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Background: People with type 2 diabetes (T2D) and chronic kidney disease (CKD) are at high risk for heart failure (HF) and premature death from cardiovascular (CV) causes. The FLOW (Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease), which enrolled participants with T2D and CKD, demonstrated that semaglutide, a glucagon-like peptide-1 receptor agonist, reduced the incidence of the primary composite outcome (persistent ≥50% decline in estimated glomerular filtration rate, persistent estimated glomerular filtration rate <15 mL/min/1.73 m 2 , kidney replacement therapy, and kidney or CV death) by 24%., Objectives: This prespecified analysis examined the effects of semaglutide on HF outcomes in this high-risk population., Methods: Participants were randomized (1:1) to once-weekly subcutaneous semaglutide 1 mg or placebo. The prespecified main outcome was a composite of HF events (new onset or worsening of HF leading to an unscheduled hospital admission or an urgent visit, with initiation of or intensified diuretic/vasoactive therapy) or CV death. HF data were collected by the investigator. CV death was adjudicated by an independent committee., Results: A total of 3,533 randomized participants were followed for a median of 3.4 years. HF was present at baseline in 342 participants (19.4%) in the semaglutide group and 336 (19.0%) in the placebo group. In the overall trial population, semaglutide increased time to first HF events or CV death (HR: 0.73; 95% CI: 0.62-0.87; P = 0.0005), HF events alone (HR: 0.73; 95% CI: 0.58-0.92; P = 0.0068), and CV death alone (HR: 0.71; 95% CI: 0.56-0.89; P = 0.0036). The risk reduction for the composite HF outcome was similar in those with (HR: 0.73; 95% CI: 0.54-0.98; P = 0.0338) and without (HR: 0.72; 95% CI: 0.58-0.89; P = 0.0028) HF at baseline. The risk of HF outcomes (HF events or CV death) was generally higher in participants categorized as NYHA functional class III and those with the HF reduced ejection fraction subtype, regardless of treatment., Conclusions: Semaglutide substantially reduced the risk of time to first composite outcome of HF events or CV death, as well as HF events and CV death alone, in a high-risk population with T2D and CKD. These effects were consistent regardless of history of HF. (A Research Study To See How Semaglutide Works Compared to Placebo in People With Type 2 Diabetes and Chronic Kidney Disease [FLOW]; NCT03819153)., Competing Interests: Funding Support and Author Disclosures The FLOW trial was funded by Novo Nordisk A/S. Dr Pratley has received speaker fees paid to his employer, AdventHealth (through December 31, 2023) from Eli Lilly, Lilly USA LLC, and Novo Nordisk; has received consulting fees directed to his institution from AbbVie, AstraZeneca, Bayer AG, Bayer HealthCare Pharmaceuticals, Corcept Therapeutics, Dexcom, Endogenex, Gasherbrum Bio, Genprex, Getz Pharma, Hanmi Pharmaceutical, Hengrui (USA) Ltd, Intas Pharmaceuticals, Eli Lilly, Lilly USA LLC, Merck, Novo Nordisk, Pfizer, Rivus Pharmaceuticals, Scholar Rock, and Sun Pharmaceutical Industries; has received grants directed to his institution from Biomea Fusion, Carmot Therapeutics, Dompe, Endogenex, Fractyl, Eli Lilly, Novo Nordisk, and Sanofi; and has received personal fees (from January 1, 2024) from AdventHealth, a nonprofit entity. Dr Tuttle has received support from National Institutes of Health research grants R01MD014712, U2CDK114886, UL1TR002319, U54DK083912, U01DK100846, OT2HL161847, UM1AI109568, and OT2OD032581, and from Centers for Disease Control and Prevention project numbers 75D301-21-P-12254 and 75D301-23-C-18264; has received investigator-initiated grant support from Travere, Bayer, and the Doris Duke Foundation outside of the submitted work; has received consulting fees from Boehringer Ingelheim, Eli Lilly, and Novo Nordisk; and has received speaker fees from Novo Nordisk. Dr Rossing has received grants from Bayer, AstraZeneca, and Novo Nordisk; has received honoraria paid to the Steno Diabetes Centre Copenhagen from AstraZeneca, Astellas, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, and Bayer; and has received consulting fees from AstraZeneca, Astellas, Boehringer Ingelheim, Gilead, Novo Nordisk, Merck, Mundipharma, Sanofi, and Bayer. Dr Perkovic has received honoraria for steering committee, data monitoring committee, or advisory board roles or for scientific presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, GSK, Janssen, Novo Nordisk, Novartis, Otsuka, Travere, Tricida, and UptoDate; and is Board Director for George Clinical, St Vincent’s Health Australia and several independent medical research institutes. Dr Mann has received grants from Novo Nordisk, the European Union, and McMaster University, Hamilton, Canada; has received consulting fees from Novo Nordisk, AstraZeneca, Bayer, and Boehringer Ingelheim; has received honoraria from Novo Nordisk, AstraZeneca, Bayer, and Novartis; and has participated on a data safety monitoring board or advisory board for AstraZeneca, Bayer, Sanofi, and Boehringer Ingelheim, as well as a leadership role in the Kidney Disease: Improving Global Outcomes group. Dr MacIsaac was a FLOW trial investigator and member of the FLOW global expert panel; has received research grants from Novo Nordisk, Servier, Medtronic, The Rebecca Cooper Medical Research Foundation, St Vincent’s Research Foundation, The Juvenile Diabetes Research Foundation, Grey Innovations, The Diabetes Australia Research Trust/Program, and The National Health and Medical Research Council of Australia; has received honoraria for lectures from Eli Lilly, Novo Nordisk, Sanofi, AstraZeneca, MSD, Novartis, and Boehringer Ingelheim; has been on the advisory boards for Novo Nordisk, Boehringer Ingelheim-Eli Lilly Diabetes Alliance, AstraZeneca, and MSD; has received travel support from Novo Nordisk, Sanofi, Boehringer Ingelheim, and AstraZeneca; and has been a principal investigator for industry-sponsored clinical trials run by Novo Nordisk, Sanofi, Bayer, Johnson-Cilag, and AbbVie. Dr Kosiborod has received research grant support from AstraZeneca and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Kamenov has received speaker fees from Actavis, AstraZeneca, Bayer-Schering, Berlin Chemie, Boehringer Ingelheim, Eli Lilly, KRKA, Merck, MLD, MSD (Merck), Mundipharma, Mylan, Novartis, Novo Nordisk, Pfizer, Sandoz, Sanofi, Servier, TEVA Pharmaceuticals, Valentis, Vedra, and Viatris. Dr Hadjadj has received grants from Asdia, Asten, AstraZeneca, Homeperf, LVL, Nestle Home Care, Pierre Fabre, and VitalAire; has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, Servier, and Valbiotis; has received speaker fees from Abbott, AstraZeneca, Boehringer Ingelheim, Bayer, Dino Santé, Eli Lilly, Novartis, Novo Nordisk, Pierre Fabre, Sanofi, Servier, and Valbiotis; and has received meeting invitations from AstraZeneca, Abbott, Dino Santé, Eli Lilly, and Novo Nordisk. Dr Bakris has received consulting fees from Bayer, KBP Biosciences, Ionis, Alnylam, AstraZeneca, Quantum Genomics, Novo Nordisk, and Dia Medica Therapeutics. Dr Mahaffey has received grants from the American Heart Association, Apple, Bayer, California Institute Regenerative Medicine, CSL Behring, Eidos, Ferring, Gilead, Google (Verify), Idorsia, Johnson and Johnson, Luitpold, Novartis, PAC-12, Precordior, and Sanifit; and has received consulting fees from Applied Therapeutics, Bayer, Bristol Myers Squibb, BridgeBio, CSL Behring, Elsevier, Fosun Pharma, Human, Johnson and Johnson, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, PhaseBio, Portola, Quidel, and Theravance; and holds equity in Human, Medeloop, Precordior and Regencor. Drs Rasmussen, Nielsen, Idorn, Hansen, and Baeres are employees of and shareholders in Novo Nordisk., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

It has been demonstrated previously that human leukocyte antigen class I ( HLA-I ) and class II ( HLA-II ) alleles may modulate JAK2 V617F and CALR mutation (CALRmut)-associated oncogenesis in myeloproliferative neoplasms (MPNs). However, the role of immunogenetic factors in MPNs remains underexplored. We aimed to investigate the potential involvement of HLA genes in CALRmut+ MPNs. High-resolution genotyping of HLA-I and -II loci was conducted in 42 CALRmut+ and 158 JAK2 V617F+ MPN patients and 1,083 healthy controls. A global analysis of the diversity of HLA-I genotypes revealed no significant differences between CALRmut+ patients and controls. However, one HLA-I allele ( C*06:02 ) showed an inverse correlation with presence of CALR mutation. A meta-analysis across independent cohorts and healthy individuals from the 1000 Genomes Project confirmed an inverse correlation between the presentation capabilities of the HLA-I loci for JAK2 V617F and CALRmut-derived peptides in both patients and healthy individuals. scRNA-Seq analysis revealed low expression of TAP1 and CIITA genes in CALRmut+ hematopoietic stem and progenitor cells. In conclusion, the HLA-I genotype differentially restricts JAK2 V617F and CALRmut-driven oncogenesis potentially explaining the mutual exclusivity of the two mutations and differences in their presentation latency. These findings have practical implications for the development of neoantigen-based vaccines in MPNs., 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 Shivarov, Tsvetkova, Micheva, Hadjiev, Petrova, Ivanova, Madjarova and Ivanova.)

Background and Objectives : Patients with atrial fibrillation and coronary artery disease represent a group with a greater risk of mortality. To evaluate patients with atrial fibrillation (AF) and a significant coronary bifurcation lesion and compare the clinical outcomes between the patients on anticoagulant treatment with Vitamin K antagonist (VKA) and those on direct anticoagulant (DOAC). Materials and Methods : This is a prospective study of patients with AF and stable coronary artery disease, who had evidence of a significant coronary bifurcation lesion. A log-rank test was used to assess the difference in mortality between patients taking VKA and those on DOAC. The primary endpoint was the incidence of all-cause and cardiovascular death at mid-term. Results : A total of 226 patients with AF and a significant bifurcation lesion were included. The mean age was 70.9 ± 9.2, and 70% were males. Of the patients, 123 (54.7%) were on VKA treatment, and 103 (45.3%) were taking DOAC. For a median follow-up time of 55 (39-96) months, overall mortality was 40%, whereas CV mortality was 31%. Both all-cause (28.2% versus 50.4%, p = 0.020) and CV death (12.7% versus 24.9%, p = 0.032) were significantly lower in patients taking DOAC versus those on VKA. In patients treated with PCI, CV mortality was significantly lower in patients taking DOAC (21.4% versus 40.5%, p = 0.032). VKA therapy was an independent predictor of cardiovascular death (HR 1.88; 95% CI 1.11-3.18; p = 0.01), together with chronic kidney disease (HR 1.81; 95% CI 1.13-2.92; p = 0.01). Conclusions : Treatment with DOAC in patients with atrial fibrillation and coronary bifurcation lesion was associated with significantly lower mortality independently of the treatment approach. VKA was an independent predictor of CV mortality.

Background: Autosomal recessive spastic ataxia ofCharlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder characterizedby early-onset cerebellar ataxia, peripheral sensorimotor neuropathy, and lowerlimb spasticity. We present clinical andgenetic data of the first Bulgarian patients diagnosed with ARSACS by wholeexome sequencing (WES)., Methods: Variant filtering was performed usinglocally established pipeline and the selected variants were analysed by Sangersequencing. All patients underwent clinical examination and testingincluding the standard rating scales for spastic paraplegia and ataxia., Results: Five different SACS gene variants, three of which novel, have been identified inpatients from three different ethnic groups. In addition to the classicalclinical triad, brain MRI revealed cerebellar atrophy, linear pontineT2-hypointensities, and hyperintense rim lateral tothalamus combined with retinal nerve fiber layer thickening on opticcoherence tomography (OCT)., Conclusion: We expand the mutation, geographic, and phenotypic spectrum of ARSACS, adding Bulgaria to the world map of the disease, and drawing attention to the fact that it is still misdiagnosed. We demonstrated that brain MRI and OCT are necessary clinical tests for ARSACS diagnosis, even if one of the cardinal clinical features is lacking., (© 2024 The Author(s). Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Introduction: Treatment for asthma and chronic obstructive pulmonary disease (COPD) is compromised, quality of life is negatively impacted, and significant financial losses result from nonadherence to the prescribed therapy., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Pityriasis lichenoides is a rare inflammatory skin condition presenting with diffuse red-brown papules with evolution polymorphism and mica-like crust on older skin lesions. We present a 60-year-old female patient with pityriasis lichenoides chronica that manifested ten days after streptococcal pharyngitis. Initially, palpable purpura appeared on the lower extremities and later, erythematous-squamous papules and plaques appeared at the site of the palpable purpura and on the upper limbs and trunk. The patient had no history of hematological malignancy, viral hepatitis, kidney involvement, systemic rheumatic disease, or ANCA-associated vasculitis. After administration of methylprednisolone 20 mg for one month and an antimalarial agent (hydroxychloroquine 200 mg, 1 tablet bid) for three months, the skin lesions subsided without recurrence., (This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq., (© 2024. The Author(s).)

Exploring the molecular basis of disease severity in rare disease scenarios is a challenging task provided the limitations on data availability. Causative genes have been described for Congenital Myasthenic Syndromes (CMS), a group of diverse minority neuromuscular junction (NMJ) disorders; yet a molecular explanation for the phenotypic severity differences remains unclear. Here, we present a workflow to explore the functional relationships between CMS causal genes and altered genes from each patient, based on multilayer network community detection analysis of complementary biomedical information provided by relevant data sources, namely protein-protein interactions, pathways and metabolomics. Our results show that CMS severity can be ascribed to the personalized impairment of extracellular matrix components and postsynaptic modulators of acetylcholine receptor (AChR) clustering. This work showcases how coupling multilayer network analysis with personalized -omics information provides molecular explanations to the varying severity of rare diseases; paving the way for sorting out similar cases in other rare diseases., (© 2024. The Author(s).)

Background: Side branch predilatation (SBPD) during coronary bifurcation interventions is a technique that is not recommended by the latest guidelines. However, the data about the clinical outcomes after SBPD are surprisingly few., Aims: The current study aimed to explore the association between SBPD and mortality in long-term follow-up., Methods: All patients with coronary bifurcation stenoses revascularized with percutaneous coronary intervention were included in a prospective registry. Patients with stable angina and a bifurcation lesion with ≥50% diameter stenosis were included in the current analysis. Patients were assigned to two groups - those with SBPD(+) and those without SBPD(-). Propensity score matching was performed to equalize the risk factors and severity of coronary artery disease between the groups. A Kaplan-Meier analysis with a log-rank test for between-group differences was also performed., Results: From January 2013 to June 2021, 813 patients were included in the final study population. The mean age was 67 (10) years. After propensity score matching, 648 patients remained for analysis - 324 in each group. At a median follow-up of 57 months patients in the SBPD(+) group had a higher all-cause mortality (n = 107 (33%) vs. n = 98 [30.2%]; P = 0.045) and cardiovascular mortality (n = 82 [25.3%] vs. n = 70 [21.6%]; P = 0.03) when compared with SBPD(-) patients. SBPD was independently associated with all-cause and cardiovascular mortality., Conclusion: SBPD treatment of coronary bifurcation stenoses is associated with worse patient survival in the follow-up of up to 8 years. SBPD treatment gives better angiographic results, but this did not translate into better clinical outcomes.

Objectives: To assess the maternal and neonatal outcomes in women with GDM treated with metformin, medical nutrition therapy (MNT) or insulin., Material and Methods: The current retrospective cohort study includes data from 233 women diagnosed with GDM who gave birth between January 2017 and January 2019 at an obstetrics and gynecology hospital in Sofia, Bulgaria. Patients were assigned to three groups, according to the treatment approach - metformin group (n = 70), insulin group (n = 40), and MNT group (n = 123). Values of fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) have been evaluated at diagnosis of GDM and the third trimester of pregnancy. A comparative analysis of pregnancy outcomes and short-term neonatal characteristics in the investigated groups has been performed., Results: Women indicated for pharmacological treatment (metformin or insulin) had significantly higher BMI (p < 0.01), FPG (p < 0.001), and HbA1c levels (p < 0.001) at baseline. However, during pregnancy, patients treated with metformin showed a significantly lower BMI (p < 0.01), FPG (p < 0.01), and HbA1c (p < 0.01). Neonates born to metformin-treated mothers had lower birth weight compared to those born to women in the MNT and insulin groups (metformin vs MNT, p < 0.001; metformin vs insulin, p = 0.03). The lowest incidence of newborns with macrosomia and neonatal hypoglycemia has been observed in the metformin cohort. Not a single newborn with an Apgar score under 7 has been identified in the metformin group., Conclusions: According to the current analysis, women with GDM treated with metformin demonstrated better maternal and neonatal outcomes. No short-term complications in newborns have been associated with metformin use during pregnancy.

Although killer-cell immunoglobulin-like receptor (KIR) gene content has been widely studied in health and disease, with the advancement of next-generation sequencing (NGS) technology the high-resolution characterization of this complex gene region has become achievable. KIR allele-level diversity has lately been described across human populations. The present study aimed to analyze for the first time the allele-level polymorphism of nine KIR genes in 155 healthy, unrelated individuals from the Bulgarian population by applying NGS. The highest degree of polymorphism was detected for the KIR3DL3 gene with 40 observed alleles at five-digit resolution in total, 22 of which were common. On the other hand, the KIR3DS1 gene was found to have the lowest degree of polymorphism among the studied KIR genes with one common allele: KIR3DS1*01301 (31.6%). To better understand KIR allelic associations and patterns in Bulgarians, we have estimated the pairwise linkage disequilibrium (LD) for the 10 KIR loci, where KIR2DL3*00501 allele was found in strong LD with KIR2DL1*00101 (D' = 1.00, R 2  = 0.742). This is the first study investigating KIR polymorphism at the allele level in a population from the South-East European region. Considering the effect of the populationally shaped KIR allelic polymorphism on NK cell function, this data could lead to a better understanding of the genetic heterogeneity of this region and can be carried into clinical practice by improvement of the strategies taken for NK-mediated diseases., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)