Exerkine response to acute exercise:Still much to discover

Strong evidence supports the benefits of regular physical activity/exercise for the prevention and management of numerous non-communicable diseases.^(1,2)However,despite important advances(particularly the implementation of complex“omics”approaches),the underlying molecular mechanisms remain to be clearly elucidated.In the past decade,the role of exerkines—a myriad of signaling moieties(e.g.,mainly cytokines but also other small peptides,peptides,nucleic acids,lipids,or metabolites,among others)released by muscles(myokines)and other tissues in response to exercise that induces endocrine(at the multisystem level),paracrine,or autocrine effects—has gained attention.^(3,4)Indeed it has been proposed that some of the salutary effects of regular exercise(i.e.,repeated sessions of acute exercise)might be due,at least partly,to the progressive accumulation of frequent,acute episodes of exerkine release.^(5)

Multifaceted superoxide dismutase 1 expression in amyotrophic lateral sclerosis patients:a rare occurrence?

Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves both upper and lower motor neurons,human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions,expanding the phenotype of ALS.Although superoxide dismutase 1(SOD1)mutations represent a minority of ALS cases,the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies.Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1(SOD1-ALS),no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation.In this narrative review,we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS.The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms,pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.

Glucagon-like peptide-1 receptor agonists:Exploring the mechanisms from glycemic control to treatment of multisystemic diseases

This editorial takes a deeper look at the insights provided by Soresi and Giannitrapani,which examined the therapeutic potential of glucagon-like peptide-1 receptor agonists(GLP-1RAs)for metabolic dysfunction-associated fatty liver disease.We provide supplementary insights to their research,highlighting the broader systemic implications of GLP-1RAs,synthesizing the current understanding of their mechanisms and the trajectory of research in this field.GLP-1RAs are revolutionizing the treatment of type 2 diabetes mellitus and beyond.Beyond glycemic control,GLP-1RAs demonstrate cardiovascular and renal protective effects,offering potential in managing diabetic kidney disease alongside renin–angiotensin–aldosterone system inhibitors.Their role in bone metabolism hints at benefits for diabetic osteoporosis,while the neuroprotective properties of GLP-1RAs show promise in Alzheimer's disease treatment by modulating neuronal insulin signaling.Additionally,they improve hormonal and metabolic profiles in polycystic ovary syndrome.This editorial highlights the multifaceted mechanisms of GLP-1RAs,emphasizing the need for ongoing research to fully realize their therapeutic potential across a range of multisystemic diseases.

COVID-19 and cardiac complications:Myocarditis and multisystem inflammatory syndrome in children

Coronavirus is an important pathogen causing disease in humans and animals.At the end of 2019,an investigation into an increase in pneumonia cases in Wuhan,Hubei Province,China,found that the cause was a new coronavirus.This disease,which spread rapidly across China and caused an outbreak worldwide,resulted in a pandemic.Although this virus has previously been referred to as 2019-nCoV,which causes coronavirus disease 2019(COVID-19),later it was named severe acute respiratory syndrome coronavirus 2.Children were usually asymptomatic and rarely severely affected.In April 2020,reports from the United Kingdom indicated that children may have Kawasaki disease or a clinical condition similar to toxic shock syndrome.This clinical picture was later defined as multisystem inflammatory syndrome in children.Since then,similarly affected children as well as cases with other cardiac complications have been reported in other parts of the world.In this review,we aimed to evaluate COVID-19 in terms of cardiac involvement by reviewing the literature.

Esophageal ulcer and multisystem inflammatory syndrome after COVID-19:A case report

BACKGROUND Multisystem inflammatory syndrome in adults(MIS-A)is a rare but severe disease occurring several weeks after severe acute respiratory syndrome coronavirus 2 infection.It develops in adults with inflammation of different organs including the gastrointestinal tract,heart,kidneys,skin and hematopoietic system.CASE SUMMARY We present a 58-year-old Chinese man diagnosed with MIS-A.His chief complaints were fever,generalized fatigue and anorexia,accompanied with rashes on his back.Further examination showed cardiac,renal and liver injury.He had melena and gastroscopy indicated esophageal ulcer and severe esophagitis.Repeated blood and sputum culture did not show growth of bacteria or fungi.Antibiotic treatment was stopped due to unsatisfactory performance.His condition improved after prednisone and other supportive treatment.CONCLUSION Gastrointestinal involvement in MIS-A is not uncommon.Intestinal involvement predominates,and esophageal involvement is rarely reported.Esophageal ulcer with bleeding could also be a manifestation of MIS-A.

DERIVATION OF 8-POINT STRAIGHT-LINE-NETS FOR BINARY 6-PHASE (n+4) MULTISYSTEMS

On the basis of the 25 9-point closed-net-diagrams given by Guo Qiti, the 8-point straight-line-net-diagrams of binary 6-phase (n+4)multisystems have been derived. Any 8-point straight-line-net-diagram constitutes part of its corresponding 9-point closed-net-diagram. It means that the removal of one appropriate invariant point from a 9-point closed-netdiagram would result in an 8-point straight-line-net-diagram. If there exists neither concave triangle(s) nor concave quadrilateral(s)in the residual part of a 9-point closed-net-

EIGHT-POINT STRAIGHT-LINE-NET-DIAGRAMS OF BINARY SIX-PHASE (n+4) MULTISYSTEMS (Ⅱ)——DERIVATION FROM THEORY OF PHYSICALLY REAL NETS

Based on the theory of physically real nets, the 8- point straight-line nets of bi-nary 6- phase (n + 4) multisystems (31 in toto) have been derived directly from the l-point straight-line nets. This result is in complete agreement with that derived fromthe theory of closed nets, indicating the incorrectness of the previous conclusion thatthere is only one 8-point straight-line net which corresponds to only one 8- pointstraight-line-net-diagram for binary 6- phase multisystems.

EIGHT-POINT STRAIGHT-LINE-NET-DIAGRAMS OF BINARY SIX-PHASE (n+4) MULTISYSTEMS (Ⅰ)——DERIVATION FROM NINE-POINT CLOSED-NET-DIAGRAMS

The 9-point closed-net-diagrams of binary 6-phase multisystems contain 2 basic types ofnon-straight-line portions. Only the removal of an invariant point which is shared by all thenon-straight-line portions in a 9-point closed-net-diagram can generate an 8-point straight-line-net-diagram. All together 67 distinct 8-point straight-line-net-diagrams have been derived forbinary 6-phase multisystems. They correspondingly belong to 31 distinct 8-point straight-line-nets (namely, 31 distinct 8-point sets), showing that the previous conclusion that there existsonly one 8-point straight-line-net-diagram for binary 6-phase multisystems is incorrect.

FUNDAMENTAL THEOREM ON UNIVARIANT CURVES IN MULTISYSTEMS

Advanced and proved by the author, the fundamental theorem on univariant curves in n + 4 phase multisystems states : though a univariant curve is associated with three invariant points in an n + 4 phase multisystem, its stable part, if any, can only occur between certain two stable iuvariant points. Based on this fundamental theorem, the com-

RELATION BETWEEN THE NUMBER OF INVARIANT POINTS IN CLOSED NETS AND THE NUMBER OF PHASES FOR UNARY n+k PHASE MULTISYSTEMS AND THE PROOF OF KUJAWA'S EMPIRICAL FORMULAE

According to the combinatorial rule, the numbers of possible and distinct invariant or univariant assemblages in unary n+k (n=1, k≥3) phase multisystems may be calculated by the following formulae:

Revolutionizing the Life Sciences by Developing a Holographic Digital Mannequin

1.The need to develop a holographic digital mannequin Life processes,including high intelligence,self-organization,and homeostasis,are characterized by the biological organism in the form of self-renewal,self-replication and self-regulation,metabolism,self-repair,and self-reproduction,which are all processes of multisystem coordinated movement[1].Research in the field of life sciences is not limited to the use of advanced observational methods to reveal microscopic structures at the subcellular or molecular level.Discoveries based on these methods alone cannot characterize the dynamic processes of life at the microscopic and molecular level[2].

STUDY ON GRAPHICAL REPRESENTATION OF PHASE EQUILIBRIA IN UNARY FIVE-PHASE (n + 4) MULTISYSTEMS

The author has proved that all possible phase relations of an n+4 phase multisystem cannot occur in a single complete net simultaneously and stably. For unary five-phase multisystems, two different complete systems of closed nets (CSCN) which are composed of a group of closed nets respectively are needed to display the all possible phase relations. One of the two CSCN’s consisting of ten six point closed nets

Cutis Laxa: A Rare Cause of Neonatal Functional Occlusion

Cutis laxa is a rare disease, related to loss of skin elasticity, which can be hereditary or acquired, with or without associated visceral damage. It is marked by great psychological and social repercussions. The purpose of this paper is to highlight a particular cause of neonatal occlusion: cutis laxa. We report a new observation about a case of cutis laxa hospitalized in the pediatric department at Mohammed V hospital in Tangier, admitted right after birth for the management of macrosomia with wrinkled and inelastic skin, suggesting the diagnosis of cutis laxa. The evolution that followed was marked by the occurrence of several occlusive episodes of a functional nature. Conclusion: visceral involvement in the cutis laxa is reported in several reviews. In our patient the neonatal occlusion was most likely related to her disease. The management of the case must be multidisciplinary.

Pediatric multisystem inflammatory syndrome associated with COVID-19: Insights in pathogenesis and clinical management

The pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection has been a major challenge to be faced in recent years.While adults suffered the highest morbidity and mortality rates of coronavirus disease 2019,children were thought to be exclusively asymptomatic or to present with mild conditions.However,around April 2020,there was an outbreak of a new clinical syndrome related to SARS-CoV-2 in children-multisystemic inflam-matory syndrome in children(MIS-C)-which comprises a severe and uncon-trolled hyperinflammatory response with multiorgan involvement.The Centers for Disease Control and Prevention considers a suspected case of MIS-C an individual aged<21 years presenting with fever,high inflammatory markers levels,and evidence of clinically severe illness,with multisystem(>2)organ involvement,no alternative plausible diagnoses,and positive for recent SARS-CoV-2 infection.Despite its severity,there are no definitive disease management guidelines for this condition.Conversely,the complex pathogenesis of MIS-C is still not completely understood,although it seems to rely upon immune dysregu-lation.Hence,in this study,we aim to bring together current evidence regarding the pathogenic mechanisms of MIS-C,clinical picture and management,in order to provide insights for clinical practice and implications for future research directions.

Multi-Systemic Inflammatory Syndrome in Children

The objective of our work is to study the multi-systemic inflammatory syndrome (PIMS) in children, to determine its frequency, by analyzing the epidemiological, clinical, paraclinical, therapeutic, and evolutionary profile of these patients. A retrospective study spanning a period of 2 years from April 2020 to March 2022. It concerns all children under the age of 16 admitted and cared for in the pediatric emergency department of the university hospital Hassan II of Fez for multi-system inflammatory syndrome (PIMS). Twenty cases of PIMS were collected over this period. Multi-system inflammatory syndrome in children has been described in temporal association with COVID-19, usually within 2 to 6 weeks of illness or exposure. The age of the patients varies between 8 months and 15 years. All patients presented with fever and cutaneous signs, followed by digestive signs and neurological signs. The inflammatory syndrome is frankly positive in all patients who had a COVID-19 PCR and/or positive serology. The treatment is based on the administration of immunoglobulins in association with corticosteroid therapy and non-specific antibiotic therapy in the majority of cases (80%). The evolution was favorable. PIMS should be considered in all children presenting with a clinical and/or biological inflammatory syndrome associated with COVID-19.

Role of children in the Bulgarian COVID-19 epidemic:A mathematical model study

BACKGROUND The coronavirus disease 2019(COVID-19)pandemic affects all aspects of our lives,including children.With the advancement of the pandemic,children under five years old are at increased risk of hospitalization relative to other age groups.This makes it paramount that we develop tools to address the two critical aspects of preserving children's health–new treatment protocols and new predictive models.For those purposes,we need to understand better the effects of COVID-19 on children,and we need to be able to predict the number of affected children as a proportion of the number of infected children.This is why our research focuses on clinical and epidemiological pictures of children with heart damage post-COVID,as a part of the general picture of post-COVID among this age group.AIM To demonstrate the role of children in the COVID-19 spread in Bulgaria and to test the hypothesis that there are no secondary transmissions in schools and from children to adults.METHODS Our modeling and data show with high probability that in Bulgaria,with our current measures,vaccination strategy and contact structure,the pandemic is driven by the children and their contacts in school.RESULTS This makes it paramount that we develop tools to address the two critical aspects of preserving children's health–new treatment protocols and new predictive models.For those purposes,we need to understand better the effects of COVID-19 on children,and we need to be able to predict the number of affected children as a proportion of the number of infected children.This is why our research focuses on clinical and epidemiological pictures of children with heart damage post-COVID,as a part of the general picture of post-Covid among this age group.CONCLUSION Our modeling rejects that hypothesis,and the epidemiological data supports that.We used epidemiological data to support the validity of our modeling.The first summer wave in 2020 from the listed here school proms endorse the idea of transmissions from students to teachers.

Delayed inflammatory pulmonary syndrome: A distinct clinical entity in the spectrum of inflammatory syndromes in COVID-19 infection?

BACKGROUND During the second wave of the coronavirus disease 2019(COVID-19)pandemic,a subset of critically ill patients developed delayed respiratory deterioration in the absence of new infection,fluid overload or extra-pulmonary organ dysfunction.AIM To describe the clinical and laboratory characteristics,outcomes,and management of these patients,and to contrast this entity with other post COVID-19 immune dysregulation related inflammatory disorders.METHODS This was a retrospective observational study of adult patients admitted to the medical intensive care unit of a 2200-bed university affiliated teaching hospital,between May and August 2021,who fulfilled clearly defined inclusion and exclusion criteria.Outcome was assessed by a change in PaO_(2)/FiO_(2) ratio and levels of inflammatory markers before and after immunomodulation,duration of mechanical ventilation after starting treatment,and survival to discharge.RESULTS Five patients developed delayed respiratory deterioration in the absence of new infection,fluid overload or extrapulmonary organ dysfunction at a median interquartile range(IQR)duration of 32(23-35)d after the onset of symptoms.These patients had elevated inflammatory markers,required mechanical ventilation for 13(IQR 10-23)d,and responded to glucocorticoids and/or intravenous immunoglobulin.One patient died(20%).CONCLUSION This delayed respiratory worsening with elevated inflammatory markers and clinical response to immunomodulation appears to contrast the well described Multisystem Inflammatory Syndrome–Adults by the paucity of extrapulmonary organ involvement.The diagnosis can be considered in patients presenting with delayed respiratory worsening,that is not attributable to cardiac dysfunction,fluid overload or ongoing infections,and associated with an increase in systemic inflammatory markers like C-reactive protein,inteleukin-6 and ferritin.A good response to immunomodulation can be expected.This delayed inflammatory pulmonary syndrome may represent a distinct clinical entity in the spectrum of inflammatory syndromes in COVID-19 infection.

Nonalcoholic fatty liver disease-A multisystem disease?

Non-alcoholic fatty liver disease(NAFLD) is one of the most common comorbidities associated with overweight and metabolic syndrome(Met S). Importantly, NAFLD is one of its most dangerous complications because it can lead to severe liver pathologies, including fibrosis, cirrhosis and hepatic cellular carcinoma. Given the increasing worldwide prevalence of obesity, NAFLD has become the most common cause of chronic liver disease and therefore is a major global health problem. Currently, NAFLD is predominantly regarded as a hepatic manifestation of Met S. However, accumulating evidence indicates that the effects of NAFLD extend beyond the liver and are negatively associated with a range of chronic diseases, most notably cardiovascular disease(CVD), diabetes mellitus type 2(T2DM) and chronic kidney disease(CKD). It is becoming increasingly clear that these diseases are the result of the same underlying pathophysiological processes associated with Met S, such as insulin resistance, chronic systemic inflammation and dyslipidemia. As a result, they have been shown to be independent reciprocal risk factors. In addition, recent data have shown that NAFLD actively contributes to aggravation of the pathophysiology of CVD, T2 DM, and CKD, as well as several other pathologies. Thus, NAFLD is a direct cause of many chronic diseases associated with MetS, and better detection and treatment of fatty liver disease is therefore urgently needed. As non-invasive screening methods for liver disease become increasingly available, detection and treatment of NAFLD in patients with MetS should therefore be considered by both(sub-) specialists and primary care physicians.

Cardiovascular impact of COVID-19 with a focus on children: A systematic review

BACKGROUND Since the beginning of the pandemic,coronavirus disease-2019(COVID-19)in children has shown milder cases and a better prognosis than adults.Although the respiratory tract is the primary target for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),cardiovascular involvement is emerging as one of the most significant and life-threatening complications of SARS-CoV-2 infection in adults.AIM To summarize the current knowledge about the potential cardiovascular involvement in pediatric COVID-19 in order to give a perspective on how to take care of them during the current pandemic emergency.METHODS Multiple searches in MEDLINE,PubMed were performed using the search terms“COVID-19”or“SARS-CoV-2"were used in combination with“myocardial injury”or"arrhythmia"or“cardiovascular involvement”or"heart disease"or"congenital heart disease"or“pulmonary hypertension”or"long QT"or“cardiomyopathies”or“channelopathies”or"Multisystem inflammatory system"or"PMIS"or“MIS-C”or”Pediatric multisystem inflammatory syndrome"or"myocarditis"or"thromboembolism to identify articles published in English language from January 1st,2020 until July 31st,2020.The websites of World Health Organization,Centers for Disease control and Prevention,and the Johns Hopkins Coronavirus Resource Center were reviewed to provide up to date numbers and infection control recommendations.Reference lists from the articles were reviewed to identify additional pertinent articles.Retrieved manuscripts concerning the subject were reviewed by the authors,and the data were extracted using a standardized collection tool.Data were subsequently analyzed with descriptive statistics.For Pediatric multisystemic inflammatory syndrome temporally associated with COVID-19(PMIS),multiple meta-analyses were conducted to summarize the pooled mean proportion of different cardiovascular variables in this population in pseudo-cohorts of observed patients.RESULTS A total of 193 articles were included.Most publications used in this review were single case reports,small case series,and observational small-sized studies or literature reviews.The meta-analysis of 16 studies with size>10 patients and with complete data about cardiovascular involvement in children with PMIS showed that PMIS affects mostly previously healthy school-aged children and adolescents presenting with Kawasaki disease-like features and multiple organ failure with a focus on the heart,accounting for most cases of pediatric COVID-19 mortality.They frequently presented cardiogenic shock(53%),ECG alterations(27%),myocardial dysfunction(52%),and coronary artery dilation(15%).Most cases required PICU admission(75%)and inotropic support(57%),with the rare need for extracorporeal membrane oxygenation(4%).Almost all of these children wholly recovered in a few days,although rare deaths have been reported(2%).Out of PMIS cases we identified 10 articles reporting sporadic cases of myocarditis,pulmonary hypertension and cardiac arrythmias in previously healthy children.We also found another 10 studies reporting patients with preexisting heart diseases.Most cases consisted in children with severe COVID-19 infection with full recovery after intensive care support,but cases of death were also identified.The management of different cardiac conditions are provided based on current guidelines and expert panel recommendations.CONCLUSION There is still scarce data about the role of cardiovascular involvement in COVID-19 in children.Based on our review,children(previously healthy or with preexisting heart disease)with acute COVID-19 requiring hospital admission should undergo a cardiac workup and close cardiovascular monitoring to identify and treat timely life-threatening cardiac complications.

Gastrointestinal and hepatic involvement during COVID-19 pandemic: A focus on pediatric population and possible future implications

Since the coronavirus disease 2019(COVID-19)pandemic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has rapidly spread worldwide,there is still limited knowledge about this condition and its natural history.Children have been relatively spared during COVID-19 pandemic but a novel syndrome known as multisystem inflammatory syndrome(MIS-C)has emerged,following a SARS-CoV-2 infection in children and adolescents.This syndrome can lead to shock and multiple organ failure requiring intensive care.Although COVID-19 clinical research focuses on respiratory symptoms,extrapulmonary involvement such as gastrointestinal(GI)and hepatic manifestations should also be considered.In fact,GI and hepatic involvement play an important role among the most common presenting symptoms of both pediatric and adult COVID-19 and MIS-C.This involvement can not only be one of the most common presenting clinical features but also one of the sequelae of these syndromes.Abdominal ultrasonography monitoring could be very useful to identify a potential involvement of the GI tract and liver.Moreover,long-term follow-up is needed and would be essential to define the long-term outcomes of these patients.