Non-coding RNAs in human health and disease: potential function as biomarkers and therapeutic targets

Human diseases have been a critical threat from the beginning of human history. Knowing the origin, course of action and treatment of any disease state is essential. A microscopic approach to the molecular field is a more coherent and accurate way to explore the mechanism, progression, and therapy with the introduction and evolution of technology than a macroscopic approach. Non-coding RNAs (ncRNAs) play increasingly important roles in detecting, developing, and treating all abnormalities related to physiology, pathology, genetics, epigenetics, cancer, and developmental diseases. Noncoding RNAs are becoming increasingly crucial as powerful, multipurpose regulators of all biological processes. Parallel to this, a rising amount of scientific information has revealed links between abnormal noncoding RNA expression and human disorders. Numerous non-coding transcripts with unknown functions have been found in addition to advancements in RNA-sequencing methods. Non-coding linear RNAs come in a variety of forms, including circular RNAs with a continuous closed loop (circRNA), long non-coding RNAs (lncRNA), and microRNAs (miRNA). This comprises specific information on their biogenesis, mode of action, physiological function, and significance concerning disease (such as cancer or cardiovascular diseases and others). This study review focuses on non-coding RNA as specific biomarkers and novel therapeutic targets. © 2023, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

CircRNAs: Key molecules in the prevention and treatment of ischemic stroke

Ischemic stroke is a prevalent disease that seriously threatens human health. It is characterized by high morbidity, mortality, disability, and recurrence rates, causing a significant economic burden on individuals and society. Circular RNA, a novel non-coding RNA, not only serves as the sponge for microRNAs and proteins but also promotes transcription of their parental genes and translates into peptides. In recent years, circRNAs have emerged as key regulators in ischemic stroke. This article aims to provide new ideas about the pathogenesis and progression of ischemic stroke by reviewing the roles of circRNAs in cerebral ischemic injury and summarizing the association between circRNAs and risk factors for ischemic stroke.

Whole-genome resequencing reveals genetic diversity, differentiation, and selection signatures of yak breeds/populations in Qinghai, China

The Qinghai Province of China is located in the northeast region of the Qinghai–Tibetan Plateau (QTP) and carries abundant yak genetic resources. Previous investigations of archaeological records, mitochondrial DNA, and Y chromosomal markers have suggested that Qinghai was the major center of yak domestication. In the present study, we examined the genomic diversity, differentiation, and selection signatures of 113 Qinghai yak, including 42 newly sequenced Qinghai yak and 71 publicly available individuals, from nine yak breeds/populations (wild, Datong, Huanhu, Xueduo, Yushu, Qilian, Geermu, Tongde, and Huzhu white) using high-depth whole-genome resequencing data. We observed that most of Qinghai yak breeds/populations have abundant genomic diversity based on four genomic parameters (nucleotide diversity, inbreeding coefficients, linkage disequilibrium decay, and runs of homozygosity). Population genetic structure analysis showed that Qinghai yak have two lineages with two ancestral origins and that nine yak breeds/populations are clustered into three distinct groups of wild yak, Geermu yak, and seven other domestic yak breeds/populations. FST values showed moderate genetic differentiation between wild yak, Geermu yak, and the other Qinghai yak breeds/populations. Positive selection signals were detected in candidate genes associated with disease resistance (CDK2AP2, PLEC, and CYB5B), heat stress (NFAT5, HSF1, and SLC25A48), pigmentation (MCAM, RNF26, and BOP1), vision (C1QTNF5, MFRP, and TAX1BP3), milk quality (OPLAH and GRINA), neurodevelopment (SUSD4, INSYN1, and PPP1CA), and meat quality (ZRANB1), using the integrated PI, composite likelihood ratio (CLR), and FST methods. These findings offer new insights into the genetic mechanisms underlying target traits in yak and provide important information for understanding the genomic characteristics of yak breeds/populations in Qinghai.

Prospective evaluation of cardiac effects of first-time marathon training, running, and recovery in middle-aged men: cohort study rationale and design

Background: Several phenomena may point to potentially detrimental cardiac effects of endurance exercise, such as elevated circulating cardiac troponin levels and reductions in systolic and diastolic function directly after marathon completion. Furthermore, while myocardial abnormalities have been reported in patients who recovered from COVID-19, the cardiac impact of extensive endurance exercise in individuals who recovered from COVID-19 remains unknown. We therefore aim to investigate (potentially detrimental) cardiac effects of first-time marathon training and participation, including a subset of participants who recovered from COVID-19, in apparently healthy middle-aged men. Study design: This exploratory prospective cohort study investigates cardiac effects of first-time marathon running in 24 middle-aged (35–50 years) healthy men. Primary outcomes are cardiac morphological changes from pre-training up to 1 month after marathon completion, measured with magnetic resonance imaging (MRI) at 4 time points: 1) baseline (4 months before the marathon), 2) pre-marathon (2 weeks before the marathon), 3) post-marathon (< 24 h post-marathon), and 4) recovery (4 weeks after the marathon). Secondary parameters include other cardiac or non-cardiac changes: 1) quantitative MRI myocardial mapping, including mean diffusivity and extracellular volume fraction, 2) echocardiographic morphology and function changes, 3) VO2max, 4) electrocardiogram changes, and 5) levels of cardiac biomarkers. Discussion: This study will contribute to our understanding of cardiac adaptations and maladaptations to first-time marathon running in middle-aged men, and the interaction between extreme endurance exercise and potential detrimental cardiac effects, also in the context of COVID-19. Results will inform on future research directions while providing new clinical insights for health professionals involved in athlete care. © 2022, The Author(s).

Neurological and Neuroradiological Manifestations in Neonates Born to Mothers With Coronavirus Disease 2019

Background: To investigate the complications that occurred in neonates born to mothers with coronavirus disease 2019 (COVID-19), focusing on neurological and neuroradiological findings, and to compare differences associated with the presence of maternal symptoms. Methods: Ninety neonates from 88 mothers diagnosed with coronavirus disease 2019 (COVID-19) during pregnancy were retrospectively reviewed. Neonates were divided into two groups: symptomatic (Sym-M-N, n = 34) and asymptomatic mothers (Asym-M-N, n = 56). The results of neurological physical examinations were compared between the groups. Data on electroencephalography, brain ultrasound, and magnetic resonance imaging abnormalities were collected for neonates with neurological abnormalities. Results: Neurological abnormalities at birth were found in nine neonates (Sym-M-N, seven of 34, 20.6%). Decreased tone was the most common physical abnormality (n = 7). Preterm and very preterm birth (P < 0.01), very low birth weight (P < 0.01), or at least one neurological abnormality on physical examination (P = 0.049) was more frequent in Sym-M-N neonates. All infants with abnormalities on physical examination showed neuroradiological abnormalities. The most common neuroradiological abnormalities were intracranial hemorrhage (n = 5;germinal matrix, n = 2;parenchymal, n = 2;intraventricular, n = 1) and hypoxic brain injury (n = 3). Conclusions: Neonates born to mothers with symptomatic COVID-19 showed an increased incidence of neurological abnormalities. Most of the mothers (96.4%) were unvaccinated before the COVID-19 diagnosis. Our results highlight the importance of neurological and neuroradiological management in infants born to mothers with COVID-19 and the prevention of maternal COVID-19 infection. © 2022 Elsevier Inc.

Congenital Infection Influence on Early Brain Development Through the Gut-Brain Axis

The mechanisms by which various pathogens cause congenital infections have been studied extensively, aiding in the understanding of the detrimental effects these infections can have on fetal/neonatal neurological development. Recent studies have focused on the gut-brain axis as pivotal in neurodevelopment, with congenital infections causing substantial disruptions. There remains controversy surrounding the purported sterility of the placenta as well as concerns regarding the effects of exposure to antibiotics used during pregnancy on neonatal microbiome development and how early exposure to microbes or antibiotics can shape the gut-brain axis. Long-term neurodevelopmental consequences, such as autism spectrum disorder, attention deficit hyperactivity disorder, and cerebral palsy, may be attributable, in part, to early life infection and changes in the immature gut microbiome. The goal of this review is thus to critically evaluate the current evidence related to early life infection affecting neurodevelopment through the gut-brain axis.

COVID-19 independently predicts poor outcomes in Acute Ischemic Stroke- Insights from a multicenter study from Pakistan and United Arab Emirates

Background: Ischemic stroke associated with coronavirus 2019 (COVID-19) has been well recognized by now. Few studies have compared COVID related versus unrelated strokes. We intend to report on a large group of Asian patients from two countries and compare COVID with non-COVID strokes admitted during the same time period. Methods: Consecutive cases of acute ischemic stroke either presenting or developing, between March 2020 and December 2021 in four tertiary care hospitals (1 in Dubai, UAE and 3 in Karachi, Pakistan) and testing positive for COVID-19 were included in the study. Patients admitted with ischemic stroke during the same time period and who tested negative for COVID-19 were also randomly selected from the four hospitals. All data was collected from the medical records of the patients and recorded on a standard questionnaire before it was entered in SPSS version 21 for analysis. Results: There were 139 COVID positive and 271 COVID negative patients with acute ischemic stroke included in the current study. There were significantly more males (80.6% vs 64.9%, p=0.001) and more large vessel strokes in the COVID positive group (41% vs 21.8%, p<0.001). Being COVID positive was an independent predictor of poor outcome at discharge, defined as a modified Rankin score of 3-6 (OR 3.87, 95% CI 2.21-6.77) after adjusting for country, age, sex, vascular comorbid conditions and stroke subtype. Conclusions: In this largest series of patients with COVID related strokes from Asia, COVID-19 was an independent predictor of poor outcomes at discharge after adjusting for other variables. © 2022 Elsevier Inc.

Multisystem inflammatory syndrome in children (MIS-C) and "Near MIS-C”: A continuum?

Introduction: Reports of multisystem inflammatory syndrome in children (MIS-C), following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, have been increasing worldwide, with an incidence varying significantly across studies based on the definition used for the diagnosis. At our tertiary medical center in Lebanon, we encountered several cases that presented a diagnostic challenge because they mimicked MIS-C but did not meet the US Centers for Disease Control and Prevention (CDC) definition. We decided to review these cases and describe their features in comparison with cases that met the CDC criteria of MIS-C and those that had an alternative diagnosis. Methods: This is a retrospective chart review of subjects aged <19 years old admitted to the American University of Beirut Medical Center (AUBMC) between March 1, 2020, and May 31, 2021, with suspected or confirmed MIS-C, following documented COVID-19 infection, with sufficient or insufficient criteria for diagnosis. Subjects were classified into 3 groups: "MIS-C”, "Near MIS-C” and "Alternative Diagnosis”. Results: A total number of 29 subjects were included in our cohort. Fever was present in all subjects. In the MIS-C group, evidence for cardiovascular system involvement was the most common feature followed by the mucocutaneous and gastrointestinal systems. In the "Near MIS-C” and "Alternative Diagnosis” group, gastrointestinal symptoms were the most common with only one patient with cardiac abnormalities and none with coagulopathy. Subjects with typical MIS-C presentation had higher inflammatory markers when compared to subjects in the other groups. Almost all the subjects had positive IgG for SARS-CoV-2. Of the 29 subjects, the Royal College of Paediatrics and Child Health (RCPCH) case definition would have identified all suspected cases without an alternative diagnosis as MIS-C, whereas the World Health Organization (WHO) and the CDC definitions would have excluded 6 and 10 subjects, respectively. Conclusion: MIS-C presents a diagnostic challenge due to the nonspecific symptoms, lack of pathognomonic findings, and potentially fatal complications. More research is needed to fully understand its pathogenesis, clinical presentation spectrum, and diagnostic criteria. Based on our experience, we favor the hypothesis that MIS-C has a continuum of severity that necessitates revisiting and unifying the current definitions.

Response to: Before blaming SARS-CoV-2 vaccinations for rhabdomyolysis, other potential triggers should be considered...Kim S, Jung J, Cho H, et al. A child with crescentic glomerulonephritis following SARS-CoV-2 mRNA (Pfizer-BioNTech) vaccination. Pediatric Nephrology. 2023,38(1):299-302

The article presents the discussion on letters to the editor.

Neurological complications associated with influenza in hospitalized children

Background: Influenza is a known respiratory and potential neurotropic virus. This study aimed to determine the prevalence and outcomes of influenza-related neurological complications among hospitalized children. Methods: All medical records of hospitalized children aged <18 years old diagnosed with influenza at a tertiary care hospital in Bangkok were retrospectively reviewed. Influenza infection was confirmed by rapid antigen or reverse transcription polymerase chain reaction tests. Neurological characteristics and clinical outcomes were analyzed using the Pediatric Cerebral Performance Category Scale. Results: From 2013 to 2018, 397 hospitalized children with a median age of 3.7 years (interquartile range [IQR]: 1.6–6.9) were included. The prevalence of neurological complications, including seizure or acute encephalopathy, was 16.9% (95% confidence interval [CI]: 13.3–20.9). Influenza A and B were identified in 73.1% and 26.9% of the patients, respectively. Among 39 (58.2%) acute symptomatic seizure cases, 25 (37.3%) children had simple febrile seizures, 7 (10.4%) had repetitive seizures, and 7 (10.4%) had provoked seizures with pre-existing epilepsy. For 28 (41.8%) encephalopathy cases, the clinical courses were benign in 20 (29.9%) cases and severe in 8 (11.9%) cases. Ten (14.9%) children needed intensive care monitoring, and 62 (93.5%) fully recovered to their baselines at hospital discharge. Predisposing factors to the neurological complications included a history of febrile seizure (adjusted odds ratio [aOR]: 20.3;95% CI: 6.6–63.0), pre-existing epilepsy (aOR: 3.6;95% CI: 1.3–10.2), and a history of other neurological disorders (aOR: 3.5;95% CI: 1.2–10.2). Conclusions: One fifth of hospitalized children with influenza had neurological complications with a favorable outcome. Children with pre-existing neurological conditions were at higher risk for developing neurological complications.

The clinical neurophysiology of COVID-19-direct infection, long-term sequelae and para-immunization responses: A literature review

The COVID-19 pandemic resulting from the SARS-CoV-2 virus is in its third year. There is continuously evolving information regarding its pathophysiology and its effects on the nervous system. Clinical neurophysiology techniques are commonly employed to assess for neuroanatomical localization and/or defining the spectrum of neurological illness. There is an evolving body of literature delineating the effects of the SARS-CoV-2 virus on the nervous system as well as para-immunization responses to vaccination against this virus. This review focuses on the use of neurophysiological diagnostic modalities in the evaluation of potential acute and long-term neurological complications in patients that experience direct infection with SARS-CoV-2 and analyzes those reports of para-immunization responses to vaccination against the SARS-CoV-2 virus. The neurophysiological modalities to be discussed include electroencephalography (EEG), evoked potentials (EPs), nerve conduction studies and electromyography (EMG/NCV), autonomic function tests, transcranial magnetic stimulation (TMS) and Transcranial Doppler ultrasound (TCD). © 2022 International Federation of Clinical Neurophysiology

Cerebral venous thrombosis secondary to ulcerative colitis: A case report with a literature review

Ulcerative colitis is an idiopathic inflammatory bowel condition that may be worsened by thromboembolic events such deep vein thrombosis, cerebral venous thrombosis, and pulmonary embolism. Cerebral venous thrombosis is a rare but critical consequence of ulcerative colitis characterized by high mortality and morbidity rate. It is thought to be caused by the hypercoagulable state that occurs during ulcerative colitis relapse. Cerebral venous thrombosis is a reversible condition with good outcomes when detected early and treated properly. In this study, we describe the case of a young woman who presented with cerebral venous thrombosis secondary to ulcerative colitis complicated by venous infarction with petechial cerebral hemorrhage. © 2022 The Authors

The New Brain Age

The pandemic is transforming neurology. Long COVID will linger, neurologic diseases will increase, and technology, artificial intelligence, and new virtual worlds will usher a new age of the brain and new roles for neurologists. The pandemic has compelled international collaboration, greatly increased communications, and accelerated drug and vaccines approvals. It also dramatized the close interconnection of cognitive, mental, and social health and their relevance to building back better health, education, work, and leisure. Brain health is the key to health, productivity, and well-being. Neurologists are best placed to lead brain knowledge integration and application through the unifying theme of brain health by becoming advocates, healers, and guardians of the brain.

Neurologic Manifestations of COVID-19

Coronavirus disease (COVID-19) caused by a new coronavirus, SARS-CoV-2, has become a serious health problem throughout the world. Although COVID-19 primarily presents as an acute respiratory tract infection, many neurological findings have also been described in patients. Neurological findings are classified into three groups as central, peripheral nervous system and musculoskeletal system. The most common central nervous system symptom is headache. Encephalitis, encephalopathy, seizures, acute ischemic stroke are also seen. The most common symptoms in the peripheral nervous system are loss of smell and taste. Myalgia, myositis and rhabdomyolysis also can be seen in musculoskeletal system involvement. Awareness of the neurological symptoms by physicians will be beneficial in early diagnosis and treatment of the disease.

VTd-PACE and VTd-PACE-like regimens are effective salvage therapies in difficult-to-treat relapsed/refractory multiple myeloma: a single-center experience

Although treatment options for multiple myeloma (MM) are rapidly evolving, there still remain difficult-to-treat situations, especially in relapsed and/or refractory (r/r) disease. When modern therapies are exhausted, or emergency treatment is needed for high tumor burden, classic chemotherapy combination regimens like the VTd-PACE regimen and its modifications (PACE-M) may also be beneficial as bridging to subsequent treatment options. This single-center retrospective analysis aimed to investigate the outcome of VTd-PACE and PACE-M salvage therapy in 31 heavily pretreated r/r MM patients. The primary objective was the overall response rate (ORR). Secondary objectives were median progression-free survival (mPFS), median overall survival (mOS), safety, and renal response. Median age was 59 years (range 39–75), and 71% of patients were male. R-ISS stratification showed high-risk MM in 48%. The median number of prior therapies was 3, with 23 patients being triple- and 12 penta-refractory (74% and 39%). ORR was 71%, including 23% of patients achieving a very good partial response. Median duration of follow-up was 15 months (range 0–29 months). mPFS and mOS were 3 months (95% CI 0.27–5.74) and 11 months (95% CI 3.66–18.35), respectively. In 26 patients (83.9%), at least one subsequent treatment (stem cell transplant or BCMA-directed) was administered. Renal function significantly improved after VTd-PACE or PACE-M treatment (p = 0.032). Non-hematological adverse events ≥ grade 3 were predominantly infections. VTd-PACE and PACE-M are effective salvage therapies in difficult-to-treat situations in heavily pre-treated r/r MM, including patients with impaired renal function. VTd-PACE and PACE-M can be successfully used as bridging therapy for subsequent treatment. © 2022, The Author(s).

Clinical and Laboratory Evaluations of Patients Diagnosed as Having Multisystem Inflammatory Syndrome Associated with Coronavirus Disease 2019 in Children: A Single Center Experience from Konya

Objective Multisystem inflammatory syndrome in children (MIS-C), characterized by fever, inflammation, and multiorgan dysfunction, was newly defined after severe acute respiratory syndrome coronavirus 2 infection. The clinical spectrum of MIS-C can be classified as mild, moderate, and severe. We aimed to evaluate demographics, clinical presentations, laboratory findings, and treatment modalities of patients with MIS-C according to clinical severity. Methods We performed a retrospective study of patients who were diagnosed as having MIS-C between September 2020 and October 2021 in the Necmettin Erbakan University Meram Faculty of Medicine, Türkiye. Results A total of 48 patients (24 females and 24 males) with a median age at diagnosis of 10.3 years (range: 42 months-17 years) were enrolled, the most common clinical severity of MIS-C was moderate. The common presentations of patients were fever (97%), nonpurulent conjunctivitis (89.6%), rashes (81.3%), fatigue (81.3%), strawberry tongue (79.2%), and myalgia (68.8%). The most common laboratory findings were lymphopenia (81.2%), thrombocytopenia (54.1%), elevated D-dimer levels (89.5%), C-reactive protein (CRP;100%), procalcitonin (97%), erythrocyte sedimentation rate (87.5%), ferritin (95.8%), interleukin 6 (IL-6) (86.1%), and probrain natriuretic peptide (pro-BNP) (97%). High levels of CRP, procalcitonin, pro-BNP, and urea were associated with the severity of MIS-C (p < 0.05). Fifteen of the patients were found to have pulmonary involvement. Ascites were the most common finding on abdominal ultrasonography (11 patients) and were not seen in a mild form of the disease. During the study period, two patients died. Conclusion It is important to make patient-based decisions and apply a stepwise approach in treating patients with MIS-C due to the increased risk of complications and mortality. © 2022. Thieme. All rights reserved.