Langerhans cell histiocytosis (LCH) is a rare disease that originates from the uncontrolled proliferation and accumulation of bone marrow-derived immature myeloid dendritic cells. Dendritic cells are a type of histiocyte that play an important role in the human immune system and are found in the bone, skin, stomach, eyes, intestines, and lungs.This systematic review aimed to collect and report published case reports of rare bone disease caused by LCH to avoid misdiagnoses or delays in diagnosis.We systematically searched Scopus, PubMed, Embase, and Web of Sciences from August 1, 2000 to December 31, 2019. Studies reporting cases of LCH with rare bone involvement were included.We identified 60 articles including 64 cases. Of the identified cases, 31 (48.4%) involved children, and 33 (51.6%) involved adults. Additionally, 46.9%  were from Asian countries. The mean age of the children was 7.6 ± 4.3 years and that of the adults was 36 ± 12 years. The findings indicated that unifocal bone involvements were the most prevalent form of the disease (68.7%), and, overall, the skull and chest wall were the most commonly affected bones in both adults and children. The spine and long bones were the second most commonly affected bones in children, and the spine and jaw were the second most commonly affected bones in adults. Pain and swelling were the most frequent presenting signs among the investigated cases, and loss of consciousness, myelopathy, nerve palsy, visual loss, torticollis and clicking sounds were rare signs. Osteolytic lesions were the most frequent radiologic feature (62.5%), and intracranial hemorrhage, fluid–fluid level, dura and intracranial extension and pathologic fractures were rare radiological features. Total excision, curettage and observation in the unifocal group of patients and systemic chemotherapy in the other groups  were the most frequent management approaches. The recovery rates of the unifocal and multifocal groups were 77.3% and 81.8%, respectively, while that of the multisystem group was 55.5%. The rates of recurrence and mortality in the multisystem group were 11% and were higher than those in the other groups.LCH is a rare disease that can affect any organ in the human body. However, bone is the most commonly involved organ, and rare bone involvements may be the first or only symptom of the disease due to the rarity of such lesions; a lack of familiarity with them may result in misdiagnosis or delayed diagnosis. BRAF or MAP2K1 mutations in most cases of LCH suggest that it is a clonal neoplasm and originates from the uncontrolled proliferation and accumulation of bone marrow-derived immature myeloid dendritic cells [Langerhans cell histiocytosis (LCH) is a rare disease with a prevalence of 2–5 cases per million in children and 1–2 cases per million in adults annually [ic cells –6. LCH pic cells  and is mic cells  and in tic cells .Abnormal dendritic cells can infiltrate any organ, and, depending on the number and site of involved organs, the disease was previously classified as unifocal LCH with a solitary bone lesion (eosinophilic granuloma), multisystem with bone involvement, diabetes insipidus, exophthalmos (Hand–Schüller–Christian disease) and disseminated involvement with risk organ dysfunction (Abt–Letterer–Siwe syndrome) . RecentlLCH can affect any bone, but more than 50% of bone lesions belong to the skull, ribs and pelvis. The auditory ossicles, inner ear, sphenoid wings, clivus, and the short tubular bones of the hands and feet are rarely involved . Pain, sThe diagnosis of bone lesions is based on imaging studies and histopathological examination. Radiography is the gold standard of imaging studies, and computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, positron emission tomography–computed tomography (PET–CT) and whole-body MRI are complementary imaging studies. The most common radiologic feature of the bone involvements is a lytic lesion that may present as a moth-eaten, punched-out, geographic or expansile form . DestrucThe treatment and outcome of bone lesions depend on the extent and severity of the disease. Unifocal bone involvements are the least severe form of the disease and are usually treated locally by excision, curettage, intralesional steroid injection or radiation therapy , 9. The Because of the relative rarity of LCH, we conducted this systematic review to collect and identify clinical presentations, methods of diagnosis, treatment and outcomes of rare cases of LCH with bone involvement to avoid misdiagnoses or delays in diagnosis.In this study, the rare osseous involvement of LCH in children and adults was reviewed. A literature search was conducted in Scopus, PubMed, Embase, and Web of Sciences from August 01, 2000 to December 31, 2019. Appropriate English keywords such as “Langerhans cell histiocytosis”, “Hand-Schueller-Christian syndrome”, “bone”, “skull”, “case report”, and other similar keywords were used to search the articles in the databases. To identify any remaining studies, we hand-searched the bibliographies of all the included studies, relevant review articles, and the internet. The full search strategy is available in the “All the case reports on rare cases of LCH disease that described and reported bone involvement and were published in the English language were included in our search regardless of patient age. Case reports that did not document (I) demographic characteristics, (II) site(s) of involvement, (III) symptoms and signs, and (IV) method of diagnosis were omitted from the list of the articles. Reviews and meta-analyses, proceeding articles, editorials and letters, news articles, posters, conference articles, book chapters, poorly described cases or case series without primary data or without a description of individual patient data and articles without author names were also excluded.In the first step, the stated data sources were searched by the third author  and the extracted articles were imported into the reference management software ENDNOTE. After removing duplicates, the remaining articles were screened by first author (Nahid Reisi) using the title and abstract information. In the second step, the full text of the articles was checked by two trained authors (Alireza Moafi and Pouran Raeissi) to assess their inclusion. Each article was reviewed by two individuals independently, and if the authors had opposing opinions about an article, the first reviewer (Nahid Reisi) evaluated the article.A “rare case” of LCH in this review was defined as follows:one involvement in unusual locations such as the auditory ossicles and internal ear, clivus, sphenoid bone with involvement of the clivus, sphenoid wings or pituitary stalk [I, Bry stalk , claviclry stalk , 12–15.typical radiographic appearance such as epiphyseal lesions, transphyseal lesions, extracranial “button sequestrum”, posterior vertebral arch lesions of the spine, fluid–fluid levels on CT or MRI, cortical bone lesions, extension of a lesion into the dura or brain substance, and pathologic fractures [II, Aractures , 13, andractures .nusual presentations such as neurologic manifestations of spinal disease resulting from vertebral collapse and impingement or from extradural extension of the lesion [III, Ue lesion  and crane lesion .IV, Unusual age—the neonatal period  and age In the final step, the required parameters and characteristics of each study were extracted and included author names, year, country of origin of the published article, demographic characteristics of the cases, symptoms and signs, sites of involvement, lesion types, method of tissue sampling and diagnosis, strategies for management and patient outcomes.The results of the initial search of databases and hand searching other sources yielded 2,101 and 22 articles, respectively; after eliminating duplicates, 1,661 articles remained. After screening the articles by title and abstract, 264 articles remained, and the remainder were excluded because they were not relevant. After reviewing the full text of the 264 articles, 113 articles that lacked eligibility information were excluded. Finally, 60 articles encompassing 64 rare cases met the eligibility criteria to enter the study , 14–67. Sixty articles were included in the final analysis, comprising 64 cases. Most of the case reports (71.7%) were published between 2010 and 2019 and were from Asian countries. More than two-thirds (70.3%) of the cases were male, and the male-to-female ratio was 2.3. Thirty-one cases (48.4%) were children (younger than 18 years), and the remainder (51.6%) comprised adults (older than 18 years). The mean age of the children was 7.3 years (SD = 4.3 years) with an age range of 5 months to 16 years, and the mean age of the adults was 36 years (SD = 12 years) with an age range of 18–66 yearsBased on the number of involved bones and other organ involvement, the cases were classified into three categories: unifocal bone involvement, multifocal bone involvement, and multisystem. Unifocal bone involvement had the highest frequency among the other groups of bone involvement and accounted for 68.7% of the cases.In general, the skull and chest wall showed the highest rate of involvement  followed by the spine and pelvis (9.4% each). Short tubular bones were involved in 3% of the cases. The demographic and clinical characteristics of the included cases are shown in Table Table Hearing loss, otalgia, otorrhea, tinnitus, vertigo, nystagmus and disequilibrium were symptoms and signs of temporal bone involvement with extension and destruction of the inner ear. Left otitis media with effusion and drainage of cerebrospinal fluid (CSF) after ventilation tube insertion was a rare presentation of mastoid involvement with destruction of the posterior wall of the external auditory canal with extension to the sigmoid sinus. Hearing loss in both ears for 10 years treated with corticosteroids and worsening following the discontinuation of corticosteroids was another sign of mastoid involvement.Headache, vomiting, loss of consciousness, swelling and soft tissue mass (progressive or tender with or without pain) were symptoms and signs of calvarium bone involvements with intracranial hemorrhage. Facial puffiness and eye proptosis was a sign of maxillary sinus involvement. Rapidly progressing visual loss occurred following optic canal involvement (1 case) and gradual visual loss following petrous apex involvement (2 cases). Bilateral abducent nerve palsy was also another sign of petrous apex involvement.Symptoms of cord compression, including pain, weakness, numbness, paresis and paresthesia, were observed in 3 cases with spinal involvements and 1 case of sacral spine (S1) involvement with extension into the neuroforamina. Torticollis was also reported in cases with cervical spine or occipital condyle involvement.The other rare symptoms in these cases were chest tightness, clicking sound , teeth mobility and gingival dehiscence. Fever was also reported in one case with sternum involvement.The findings indicated that most of the cases showed unifocal bone involvement (68.75%). Multifocal and multisystem bone involvements were observed in (17.19%) and 14.06%) of the cases, respectively. The sites of bone involvement in children and adults for the three stated categories are presented in Table .06% of tOf the 64 identified cases, 31 were children and 33 were adults; the prevalence of the disease did not differ between the two groups based on our findings. For the two groups, the most common affected bones were as follows: in children: skull (48.4%), chest wall (22.6%), spine and long bones (each 9.7%); in adults: skull (36.4%), chest wall (21.2%), spine (9.1%) and jaw (6.1%). TPelvic bone involvement was observed exclusively in adults, and involvement of the short tubular bones of the hand and foot did not differ between the two age groups Table .Fig. 5SiIn the skull, calvarium involvements were more prevalent than in the skull base, and mostly involved children. However, the parietal and occipital regions were the most affected sites, and intracranial hemorrhage was exclusively observed in children. Skull base involvements, which mostly affected the inner ear, were more prevalent in adults Table .Table The most common types of imaging studies used in all the patient groups were CT  and MRI , followed by plain radiography (46.9%), bone scintigraphy (34.4%), bone survey (21.9%) and PET-CT (15.6%).Radiologically, osteolytic lesions, with a prevalence of 62.5% (n = 40), were the most common bone involvement among the cases, followed by destructive, expansile lytic and erosive forms, in that order. In a 66-year-old man with a parietal osteolytic lesion, a sequestered fragment within the lesion (button sequestrum) was reported. Another study reported a 4 year old with LCH discrete fluid–fluid levels within the epidural component.The findings indicated that, in 98.4% (n = 63) of cases, the diagnoses of bone LCH was confirmed by histopathological and immunohistochemical examination on tissue sampling of the lesion. In one case, tissue sampling of the lesion was not performed, and the diagnosis was merely made based on the clinical background of LCH and imaging examinations. Surgical biopsy (43.7%) and closed biopsy (18.7%) were the most frequent methods of sampling.Table In the unifocal group, total excision (40.9%), curettage (20.5%) and observation (9%) were the most frequent modalities applied to treat the patients, followed by “excision plus chemotherapy”, “curettage plus radiotherapy”, “systemic chemotherapy”, and “conservative management” (4.5% each). However, “subtotal excision plus radiotherapy” or “sub-total excision plus chemotherapy”, “radiotherapy plus epidural steroid injection”, radiotherapy and radiosurgery alone were the least common modalities applied to treat LCH patients (2.5% each).Among the multifocal and multisystem categories, “systemic chemotherapy” was the most frequent management approach applied , followed by total excision in the multifocal cases and combination therapies  in the multisystem group . Two patients in the unifocal group and 1 patient in the multisystem and multifocal groups were treated by conservative management.Following the initial treatments, 77.3% of the unifocal, 81.8% of the multifocal and 55.5% of the multisystem cases completely recovered, but permanent complications were reported in six patients (9.4%) . The multisystem group had more recurrences than the unifocal and multifocal groups , and the mortality rate in this group was higher than that in the other two groups (11% vs 0.0%).The results of this systematic review of rare case reports of LCH bone involvements showed differences and similarities with the existing literature. The cause may be that the available statistics are mostly based on studies concerning LCH in general and not rare cases. Furthermore, most of the findings of rare cases were obtained from a few cases, not systematic reviews, highlighting the need for these studies.Our findings showed that most cases (70%) of rare LCH bone involvements occurred in male patients and the M/F ratio was 2.3. This finding was consistent with previous study findings , 11. HowAdditionally, the mean age of the children in this study was 7.6 years, higher than that of children with the disease in other studies 3 years) [ years 3.Our findings also revealed that the unifocal form (68.7%) was the most common form of bone involvement and the unifocal/multifocal ratio was 4:1. Singh et al.  also repBased on the available statistics, the skull is the most common site of bone involvement of LCH (40–60% of cases) , 67, 69,The prevalence of bone involvements in children and adults showed the following differences: long bones 17%) with a higher tendency in children 7% with a, 69, pelIn the present study, the prevalence of bone involvement of LCH disease was as follows:In children: skull (48.4%), chest wall (22.6%), spine and long bones 9.7% each); in adults: skull (36.4%), chest wall 21.2%), spine (9.1%) and jaw (6.1%). Consistent with previous studies [.2%, spin.7% each;Calvarium lesions were more common in children, and mostly involved the occipital and parietal regions. The skull base involvements mostly involved the clivus, sphenoid bone and inner ear and were more common in adults. The chest wall, particularly the clavicle and sternum, was the second most common site involved after the skull. We could not find exact data on clavicular involvement, but some studies have reported its incidence in LCH disease , 37–39. The forearms, metacarpals and metatarsals were the other rare sites found in our study, and they were previously reported to be rare or sporadic , 14, 15.As expected, localized pain and swelling or both were the most presenting signs in these patients; however, depending on the involved site and its severity, the symptoms were different. Our findings revealed the loss of consciousness with or without headache and vomiting due to extradural hematoma with LCH and myelopathy signs due to spinal cord compression, nerve palsy due to petrous apex involvement, and visual loss due to optic canal involvement, which are rare presentations of LCH , 12. TheCord compression and neurologic deficits due to spinal involvement are extremely rare, and the threatening event of LCH usually present as localized or radiating pain, restricted mobility, numbness, weakness and paresthesia –35. KhunConsistent with previous studies, our findings revealed that imaging analyses, including plain radiograph, CT and MRI play crucial roles in the diagnosis of bone involvements. Based on the available study findings , 11, 13,As mentioned previously, the treatment and outcome of bone lesions depend on their location, extent, and severity , 9. UnifConsistent with previous study findings , 49, 62,I. Given the incomplete data concerning patient follow-up in this review and lack of long-term follow-up for cases, we cannot make judgments regarding the long-term outcomes and reoccurrences of rare bone lesions of LCH in children or adults after treatment. Therefore, we suggest that future studies focus on exploring the long-term outcomes of treating “unusual sites of bone involvement in LCH patients”.II. Additionally, our findings were derived from case reports, which rank at the bottom of the hierarchy of evidence. This inherent limitation in the study designs of the original articles covered in this systematic review restricts reaching a precise conclusion regarding the patient outcomes .LCH is a rare disease that can affect any organ in the human body. The bone is the most commonly involved organ, and rare bone involvements may be the first or only symptoms of the disease. Because of the rarity of these lesions, their unfamiliarity may lead to misdiagnoses or delays in diagnosis. This review collected the clinical presentations, methods of diagnosis, radiologic features, management approaches, and outcomes of rare bone lesions of LCH in children and adults. Hopefully, our findings not only add to the body of literature concerning LCH but also provide some clues or guidance for physicians when encountering these cases.


Seizures are the most common neurological disorder in newborns and are most prevalent in the neonatal period. They are mostly caused by severe disorders of the central nervous system (CNS). However, they can also be a sign of the immaturity of the infant’s brain, which is characterized by the presence of specific factors that increase excitation and reduce inhibition. The most common disorders which result in acute brain damage and can manifest as seizures in neonates include hypoxic-ischemic encephalopathy (HIE), ischemic stroke, intracranial hemorrhage, infections of the CNS as well as electrolyte and biochemical disturbances. The therapeutic management of neonates and the prognosis are different depending on the etiology of the disorders that cause seizures which can lead to death or disability. Therefore, establishing a prompt diagnosis and implementing appropriate treatment are significant, as they can limit adverse long-term effects and improve outcomes. In this review paper, we present the latest reports on the etiology, pathomechanism, clinical symptoms and guidelines for the management of neonates with acute symptomatic seizures.  Acute symptomatic seizures are the most common neurological emergency in newborns and are most prevalent in the neonatal period. They are early signs of brain damage and can severely disturb the development of the infant’s immature brain. Seizures affect 1–3 neonates per 1000 live births . The preThe paper presents a summary of the results of the latest research on neonatal seizures. The collected data were divided into sections, representing various aspects related to the disorder, i.e., pathophysiology, etiology, spectrum of symptoms, classification, diagnosis, treatment and outcomes.The search strategy consisted of controlled vocabulary and keywords. The following databases were searched: PubMed, Medline and Google Scholar. The main search concept was to combine “neonatal seizures” with related terms, such as “pathophysiology”, “etiology”, “genetic(s)”, “symptoms”, “diagnosis”, “treatment” and “outcomes”. Filters which were applied to limit the retrieval included the language and the date of publication. For this reason, only English language papers published within the previous 10 years were considered for this review. Exclusion criteria included articles not containing the related terms, articles written in a language other than English or articles published more than 10 years ago. Each database was searched individually, and search terms were applied line by line and were replicated in every source. The entire process of searching relevant papers lasted from April 2020 to October 2020, with numerous subsequent updates on the latest scientific reports. Titles, abstracts and full-text articles were screened against the inclusion criteria by two reviewers. Next, manual search and reference and citation tracking were undertaken by two reviewers (KK and SK) who established the final selection of papers. Any disagreement was resolved by discussion. In the case of no agreement, a third independent reviewer made the final decision. Throughout the search process, 57 articles were found and 40 of them were included in the final analysis. The articles included in the review were grouped into the neonatal seizure-related thematic categories for better organization, e.g., “etiology”, ”diagnosis” or “outcomes”. A receptor, the outflow of chloride ions and depolarization of the neuronal cell membrane increases, which implies higher sensitivity of neurons to stimulation and generation of action potential [A receptor in the neonate’s brain where NKCC1 is predominant, depolarization caused by chloride ion efflux also triggers internal calcium currents and removes the voltage-dependent magnesium block of N-methyl D-aspartate (NMDA) receptors [In the mature brain, gamma aminobutyric acid (GABA), which is the main inhibitory messenger, induces the influx of chloride ions and hyperpolarization of a neuronal membrane after binding of the GABA receptor agonist, which makes the neuron unable to conduct the impulse. This is due to high expression of potassium-chloride cotransporter 2 (KCC2) and low expression of sodium-potassium-chloride cotransporter 1 (NKCC1). Preclinical models showed that in the immature brain of newborns, the proportion of cotransporter expression was different . Due to otential . These sotential . When GAeceptors ,17. Thiseceptors ,17. Addieceptors . The process of a dynamic increase in the number and density of synapses and dendrites (synaptogenesis), which occurs in the neonatal period, is also important in the pathophysiology of seizures. Then, physiologically enhanced excitation in the neonatal period is necessary for the proper development of newly formed neurons . However, it also makes the neonatal brain more susceptible to seizures ,19.Neonatal seizures are a nonspecific heterogeneous symptom of brain injury that has many different causes. Etiology of seizures depends on the gestational age of the newborn. Among term neonates and late premature neonates , the most common causes of brain damage manifested by seizures include HIE, ischemic stroke, ICH, transient metabolic and electrolyte disturbances, systemic or central nervous system (CNS) infections ,20,21. TEscherichia coli) can also be involved [HIE is the most common cause of acute seizures and accounts for approximately 40% of all neonatal seizures ,24. Amoninvolved . Due to involved . Congeniinvolved ,32. Suchinvolved . ConsideAlthough there are many causes of neonatal seizures, clinicians should be vigilant when establishing the diagnosis, bearing in mind the fact that about 50% of neonates have more than one cause of seizures . Due to The percentage of each cause of seizures varies depending on the study. For this reason, we decided to average the data from these studies and present a schematic diagram that allowed us to visualize the most common causes of neonatal seizures more easily .The knowledge of seizures and their etiology has been growing for many years. It is already known that some causes of neonatal seizures are characterized by a genetic basis . It is ePAFAH1B1, TSC1 and TSC2, DCX, ARX, DEPDC5) [Developmental defects of the cerebral cortex account for approximately 4% of all neonatal seizures ,24,34 an DEPDC5) ,31,37. T DEPDC5) . Abnorma DEPDC5) ,31. Intr DEPDC5) ,37. TherInborn errors of metabolism are most often suspected on the basis of clinical manifestations  and biochemical test results  ,39. The ALDH7A1 and PROSC genes) is one of the most common inborn errors of metabolism that results in neonatal seizures. It is an autosomal recessive disorder that manifests as a result of deficiency of α-aminoadipic semialdehyde dehydrogenase in the lysine degradation pathway [PNPO gene, neonates may also respond well to vitamin B6, although they still have similar clinical manifestations [BTD gene, autosomal recessive inheritance), nonketotic hyperglycinemia , molybdenum cofactor and sulfite oxidase deficiency  [Pyridoxine-dependent epilepsy  ,37,43,46iciency) ,48. OtheSeizures in neonates can often manifest as part of the genetic syndrome, which commonly affects many systems, and the characteristic dysmorphic features are evident. Such syndromes can be divided according to the type of disease. The following can be distinguished among chromosomal disorders associated with neonatal seizures: Down syndrome, Patau syndrome, Edwards syndrome, Wolf–Hirschorn syndrome and the 22q11.2 deletion syndrome . It was KCNT1, KCNQ2, CACNA1A or SCN2A genes, which are responsible for the regulation of calcium, sodium or potassium channels [KCNQ2 and KCNQ3 genes, which are responsible for voltage-gated potassium channels and one chromosomal inversion [STXBP1, TBC1D24, SIK1, CDKL5 and BRAT1 genes [Neonatal seizures can also occur as main symptoms resulting from mutations in one gene, which is mainly related to genes involved in the regulation of ion channels, synaptic function and intercellular signaling ,37. Chanchannels ,37,49,50channels ,32,51,52channels ,32,51,52nversion ,32,51,52T1 genes ,49,50. ST1 genes . These sT1 genes . ARX, CDKL5, SLC25A22, STXBP1, KCNQ2, SPTAN1 and SCN2A) [STXBP1, TBC1D24 and GABRA1 genes [KCNT1, SCN2A, SCN1A, SLC25A22, PLCB1, TBC1D24 and QARS genes [Self-limited neonatal seizures are also known as "fifth day fits" due to the time of their occurrence  ,53. Seizd SCN2A) ,35. Patid SCN2A) ,55. EIEEd SCN2A) . EME is A1 genes ,43,53. ERS genes ,56. The Despite the development of molecular diagnostics, the correlation between genotype and phenotype still poses some difficulty. As a result, the same genetic syndrome can be caused by variants in different genes, and abnormal gene variants can lead to different clinical phenotypes in different neonates .Seizures are the most common paroxysmal, stereotypical and repetitive neurological events. Therefore, any abnormal behavior in neonates should be considered a potential seizure, requiring confirmation by electroencephalography . In addition to typical symptoms such as tonic, clonic and myoclonic seizures, other subtle manifestations of clinical seizures are reported  . SometimA wide range of etiologies of neonatal seizures indicates high variability in seizure types and poses a diagnostic challenge for clinicians. In 2017, the International League Against Epilepsy (ILAE) introduced a revised classification of seizure types . This clThe neonatal period is a unique period in many respects. As a result, not all guidelines for seizure classification can be applied. Apart from the previously mentioned inability to assess consciousness in neonates, several types of seizures cannot be diagnosed due to the difficulties in communication with neonates  . These tThe aim of the unification of the classification system and terminology when describing individual seizures is to improve communication related to health care professionals, parents and medical care assistants. Classification also allows grouping of patients for therapies. Currently, some regulatory agencies approve drugs or medical devices indicated for specific types of seizures .Neonatal seizures are an emergency and therefore, diagnostic and therapeutic procedures should be performed simultaneously. In the diagnosis of acute symptomatic neonatal seizures, it is necessary to initially exclude reversible systemic disorders (such as electrolyte disturbances or hypoglycemia). However, if such disorders are confirmed, neuroactive anticonvulsants do not have to be administered and there is no need to perform other tests that may often be invasive. If possible, continuous video electroencephalographic (cEEG) monitoring, which is the gold standard in the diagnosis of neonatal seizures, should be immediately used ,13. ThisAdditionally, apart from electroencephalographic studies, neuroimaging  is also used. Cranial ultrasound is the method of choice for neuroimaging because it has many benefits. The advantages include easy availability of the equipment, the possibility of bedside examination and its use among neonates in any clinical condition . Head ulNext to monitoring neonates with EEG and neuroimaging studies, the complete clinical examination should also be performed. It should include the physical examination, an interview with parents (if possible) about the neonate, family history, parental diseases, information about pregnancies and deliveries, which is of crucial importance . ParticuThe clinical diagnosis of neonatal seizures and the underlying causes is a challenge for clinicians. Of note, both underdiagnosis (associated with the lack of further search for causes and delayed treatment initiation) as well as overdiagnosis  may be related to the deterioration of health and complications in neonates. Therefore, multidisciplinary vigilance, individual approach to each neonate and treatment compliance that limit false positive or false negative diagnosis are of crucial importance. Acute neonatal seizures are an emergency and should be treated promptly. Treatment should be initiated immediately after the diagnosis of EEG seizures . DependiPharmacotherapy for neonatal seizures is empirical and varies greatly. Among many anticonvulsants, phenobarbital is the first-line drug, although its efficacy is only about 50% ,72,73,74KCNQ2, KCNQ3 or SCN2a epilepsy respond well to treatment with low-dose sodium channel blockers, such as carbamazepine or oxcarbazepine [When the acute symptomatic cause of seizures cannot be identified and a neonate presents with symptoms of tonic seizures, neonatal epilepsy should be suspected . Initialbazepine ,31,85,87bazepine ,85. p <0.0005) [p < 0.002) [p = 0.009) [The development of neonatal intensive care and the increasing availability of continuous video-EEG have significantly improved the treatment outcomes of neonates with seizures. However, this condition can still lead to disability or death. The occurrence of seizures in the neonatal period contributes to the pathological intensification of synaptic connections in the hippocampus . This oc<0.0005) . Interesp < 0.005) [The most common neurological sequelae of neonatal seizures include developmental delay (30–50%) ,7, epile< 0.005) .Although neonatal seizures are a relatively rare neurological disorder, they can be associated with severe sequelae, often affecting the patient’s normal life. Therefore, the vigilance of physicians who provide care for neonates in the first days of their lives and a rapid diagnostic process are of paramount importance. Technological progress and wider availability of video-EEG, aEEG and MRI are also crucial. To effectively treat seizures, the etiology should be determined with the greatest possible accuracy. Therefore, sometimes it is necessary to perform highly specialized and expensive metabolic or genetic tests. The key to therapeutic success seems to be the immediate management of the cause and the introduction of appropriate treatment, which will reduce adverse long-term effects and improve the results. Therefore, in certain clinical situations, treatment should be carried out simultaneously with the initial diagnosis. The reports on the approach to the diagnosis or treatment of seizures and the results obtained with the use of various therapeutic methods allow for the exchange of experience among clinicians and constitute a broad base of practical knowledge.


Pandemic coronavirus disease 2019 (COVID-19) may lead to significant mental health stresses, potentially with modifiable risk factors. We performed an internet-based cross-sectional survey of an age-, sex-, and race-stratified representative sample from the US general population. Degrees of anxiety, depression, and loneliness were assessed using the 7-item Generalized Anxiety Disorder-7 scale (GAD-7), the 9-item Patient Health Questionnaire, and the 8-item UCLA Loneliness Scale, respectively. Unadjusted and multivariable logistic regression analyses were performed to determine associations with baseline demographic characteristics. A total of 1,005 finished surveys were returned of the 1,020 started, yielding a completion rate of 98.5% in the survey panel. The mean (standard deviation) age of the respondents was 45 (16) years, and 494 (48.8%) were male. Overall, 264 subjects (26.8%) met the criteria for an anxiety disorder based on a GAD-7 cutoff of 10; a cutoff of 7 yielded 416 subjects (41.4%), meeting the clinical criteria for anxiety. On multivariable analysis, male sex , identification as Black , and living in a larger home  were associated with a decreased odds of meeting the anxiety criteria. Rural location , loneliness , and history of hospitalization  were associated with increased odds of meeting the anxiety criteria. Two hundred thirty-two subjects (23.6%) met the criteria for clinical depression. On multivariable analysis, male sex , identifying as Black , increased time outdoors , and living in a larger home  were associated with decreased odds of meeting depression criteria. Having lost a job , loneliness , and history of hospitalization  were associated with an increased odds of meeting depression criteria. Income, media consumption, and religiosity were not associated with mental health outcomes. Anxiety and depression are common in the US general population in the context of the COVID-19 pandemic and are associated with potentially modifiable factors. The coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented levels of movement restriction, job losses, and economic uncertainty in the United States and around the world , health status, socioeconomic status, residence size, time spent outdoors, and other baseline demographic characteristics. These baseline characteristics were chosen given their potential relevance for developing future risk models and their potential modifiability. A better understanding of the prevalence of these mental health outcomes and their putative risk factors may help guide public policy, research, and interventions.This study is a cross-sectional, internet-based survey performed via age, sex, and race stratification to reflect the makeup of the general US population, conducted between March 29, 2020, and March 31, 2020. Responses to all survey questions were recorded . This study was deemed exempt by the Ascension Health institutional review board.We developed an online survey using the Qualtrics platform  after iterative online pilot testing. The survey was distributed to a representative sample of the US population using Prolific Academic , an established platform for academic survey research . ProlifiThis internet-based survey was stratified by age, sex, and race to reflect the makeup of the general US population. Sample size calculations were conducted for the primary endpoint of detecting a 10% difference in the Generalized Anxiety Disorder-7 scale (GAD-7) between those that were and were not under a stay-at-home order at the time of survey completion. Six hundred eighty-two subjects (341 per group) would be adequate to detect a 10% change in GAD-7 with 80% power and with an α of 0.05, assuming a baseline GAD-7 mean of 11.6 with a standard deviation (SD) of 5.4 and assuming equal group sizes . We inflFor our main outcome measures, anxiety and depression, validated scales were used. Anxiety was assessed using the GAD-7, a validated self-report scale for anxiety, with scores ranging from 0 (no anxiety) to 21 (extreme anxiety). Prior psychometric research suggested cutoffs as 0–4 (no anxiety), 5–9 (mild anxiety), 10–14 (moderate anxiety), and 15–21 (severe anxiety) .Depression was assessed with the Patient Health Questionnaire-9 (PHQ-9), a validated measure for clinical depression . Scores Loneliness was quantified with the UCLA Short-Form Loneliness Scale (ULS-8), a validated measure of loneliness . Scores Age, sex, rural area residence, and race were included based on self-report. Binary choices were provided for sex selection. Race was divided into six categories: White, Black/African American, American Indian/Alaskan Native, Asian, Native Hawaiian/Pacific Islander, and other. Religiosity was defined based on self-report of whether the participant considered themselves a religious person, including an ambivalent option. Media consumption was assessed by the number of hours spent watching or reading about the pandemic over the preceding 3 days. Time spent outdoors was measured by self-report on number of hours spent outside over the preceding 3 days, with options for 0, <1, 1–3, 3–5, and more than 5. Income was based on self-report using a range of 12 options from <$10,000 per year to more than $150,000 per year. Home size was based on self-report, with options ranging from <500 square feet to more than 2,000 square feet.t Tests and χ2 tests were used as appropriate for baseline continuous and categorical variables. Subgroup comparisons of non–normally distributed data were performed using the Kruskal–Wallis test. Unadjusted and multivariable (adjusting for the nonmodifiable variables of age and sex) logistic regression odds ratios (ORs) of association were assessed between the dependent variables of anxiety or depression, presented as dichotomous outcomes using the established cutoffs of 10 for both the GAD-7 and PHQ-9, and putative risk factors.Normally distributed baseline demographic data are presented as mean values with 95% confidence intervals (CIs). Outcomes that were not normally distributed are presented as medians with interquartile ranges (IQRs). All statistical analyses were performed using Stata 13 for Mac .n = 663, 66.2%) and were not  under a shelter-in-place or stay-at-home order (defined by self-report), with the exception of sex and geographic location . The median (IQR) ULS-8 score for loneliness was 16 (12–20), similar to baseline estimates from previous studies  age of the respondents was 45 (16) years, and 494 (48.8%) of the respondents were male; baseline respondent characteristics are outlined in  studies –27.p = 0.128). Overall, 264 subjects (26.8%) met the criteria for an anxiety disorder based on a GAD-7 cutoff of 10 (p = 0.002) and those living in rural areas (p = 0.041) reported more severe anxiety than men and those in urban areas, respectively.The median (IQR) GAD-7 score was 5 (1–10), and 513 subjects (52.1%) of the subjects had at least mild anxiety. Median GAD-7 scores did not differ significantly by shelter-in-place order status , male sex , and having a larger home size  were associated with a decreased odds of meeting the anxiety criteria. Loneliness  was associated with an increased odds of meeting the anxiety criteria in the fully adjusted model.Unadjusted logistic regression analysis demonstrated that men  and those who identified as Black  were less likely to meet the criteria for anxiety, whereas, those who lost their job , had been hospitalized within the past 2 years , or were in the most lonely quartile  were more likely to meet the criteria for anxiety. On multivariable analysis controlling for age and sex as confounders, male sex , identifying as Black , and living in a larger home  were associated with a decreased odds of meeting the anxiety criteria. Rural location , loneliness , and history of hospitalization within the past 2 years  were independent risk factors for meeting the anxiety criteria . In a fup = 0.743). A total of 232 subjects (23.6%) met the criteria for clinical depression. Women (p = 0.008) and unmarried subjects (p < 0.0001) reported more severe depression than men and those who are married, respectively.The median (IQR) PHQ-9 score was 4 (1–9), and 465 (47.3%) of the subjects reported at least mild depression by screening . Median p > 0.10 on univariable analyses, identifying as Black , identifying as Asian , increasing age , and spending 5 h or more outside over the past 3 days  were associated with a decreased odds of meeting depression criteria. Loneliness  was associated with an increased odds of meeting depression criteria in the fully adjusted model.Unadjusted logistic regression analysis demonstrated that men were less likely to meet the criteria for depression , whereas those who lost their job , had been hospitalized within the past 2 years , or were in the most lonely quartile  were more likely to meet the criteria for depression. On multivariable analysis controlling for age and sex as confounders, male sex , identifying as Black , increased time outdoors , and living in a larger home  were associated with a decreased odds of meeting depression criteria. Having lost a job , loneliness , and history of hospitalization within the past 2 years  were associated with meeting depression criteria . In a fuIn this first study of general US population mental health during the COVID-19 pandemic, we found high baseline levels of both anxiety and depression, independent of living under a shelter-in-place or stay-at-home order. More than half (52.1%) of the respondents had at least mild anxiety, and 47.3% of the subjects had at least mild depressive symptoms. This high burden of mental health concerns in the general population in the pandemic context suggests the need for further study and consideration for intervention. That said, the prevalence of mental health outcomes is fairly high in the US population at baseline, where estimates have suggested the prevalence of anxiety and depression is on the order of 19% and 24%, respectively , 29.We found that respondents who identify as Black were less likely to meet the criteria for anxiety on both univariate and adjusted analyses and less likely to meet the criteria for depression on adjusted analyses. Those who identified as Asian had decreased odds of meeting both anxiety and depression on fully adjusted analyses. This finding suggests the need for further study, although they echo prepandemic research that has suggested a lower prevalence of self-reported anxiety in respondents who identify as Black –32. EstiLiving in a larger home was associated with a reduced risk of both anxiety and depression; this effect was seen despite the lack of any association between anxiety or depression and household income and persisted when including income and number of household members in a multivariable model. Similarly, we found that increased time spent outdoors correlated with a reduction in depression (but not anxiety) risk, and those who spent more than an hour a day outdoors had approximately half the risk of depression as those who spent no time outdoors. This association of depression with time outdoors echoes prior research on associations with time spent outdoors and its impact on mental health , 38. OurHistory of hospitalization, a rough measure of overall health status, was associated with an increased risk of both anxiety and depression. This effect persisted even when controlling for age and history of anxiety and depression, respectively, suggesting that those with a poorer health status may be at increased risk of adverse mental health outcomes in the context of the COVID-19 pandemic.Media consumption was not associated with the presence of anxiety or depression. Similarly, we did not detect significant associations between likelihood of meeting the criteria for anxiety or depression and household income or religiosity on adjusted multivariable analyses.Notably, we found that fewer than half of the respondents had no anxiety; that is, more than half of the subjects reported a level of anxiety that would at least be classified as mild. Conversely, 13.4% of the subjects demonstrated severe anxiety, a higher proportion than has been reported even in healthcare workers responding to pandemic COVID-19 . The hetLoneliness is an established risk factor for both anxiety and depression , 40, andThis study has several limitations. First, as with any survey-based research, its generalizability may be limited. We used Prolific Academic for survey distribution in order to maximize our generalizability to the general US population by using an age-, sex-, and race-stratified survey panel design with a large and validated sampling frame. As with any survey data, however, the sample willing to participate may not fully reflect the population of interest, and stratifying by these variables does not guarantee that the sample population reflects the general population in any other way. Second, our study took place during the early phase of the COVID-19 pandemic, when shelter-in-place and stay-at-home orders were only just beginning. If anything, however, this underestimates the prevalence of anxiety and depression as these outcomes would only be expected to increase as restrictions persist and highlights that even the anticipation of such restrictions may present a stressor. Third, as with any survey study, response bias and social desirability bias may play a role, although the anonymous survey design may help mitigate these concerns. Fourth, while our study relied on validated scales wherever possible, some survey questions were the product of pilot testing alone, and therefore their methodology—although consistent with the survey development literature—has not been fully vetted. Fifth, our selection of independent variables was not exhaustive, and other important variables, such as sleep , family In this first study of mental health outcomes in the US population during the COVID-19 pandemic, we found high rates of depression and anxiety, with the most profound mental health effects in women, those with a history of hospitalization over the past 2 years, those who were most lonely, and those living in smaller homes, and (for depression) those spending the least time outdoors. These findings may be considered in future public health efforts and in developing national and international pandemic responses.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ascension Health IRB. The patients/participants provided their written informed consent to participate in this study.BK and JK: study conception, design, writing, statistics. JK: oversight. All authors contributed to the article and approved the submitted version.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.


Background: Methemoglobinemia (MET) should be suspected in cases where cyanosis is not associated with signs and symptoms of lung and/or heart disease, or in a cyanotic child exhibiting discrepancies in the partial pressure of oxygen in the arterial blood, the blood oxygen saturation, and the clinical assessment. Case presentation: A 10-month-old girl was taken to the Pediatric Emergency Department for the acute, sudden development of significant peroral cyanosis associated with gray pigmentation of the skin. The problem was evidenced approximately one hour after she ingested a homemade puree of mixed vegetables, mainly composed of potatoes and chards that had been prepared three days before and had been kept in the refrigerator since then. Physical examination revealed that the child was very pale, conscious, and without respiratory distress. Oxygen saturation of hemoglobin in the arterial blood (SpO2) was 94%. Respiratory, cardiovascular, and abdominal evaluations did not reveal any signs of disease. A venous blood sample showed chocolate-colored blood with a pH of 7.404, a partial pressure of CO2 (pCO2) of 40.6 mmHg, a partial pressure of oxygen (pO2) of 21.3 mmHg, a bicarbonate level of 24 mmol/L, and an oxygen saturation (SO2%) of 47.7%. CO-oximetry carried out simultaneously identified a methemoglobin level of 22%. MET was suspected, and oxygen via nasal cannula at a rate of 4 L/min was given with only a slight increase in oxygen saturation (96%). Slow intravenous injection of methylene blue 1 mg/kg over a period of 5 min was initiated. The peripheral oxygen saturation (SpO2) gradually improved to 100% over the next 20 min. Forty minutes later, venous blood gas analysis showed a methemoglobin level of 0.9% with a complete resolution of cyanosis; supplemental oxygen via nasal cannula was therefore discontinued. During the next 36 h, the patient remained hemodynamically stable with good oxygenation on room air. Conclusions: This case report shows that recognition of acquired MET in a child with sudden cyanosis onset requires a high index of suspicion. In daily activities, there is a need to pay particular attention when homemade vegetable soups for child alimentation are prepared. The consumption of vegetable soups must occur immediately after preparation. Storage in a refrigerator must last no more than 24 h and if longer storage is needed, vegetable soups should be frozen. Cyanosis, i.e., a bluish discoloration of the skin and mucosa, results from the presence of at least 5 g/dL of deoxygenated hemoglobin in the circulation. This pathologic condition can be due to four different mechanisms: pulmonary venous desaturation, extrapulmonary right to left shunting, transposition physiology, and hemoglobin disorders affecting the affinity to oxygen . DiagnosMET is a rare blood disease in which the iron component of hemoglobin is oxidized from the ferrous to the ferric state, leading to a reduced release of oxygen in the tissues . ClinicaSeveral conditions are potential inducers of MET. Among them are acute diarrhea; consumption of high-nitrate water and food; use of certain drugs such as topical anesthetic agents, silver nitrate, sulfonamides, phenacetine, and sodium valproate; or exposure to aniline dyes, coloring compounds, or cleaning solutions ,5,6,7,8.A 10-month-old girl was taken to the Pediatric Emergency Department of the Children’s Hospital of the University of Parma, Parma, Italy, for the acute, sudden development of significant peroral cyanosis associated with gray pigmentation of the skin. No other signs or symptoms of disease were reported by her parents. The problem was evidenced approximately one hour after she ingested a homemade puree of mixed vegetables, mainly composed of potatoes and chards that had been prepared three days before and had been kept in a refrigerator since then.2) was 94%. Respiratory, cardiovascular, and abdominal evaluations did not reveal any signs of disease. The chest X-ray and the electrocardiogram were negative. A venous blood sample was withdrawn when the patient breathed room air and showed chocolate-colored blood with a pH of 7.404, a partial pressure of CO2 (pCO2) of 40.6 mmHg, a partial pressure of oxygen (pO2) of 21.3 mmHg, a bicarbonate level of 24 mmol/L, and an oxygen saturation (SO2%) of 47.7%. CO-oximetry carried out simultaneously identified a methemoglobin level of 22%; oxyhemoglobin of 36.9%; and carboxyhemoglobin of 0.6%. MET was suspected, and oxygen via nasal cannula at a rate of 4 L/min was given with only a slight increase in oxygen saturation (96%). Slow intravenous injection of methylene blue 1 mg/kg over a period of 5 min was initiated. After a transient decrease during methylene blue administration, peripheral oxygen saturation (SpO2) gradually improved to 100% over the next 20 min.At admission, it was defined that both the family history and the personal history of the patient were negative for previous significant diseases. In particular, no recent episode of diarrhea was reported. Moreover, it was established that the family was living in an area with continuous control of potable water, the girl had not taken any kind of drugs, and there had been no accidental ingestion of foreign substances present in the house for personal hygiene and room cleaning. Physical examination revealed that the child was very pale, conscious, and without respiratory distress. Body temperature was 36.8 °C, heart rate was 140 beats/min, blood pressure was 90/60 mmHg, respiratory rate was 34 breaths/min, and oxygen saturation of hemoglobin in the arterial blood  and creatine phosphokinase .The patient was subsequently admitted to the ward for close monitoring with continuous pulse oximetry and serial methemoglobin level checks. During the next 36 h, the patient remained hemodynamically stable with good oxygenation on room air; venous gas analysis taken on air at 9 and 30 h post-admission showed methemoglobin levels of 0.7% and 0.5%, respectively. The patient had a full recovery and was discharged home.The management of this patient was approved by the Ethics Committee of Emilia-Romagna Area Vasta Nord (PED-2020-03), and both parents provided written informed consent for the evaluation of the child. The Ethics Committee of Emilia-Romagna Area Vasta Nord approved the publication of this case, and both parents provided written informed consent for the publication of this manuscript.2 does not normalize with the administration of supplemental oxygen should raise the suspicion of MET. Additional diagnostic clues include chocolate-brown-colored blood, a normal partial pressure of oxygen (PO2) on arterial blood gas, and an oxygen saturation gap greater than 5% between the arterial blood gas analysis and pulse oximetry.This case report shows that recognition of acquired MET in a child with sudden cyanosis onset requires a high index of suspicion and a series of clinical and laboratory tests to exclude the possibility that cyanosis can depend on cardiovascular and/or respiratory problems. Any cyanotic-appearing patient without demonstrable respiratory or cardiac disease whose SpOOnce suspected, MET diagnosis is confirmed via multiple-wavelength CO-oximetry by direct measurement of methemoglobin levels in the blood . HoweverRisk of MET development occurs when the diet is mainly based on vegetables containing very large amounts of nitrates, and/or when the storage of previously prepared vegetable-based foods is suboptimal. Infants under 6 months of age are the subjects with the greatest risk, as they have low stomach acid production, more nitrate-reducing bacteria in the gut microbiota, incomplete development of the methemoglobin reductase system, and a certain amount of fetal hemoglobin that is more easily oxidized ,10,11. HAlthough the potential hazard of vegetable-borne nitrate for infants is already known, considering the increase in the number of infants and children who receive vegan or vegetarian diets , useful


Allium sativum L.) landraces, 34 genotypes including commercial ones were grown in the same field and their content in organosulfur compounds, pyruvate, total sugars, and total phenolics, alongside antioxidant capacity, was determined. The organosulfur compounds were studied by Gas Chromatography–Mass Spectrometry (GC–MS) after ultrasound-assisted extraction in ethyl acetate, identifying 2-vinyl-4H-1,3-dithiin and 3-vinyl-4H-1,2-dithiin as the predominant compounds, albeit in different ratios among genotypes. The bioactivity and the polar metabolites were determined in hydromethanolic extracts. A great variability was revealed, and nearly one-third of landraces had higher concentration of compounds determining bioactivity and organoleptic traits than the imported ones. We recorded strong correlations between pyruvate and total organosulfur compounds, and between antioxidant capacity and phenolics. In conclusion, chemical characterization revealed great genotype-dependent variation in the antioxidant properties and the chemical characters, identifying specific landraces with superior traits and nutritional and pharmaceutical value.In order to assess the diversity of Greek garlic ( Allium sativum L., family Alliaceae) is the second most widely consumed bulb crop and one of the most cultivated bulb vegetables in Greece and worldwide, with an annual production of 28,494,130 tons and a total harvested area of 1,546,741 hectares 3+ to [Fe(TPTZ)2]2+ 2+ . In deta radical . For thir > 0.90, r > 0.70, r > 0.50, r > 0.30 are interpreted as very high, high, moderate, and low coefficients, respectively. The SPSS software version 25.0  was used for data analysis. Value standardization and heatmap were performed with PRISM 8 .Spearman’s correlation was performed for all variable pairs at a significance level of 95% (α = 0.05) and UAE was used for the extraction of garlic volatiles based on the methodology earlier described ; in thatv/w) (AS06) to 0.30% v/w (AS30) as presented in The yield of ethyl acetate extract varied among the genotypes from 0.04% volume/weight (v/w) AS0 to 0.30%Among those organosulfur compounds, 2-VDT, 3-VDT, and DDS were detected and quantified in all genotypes examined, while 3-VDT and 2-VDT were the predominant compounds  . An orgaThe detection of vinyl-dithiins in most of the tested genotypes is in accordance with studies performed in raw garlic where the plant material is not subjected to high temperatures. The cyclic dithiins are presumed to be the first products of allicin transformation, while acyclic compounds are produced during the thermal degradation of cyclic dithiins . Indeed,Even if a part of allicin is converted during GC analysis to divinylthiins and other organosulfur compounds , the difIn a recent study, pyruvate constituted up to 61% of total organic acids in garlic . Determir = 0.690, p < 0.01). In contrast, a high correlation was observed between the pyruvic acid content and the total organosulfur volatiles content detected by GC-MS , as well as between the ethyl acetate extract yield and the total organosulfur volatiles content . These results confirm earlier studies showing that pyruvate levels are significantly and positively correlated with individual and total organosulfur content in garlic [A moderate correlation was observed between pyruvic acid content and nonpolar extract (ethyl acetate) yield  intensity  and anti2O2 scavenging) at a physiological pH and one single electron transfer assay (FRAP) at a low pH (3.6). In parallel, the content of total phenolics and sugars was estimated. As shown in Due to the complexity of redox mechanisms in humans, there is not a single in vitro assay for the estimation of total antioxidant capacity of food but plenty of them which employ different mechanisms and probably estimate the activity of different chemical compounds. In this study, two complementary assays were used for the in vitro assessment of antioxidant capacity, one hydrogen atom transfer assay , and antioxidant properties enabling us to identify local Greek landraces with superior characteristics which could be further exploited. It has been earlier demonstrated that the successive accumulation of somatic mutations in ancestral cultivars combined with clonal propagation leads to heterogeneity of cultivated clones. This could be the case for the dissimilarities observed in landraces obtained from the same or nearby regions in our study. Another explanation could be the exchange of germplasm between farmers and the deliberate introduction of genetic material from remote origin with different organoleptic traits.Nearly one-third of the tested genotypes had higher pyruvate and total organosulfur concentration than the imported cultivated varieties. Among the tested genotypes, AS12 and AS36 had the highest pyruvate content and high concentrations of total sugars, AS15, AS36, and AS25 were the most abundant in organosulfur volatiles, while AS15 had the best overall performance in all the measurements. On the other hand, the high prevalence of superior characteristics in landraces originating from the Ionian islands, that is, Kefalonia and Lefkada and the neighboring Peloponnese areas of Arkadia and Messinia prompts us to further valorize these localities for the identification of promising garlic landraces. The selection of superior genotypes could be used in breeding efforts to produce distinct garlic varieties of specific origin with high content of bioactive ingredients and great nutritional, nutraceutical, and pharmaceutical value.


Acute or intense exercise is sometimes related to infections of the urinary tract. It can also lead to incorrect hydration as well as incorrect glomerular filtration due to the presence of high-molecular-weight proteins that cause damage to the kidneys. In this context, our study lays the foundations for the use of a urine test in a team of twelve male basketball players as a means of monitoring numerous biochemical parameters, including pH, specific weight, color, appearance, presence of bacterial cells, presence of squamous cells, leukocytes, erythrocytes, proteins, glucose, ketones, bilirubin, hemoglobin, nitrite, and leukocyte esterase, to prevent and/or treat the onset of pathologies, prescribe personalized treatments for each athlete, and monitor the athletes’ health status. The analysis of stress induced by intense physical exercise encompasses the quantification and measurement of the parameters of strength, speed, power, and physical recovery to allow the coach and the medical health staff to calibrate the right training program for each athlete . RecentlIn this scenario, urine has been catalogued as containing valid and rapid biomarkers of pathologies that can affect the athlete by undermining physical integrity . Urine pFurthermore, hydration levels affect urinary biomarker concentrations. Therefore, it is possible to highlight both conditions of hypohydration and hyperhydration in the athlete. Hypohydration conditions are known to affect and decrease plasma volume, cardiac activity, sweating, cutaneous blood flow, and stamina. Conversely, hyperhydration conditions can cause brain nausea (a sensation of an urge to vomit that is controlled by the brain) and confusion due to the enlargement of the brain via an overdose of water. This is why monitoring an athlete’s hydration is essential ,37. MoreIn recent years, the scientific community has become aware that intense and prolonged exercise can lead to opportunistic infections ,42,43. IUrinary tract infections are one of the most common types of infections. Women are more affected  than menLactobacillus crispatus, may play an important role in protection against colonization by uropathogens [Recent studies have identified a resident microbial community in the urinary tract (UT). The contribution of the UT microbiome to a UTI is not yet clearly understood. It has been suggested that commensal species within the UT microbiome and the urogenital tract (UGT) microbiome, such as athogens .It is also crucial to recognize and treat urinary tract infections in order to prevent them from becoming complicated by infecting essential organs of the body. However, above all, it is essential to treat them correctly, as resistant bacteria can withstand treatment.Bacterial resistance is one of the most dangerous clinical challenges. Therefore, rapid identification of the pathogen is necessary for the provision of adequate care. Athletes who share toilets, showers, and changing rooms can more easily contract these infections .Escherichia coli, which is found in 75% of UTIs in men and 95% of UTIs in women. Less common pathogens include other Enterobacteriaceae, such as Klebsiella pneumoniae and Proteus mirabilis [Pseudomonas, Enterococci, and Staphylococci have also been found in athletes with recent hospitalizations [In some cases, pathogenic microorganisms enter the lower urinary tract (the bladder) through the venous and lymphatic pathways . Bacteriirabilis . Bacteriizations . Generalizations .Unfortunately, 20% of all people, but especially women, experience a second infection after the first (a recurrent infection), and some people suffer for a long time and incessantly (recurrent infections) . SometimExercise can also induce kidney dysfunction, causing a series of changes that include proteinuria, hematuria, a reduced renal blood flow, and a reduced glomerular filtration rate. Several issues can arise due to functional or temporary proteinuria after physical activity . In athlThis study aimed to examine the urinary modifications in basketball players during training, competition, and the recovery period in order to verify if urine could be used to develop a valid, reliable, and sensitive sport-specific test for the continuous monitoring of athletes.We evaluated via urine the possible infections affecting professional basketball players using the stress caused by physical exercise during a season of competition as a dependent variable. The study was designed following the recommendations for clinical research contained in the Helsinki Declaration of the World Medical Association. The protocol was approved by the Ethics Committee of the School of Medicine, University of Naples Federico II (protocol number 200/17).n = 12) in this study. Participants were men and were informed about the research and the protocols used. The physical characteristics of the players, expressed as the mean (±SD), were: age, 25 ± 6 (years); weight, 92 ± 10 (kg); and height, 195 ± 9 (cm). None of the subjects smoked, drank alcohol, or took drugs known to alter the chemical parameters of the leukocyte or hormonal formula. All individuals followed a similar diet throughout the season and, most importantly, the same diet during the study period. The participants’ diet was monitored continuously by the team doctors. The players followed the same training program. They trained every day in two sessions: a morning session that consisted of a 2-h gym workout and an afternoon session that consisted of a 3-h basketball practice period. This training program was followed daily, except for days on which official games were played during the season (two games per week).We included professional basketball players , one month after the start of the season, and three months after the start of the season. We evaluated the following parameters of the urine samples: pH (5.5–7 mg/dL), specific weight (1005–1030), color, appearance, presence of bacterial cells (0–1000 n/µL), presence of squamous cells (0–20 n/µL), leukocytes (0–18 n/µL), erythrocytes (0–14 n/µL), proteins (0–20 mg/dL), glucose, ketones, bilirubin, hemoglobin, nitrite, and leukocyte esterase. The urine samples were taken in the morning before training for all athletes. Before proceeding with the collection of urine, we recommended that each athlete: (1) wash their hands thoroughly with soap and water and dry them with a cloth; (2) wash their genital organs thoroughly with soap and water (after having retracted the foreskin on the glans) and dry them; and (3) discard the first jet of urine in the W.C. and collect the second jet of urine in a sterile container without interrupting the urination.First-morning urine samples were collected from athletes and analyzed within 4 h of arrival by the combined use of an automated urine chemistry analyzer  and a fluorescence flow cytometer  according to the manufacturer’s instructions. Where necessary, we conducted an examination using an optical microscope.p < 0.05 were considered significant.All statistical analyses were performed using GraphPad Prism 8.4.0 software . Data are expressed as the mean ± standard deviation. As appropriate, comparisons among groups were made by analysis of variance ANOVA followed by Bonferroni or Tukey’s multiple comparison tests. Values of To evaluate the hydration status of athletes, we analyzed the urinary parameters pH , specifiTo monitor the presence or absence of bacterial populations within the group of professional athletes, we considered the following urinary parameters: bacteria (B) , squamouAt 0 months, 83% of the athletes had a bacterial population between 0 and 200 n/µL, 9% had a bacterial population between 201 and 500 n/µL, and 8% had a bacterial population between 501 and 1000 n/µL . At one Moreover, we evaluated the SC. At 0 months, 75% of the athletes had an SC population between 0 and 5 n/μL, 8% had an SC population between 6 and 10 n/µL, and 17% had an SC population between 11 and 20 n/μL . At one In addition, at 0 months, 58% of the athletes had a leukocyte population between 0 and 4 n/μL, 17% had a leukocyte population between 5 and 9 n/µL, and 25% had a leukocyte population between 10 and 18 n/µL . At one Escherichia coli in all samples containing bacteria [Furthermore, on the 12 urine samples obtained from the athletes, gram staining was performed; thus through optical microscopy we identified the presence of gram negative bacteria. Later, to determine the type of bacterium, we performed culture examination of the sample colonies on McConkey agar to observe whether or not lactose fermentation had taken place. In our case, the test was positive; we then continued with the methyl red test (MR-VP) to verify if the highlighted bacteria could carry out glucose fermentation, and this too was positive. Finally, through the electron microscope we carried out analysis of the colonies, highlighting the presence of bacteria ,70.Finally, we carried out a statistical analysis of the values for bacteria (B), squamous cells (SC), and leukocytes (L) A–C. In tTo shed light on the presence of hematuria and/or proteinuria, we evaluated the following urinary parameters: erythrocytes (E)  and protAt 0 months, 50% of the athletes had an erythrocyte population (E) between 0 and 3 n/μL, 33% had an E between 4 and 7 n/μL, and 17% had an E between 8 and 14 n/μL . At one Furthermore, we evaluated the protein (P) content. At 0 months, 75% of the athletes had P content between 0 and 15 mg/dL, 17% P content between 16 and 50 mg/dL, and 8% P content between 51 and 100 mg/dL . At one Finally, we carried out a statistical analysis of the values for erythrocytes (E) and proteins (P) A,B. In tTo evaluate the general health of the athletes, we also monitored the following parameters: glucose, ketones, bilirubin, hemoglobin, nitrite, and leukocyte esterase.In the three months of monitoring, none of the parameters were detected within the examined population of professional athletes .Laboratory medicine plays a central role in sport and monitoring athletes’ health ,66,67. NFirstly, we assessed each athlete’s hydration status, analyzing pH, specific weight, color, and appearance. It is known that insufficient hydration (hypohydration) or excessive hydration (hyperhydration) can be harmful to an athlete’s performance ,38,39,40This trend was also confirmed by the statistical analysis carried out. We then evaluated the color of the urine. At 0 months, 92% of the athletes had urine with a straw yellow color and 8% had urine with an amber color. At one month, the population with straw yellow urine decreased by 9% and, consequently, the population with amber urine increased. However, at three months, the entire population of athletes examined (100%) had urine with a straw yellow color, which, therefore, reflected that the urinary tract was in an excellent state of health. Moreover, we evaluated the appearance of the urine. At 0 months, 83% of the athletes had urine with a bright appearance, 9% had urine with an opalescent appearance, and 8% had urine with a cloudy appearance. At one month, the population with clear urine decreased by 8% and that with cloudy urine increased. By three months, the whole population had urine with a bright appearance. The analysis of these four parameters suggested that, between month 0 and month one, the athletes slightly lacked hydration, most likely because their bodies needed to get used to the intensity of the training. At the same time, sharing spaces can lead to the occurrence of some urinary tract infections that alkalize the pH, increase the specific weight, and cloud the color and appearance of urine; a condition that resolves after three months when the body has adapted to training stress and possible infections have been eradicated with appropriate treatments.To evaluate the susceptibility to a UTI ,49,51,55It is known that competitive activity can cause hematuria and proteinuria ,60,61,64These values do not indicate glomerular damage ,67,68,71Therefore, we can say that the urine test allowed us to monitor the health of the athletes, highlighting that between 0 and one months an athlete’s body and, therefore, the organs that constitute it, undergo stimuli that can lead to fatigue, reduced hydration, the appearance of infections, and slight hematuria and proteinuria. Then, these parameters seem to fall away entirely after three months.The biochemical parameters analyzed in this work were used as indices to evaluate and monitor the physical condition of professional athletes over three months, to protect the athletes’ health, and also to prevent the athletes’ performance from deteriorating due to the onset of urinary tract disease. This work lays the foundation for outlining how a simple and inexpensive laboratory investigation such as urinalysis can generate a panel of specific markers that can be applied to individual athletes. The results obtained would guarantee for each athlete the prevention of new infections and timely targeted antibiotic treatment by sports doctors of existing infections, thereby reducing the continuation of infections that can be aggravated by intense physical exercise.In conclusion, the urine test could be included in the laboratory analyzes  that wou


In this study, Lithium chloride (LiCl) was used for ADSCs were isolated from the rats’ perinephric region using Dulbecco΄s Modified Eagle΄s Medium (DMEM) with Fetal Bovine Serum (FBS), cultured for 3 passages, characterized by flowcytometry and differentiation into adipogenic and osteogenic phenotypes. The ADSCs were exposed to 0.1, 0.5, 1, 1.5, 2, 5, and 10 millimolar (mM) LiCl without serum for 24 hr. The optimum dose of LiCl was selected according the maximum viability of cells. The expression of neurofilament light chain (NfL), neurofilament high chain (NfH), and nestin was evaluated by immunocytochemistry. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate the amount of synaptophysin, neurogenin-1, neuroD1, NfL, NfH, and nestin genes’ expression in ADSCs and NLCs.The optimum dose of LiCl was 1 mM in 24 hr. The transdifferentiated ADSCs showed cytoplasmic extension with synapse-like formation. Synaptophysin, neurogenin-1, neuroD1, NfL, NfH, and nestin genes were significantly expressed more in NLCs than in ADSCs.LiCl can induce ADSCs into neural phenotype cells with higher expression of neural and neuronal genes. Cell therapy is a feasible approach for treating neurological disorders when adult stem cells in the nervous system cannot produce appropriate response for neuronal loss. In other words, cell therapy is considered a mode of replacement therapy . Stem ceOne of the strategies for choosing the source stem cells is to select the cells from the tissues that can be easily accessed with low risk , such asThe process of transdifferentiation requires neural inducers such as dimethyl sulfoxide and retinoic acid for differentiating stem cells into neural phenotype cells , 6. HoweIn the present study, ADSCs were induced into neuron-like cells (NLCs) by LiCl and the level of neural and neuronal genes was quantitatively evaluated using quantitative reverse transcription polymerase chain reaction (qRT-PCR).Isolation of ADSCs°C incubator with gentle shaking and pipetting. Finally, a milky solution was obtained and the enzyme was neutralized with a medium containing 10% fetal bovine serum (FBS). Then it was centrifuged at about 1800 RPM for 10 min. The supernatant was discarded and the cells at the bottom were cultured in a flask containing Dulbecco΄s Modified Eagle΄s Medium (DMEM) medium (supplemented with penicillin/streptomycin and 10% FBS), which was placed in a 37 °C humidified incubator with 5% CO2 for 5 days. When the confluency reached about 70 ~ 80%, the cells were washed three times with PBS, harvested with trypsin and ethylenediaminetetraacetic acid (EDTA) solution, centrifuged and cultured. This process continued until passage 3 . The work was approved in the Ethical Committee of Tarbiat Modares University  based on Helsinki ethical code. The animals were completely anesthetized with chloroform and their perinephric region was shaved and treated with betadine. An incision was made, the adipose tissue was exposed, and under sterile conditions, the adipose tissue was sampled. Then it was transferred to a Falcon tube containing sterile phosphate buffer saline (PBS) with Penicillin 100 IU and Streptomycin 100 mg per ml (penicillin/streptomycin). Next, fresh adipose tissue was washed several times with sterile PBS to remove blood contaminations. Then the tissue was cut with a sterile surgical knife and incubated with 0.075% collagenase type 1  for 30 min in a 37 assage 3 , 22.Characterization of the isolated cellsThe ADSCs were evaluated for adipogenesis and osteogenesis where the cells at the third passage were cultured in two plates, one having adipogenic differentiation medium , and the other having osteogenic differentiation medium  for 21 days. The adipogenic and osteogenic differentiation of ADSCs was confirmed with Oil Red O and Alizarin Red S, respectively. On the other hand, the surface markers were evaluated with flowcytometry using CD90, CD44, CD73 (positive markers), and CD34 (hematopoietic marker) . This exEvaluation of the viability of ADSCsTrypan blue exclusion test was done to evaluate the viability of ADSCs. The cells were suspended in PBS, a sample was stained with 0.4% Trypan blue , and then their viability was estimated with Neubauer chamber under a light microscope. The viability was 97%.Determination of LiCl’ optimal dose Determination of the optimal dose of LiCl  for induction was performed using 0.1, 0.5, 1, 1.5, 2, 5, and 10 mM of LiCl . The celIdentification of cells after inductionThe LiCl-induced ADSCs were evaluated morphologically using an invert microscope. The differentiation was checked by immunostaining with neurofilament light chain (NfL) , neurofilament heavy chain (NfH) , and nestin . The cells were seeded on a cover slip for 24 hr, and cultured in DMEM containing LiCl (1 mM) for 24 hr. Then the cells were fixed with 4% paraformaldehyde. After treatment with the blocking solution, the cells were immunostained with primary antibodies, and finally, labeled with the secondary antibodies. Quantitative expression of neural and neuronal genes The RNA of the induced cells with LiCl was extracted using . Then the cDNA was synthesized using Thermo kit, UK. Next, the level of synaptophysin, neurogenin-1, neuroD1, NfL, NfH, and nestin genes’ expression in NLCs and ADSCs was determined using qRT-PCR and then their relative gene expression was estimated. GAPDH was also used as an internal control (housekeeping gene) , 24. TheP<0.05); in the LiCl-treated groups, it was significantly higher than in the negative control one (P<0.05). The highest viability was noticed in the dose of 1 mM (90.83±2.99), which was significantly higher than 10 mM, while the differences among other concentrations were not significant. After 24 hr of induction of the cells by LiCl, using phase contrast microscopy, the induced ADSCs showed extension with bipolar or multipolar morphology, and formed connections with other cells by axon-like structure (P<0.05). An increase was seen in the expression of neurogenin-1 and neuroD1, while the lowest expression was in nestin and NfL. NfH was fairly expressed. The qRT-PCR results are presented in The isolated cells’ morphology is presented in the phase contrast image . The liptructure . Immunostructure . In RT-Pet al. reported that bHLH motifs modulate critical events in the development of the mammalian neocortex where neurogenin-1 is involved in transition from proliferative phase to neurogenesis phase (et al. documented that the simultaneous up-regulation of neurogenin-1 and neuroD1 could lead to an accelerated neuronal differentiation (et al. reported that nestin expressing mesenchymal stem cells may result from isolation and cultivation regimes (The purpose of this study was to investigate the effect of LiCl on transdifferentiation of ADSCs into NLCs at 1 mM dose incubated for 24 hr. The transdifferentiation was confirmed by morphology, immunocytochemistry, and qRT-PCR. These results are consistent with the findings of others , 25. As is phase , resultiis phase . Researcis phase . Human eis phase . Similaris phase . Khalfalntiation . The expntiation , Mo et a regimes .Nfs are intermediate and main cytoskeletal proteins in mature neurons that contribute to neuronal development and function, though NfH usually express after NfL , 42. TheIn this study, the morphological, immunocytochemical, and molecular evaluations confirmed the transdifferentiation of ADSCs into NLCs. However, the qRT-PCR results showed increased expression in all genes but nestin, as a gene of the early stages of development and differentiation, and synaptophysin, as a gene of the late stages of development and differentiation had no significant difference compared with the control group. Also it seems that given the great difference in the expression of NfH compared with the ADSCs group and the highest difference compared with other genes that were significant, it seems that these cells have reached maturity, but they are not yet functional. So, it can be said that this transdifferentiation has proceeded for post-mitotic neurons; however, the process of differentiation has not yet been fully achieved, and may require more incubation time with LiCl or secondary inducer to accelerate the post-mitotic neuron differentiation. Of course, whether these cells are functional cells or not, will require further investigation. Also it is important to mention that although the viability of the positive control was significantly higher than that of the other groups, it was significantly higher in the LiCl-treated groups than in the negative control group, so it can be due to the addition of FBS to the positive control only, while the treatment groups and negative control were deprived of FBS. Moreover, FBS is required for cell survival, LiCl is able to increase viability with the negative control. FBS can increase cell proliferation. The reason that it affects cell viability seems to be that it can affect normal mitochondrial function, hold the amount of mitochondrial protein, and retain the balance of the gene expression associated with oxidant. On the other hand, it prevents the aggregation of ROS and suppresses the expression of P53, P51, and p21; so, it can be said it inhibits apoptosis , 48. TheIn cell therapy, it is difficult to obtain endogenous neural stem cells because they are located in subventicular and subgranular zones. Induced neural stem cells such as ADSCs are a feasible alternative source, which is a safe and efficient option. On the other hand, LiCl is an inducer that has considerable safety and can induce stem cells in a very short time, which can be helpful in regenerative medicine.LiCl can induce adipose-derive stem cells into neuronal phenotype and expression of neurogenin-1, neuroD1, NfL, and NfH, except nestin and synaptophysin genes were significantly expressed in transdifferentiated cells. Because of the importance of time factor along with selection of available cellular source and appropriate inducer, it seems that using ADSCs with LiCl can be a good choice for curing the nervous system diseases.


The total number of items was n = 65, with n = 29 included in the meta-analysis. Based on the different measurement tools used, the prevalence of depression pre-CABG ranges from 19–37%, and post-CABG from 15–33%. There is a considerable presence of depression in this type of patient, but this varies according to the measurement tool used and the quality of the study. Systematically detecting depression prior to cardiac surgery could identify patients at potential risk.Coronary artery bypass graft surgery (CABG) might adversely affect the health status of the patients, producing cognitive deterioration, with depression being the most common symptom. The aim of this study is to analyse the prevalence of depression in patients before and after coronary artery bypass surgery. A systematic review and meta-analysis was carried out, involving a study of the past 10 years of the following databases: CINAHL, LILACS, MEDLINE, PsycINFO, SciELO, Scopus, and Web of Science. The total sample comprised  Coronary artery disease (CAD) is one of the leading causes of death in developed countries, and it is associated with deteriorated quality of life, disability, and premature death . The usuAlthough CABG surgery increases life expectancy , it is aShort-term recovery factors include a longer hospital stay, pain, and infection, which may predispose towards cognitive disorders, like anxiety and depression . In the In particular, depression is considered to be one of the main reasons for reduced well-being, having a negative impact on a patient’s quality of life, as well as their social and family life. It is a strong risk factor for mortality, being related to the occurrence of new cardiac events and reduced functionality up to six months post-CABG surgery, increasing the risk of hospital readmission in up to 20% of patients, due to complications including infection, arrhythmia, and volume overload .Diagnosis is sometimes difficult, since symptoms, such as loss of appetite, sleep cycle disturbance, and constant fatigue, may be superimposed over the same symptoms that were derived from surgery. For this reason, determining the degree to which a CABG can affect a patient’s mental, psychological, and social skills, and, specifically, analysing the level of depression, requires the use of multiple tools validated during a clinical interview ,10.A number of factors seem to influence the relationship between depression and CABG, including biological alterations  . HoweverEven though the effects of CABG have been studied in terms of morbidity, mortality, and organ function, the effect or influence it has on mood disorders, like depression, remains unclear. It seems that depression predicts how much a patient’s health will deteriorate. Therefore, it is extremely important to assess how the disease affects a patient, as this can influence the therapeutic benefit and, consequently, which interventions and care are prioritised, and which self-care strategies are implemented both before and after surgery ,14.Although depression is considered to have a negative impact on patient recovery, few studies have examined the association between CABG and depression. Some systematic reviews have analysed the risk factors , and theDescribing the levels of depression in CABG patients is essential for analysing the importance of this surgery with regard to depression levels. The purpose of this work is, therefore: (1) to analyse the prevalence of depression in patients both before and after CABG surgery; and, (2) to analyse the depression levels over time.The data were extracted and analysed based on the recommendations of preferred reporting items for systematic review and meta-analysis (PRISMA) 2015 .A search was conducted of CINAHL, LILACS, MEDLINE, PsychINFO, SciELO, Scopus, and Web of Science in January 2020. MeSH descriptors were used, with the search strategy being: “(depression OR depressive disorder) AND (coronary artery bypass grafting)”.The inclusion criteria were the following: (1) full text of quantitative primary studies; (2) men and women aged over 18; (3) no psychiatric pathology or illness; (4) CABG surgery; (5) study of depression levels prior to or after CABG; (6) the use of a validated scale; (7) written in English, Portuguese, Spanish, or French; and, (8) published in the last 10 years.The exclusion criteria were the following: (1) paediatric population; (2) a different type of cardiac surgery that was not exclusively CABG ; (3) measurement of depression in relatives; (4) patients with an active treatment deriving from a psychiatric disorder; (5) data from duplicate articles in previous studies; and, (6) no depression data extracted using a validated scale.Firstly, two authors checked the title and abstract, and, secondly, the full text of the article. A third author was consulted in the case of discrepancy.For the meta-analysis, we selected the data from those studies that used the same measurement tool, since the inclusion of several measurement tools would not permit the results to be integrated, due to different scores.The following variables were recorded: (1) data on the study ; (2) type of CABG ; (3) study characteristics ; (4) measurement tool; and, (5) mean, standard deviation, prevalence of depression. For clinical trials or quasi-experimental studies, we selected only the levels of depression prior to the programme intervention (baseline) or those relating to the control group.We used the intraclass correlation coefficient to analyse coding reliability, obtaining an average value of 0.97 , and the Cohen’s kappa coefficient with a mean value of 0.94 .Two independently authors assessed the quality of the studies, consulting with a third party in the event of a disagreement.For observational studies , we followed the guidelines in “Strengthening the Reporting of Observational Studies in Epidemiology” (STROBE) . We follWe used a second quality assessment tool to analyse the level of evidence in accordance with the recommendations of the Oxford Centre for Evidence-Based Medicine  Table 1Table 1.The meta-analysis included those studies that used the same tool for measuring depression. We performed six meta-analyses using a random-effects model and two meta-analyses using a fixed-effect model, for prevalence levels and confidence intervals, through the statistical package StatsDirect .2 to analyse the heterogeneity, grouping values into low (25%), moderate (50%), or high (75%) heterogeneity [We used Iogeneity . The pubn = 1874 articles. After reading the title and abstract, 662 were excluded. The search yielded a total of n = 54). Most of the studies were cohort studies (n = 34), followed by cross-sectional studies (n = 12). Thirteen studies evaluated the levels prior to surgery, 23 after surgery, and 29 both before and after. Most of the studies were carried out in the USA (n = 17), followed by Germany (n = 7), Iran (n = 7), and Australia (n = 6)  . The depn = 18), Beck Depression Inventory (BDI) (n = 17), nine-item Patient Health Questionnaire (PHQ-9) (n = 9), and Centre for Epidemiological Studies Depression Scale (CES-D) (n = 4) were the measurement tools used   was 19% (95% CI = 9–31) with a high degree of heterogeneity (I2 = 93.4%), while the prevalence after surgery (n = 394) was 19% (95% CI = 13–26) with I2 = 92.2%, according to the random effects model  was 37% (95% CI = 28–46) with a high degree of heterogeneity (I2 = 89.4%), while the prevalence afterwards (n = 97) was 33% (95% CI = 12–59) with a high degree of heterogeneity (I2 = 96.6%), according to the random effects model  was 22% (95% CI = 12–33) with a high degree of heterogeneity (I2 = 97.5%) according to the random effects model; and, the prevalence of depression after surgery (n = 48), using the fixed effects model, was 18% (95% CI = 14–23) (2 = 2%).According to the PHQ-9 tool, the prevalence prior to surgery (= 14–23) , with a n = 61) using the random effects model was 28% (95% CI = 17–40) with a moderate degree of heterogeneity (I2 = 66.9%); while the prevalence after surgery (n = 57) was 15% (95% CI = 12–19) with a low degree of heterogeneity (I2 = 2%), according to the fixed effects model (Finally, for CES-D, the prevalence of pre-CABG depression (ts model Prior to CABG surgery, most of the authors report depression levels within the normal range, although others found mild ,58,83,86Post-surgery, most authors report normal levels, while others found mild ,83,85,88The majority of authors observed a positive impact on depression prevalence and levels after surgery, as well as in the short and medium term, although others found that these levels increased after surgery ,55,57,89The prevalence of depression obtained in this study varied between 19% and 37% prior to surgery, and between 15% and 33% after surgery, depending on the type of measurement tool used. Other studies that combine CABG with valve replacement have reported similar percentages, with depression prevalence ranging from 15% pre-CABG  to 37.7%Normal levels of pre-CABG depression are observed, although other studies have indicated higher levels, from moderate to severe . HoweverHigh levels of depression prior to the operation predict a worse quality of life ,95, worsWe have observed that depression levels did not go to remission, but they tend to improve in depressive symptoms, which is probably due to an improvement in the patient’s quality of life , and eveAlthough there is a relationship between depression and CABG, its temporal onset is not clear. Depression can be a pre-existing condition, which increases the risk of cardiovascular disease that is related to behavioural alterations in diet, physical activity level, toxic habits, or poor adherence to treatment and recommendations ; or, canWithout evaluation, it is unlikely that depression is being treated correctly. Some authors report that more than 50% of patients were receiving medical treatment for depression, even though they had no symptoms of depression . For thiThe current study highlights the importance of depression measures before and after CABG in assessing clinically meaningful mood disturbance, in order to provide early intervention. Systematic screening for depression in the period both before and after this procedure is crucial. Planned coaching combined with counselling can reduce these levels . CardiacDepression counselling prior to surgery can influence the post-surgical depression levels by positively improving a patient’s perception of illness control and management . PlanninFrom a clinical perspective, these results suggest that strategies that are aimed to improve depression as a disorder, such as the application of policies and depression assessment protocols prior to CABG by health care providers, are essential, because the depression level might help risk stratification in patients undergoing CABG identifying the high-risk groups and the trajectory of recovery experienced .This study has several limitations. Firstly, the heterogeneity in terms of prevalence is due to different estimation methods over time, differences in the timing of assessment and demographic differences between samples, different uses of cut-offs on questionnaire measures, as well as the use of various tools for assessing the symptoms of depression. Secondly, the measuring tools assess the severity of depression symptoms, but they do not replace a formal clinical diagnosis of depression.There is a high presence of depression both before and after CABG surgery. While this study found an overall improvement in depressive symptoms after CABG, depression persists after the surgery for the majority of patients. The depression levels present prior to the operation may affect postoperative recovery.Given the prevalence of depression and its impact, early detection is crucial, since it enables the identification of at-risk patients, through a clinical interview that uses validated measurement tools. This enables the medical team to implement preventive strategies as well as monitor the development of the depression.