (28.8) kg and body mass index of 50.3 (8.6) kg/m2. At baseline, 59 patients had type 2 diabetes (T2D), 60 had hypertension and 35 had obstructive sleep apnoea syndrome treated with continuous positive airway pressure (CPAP). 84 patients (60.4%) underwent gastric bypass and 55 (39.6%) underwent sleeve gastrectomy. There were no significant differences in weight loss, glycated haemoglobin (HbA1c) or lipid profile categorized by genotype status, sex or median age. There was significant weight reduction after bariatric surgery with a postoperative BMI of 34.1 (6.8) kg/m2 at 24 months ( p  < 0.001)., Conclusion: While GRL polymorphisms with a known deleterious effect on adipose tissue mass and function may have a small, additive effect on the prevalence of obesity and related metabolic disorders in the population, we suggest that the relatively weak biological influence of these SNPs is readily overcome by bariatric surgery.

Introduction: Hydatid cysts are among many cysts that can develop in the pancreas. Both the size and location of these cysts significantly influence clinical presentation and surgical approach required for management. This study aims to review the literature concerning pancreatic hydatic cysts, their presentations, and management strategies., Methods: A comprehensive search was conducted across CINAHL, Pubmed/Medline, Cochrane Library, Web of Science, and EMBASE Databases to identify English-language studies published up to January 2nd, 2024., Results: The mean age of the patients was 35.4 ± 17.4years, with females comprising 92 (59.0 %) of the cohort. Abdominal pain was the most common complaint, reported by 92 (59.0 %) patients. Serological testing for the echinococcal antigen demonstrated highest sensitivity at 67.0 %, whereas computed tomography exhibited a sensitivity of 34.1 %, and ultrasonography showed a sensitivity of 27.7 %. Among surgical interventions, laparotomy was the most frequently performed approach, utilized in 42(26.9 %) of the cases., Conclusion: Although pancreatic hydatid cysts are rare and can be challenging to diagnose, their prognosis is generally favorable when appropriate therapeutic measures are employed. Surgical intervention, often combined with Albendazole, remains the mainstay of treatment., Competing Interests: Conflicts of interest The author(s) have no conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: Echinococcosis is a widespread zoonotic disease caused by tapeworms of the Echinococcus genus, manifesting in mature or larval forms. Cystic echinococcosis (CE) and alveolar echinococcosis (AE) are the primary types affecting humans, linked, respectively, to Echinococcus granulosus and Echinococcus multilocularis . This study is a systematic review and meta-analysis of the risk factors associated with CE and AE in humans., Methods: Relevant English publications were found through a thorough search of eligible databases. The inclusion criteria focused on cross-sectional and case-control studies investigating risk factors for human echinococcosis. Collected data included author, country, study design, demographics, sample size, literacy, occupation, drinking water source, dog ownership, and hand hygiene., Results: A total of 1,594 studies were found in the initial search, with only 36 papers (involving 1,207,436 cases) meeting the inclusion criteria. Most of the study population (99.35%) showed no echinococcosis infection, while 0.65% were infected. Of the infected cases, 77.92% had CE, while 22.08% had AE. Among 629,996 (52.18%) females, 4,830 (0.76%) were infected, compared to 2,968 (0.52%) infections among 565,872 (46.86%) males ( p  < 0.001). Rural areas, low education levels, agricultural/livestock workers, dog owners, water sources, and poor hand hygiene were all significantly associated with the infection ( p  < 0.05)., Conclusion: Echinococcosis remains a global health concern, particularly among rural residents, those with lower education, agricultural workers, and dog owners. Targeted public health measures, including improved hygiene practices and access to clean water, are essential to reducing its impact., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kakamad, Anwar, Ahmed, Habibullah, Kaka Ali, Nasralla, Abdullah, Tahir, Kareem, Hasan, Gharib, Asaad, Mohammed, Abdalla, Esmaeil, Rashid and Hamahussein.)

Background: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder. This study aimed to study the genotype distribution of FCS-causing genes in the United Kingdom, genotype-phenotype correlation, and clinical differences between FCS and multifactorial chylomicronemia syndrome (MCS)., Methods: The study included 154 patients (FCS, 74; MCS, 80) from the UK FCS national registry and the UK arm of the FCS International Quality Improvement and Service Evaluation Project., Results: FCS was relatively common in non-Europeans and those with parental consanguinity ( P <0.001 for both). LPL variants were more common in European patients with FCS (European, 64%; non-European, 46%), while the genotype was more diverse in non-European patients with FCS. Patients with FCS had a higher incidence compared with patients with MCS of acute pancreatitis (84% versus 60%; P =0.001), recurrent pancreatitis (92% versus 63%; P <0.001), unexplained abdominal pain (84% versus 52%; P <0.001), earlier age of onset (median [interquartile range]) of symptoms (15.0 [5.5-26.5] versus 34.0 [25.2-41.7] years; P <0.001), and of acute pancreatitis (24.0 [10.7-31.0] versus 33.5 [26.0-42.5] years; P <0.001). Adverse cardiometabolic features and their co-occurrence was more common in individuals with MCS compared with those with FCS ( P <0.001 for each). Atherosclerotic cardiovascular disease was more prevalent in individuals with MCS than those with FCS ( P =0.04). However, this association became nonsignificant after adjusting for age, sex, and body mass index. The prevalence of pancreatic complications and cardiometabolic profile of variant-positive MCS was intermediate between FCS and variant-negative MCS., Conclusions: The frequency of gene variant distribution varies based on the ethnic origin of patients with FCS. Patients with FCS are at a higher risk of pancreatic complications while the prevalence of atherosclerotic cardiovascular disease is lower in FCS compared with MCS. Carriers of heterozygous pathogenic variants have an intermediate phenotype between FCS and variant-negative MCS., Competing Interests: H. Soran received personal fees from Amgen, Akcea, Synageva, Napp, Novartis, Takeda, Sanofi, Pfizer, and Kowa and research grants and donations from Akcea, Pfizer, Merck Sharp & Dohme, Amgen, Genzyme-Sanofi, Synageva, Amryt, Synageva, and Alexion. A.S. Wierzbicki is a site investigator on trials from Akcea and Regeneron; received royalties from Elsevier for a book on familial chylomicronemia syndrome; and is a board member for the Familial Hyperlipidaemia group, Europe. D. Datta received honoraria for advisory board from Swedish Orphan Biovitrum. N. Forrester received honoraria for presentations from SOBI. Y. Teoh received speakers fee from Daiichi Sankyo and Amarin. P. Downie received honoraria from SOBI, Novartis, Amgen, and Daiichi Sankyo. R.A. Hegele received consulting fees from Acasti, Aegerion, Akcea/Ionis, Amgen, Arrowhead, HLS Therapeutics, Pfizer, Novartis, Regeneron, Sanofi, and UltraGenyx. The other authors report no conflicts.

Crohn's disease (CD) is a granulomatous inflammatory bowel disease. Around 25% of CD patients exhibit extraintestinal manifestations, though pulmonary involvement is rare. This study presents a case of CD causing pleural effusion. A 43-year-old man visited the pulmonology clinic with a dry cough for one-month, right-side pleuritic chest pain, and exertional dyspnea. He was treated with antihistamines and antitussive syrup, with incomplete relief. A chest CT scan showed bilateral mild pleural effusion. Given his occasional black stools and high serum calprotectin, a colonoscopy confirmed CD. Pulmonary manifestations may involve airway, parenchymal, and interstitial pathologies, but no distinctive pathological findings differentiate CD's pulmonary manifestations from other causes. In conclusion, isolated bilateral pleural effusion and the underlying pleuritis as a pulmonary manifestation of CD-characterized by dry cough and pleuritic chest pain, particularly preceding the diagnosis of CD-is extremely rare but possible., Competing Interests: The authors declare that they have no competing interests., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Bariatric surgery (BS) has emerged an effective intervention in achieving significant and sustained weight loss in patients with type 2 diabetes (T2D). However, comprehensive data on the long-term impact of BS on hypertension is scarce. We aimed to investigate the long-term impact of BS on blood pressure management in individuals within a T2D cohort., Methods: This retrospective cohort study was conducted on 119 patients who underwent BS between 2009 and 2012. Baseline and follow-up observations, including blood pressure, HbA1c, BMI, and antihypertensive medication use were obtained from electronic patient records at regular intervals up to and beyond 10-year follow-up., Results: The median follow-up period for the 119 patients was 11.5 years. Mean fall in BMI 4-8 weeks post-surgery was 12%. A sustained reduction in systolic BP was observed up to 10 years post-surgery (154.5 mmHg pre-op vs. 132.8 mmHg at 10 years; p < 0.0001. From 5 years onwards, there were increases in mean glycated hemoglobin (HbA1c) and body mass index (BMI). At latest follow-up (> 5 years after bariatric surgery), the number of individuals prescribed an antihypertensive agent started to increase. This is in the context of the number of the number of individuals on 2-3 antihypertensive agents declining up until 5 years post-BS. Specifically, there was a reduction in the number of prescriptions of an antihypertensive agent over time from 164 prescriptions pre-operatively to 81 at 8 weeks post-operatively, 78 at 6 months, 72 at 1 year, 66 at 5 years before rising at 10 years to 95 prescriptions., Conclusions: Our study shows an overall benefit in the years after bariatric surgery in terms of blood pressure and requirement for antihypertensive medication. However, at 5 years and beyond after surgery, the beneficial effect of bariatric surgery diminishes with respect to an increase in number of antihypertensive medication prescriptions, BMI, and HbA1c., (© 2024. The Author(s).)

Aims: Historically, atherosclerotic cardiovascular disease (ASCVD) risk profile mitigation has had a predominant focus on low density lipoprotein cholesterol (LDL-C). In this narrative review we explore the residual ASCVD risk profile beyond LDL-C with a focus on hypertriglyceridaemia, recent clinical trials of therapeutics targeting hypertriglyceridaemia and novel modalities addressing other residual ASCVD risk factors., Findings: Hypertriglyceridaemia remains a significant ASCVD risk despite low LDL-C in statin or proprotein convertase subtilisin/kexin type 9 inhibitor-treated patients. Large population-based observational studies have consistently demonstrated an association between hypertriglyceridaemia with ASCVD. This relationship is complicated by the co-existence of low high-density lipoprotein cholesterol. Despite significantly improving atherogenic dyslipidaemia, the most recent clinical trial outcome has cast doubt on the utility of pharmacologically lowering triglyceride concentrations using fibrates. On the other hand, purified eicosapentaenoic acid (EPA), but not in combination with docosahexaenoic acid (DHA), has produced favourable ASCVD outcomes. The outcome of these trials suggests alternate pathways involved in ASCVD risk modulation. Several other pharmacotherapies have been proposed to address other ASCVD risk factors targeting inflammation, thrombotic and metabolic factors., Implications: Hypertriglyceridaemia poses a significant residual ASCVD risk in patients already on LDL-C lowering therapy. Results from pharmacologically lowering triglyceride are conflicting. The role of fibrates and combination of EPA and DHA is under question but there is now convincing evidence of ASCVD risk reduction with pure EPA in a subgroup of patients with hypertriglyceridaemia. Clinical guidelines should be updated in line with recent clinical trials evidence. Novel agents targeting non-conventional ASCVD risks need further evaluation., Competing Interests: HS: Received personal fees from Amgen, Akcea, Synageva, NAPP, Novartis, Takeda, Sanofi, Pfizer and Kowa & received research grants and donations from Akcea, Pfizer, MSD, AMGEN, Genzyme-Sanofi, Synageva, Amryt, Synageva and Alexion. DA: reports research grants from Boehringer-Ingelheim, Bristol Myers Squibb, Janssen, and the LEO Foundation. JS: received grants and research support from Astra Zeneca, Daiichi-Sankyo, Eli Lilly and Company and Novo Nordisk; speaker fees from Novartis, Astra Zeneca, Daiichi-Sankyo and Sanofi; and consultancy fees from Amgen, Boehringer Ingelheim, Eli Lilly and Company and Sanofi. PD: Received honoraria from Sobi, Novartis, Amgen, Daiichi Sankyo, Sanofi and Amarin. SR: Received honoraria from NOVARTIS, AMGEN, Astra Zeneca, Ultragenyx, Sanofi, Foresite Labs, and research grants from Astra Zeneca. IG-B: received personal honoraria for consulting from Amgen, Regeneron, Aegereon, Akcea Therapeutics, Daiichi-Sankyo, Novartis, Ultragenyx, Sanofi and Amarin. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Bashir, Schofield, Downie, France, Ashcroft, Wright, Romeo, Gouni-Berthold, Maan, Durrington and Soran.)

Purpose of Review: This review endeavours to explore the aetiopathogenesis and impact of severe hypertriglyceridemia (SHTG) and chylomicronaemia on cardiovascular, and pancreatic complications and summarizes the novel pharmacological options for management., Recent Findings: SHTG, although rare, presents significant diagnostic and therapeutic challenges. Familial chylomicronaemia syndrome (FCS), is the rare monogenic form of SHTG, associated with increased acute pancreatitis (AP) risk, whereas relatively common multifactorial chylomicronaemia syndrome (MCS) leans more towards cardiovascular complications. Despite the introduction and validation of the FCS Score, FCS continues to be underdiagnosed and diagnosis is often delayed. Longitudinal data on disease progression remains scant. SHTG-induced AP remains a life-threatening concern, with conservative treatment as the cornerstone while blood purification techniques offer limited additional benefit. Conventional lipid-lowering medications exhibit minimal efficacy, underscoring the growing interest in novel therapeutic avenues, that is, antisense oligonucleotides (ASO) and short interfering RNA (siRNA) targeting apolipoprotein C3 (ApoC3) and angiopoietin-like protein 3 and/or 8 (ANGPTL3/8)., Summary: Despite advancements in understanding the genetic basis and pathogenesis of SHTG, diagnostic and therapeutic challenges persist. The rarity of FCS and the heterogenous phenotype of MCS underscore the need for the development of predictive models for complications and tailored personalized treatment strategies. The establishment of national and international registries is advocated to augment disease comprehension and identify high-risk individuals., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: To review the discoveries which led to the concept that serum paraoxonase 1 (PON1) is inversely related to atherosclerotic cardiovascular disease (ASCVD) incidence, how this association came to be regarded as causal and how such a role might have evolved., Recent Findings: Animal models suggest a causal link between PON1 present on HDL and atherosclerosis. Serum PON1 activity predicts ASCVD with a similar reliability to HDL cholesterol, but at the extremes of high and low HDL cholesterol, there is discordance with PON1 being potentially more accurate. The paraoxonase gene family has its origins in the earliest life forms. Its greatest hydrolytic activity is towards lactones and organophosphates, both of which can be generated in the natural environment. It is active towards a wide range of substrates and thus its conservation may have resulted from improved survival of species facing a variety of evolutionary challenges., Summary: Protection against ASCVD is likely to be the consequence of some promiscuous activity of PON1, but nonetheless has the potential for exploitation to improve risk prediction and prevention of ASCVD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence., Methods: In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis., Findings: The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037)., Interpretation: Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life., Funding: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health., Competing Interests: Declaration of interests BAH received a research grant from Silence Therapeutics. GKH reports research grants from the Klinkerpad fonds, and part-time employment at Novo Nordisk (Søborg, Denmark) since April, 2019. GKH is shareholder of Novo Nordisk. DJB reports clinical trial fees paid to their institution from LIB Therapeutics, Novartis, Silence Therapeutics, and IONIS; speaker fees from Amgen, Sanofi, Organon, MSD, Amryt, and Novartis; and consulting fees from Amryt. ALC has received research grants or support from Amarin, Amgen, Menarini, Mylan, Sanofi, and Sanofi Regeneron, and served as a consultant for or received honoraria from Akcea, Amarin, Amgen, Daiichi Sankyo, Esperion Therapeutics, Ionis, Kowa, Medco, Menarini, MSD, Mylan, Novartis, Recordati, Regeneron, Sanofi, and The Corpus. MC reports institutional support for the conduction of clinical trials from Regeneron Pharmaceuticals and Regenxbio, and consulting fees from Amryt Pharma. AG received grants and personal fees from Amgen, Sanofi–Regeneron, Mylan Viatris, MSD, Akcea Therapeutics, Amryt, Servier, Novartis, and Ultragenyx. FJR reports receiving advisory board fees and lecture fees from Amgen, Sanofi-Aventis, Regeneron Pharmaceuticals, Novartis, and LIB Therapeutics. KKR reports grants from Amgen, Sanofi–Regeneron, Pfizer, Merck Sharp & Dohme, Daiichi Sankyo, and Ultragenyx; consulting fees from AstraZeneca, Kowa, Novartis, Sanofi, Amgen, Eli Lilly, Algorithm, Boehringer Ingelheim, Novo Nordisk, Silence Therapeutics, Bayer, Esperion, Daiichi Sankyo, Abbott, New Amsterdam, SCRIBE, CRISPR, VAXXINITY, EMENDOBIO, Cargene, Viatris, Amarin, Nodthera, and Resverlogix; honoraria for lectures from AstraZeneca, Novartis, Sanofi, Amgen, Algorithm, Boehringer Ingelheim, Novo Nordisk, Esperion, Daiichi Sankyo, and Amarin; and stock options in New Amsterdam, PEMI 31, and SCRIBE. HS reports research grants from Amgen, MSD, Synageva, Amryt, Alexion, and Akcea; consulting fees from Amgen, Alexion, Daiichi-Sankyo, Novartis, Pfizer, and Akcea; and speaker fees from Amgen, Daiichi-Sankyo, Sanofi, and Akcea. AW reports research grants from Amgen, Esperion, Novartis, Regeneron, Sanofi, Silence Therapeutics, and Ultragenyx; consulting fees from Chiesi and Novartis; and speaker fees from Algorithm, Sanofi, and Ultragenyx. All other authors declare no competing interests. The declaration of interests of individual collaborators are listed in the appendix (p 27)., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Thoracic outlet syndrome (TOS) caused by superior mediastinal soft tissue mass has never been reported in the literature, the aim of this study is to discuss a case of TOS caused by a superior mediastinal mass in which the histopathological examinations of the mass showed vascular malformation., Case Report: A 45-year-old female presented with left upper limb pain and numbness for three months, associated with swelling and attacks of shortness of breath. Imaging studies showed soft tissue mass involving the superior mediastinum. The condition of the patient deteriorated and the signs and symptoms of TOS became clearer, all provocative tests and nerve conduction studies were positive. The patient underwent thoracic outlet decompression. The patient did not respond and the symptoms deteriorated further. After a multidisciplinary board discussion, the patient was prepared for median sternotomy under general anesthesia. A total resection of the mass was done. The patient was totally relieved a few hours after the operation., Discussion: The etiology of TOS can be multifaceted. Several factors contribute to its onset, and these can be categorized as congenital or acquired. Congenital causes include anatomical anomalies such as a cervical rib, or an elongated transverse process of the cervical vertebrae. These anatomical deviations can reduce the size of the thoracic outlet and make it prone to compression., Conclusion: Although it is rare, TOS could be due to superior mediastinal mass and the treatment of choice is total resection either through median sternotomy or thoracoscopic procedure., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III., Methods: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis., Results: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group., Conclusions: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.)., (Copyright © 2024 Massachusetts Medical Society.)

Purpose: There are inconsistent reports of an association between low cholesterol, use of lipid-lowering agents, and carcinogenesis. The purpose of this paper was to examine the relationship between cancer, lipids, statin use, and use of other lipid-lowering therapies., Methods: This comprehensive literature review incorporated article searches in electronic databases (Embase, PubMed, OVID) and reference lists of relevant articles, with the authors' expertise in lipidology. This review considered seminal and novel research looking at the relationship between cholesterol, lipid-lowering therapies, and cancer., Findings: Statin use has been reported to reduce the risk for incident cancer or progression of cancer; however, it is unknown whether this reduced risk of carcinogenesis is due to the pleotropic properties of statins or the effects of low cholesterol. The effect of ezetimibe on carcinogenesis has been regarded as neutral, despite earlier concerns of increased cancer risk with its use. Proprotein convertase subtilisin/kexin (PCSK)-9 monoclonal antibodies have been shown to have a neutral effect on carcinogenesis. Despite anti-cancer effects of fibrates in vitro, studies in humans have yielded inconsistent outcomes leaning toward protection against the development and progression of cancer., Implications: Statins, fibrates, PCSK9 monoclonal antibodies, and ezetimibe have a neutral effect on cancer risk, and the first three may provide some protection. PSCK9 monoclonal antibodies have the potential to enhance the response to checkpoint inhibitor therapy for cancer. Further research is needed to determine which drugs can be issued in adjuvant therapy to improve outcomes in patients undergoing cancer treatment., Competing Interests: Declaration of competing interest H.S. has received received research grants from Alexion, AKCEA, Amgen, Pfizer, MSD, Genzyme-Sanofi, Amryt, Synagenva, Alexion; personal fees and education grants from Aegerion, Amgen, Amarin, Daichii Sankyo, Janssen Cilag Ltd, Lilly, MSD, Novartis, Pfizer, Sanofi, NAPP, Novartis, Medicines Company, Alexion. Consultancy and advisory boards from Sanofi, Amryt, AKCEA, AMGEN, Medicine’s Company, Novartis. S.A has received honoraria for educational meetings from Astra Zeneca, Lilly, Menarini, and Sanofi. The authors have indicated that they have no other conflicts of interest with regard to the content of this article., (Copyright © 2024. Published by Elsevier Inc.)

Background and Aims: Prognosis and management differ between familial chylomicronaemia syndrome (FCS), a rare autosomal recessive disorder, and multifactorial chylomicronaemia syndrome (MCS) or severe mixed hyperlipidaemia. A clinical scoring tool to differentiate these conditions has been devised but not been validated in other populations. The objective of this study was to validate this score in the UK population and identify any additional factors that might improve it., Methods: A retrospective validation study was conducted using data from 151 patients comprising 75 FCS and 76 MCS patients. All participants had undergone genetic testing for genes implicated in FCS. Validation was performed by standard methods. Additional variables were identified from clinical data by logistic regression analysis., Results: At the recommended FCS score threshold ≥10 points, the sensitivity and specificity of the score in the UK population were 96% and 75%, respectively. The receiver operating characteristic (ROC) curve analysis yielded an area under the curve (AUC) of 0.88 (95% CI 0.83-0.94, p < 0.001). This study identified non-European (predominantly South Asian) ethnicity, parental consanguinity, body mass index (BMI) < 25 kg/m 2 , and recurrent pancreatitis as additional positive predictors, while BMI >30 kg/m 2 was found to be a negative predictor for FCS. However, inclusion of additional FCS predictors had no significant impact on performance of standard FCS score., Conclusions: Our study validates the FCS score in the UK population to distinguish FCS from MCS. While additional FCS predictors were identified, they did not improve further the score diagnostic performance., Competing Interests: Declaration of competing interest HS: Received personal fees from Amgen, Akcea, Synageva, NAPP, Novartis, Takeda, Sanofi, Pfizer, SOBI and Kowa and research grants and donations from Akcea, Pfizer, MSD, Amgen, Genzyme-Sanofi, Synageva, Amryt, Synageva and Alexion. ASW: Received grants from Akcea, Regeneron; Royalties from Elsevier and is a board member for familial hyperlipidaemia group, Europe. DD: Received honoraria for advisory boards from SOBI. NF: Received honoraria for presentations from SOBI. YT: Received speakers fee from Daiichi Sankyo and Amarin. PD: Received honoraria from SOBI, NOVARTIS, AMGEN and Daiichi Sankyo. PM: Participated on a Data Safety Monitoring Board and Advisory Board for Ionis, AKCEA, AMRYT, AMARIN, Ultragenix AG: received research grants from AMGEN, SANOFI, AMRYT, ULTRAGENYX, Consulting fee or honoraria from AMGEN, SANOFI, AMRYT, ULTRAGENYX, NOVARTIS, AKCEA, SERVIER. BB, SK, CD, AJ, FJ, MM, HD, PH, MM, AA, DO, PND: None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Importance: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by extremely increased low-density lipoprotein (LDL) cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Heterozygous familial hypercholesterolemia (HeFH) is more common than HoFH, and women with HeFH are diagnosed later and undertreated compared to men; it is unknown whether these sex differences also apply to HoFH., Objective: To investigate sex differences in age at diagnosis, risk factors, lipid-lowering treatment, and ASCVD morbidity and mortality in patients with HoFH., Design, Setting, and Participants: Sex-specific analyses for this retrospective cohort study were performed using data from the HoFH International Clinical Collaborators (HICC) registry, the largest global dataset of patients with HoFH, spanning 88 institutions across 38 countries. Patients with HoFH who were alive during or after 2010 were eligible for inclusion. Data entry occurred between February 2016 and December 2020. Data were analyzed from June 2022 to June 2023., Main Outcomes and Measures: Comparison between women and men with HoFH regarding age at diagnosis, presence of risk factors, lipid-lowering treatment, prevalence, and onset and incidence of ASCVD morbidity (myocardial infarction [MI], aortic stenosis, and combined ASCVD outcomes) and mortality., Results: Data from 389 women and 362 men with HoFH from 38 countries were included. Women and men had similar age at diagnosis (median [IQR], 13 [6-26] years vs 11 [5-27] years, respectively), untreated LDL cholesterol levels (mean [SD], 579 [203] vs 596 [186] mg/dL, respectively), and cardiovascular risk factor prevalence, except smoking (38 of 266 women [14.3%] vs 59 of 217 men [27.2%], respectively). Prevalence of MI was lower in women (31 of 389 [8.0%]) than men (59 of 362 [16.3%]), but age at first MI was similar (mean [SD], 39 [13] years in women vs 38 [13] years in men). Treated LDL cholesterol levels and lipid-lowering therapy were similar in both sexes, in particular statins (248 of 276 women [89.9%] vs 235 of 258 men [91.1%]) and lipoprotein apheresis (115 of 317 women [36.3%] vs 118 of 304 men [38.8%]). Sixteen years after HoFH diagnosis, women had statistically significant lower cumulative incidence of MI (5.0% in women vs 13.7% in men; subdistribution hazard ratio [SHR], 0.37; 95% CI, 0.21-0.66) and nonsignificantly lower all-cause mortality (3.0% in women vs 4.1% in men; HR, 0.76; 95% CI, 0.40-1.45) and cardiovascular mortality (2.6% in women vs 4.1% in men; SHR, 0.87; 95% CI, 0.44-1.75)., Conclusions and Relevance: In this cohort study of individuals with known HoFH, MI was higher in men compared with women yet age at diagnosis and at first ASCVD event were similar. These findings suggest that early diagnosis and treatment are important in attenuating the excessive cardiovascular risk in both sexes.

Competing Interests: Declaration of competing interest None.

Bariatric surgery improves dyslipidaemia and reduces body weight, but it remains unclear how bariatric surgery modulates gene expression in fat cells to influence the proprotein convertase subtilisin/kexin type 9 (PCSK-9) and low-density lipoprotein receptor (LDLR) gene expression. The expression of the PCSK9/LDLR/tumor necrosis factor-alpha (TNFα) gene in adipose tissue was measured in two groups of Zucker Diabetic Sprague Dawley (ZDSD) rats after Roux-en-Y gastric bypass (RYGB) surgery or 'SHAM' operation. There was lower PCSK9 ( p = 0.02) and higher LDLR gene expression ( p = 0.02) in adipose tissue in rats after RYGB. Weight change did not correlate with PCSK9 gene expression (r = -0.5, p = 0.08) or TNFα gene expression (r = -0.4, p = 0.1). TNFα gene expression was positively correlated with PCSK9 gene expression (r = 0.7, p = 0.001) but not correlated with LDLR expression (r = -0.3, p = 0.3). Circulating triglyceride levels were lower in RYGB compared to the SHAM group (1.1 (0.8-1.4) vs. 1.5 (1.0-4.2), p = 0.038) mmol/L with no difference in cholesterol levels. LDLR gene expression was increased post-bariatric surgery with the potential to reduce the number of circulating LDL particles. PCSK9 gene expression and TNFα gene expression were positively correlated after RYGB in ZDSD rats, suggesting that the modulation of pro-inflammatory pathways in adipose tissue after RYGB may partly relate to PCSK9 and LDLR gene expression.

Bariatric surgery in people with obesity can lead to long-term remission of type 2 diabetes mellitus (T2DM) and a reduction in the incidence of macrovascular complications. The impact of bariatric surgery on microvascular complications is less clear. In this narrative review, we sought to evaluate the effect of bariatric surgery on microvascular complications in patients with and without diabetes. The risk of developing microvascular complications is increased in people with obesity, and this is amplified in those with T2DM. The impact of metabolic surgery on microvascular complications is limited to a subgroup analysis of studies or statistical modeling to predict the glycemia-independent effect of bariatric surgery. While bariatric surgery halts the progression of retinopathy in those with minimal retinopathy, it may worsen in those with advanced retinopathy. Bariatric surgery improves proteinuria and major renal outcomes, regardless of the severity of renal impairment. Bariatric surgery in patients with obesity with or without diabetes is associated with an improvement in neuropathic symptoms and regeneration of small nerve fibers. In conclusion, bariatric surgery is associated with an improvement in microvascular complications. Further studies are needed to elucidate the underlying mechanisms for the favorable effect of bariatric surgery on microvascular outcomes., (© 2023 World Obesity Federation.)

Purpose of Review: The aim of this review was to provide an overview of the role of novel biomarkers in metabolic syndrome, their association with cardiovascular risk and the impact of bariatric surgery on these biomarkers., Recent Findings: Metabolic syndrome encompasses an intricate network of health problems, and its constituents extend beyond the components of its operational definition. Obesity-related dyslipidaemia not only leads to quantitative changes in lipoprotein concentration but also alteration in qualitative composition of various lipoprotein subfractions, including HDL particles, rendering them proatherogenic. This is compounded by the concurrent existence of obstructive sleep apnoea (OSA) and nonalcoholic fatty liver disease (NAFLD), which pave the common pathway to inflammation and oxidative stress culminating in heightened atherosclerotic cardiovascular disease (ASCVD) risk. Bariatric surgery is an exceptional modality to reverse both conventional and less recognised aspects of metabolic syndrome. It reduces the burden of atherosclerosis by ameliorating the impact of obesity and its related complications (OSA, NAFLD) on quantitative and qualitative composition of lipoproteins, ultimately improving endothelial function and cardiovascular morbidity and mortality., Summary: Several novel biomarkers, which are not traditionally considered as components of metabolic syndrome play a crucial role in determining ASCVD risk in metabolic syndrome. Due to their independent association with ASCVD, it is imperative that these are addressed. Bariatric surgery is a widely recognized intervention to improve the conventional risk factors associated with metabolic syndrome; however, it also serves as an effective treatment to optimize novel biomarkers., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: There are multiple management modalities for idiopathic granulomatous mastitis, but the treatment of choice is still under debate. This study aims to evaluate the diagnosis and outcomes of different management modalities in patients with idiopathic granulomatous mastitis and to identify the risk factors associated with recurrence., Method: This is a single-group cohort study that included those patients who had idiopathic granulomatous mastitis. Ultrasonography was conducted for all of the cases using LOGIQ E9 with an ML6-15 transducer (5-15 MHz). A core needle biopsy was conducted to take samples from the cases for histopathological examination. The patients were put on steroid therapy. Whenever the cases did not respond to the steroid therapy, treatment with a combination of low-dose steroids and methotrexate was started. In the lack of response to conservative treatments, surgical interventions were started., Results: Sixty-three cases with a confirmed histopathological diagnosis of granulomatous mastitis were included. The mean age of patients was 35.7 years. The history of more than one childbirth was positive in a large portion of the cases (82.5%). The lesion side was unilateral in 58.7% of the cases. A large proportion of the lesions were classified as BIRADS category 2. The best treatment outcome was yielded by a combination of low-dose steroids and incision and drainage. The factors of age, lesion area (cm 2 ), skin thickening, and white blood cell count enhanced the chance of recurrence., Conclusion: Incision and drainage in combination with a low dose of steroids can give an acceptable outcome with a low rate of recurrence., Competing Interests: All authors declare that they have no conflict of interest., (Copyright © 2023 by S. Karger AG, Basel.)

Renal cell carcinoma (RCC) is a heterogeneous and complex disease with numerous pathophysiologic variants. ~40% of patients succumb due to the progression of the disease, making RCC the most fatal of the common urologic malignancies. Prognostic factors are indicators of the progression of the disease, and the precise determination of these factors is important for evaluating and managing RCC. In the present study, it was aimed to determine and find associations among the histopathological features of RCCs and their impact on survival and metastasis. This is a cross-sectional study of RCC cases who have undergone partial or radical nephrectomy from March 2008 to October 2021 and have been pathologically reviewed at Shorsh General Teaching Hospital in Sulaimani, Iraq. The data in the pathology studies were supplemented by follow-up of the patients to obtain information about survival, recurrence and metastasis. In total, 228 cases of RCC were identified, among whom 60.5% were men and 39.5% were women, with a median age of 51 years. The main tumor types were clear cell RCC (71.1%), papillary RCC (13.6%), and chromophobe RCC (11%). Various measures of aggressiveness, including tumor necrosis, sarcomatoid change, microvascular invasion, and parameters of invasiveness (invasion of the renal sinus and other structures), were significantly correlated with each other, and they were also associated with reduced overall survival and an increased risk of metastasis on univariate analysis. However, on multivariate analysis, only tumor size and grade, and microvascular invasion retained statistical significance and were associated with a lower survival rate. In conclusion, pathological parameters have an impact on prognosis in RCC. The most consistent prognostic factors can be tumor size and grade, and microvascular invasion., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Ali et al.)

Background and Aims: The VOL4002 study assessed the efficacy and safety of volanesorsen in 22 adults with genetically confirmed familial chylomicronaemia syndrome (FCS) treated in the UK Early Access to Medicines Scheme (EAMS), with ("prior exposure") or without ("treatment naive") previous treatment in the APPROACH and/or APPROACH-OLE volanesorsen phase 3 studies., Methods: Data collection focused on triglyceride (TG) levels, platelet counts and pancreatitis events. Pancreatitis incidence during volanesorsen treatment was compared against the 5-year period preceding volanesorsen exposure. Volanesorsen 285 mg was self-administered subcutaneously once every 2 weeks., Results: Individual patient volanesorsen exposure ranged from 6 to 51 months (total cumulative exposure, 589 months). Among treatment-naive patients (n = 12), volanesorsen treatment resulted in an averaged median 52% reduction (-10.6 mmol/L) from baseline (26.4 mmol/L) in TG levels at 3 months, which were maintained through time points over 15 months of treatment (47%-55% reductions). Similarly, prior-exposure patients (n = 10) experienced a 51% reduction (-17.8 mmol/L) from pre-treatment baseline (28.0 mmol/L), with reductions of 10%-38% over 21 months of treatment. A comparison of pancreatitis event rates found a 74% reduction from the 5-year period before (one event/2.8 years) and during (one event/11.0 years) volanesorsen treatment. Platelet declines were consistent with observations in phase 3 clinical trials. No patient recorded a platelet count <50 × 10 9 /L., Conclusions: This longitudinal study supports the efficacy of volanesorsen in patients with FCS for lowering TG levels over treatment periods up to 51 months with no apparent safety signals related to increased duration of exposure., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:AJ has no conflicts of interest to declare.KP has no conflicts of interest to declare.ASW is a site investigator for clinical trials for Akcea, Amgen, Regeneron, and Sanofi.RR has no conflicts of interest to declare.MM has no conflicts of interest to declare. CD has no conflicts of interest to declare.AOF has no conflicts of interest to declare.HS has received research and education grants and honoraria from Akcea Therapeutics.FJ has no conflicts of interest to declare.IM has no conflicts of interest to declare.PD has received speaker fees and honoraria from Akcea Therapeutics for attendance at Advisory boards.PH has no conflicts of interest to declare.RJ was an employee of Akcea Therapeutics at the time the study was undertaken., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Acute pancreatitis is an inflammatory disease that can affect both the peripancreatic tissues and distant organs. There are few reports of acute pancreatitis caused by endourological procedures. However, an obstructing ureteral calculus causing acute pancreatitis is very rare., Case Presentation: A 36-year-old male patient presented with epigastric, and right loin pain with decreased urine output for 3 days. On physical examination, he had central abdominal and right flank tenderness. An abdominal ultrasound showed mild to moderate ascites, a hyperechoic pancreas, a small (26×77 mm) left kidney with increased echogenicity, right renal hypertrophy with moderate hydronephrosis, and a dilated upper ureter due to a 10 mm obstructing stone with a perirenal fluid collection. The diagnosis of acute pancreatitis with an obstructing right upper ureteric stone was established. Under spinal anesthesia, an emergency ureteroscopy with laser fragmentation of the stone was performed, and a JJ stent was inserted. He developed postobstructive diuresis and his renal function was improved with a rapid decline of pancreatic enzymes as well., Clinical Discussion: Two theories explain the presentation of acute pancreatitis by ureteral obstruction. First, the obstructed severe hydronephrotic kidney compresses the duodenum and head of the pancreas, obstructing the distal part of the common bile duct and triggering the elevation of pancreatic duct pressure, bile reflux, trypsin activation, and pancreatic autodigestion. The second theory states that acute pancreatitis develops when urine is extravasated from an obstructed kidney into the adjacent tissues, irritating the uncinate process of the pancreas., Conclusion: Although mentioning ureteral obstruction as a cause of pancreatitis is scarce, the clinician should be aware that in each case of ureteral obstruction, the emergence of acute pancreatitis is a possible complication., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Familial chylomicronemia syndrome (FCS) is a rare, autosomal recessive genetic disorder characterized by a marked increase in plasma triglyceride (TG) levels and recurrent episodes of pancreatitis. The response to conventional TG-lowering therapies is suboptimal. Volanesorsen, an antisense oligonucleotide that targets hepatic apoC-III mRNA, has been shown to significantly reduce TGs in patients with FCS., Objective: To further evaluate the safety and efficacy of extended treatment with volanesorsen in patients with FCS., Methods: This phase 3 open-label extension study evaluated the efficacy and safety of extended treatment with volanesorsen in three groups of patients with FCS: Those who had previously received volanesorsen or placebo in the APPROACH and COMPASS studies, and treatment-naive patients not participating in either study. Key endpoints included change in fasting TG and other lipid measurements, and safety over 52 weeks., Results: Volanesorsen treatment resulted in sustained reductions in plasma TG levels in previously treated patients from the APPROACH and COMPASS studies. Volanesorsen-treated patients from the three populations studied had mean decreases in fasting plasma TGs from index study baseline to months 3, 6, 12 and 24 as follows: decreases of 48%, 55%, 50%, and 50%, respectively (APPROACH); decreases of 65%, 43%, 42%, and 66%, respectively (COMPASS); and decreases of 60%, 51%, 47%, and 46%, respectively (treatment-naive). Common adverse events were injection site reactions and platelet count decrease, consistent with previous studies., Conclusion: Extended open-label treatment with volanesorsen in patients with FCS resulted in sustained reductions of plasma TG levels and safety consistent with the index studies., Competing Interests: Declaration of Competing Interest JLW is a consultant to Ionis Pharmaceuticals and ST is an employee of Ionis Pharmaceuticals. JLW and ST are co-inventors and receive royalties from patents owned by the University of California, San Diego on oxidation-specific antibodies and of biomarkers related to oxidized lipoproteins. They are co-founders and have an equity interest in Oxitope, Inc and its affiliates (“Oxitope”) as well as in Kleanthi Diagnostics, LLC (“Kleanthi”). Although these relationships have been identified for conflict of interest management based on the overall scope of the project and its potential benefit to Oxitope and Kleanthi, the research findings included in this particular publication may not necessarily relate to the interests of Oxitope and Kleanthi. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. DG reports grants and personal fees from Ionis Pharmaceuticals during the conduct of the study; grants and personal fees from Allergan, Amgen, Amryt, Arrowhead, Eli Lilly, Novartis, NovoNordisk, Regeneron, and Sanofi outside the submitted work; grants from Acasti, Aegerion, Applied Therapeutics, AstraZeneca, Boehringer-Ingelheim, Ceapro, Dalcor, Esperion, Kowa, The Medicine Company, and Uniqure outside the submitted work; and personal fees from CRISPR Therapeutics, Saliogen, and Verve Therapeutics outside the submitted work. MA has received research grant support and lecturing fees from Alfasigma, Amgen, Amryt, Daiichi Sankyo, Ionis/Akcea, Novartis, Pfizer, Regeneron, and Sanofi. AJ has provided services to the following companies: Akcea, Amgen, Sanofi, and SOBI. HS received research and education grants and honoraria from Akcea Therapeutics, Alexion, Amryt, Synageva, Kowa, MSD, NAPP, Novartis, Pfizer, Sanofi, Synageva, and Takeda. IG-B has received personal honoraria from Aegerion, Akcea, Amarin, Amgen, Daiichi Sankyo, Novartis, Regeneron, and Sanofi; and nonfinancial support from Akcea, Amgen, and Sanofi. ESGS has received advisory board/lecturing fees, paid to institution, from: Amgen, Sanofi, NovoNordisk, AstraZeneca, Esperion, Daiichi-Sankyo, and Ionis/Akcea. No patents/stocks. VJA, LW, and SX are employees of Ionis Pharmaceuticals. RJ was an employee of Akcea Therapeutics at the time of the study and manuscript development and may own stock in Ionis Pharmaceuticals, parent company of Akcea Therapeutics., (Copyright © 2023 National Lipid Association. All rights reserved.)

We have reviewed the genetic basis of chylomicronaemia, the difference between monogenic and polygenic hypertriglyceridaemia, its effects on pancreatic, cardiovascular, and microvascular complications, and current and potential future pharmacotherapies. Severe hypertriglyceridaemia (TG > 10 mmol/L or 1000 mg/dL) is rare with a prevalence of <1%. It has a complex genetic basis. In some individuals, the inheritance of a single rare variant with a large effect size leads to severe hypertriglyceridaemia and fasting chylomicronaemia of monogenic origin, termed as familial chylomicronaemia syndrome (FCS). Alternatively, the accumulation of multiple low-effect variants causes polygenic hypertriglyceridaemia, which increases the tendency to develop fasting chylomicronaemia in presence of acquired factors, termed as multifactorial chylomicronaemia syndrome (MCS). FCS is an autosomal recessive disease characterized by a pathogenic variant of the lipoprotein lipase ( LPL ) gene or one of its regulators. The risk of pancreatic complications and associated morbidity and mortality are higher in FCS than in MCS. FCS has a more favourable cardiometabolic profile and a low prevalence of atherosclerotic cardiovascular disease (ASCVD) compared to MCS. The cornerstone of the management of severe hypertriglyceridaemia is a very-low-fat diet. FCS does not respond to traditional lipid-lowering therapies. Several novel pharmacotherapeutic agents are in various phases of development. Data on the correlation between genotype and phenotype in FCS are scarce. Further research to investigate the impact of individual gene variants on the natural history of the disease, and its link with ASCVD, microvascular disease, and acute or recurrent pancreatitis, is warranted. Volanesorsen reduces triglyceride concentration and frequency of pancreatitis effectively in patients with FCS and MCS. Several other therapeutic agents are in development. Understanding the natural history of FCS and MCS is necessary to rationalise healthcare resources and decide when to deploy these high-cost low-volume therapeutic agents.

Bronchogenic carcinoma comprises >90% of primary lung tumors. The present study aimed to estimate the profile of patients with bronchogenic carcinoma and assess the cancer resectability in newly diagnosed patients. This is a single-center retrospective review conducted over a period of 5 years. A total of 800 patients with bronchogenic carcinoma were included. The diagnoses were mostly proven with either cytological examination or histopathological diagnosis. Sputum analysis, cytological examination of pleural effusion and bronchoscopic examination were performed. Lymph node biopsy, minimally invasive procedures (mediastinoscopy and video-assisted thoracoscopic surgery), tru-cut biopsy or fine-needle aspiration was used to obtain the samples for diagnosis. The masses were removed by lobectomy and pneumonectomy. The age range was between 22 and 87 years, with a mean age of 62.95 years. Males represented the predominant sex. Most of the patients were smokers or ex-smokers. The most common symptom was a cough, followed by dyspnea. Chest radiography revealed abnormal findings in 699 patients. A bronchoscopic evaluation was performed for the majority of patients (n=633). Endobronchial masses and other suggestive malignancy findings were present in 473 patients (83.1%) of the 569 who underwent fiberoptic bronchoscopy. Cytological and/or histopathological samples of 581 patients (91.8%) were positive. Small cell lung cancer (SCLC) occurred in 38 patients (4.75%) and non-SCLC was detected in 762 patients (95.25%). Lobectomy was the main surgical procedure, followed by pneumonectomy. A total of 5 patients developed postoperative complications without any mortality. In conclusion, bronchogenic carcinoma is rapidly increasing without a predilection for sex in the Iraqi population. Advanced preoperative staging and investigation tools are required to determine the rate of resectability., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Marie et al.)

Diabetes is a metabolic disorder with an increased risk of developing heart failure. Inflammation and damaged vasculature are the cardinal features of diabetes-induced cardiac damage. Moreover, systemic metabolic stress triggers discordant intercellular communication, thus culminating in cardiac dysfunction. Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone transducing cellular signals via fibroblast growth factor receptor 1 (FGFR1) and its co-receptor beta-klotho (β-KL). This study first demonstrated a decreased expression or activity of FGFR1 and β-KL in both human and mouse diabetic hearts. Reinforcing cardiac FGFR1 and β-KL expression can alleviate pro-inflammatory response and endothelial dysfunction upon diabetic stress. Using proteomics, novel cardiomyocyte-derived anti-inflammatory and proangiogenic factors regulated by FGFR1-β-KL signaling were identified. Although not exhaustive, this study provides a unique insight into the protective topology of the cardiac FGFR1-β-KL signaling-mediated intercellular reactions in the heart in response to metabolic stress., Competing Interests: The authors declare no conflict of interest., (© 2023 Published by Elsevier Ltd.)

Early diagnosis and appropriate staging workup are crucial for cancer patients. Whole-body magnetic resonance imaging (WB-MRI) has been proposed as another practical whole-body approach for assessing local invasiveness and distant metastases in patients newly diagnosed with cancer. The current study aimed to evaluate the efficacy of WB-MRI in assessing metastasis in patients newly diagnosed with cancer using histopathologic data as the reference method. A prospective observational study was performed from April 2018 to July 2020. MRI sequences were utilized to acquire anatomical and functional images in three orthogonal planes. The discovery was classified as nodal, skeletal and visceral metastases. Patient-based analysis was used for visceral metastasis and region-based for skeletal, systemic and lymph node metastases. A total of 43 consecutive patients (mean age, 56±15.2 years) were assessed successively. In 41 patients, there was a concordance between the WB-MRI and histological confirmation. The most prevalent site of metastasis was the skeletal system (18 patients). There were 12 individuals with liver metastasis, 10 with lung metastasis and 4 with peritoneal metastasis, with just one brain metastatic lesion found. On WB-MRI, 38 lymph node groups were deemed positive. Out of the total, 66 skeletal locations contained metastases. The accuracy of WB-MRI for nodal, skeletal and visceral metastases was (98.45, 100 and 100%, respectively). In conclusion, WB-MRI in three orthogonal planes, including the diffusion-weighted MRI with background body signal suppression sequence, may be utilized efficiently and accurately for assessing metastasis staging and may thus be utilized in patients with newly diagnosed cancer., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Rashid et al.)

The dominant sensory phenotype in patients with diabetic polyneuropathy and neuropathic pain is a loss of function. This raises questions as to which mechanisms underlie pain generation in the face of potentially reduced afferent input. One potential mechanism is spinal disinhibition, whereby a loss of spinal inhibition leads to increased ascending nociceptive drive due to amplification of, or a failure to suppress, incoming signals from the periphery. We aimed to explore whether a putative biomarker of spinal disinhibition, impaired rate-dependent depression of the Hoffmann reflex, is associated with a mechanistically appropriate and distinct pain phenotype in patients with painful diabetic neuropathy. In this cross-sectional study, 93 patients with diabetic neuropathy underwent testing of Hoffmann reflex rate-dependent depression and detailed clinical and sensory phenotyping, including quantitative sensory testing. Compared to neuropathic patients without pain, patients with painful diabetic neuropathy had impaired Hoffmann reflex rate-dependent depression at 1, 2 and 3 Hz ( P ≤ 0.001). Patients with painful diabetic neuropathy exhibited an overall loss of function profile on quantitative sensory testing. However, within the painful diabetic neuropathy group, cluster analysis showed evidence of greater spinal disinhibition associated with greater mechanical pain sensitivity, relative heat hyperalgesia and higher ratings of spontaneous burning pain. These findings support spinal disinhibition as an important centrally mediated pain amplification mechanism in painful diabetic neuropathy. Furthermore, our analysis indicates an association between spinal disinhibition and a distinct phenotype, arguably akin to hyperpathia, with combined loss and relative gain of function leading to increasing nociceptive drive., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Paraoxonase 1 (PON1), residing almost exclusively on HDL, was discovered because of its hydrolytic activity towards organophosphates. Subsequently, it was also found to hydrolyse a wide range of substrates, including lactones and lipid hydroperoxides. PON1 is critical for the capacity of HDL to protect LDL and outer cell membranes against harmful oxidative modification, but this activity depends on its location within the hydrophobic lipid domains of HDL. It does not prevent conjugated diene formation, but directs lipid peroxidation products derived from these to become harmless carboxylic acids rather than aldehydes which might adduct to apolipoprotein B. Serum PON1 is inversely related to the incidence of new atherosclerotic cardiovascular disease (ASCVD) events, particularly in diabetes and established ASCVD. Its serum activity is frequently discordant with that of HDL cholesterol. PON1 activity is diminished in dyslipidaemia, diabetes, and inflammatory disease. Polymorphisms, most notably Q192R, can affect activity towards some substrates, but not towards phenyl acetate. Gene ablation or over-expression of human PON1 in rodent models is associated with increased and decreased atherosclerosis susceptibility respectively. PON1 antioxidant activity is enhanced by apolipoprotein AI and lecithin:cholesterol acyl transferase and diminished by apolipoprotein AII, serum amyloid A, and myeloperoxidase. PON1 loses this activity when separated from its lipid environment. Information about its structure has been obtained from water soluble mutants created by directed evolution. Such recombinant PON1 may, however, lose the capacity to hydrolyse non-polar substrates. Whilst nutrition and pre-existing lipid modifying drugs can influence PON1 activity there is a cogent need for more specific PON1-raising medication to be developed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Durrington, Bashir and Soran.)

Many individuals with marginally abnormal thyroid function test (TFT) results may be treated and it is unknown if the limits of the thyrotropin (TSH) and free thyroxine (FT4) reference intervals reported alongside the laboratory results are associated with the prevalence of levothyroxine treatment. We obtained information regarding reported TFT reference intervals from UK National Health Service (NHS) laboratories and evaluated its relationship with the prevalence of levothyroxine treatment for corresponding health areas for 2014. The upper limit of serum TSH was significantly, linearly, independently, and negatively associated with prevalent levothyroxine treatment: -0.54% (95% CI, -0.68% to -0.40%). The lower limit of serum FT4 was significantly and independently associated with the prevalence of levothyroxine treatment in a non-linear (J-shaped) manner with an increase being noted from a FT4 level of ≈9.5 pmol/L onwards. We conclude that minor changes in the reference range limits for serum TSH and FT4 are associated with levothyroxine treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Renal cell carcinoma (RCC) accounts for 1-2% of all malignancies and is the most common renal tumor in adults. Imaging studies are used for diagnosis and staging. Tumor-Node-Metastasis staging strongly affects prognosis and management, while contrast-enhanced computed tomography (CECT) is regarded as a standard imaging technique for local and distant staging. The present study aimed to evaluate the accuracy of CECT for the preoperative staging of RCC by using surgical and pathological staging as the reference methods. This single-center prospective study was conducted between October 2019 and November 2021. The preoperative abdominal CT scans of patients suspected of having RCC were reviewed. Imaging data were collected, including tumor side and size, and perinephric fat invasion. Intraoperative notes were recorded, including the operation type, perinephric fat invasion, renal vein (RV) or inferior vena cava (IVC) tumor extension, and surrounding organ invasion. pathological data were collected on tumor size, RCC type, presence of clear margins, presence of renal capsule or perinephric fat invasion, renal sinus or pelvicalyceal system (PCS) invasion, segmental or main RV extension, and the involvement of Gerota's fascia and nearby organs. Preoperative CECT revealed that 42 out of 59 tumors had a greater maximum diameter than the pathological specimen, with an overall disparity of 0.25 cm. The specificity of CT for the detection of tumor invasion of the perinephric and renal sinus fat and PCS was 95%, and the sensitivity ranged from 80 to 88%. CT had an 83% sensitivity and a 95 specificity in detecting T4 stage cancer, with a 100% specificity for adrenal invasion. The concordance between radiographic and histological results for RV and IVC involvement was high, with specificities of 94 and 98%, and sensitivities of 80 and 100%, respectively. Overall accuracy for correct T staging was 80%. In conclusion, CECT is accurate in the local T staging of RCC, with high sensitivity and specificity for estimating tumor size and detecting extension to nearby structures and venous invasion., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Fateh et al.)

There are controversies regarding the normal size of the adult spleen and its correlation with age, sex and body parameters. The present study aimed to establish a reference value of splenic dimensions, volume and their correlations with different body parameters. The present cross-sectional study was conducted on 300 healthy adult volunteers of both sexes. Age, sex, height, weight and body mass index (BMI) were recorded. The ultrasound measurements of spleen parameters included length, thickness and width. The spleen volume was calculated using the standard prolate ellipsoid formula (length x thickness x width x0.523). The mean ± SD age was 38.7±14 years, the mean height was 166±9.9 cm, the mean weight was 74.7±15.8 kg and the mean BMI was 27±5 kg/m 2 . The mean spleen length, thickness, width and volume were 10.68±1.28 cm, 4.1±0.58 cm, 7.3±0.9 cm and 174.4±52.4 ml, respectively. Males had larger spleen parameters than females. Spleen volume significantly correlated with the subjects' height (r=0.655, P<0.001) and weight (r=0.643, P<0.001). However, weaker correlations were detected between age (r=-0.238, P<0.001) and BMI (r=0.299, P<0.001) with spleen volume. A higher significant correlation was found between spleen volume and spleen length rather than with its thickness and width. In the present study, the normative data of splenic dimensions and volume have been provided and may be used in certain clinical situations., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Fateh et al.)

Background: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels., Methods: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes., Results: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease., Conclusions: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.)., (Copyright © 2022 Massachusetts Medical Society.)

Purpose of Review: Guidelines for cholesterol-lowering treatment generally include extensive review of epidemiological and clinical trial evidence. However, the next logical step, the translation of evidence into clinical advice, occurs not entirely by reasoning, but by a form of consensus in which the prejudices and established beliefs of the societies with interests in cardiovascular disease convened to interpret the evidence are prominent. Methods, which are the subject of this review, have, however, been developed by which clinical trial evidence can be translated objectively into best practice., Recent Findings: Guidelines differ in their recommended goals for cholesterol-lowering treatment in the prevention of atherosclerotic cardiovascular disease (ASCVD). Proposed goals are LDL-cholesterol 2.6 mmol/l (100 mg/dl) or less in lower risk, LDL-cholesterol 1.8 mmol/l (70 mg/dl) or less in higher risk, non-HDL-cholesterol decrease of at least 40% or LDL-cholesterol 1.8 mmol/l (70 mg/dl) or less or decreased by at least 50% whichever is lower. Evidence from clinical trials of statins, ezetimibe and proprotein convertase subtilisin/kexin type 9-inhibitors can be expressed in simple mathematical terms to compare the efficacy on ASCVD incidence of clinical guidance for the use of cholesterol-lowering medication. The target LDL-cholesterol of 2.6 mmol/l (100 mg/dl) is ineffective and lacks credibility. Cholesterol-lowering medication is most effective in high-risk people with raised LDL-cholesterol. The best overall therapeutic target is LDL-cholesterol 1.8 mmol/l (70 mg/dl) or less or decreased by at least 50% whichever is lower. The use of non-HDL-cholesterol as a therapeutic goal is less efficacious. Aiming for LDL-cholesterol 1.4 mmol/l (55 mg/dl) or less as opposed to 1.8 mmol/l produces only a small additional benefit. Evidence for apolipoprotein B targets in hypertriglyceridaemia and in very high ASCVD risk should be more prominent in future guidelines., Summary: The LDL-cholesterol goal of 2.6 mmol/l or less should be abandoned. Percentage decreases in LDL-cholesterol or non-HDL-cholesterol concentration are better in people with initial concentrations of less than 3.6 mmol/l. The LDL-cholesterol target of 1.8 mmol/l is most effective when initial LDL-cholesterol is more than 3.6 mmol/l in both primary and secondary prevention., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)