Extracorporeal membrane oxygenation (ECMO) support for respiratory failure in the intensive care unit continues to have an expanded role in select patients. While acute respiratory distress syndrome remains the most common indication, ECMO may be used in other causes of refractory hypoxemia and/or hypercapnia. The most common configuration is veno-venous (V-V) ECMO, however in specific cases of refractory hypoxemia or right ventricular failure, some patients may benefit from veno-pulmonary (V-P) ECMO or veno-venoarterial (V-VA) ECMO. Patient selection and extracorporeal circuit management are essential to successful outcomes. This narrative review explores the physiology of ECMO, indications and contraindications, ventilator management, extracorporeal circuit management, troubleshooting hypoxemia, complications, and ECMO weaning in patients with respiratory failure. As the footprint of ECMO continues to expand it is essential that clinicians understand the underlying physiology and management of these complex patients.

Lyme disease is a highly prevalent tick-borne infection caused by Borrelia burgdorferi spirochetes in North America and Eurasia. Diagnosis of the early disease remains difficult with the currently approved serological tests in the absence of noticeable tick bite or erythema migrans due to presentation of non-specific symptoms and the absence of antibodies early in infection. Furthermore, it is difficult to distinguish persistence of disease and reinfection in the endemic regions. If not treated early, infection spreads throughout the body and affects most organs with disease manifestations including arthritis, musculoskeletal pain, neuroborreliosis and acrodermatitis chronicum atrophicans. Although most patients recover after antibiotic treatment, ~10-12% of show recurrence of symptoms known as post-treatment Lyme disease syndrome (PTLDS). Various causes of PTLDS are not well-defined; however, the spirochete persisters, antigenic debris, dysregulation of immunological response in individuals or a combination of these factors are proposed to result in continuation of Lyme disease manifestations. Based on these considerations, this review highlights currently employed treatment approaches with antimicrobials and vaccines being tried for prevention of B. burgdorferi infection. We also summarize combinatorial approaches that could be employed to alleviate symptoms to improve the quality of life of the individuals suffering from long Lyme disease.

Myalgic Encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/CFS) and Long COVID are characterized by debilitating post-exertional malaise and other core symptoms related to immune dysregulation resultant from post-viral infection, including mitochondrial dysfunction, chronic neuroinflammation and gut dysbiosis. The reported associations between altered microbiota composition and cardinal symptoms of ME/CFS and Long COVID, suggesting that use of microbial preparations, such as probiotics, by restoring the homeostasis of the brain-immune-gut axis may help in the management of symptoms in both conditions. Therefore, this review aims to investigate the implications of alerted gut microbiome and assess the evidence supporting use of microbial-based preparations, including probiotics, synbiotics, postbiotics alone and/or in combination with other nutraceuticals in the management of fatigue, inflammation, as well as neuropsychiatric and gastrointestinal symptoms among patients with ME/CFS and Long COVID.

Thrombosis after severe acute respiratory syndrome coronavirus 2 vaccination is a serious complication in patients who have a thrombophilic predisposition. In this case, a female patient with no family history of thrombophilia who had pediatric antiphospholipid syndrome (APS) developed deep vein thrombosis (DVT) when she was 6 years old; 6 months after receiving a second dose of the BNT162b2 vaccine, DVT reoccurred. The original thrombi were found in the right common iliac vein and the inferior vena cava, with concomitant left pulmonary infarction. The patient was treated with anticoagulants for 6 years after DVT onset, with subsequent treatment cessation for 5 years without recurrence. She received the BNT162b2 vaccine at 17 years of age, 1 week before a routine outpatient visit. Platelet factor 4 elevation was detected 14 days after the first vaccination, persisting for 5 months without thrombotic symptoms. Six months after the second vaccine dose, the DVT recurred and was treated with a direct oral anticoagulant. The vaccine exacerbated the patient’s APS by activating coagulation, causing thrombosis recurrence. Platelet factor 4 levels may indicate coagulation status. When patients predisposed to thrombosis are vaccinated, coagulation status and platelet activation markers should be monitored to prevent DVT development.

LONP1 is the principal AAA+ unfoldase and bulk protease in the mitochondrial matrix, so its deletion causes embryonic lethality. The AAA+ unfoldase CLPX and the peptidase CLPP also act in the matrix, conspicuously during stress periods, but their substrates are poorly defined. Mammalian CLPP deletion triggers infertility, deafness, growth retardation, and cGAS-STING activated cytosolic innate immunity. CLPX mutations impair heme biosynthesis and heavy metal homeostasis. CLPP and CLPX are conserved from bacteria to human, despite their secondary role for proteolysis. Based on recent proteomic-metabolomic evidence from knockout mice and patient cells, we propose that CLPP acts on phase-separated ribonucleoprotein granules, and CLPX on multi-enzyme condensates, near the inner mitochondrial membrane, as first-aid system. Trimming within assemblies, CLPP rescues stalled processes in mitoribosomes, in mitochondrial RNA granules and nucleoids, and in D-foci-mediated degradation of toxic double-stranded mtRNA / mtDNA. Unfolding multi-enzyme condensates, CLPX maximizes PLP-dependent delta-transamination, and rescues malformed nascent peptides. Overall, their actions occur in granules with multivalent or hydrophobic interactions, separated from the aqueous phase. Thus, the role of CLPXP in the matrix is compartment-selective, like peptidases MPP at precursor import pores, m-AAA and i-AAA at either IMM face, PARL within the IMM, and OMA1/HTRA2 in the intermembrane space.

Fragile X syndrome (FXS) is a genetic disorder caused by a mutation in the fragile X messenger ribonucleoprotein 1 (FMR1) gene and known to be a leading cause of inherited intellectual disability globally. It results in a range of intellectual, developmental, and behavioral problems. Fragile X premutation associated conditions (FXPAC), also caused by a smaller CGG expansion (55 to 200 CGG repeats) in the FMR1 gene, is linked to other conditions that increase morbidity and mortality for affected persons. Limited research has been conducted on the burden, characteristics, diagnosis, and management of these conditions in Africa. This comprehensive review provides an overview of the current literature on FXS and FXPAC in Africa, epidemiology, clinical features and challenges faced, such as discrimination against affected persons, limited awareness and research, poor access to resources and genetic services and treatment. It further provides an in-depth analysis of the existing worldwide data for the diagnosis and treatment of these disorders. This review will improve understanding of FXS and FXPAC in Africa by incorporating existing knowledge, identifying research gaps, and potential topics for future research to enhance the well-being of individuals and families affected by FXS and FXPAC in the region.

Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.

Systemic amyloidosis is a multisystem illness characterized by fibrillary protein deposition, which causes dysfunction in the afflicted organ systems. Its diagnosis is frequently delayed since the disease's symptoms are unpredictable and non-specific. Its two main variants are light chain (AL) amyloidosis and transthyretin-related ATTR amyloidosis, which has both a sporadic (wildtype, ATTRwt) and hereditary (mutated, ATTRv) subtype. We discuss a case of Amyloidosis emerging in the kidneys and heart as a result of chronic inflammation caused by failure to treat TB, as well as its typical radiological characteristics, clinical presentation, imaging and instrumental evaluations, and therapeutic plan. This case report serves as a good reminder to medical personnel to ensure thorough patient follow-up in order to avoid extremely unusual and late complications resulting from treatment default.

Fragile X syndrome (FXS), the most common monogenic cause of inherited intellectual disability and autism spectrum disorder, is caused by a full mutation (>200 CGG repeats) in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene. Individuals with FXS experience a wide range of challenges related to social interaction (SI). Animal models, such as Drosophila melanogaster model for FXS where the only ortholog of human FMR1 (dFMR1) is mutated, have played a crucial role in understanding of FXS. The aim of this study was to investigate SI in the dFMR1B55 mutants using the novel Drosophila Shallow Chamber and a Python data processing pipeline based on social network analysis (SNA). In comparison with wild-type flies (w1118), SNA analysis in dFMR1B55 mutants revealed hypoactivity, fewer connections in their networks, a lower ability to efficiently transmit information, fewer alternative pathways for information transmission, a higher variability in the number of interactions they achieved, and tended to stay near the boundaries of the testing chamber. These observed alterations indicate the presence of characteristic strain-dependent social networks in dFMR1B55 flies, commonly referred to as the group phenotype. Finally, a combination of novel research tools is a valuable method for SI research in fruit flies.

Rubella infection is typically mild or asymptomatic except when infection occurs during pregnancy. Infection in early pregnancy can cause miscarriage, stillbirth, or congenital rubella syndrome. Only individuals that are still susceptible to rubella infection during child-bearing age are vulnerable to this burden. Rubella containing vaccine (RCV) is safe and effective, providing life-long immunity. However, average age-at-infection increases with increasing vaccination coverage, which could potentially lead to increased disease burden as well, if the absolute risk of infection during child-bearing age increases. Dynamics of rubella transmission were explored using EMOD, a software tool for building stochastic, agent-based infection models. Simulations of pre-vaccine, endemic transmission of rubella virus introduced RCV at varying levels of coverage to determine the expected future trajectories of disease burden. Introducing RCV reduces both rubella virus transmission and disease burden for a period of around 15 years. Increased disease burden is only possible more than a decade post-introduction, and only for contexts with low current burden and high transmission intensity. Low or declining rubella virus transmission intensity is concurrently associated with both greater disease burden and greater vaccine effectiveness. The risk of increasing burden through vaccination only exists for locations with persistently high infectivity, high connectivity, and high fertility. A trade-off between the risk of a small, future burden increase and a large, immediate burden decrease strongly favors RCV introduction.

GCTs are developmental tumors and likely to reflect ontogenetic and teratogenetic determinants. The objective was to identify syndromes with or without congenital anomalies and non-syndromic defects as potential risk factors. Patients with extracranial GCTs (eGCTs) registered in MAKEI 96/MAHO 98 between 1996 and 2017 were used. According to Teilum's holistic concept malignant and benign teratomas were registered. We used a case control study design with Orphanet as a reference group for syndromic defects and the Mainz birth registry (EUROCAT) for congenital anomalies at birth. Co-occurring genetic syndromes and/or congenital anomalies were assessed accordingly. Odds ratios and 95% confidence intervals were calculated and p-values for Fisher’s exact test with Bonferroni correction if needed. A strong association was confirmed for Swyer (OR 338.6, 95% CI 43.7-2623.6) and Currarino syndrome (OR 34.2, 95% CI 13.2-88.6). We additionally found 17 isolated cases of eGCT with a wide range of syndromes, however not significantly associated following Bonferroni correction. All these cases pertained to girls. Regarding non-syndromic defects, no association with eGCTs could be identified. In our study we confirmed a strong association for Swyer and Currarino syndromes with additional congenital anomalies.

TAFRO syndrome (TS) is a rare variant of idiopathic multicentric Castleman's disease (iMCD) characterized by a confluence of symptoms: thrombocytopenia (T), anasarca (A), fever (F), reticulin myelofibrosis (R), and organomegaly (O). First described in Japan in 2010, the pathogenesis of the disease remains unclear. Due to its heterogeneous presentation and potential life-threatening delays in diagnosis, precise diagnosis is essential. According to the literature, no specific imaging modality has been recommended for the work-up of patients with suspected TS. Here, we report a case of TS and its management using 18F-FDG-PET/CT imaging as an attractive complementary diagnostic tool.

The human gastrointestinal gut contains about 100 trillion of microorganisms including up to 5000 different types of bacteria called the "gut microbiome". Alterations in the composition of gut microorganisms (dysbiosis) can cause threatening for life diseases. This present seeks to evaluate if finally diet and more specifically functional foods affect the intestinal microbiome, and if obesity and the metabolic syndrome (Mets) are associated with the intestinal microbiome. This systematic review was accomplished according to PRISMA guidelines mostly using the key words functional foods, microbiome, obesity, Mets, Mediterranean diet. The search was carried out of recent scien-tific articles from the databases Pubmed, Scopus, and Google Scholar. The most studies discussed in this review showed a potential therapeutic effect of the Mediterranean diet rich in beneficial nutrients, on body weight, fat deposition, in correlation with modulation of the synthesis of gut microbiome. This literature review demonstrates a possible relationship between the metabolites of the microflora, the endotoxemia, obesity and Mets. The role of probiotics, prebiotics, and polyphe-nols in the prevention of obesity and Mets is of high importance in promoting healthy aging. The future challenge is to understand how different dietary patterns can regulate the composition of the gut microflora and whether these changes could be long-term.

Hamman’s syndrome is a rare condition that mostly affects young males, often with a predisposition of asthma. It includes the presence of free air in the mediastinum and subcutaneous emfysema with no other underlying cause such as trauma or infection. It occurs spontanously and often in association with prolonged valsalva manouvre. This might explain why there are some cases of Hamman syndrome among young females giving birth. Here we present a case report of a 24-year- old primigravida with Hamman’s syndrome. She presented with symptoms a few hours after an uncomplicated vaginal delivery at 40+1 pregnancy week. The symptoms resolved spontanously after a few days of observation. We also give a systemic review of reported cases since 2000 to provide overview on pathomechanism, symptoms, diagnostics, treatment and management of this condition. Hamman’s syndrome is a rare, usually benign, but potentially serious complication that can occur during the second stage of labour. Diagnostics include inquiring about typical symptoms, clinical examination and chest x-ray or CT scan. Treatment is usually conservative with oxygen, bronchodilators and pain relief. The reccurence rate is low and there is no contraindication to vaginal delivery in future pregnancies. However, it is suggested that physicians and midwives be cautious and consider low threshold for instrumental delivery or caesarean section to avoid excessive valsalva manoeuvre.

Background: People with Down syndrome (DS) have a trisomy of chromosome 21 and marked deficits in verbal memory but relatively preserved visuospatial perception. Verbal memories are related to semantic knowledge. Little is known about the organization of semantic knowledge in people with DS, which was the aim of this study. Aims: The extent of false memory in people with DS was examined. Possible differences in the number of false memories induced by nominal and verbal themes were examined. Methods and Procedures: In the study phase, ten word lists with semantically related associates were presented. In the recognition phase, participants made judgments on whether each word had been represented previously as semantically related lures, old words, and semantically unrelated new words. Outcomes and Results: Differences in the processing of nominal and verbal theme-related lures were observed among people with DS. When processing nominal theme-related lures, people with DS showed delayed false positives. When processing verbal theme-related lures, people with DS showed no differences compared to controls. Similar patterns have been observed in people with DS when processing nominal theme-related associates and verbal theme-related associates. People with DS have delayed recognition of associates. When processing unrelated words, they showed significantly higher false positives than controls for both nominal and verbal eliciting themes. Further analyses of the themes revealed differences in false positives across syntactic categories among groups. Conclusions and Implications: People with DS showed a delayed recognition of associates and deviance in recognizing unrelated words in the nominal and verbal theme categories. People with DS were delayed in terms of nouns, but deviated with verbs in associated and unrelated words. Additionally, people with DS showed distinct patterns in processing five nominal lures and three verbal lures, suggesting that they formed false memories differently based on distinct syntactic categories. Thus, it was concluded that people with DS develop a deviant semantic structure. Category-based interventions for people with DS should be implemented in order to improve their semantic knowledge through lexical connections.

Background: Cardiovascular (CV) morbidity and mortality are many times higher in chronic kidney disease (CKD), as well as IgA nephropathy (IgAN), than in the general population. The occurrence of metabolic syndrome (MetS) and metabolic risk factors are independent risk factors for CV disease and renal progression. The study aimed to determine the prognostic role of metabolic profiles in a homogenous group of CKD patients. Methods: One hundred and forty-five IgA nephropathy patients (92 male, 53 female, age 54.7 ± 13 years) with CKD stage 1-4 were investigated and followed for a median of 190 months. The composite (CV and renal) endpoints included all-cause mortality and any CV event such as stroke, myocardial infarction, revascularization (CV), end-stage renal disease, and renal replacement therapy (renal). Results: Patients with MetS had significantly more endpoint events (16/27 patients vs. 15/98 patients, p = 0.001) compared to the nonMetS group. Of the secondary endpoints (CV or renal separately), the rate of the renal and CV endpoints was significantly higher in the MetS group (p = 0.001 and p = 0.029). The primary endpoint independent predictors of survival were dyslipidemia, eGFR, hemoglobin, urine albuminuria, and diabetes mellitus, as determined by Cox regression analysis. Independent predictors of secondary renal endpoint were dyslipidemia, hemoglobin, urine albumin, and eGFR. Predictors of secondary cardiovascular endpoints were gender, BMI, and diabetes. Kaplan-Meier curves showed significant differences in MetS and non-MetS when examined at the combined endpoints (CV and renal) or at each endpoint separately. The primary endpoint rate increased significantly with the increased number of MetS components (MetS comp. 0 vs. MetS comp. 2+, primary endpoints, p = 0.012). Conclusion: Our results showed that the metabolic profile has a prognostic role not only for renal endpoints but also for CV endpoints in IgAN. BMI, hyperuricemia, hypertension, and diabetes have a predictive value for the prognosis of IgA nephropathy.

We document for the first time epsilon waves on the electrocardiogram of a patient with Dravet syndrome (DS) who does not exhibit structural cardiac pathology. DS, a severe form of pediatric epilepsy, involves mutations in the SCN1A gene, which disrupt sodium ion flow and increase the risk of sudden unexpected death in epilepsy. The epsilon waves, typically associated with arrhythmogenic right ventricular dysplasia, may also suggest a link between neuronal and cardiac dysfunctions. In our case, the epsilon waves appear to originate from abnormalities in sodium channels rather than structural changes in the myocardium. This finding underscores the importance of assessing both neurological and cardiac manifestations in patients with severe epilepsy, opening new avenues for the research and treatment of these interactions in DS.

Acute and chronic respiratory diseases impose a significant economic and health burden. Distal small airway assessment requires invasive procedures such as a bronchoscopy and bronchoalveolar lavage. The Particles in Exhaled Air (PExA) device provides a non-invasive means of assessing small airways; it captures distal airway particles sized around 0.5-7m and contains particles of respiratory tract lining fluid (RTLF) that originate during airway closure and opening. The PExA device can measure particle count and mass according to particle size. Subsequent capture of particles in a thin membrane enables application of various analytical methods to assess a broad range of biomolecules including phospholipids, proteins, inflammatory profile, and other metabolites to characterise inflammation and diseases processes such as asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, lung cancer, and more recently acute infections such as COVID-19. PExA analysis provides a promising alternative to traditional investigative methods in the assessment, diagnosis, and management of respiratory conditions. By evaluating specific biomarkers in the RTLF associated with airway inflammation, PExA may offer a more accurate and comprehensive understanding of the molecular-level changes in the small airways of patients with acute and chronic lung diseases.

This study aimed to investigate the efficacy of manual therapy and exercise versus synchronized telerehabilitation with self-manual therapy and exercise in treating Subacromial Pain Syndrome (SPS). Sixty individuals diagnosed with SPS, aged 18-50 years, were randomly assigned to home exercise (HE), manual therapy (MT), and telerehabilitation (TR) groups. Treatment protocols were administered over 8 weeks and included specific exercises and therapy interventions. Out-come measures included Visual Pain Scale (VAS), shoulder range of motion (ROM) via gonio-metric measurements, Quick Disability Arm-Shoulder-Hand Problems Survey (Q-DASH), and patient satisfaction. Results revealed that both MT and TR groups exhibited reduced pain, in-creased ROM, lower Q-DASH scores, and higher patient satisfaction compared to the HE group. However, no significant differences were found between MT and TR groups in pain levels, ROM, Q-DASH scores, or patient satisfaction. The study concludes that both telerehabilitation and manual therapy effectively alleviate pain and are well-received by patients with SPS. Addition-ally, manual therapy demonstrates superiority in enhancing functional levels compared to exer-cise-based interventions. (Registration: NCT05200130)

A multisystem chronic autoimmune disorder, Sjogren syndrome, is characterized by lymphocytic infiltrates in the exocrine glands. Keratoconjunctivitis sicca and xerostomia are the two pathognomic findings in Sjogren syndrome. Here, we present a case of a 30-year-oldan old Indian woman presenting with primary Sjogren syndrome. The clinical features, diagnostic modalities, treatment options, and management of complications have been discussed.

We present a case report of a young patient with pectus carinatum who experienced a small right apex pneumothorax and exhibited Brugada patterns on electrocardiogram tracing. This is the first clinical case reporting Brugada pattern presentation in both a patient with pectus carinatum and a small pneumothorax. We conducted a clinical, anatomical, and electrocardiographic analysis to explore a physiopathological explanation for these findings, considering our patient had no history or clinical signs of Brugada Syndrome. We conclude that: 1. Pectus carinatum may create a window that facilitates the less resistive measurement of cardiac action potentials; 2. Small pneumothoraces can induce modifications in the cardiac electrical signal detected by surface electrodes, and pectus carinatum could unmask these modifications; and 3. Surface electrodes may measure subepicardial potentials that include and are modified by adjacent pericardial tissues, potentially resulting in alterations in transmural potential differences, thus producing fictitious Brugada patterns. Similarly, there is a possibility that the right ventricular outflow tract may be included within the subendocardial potentials.

Lynch syndrome (LS) is one of the most common hereditary cancer syndrome in human populations, associated with germline variants in MLH1, MSH2/EPCAM, MSH6 and PMS2 genes. The advent of next generation sequencing has proven a significant impact in germline variant detection in the causative genes; however, a large proportion of patients with clinical criteria still receive uncertain or negative results. PMS2 is the least frequent reported gene, associated with up to 15% of LS cases with late-onset disease and low penetrance phenotype; however, the proportion of PMS2-LS cases is considered to be highly underestimated. In this context, we consulted public available databases (ClinVar, LOVD) for missense and intronic PMS2 variants and performed an in silico analysis of the genomic sequence. Splicing bioinformatics tools proven effective in other genes were used to assess both the wild-type DNA sequence and reported genetic variants. Splicing alterations were predicted in silico and using GTEx short-read RNA expression data. Out of the 2384 missense variants discovered, 90% were classified with uncertain significance (VUS). 4.9% of missense variants were shown to have a potential splicing consequence (DS > 0.2) using SpliceAI. As described in the original publication, SpliceAI-visual was proven effective in annotation of short intronic variants (< 50 bp). Four short intronic variants were identified using SpliceAI-visual as potentially splicing disturbing, in spite of using a lower threshold (DS > 0.1). Moreover, we observed that Splicing Regulatory Elements (SREs) may play a fundamental role in alternative splicing in PMS2 gene, ESE motifs being overrepresented in highly expressed exons 5, 11 and 14. Computational analysis performed in our study serves as a valuable filtering step for guiding further RNA sequencing experiments. Additional functional data is necessary to evaluate the significance of our findings.

Brain imaging studies have recently provided some evidence in favour of covert cognitive processes ongoing in patients with disorders of consciousness (DoC) (e.g., minimally consciousness states, vegetative state/unresponsive wakefulness syndrome) engaged in passive sensory stimulation or active tasks such as motor imagery. In this exploratory study, we used transcranial magnetic stimulation (TMS) of the motor cortex to assess modulations of corticospinal excitability induced by action observation in eleven patients with DoC. Action observation is known to facilitate corticospinal excitability in healthy subjects, unveiling how the observer’s motor system maps others’ actions onto her/his motor repertoire. Additional stimuli were non-biological motion and acoustic startle stimuli, provided that sudden and loud acoustic stimulation is known to lower corticospinal excitability in healthy subjects. Results indicate that some form of motor resonance is spared in a subset of patients with DoC with some significant difference between biological and non-biological motion stimuli. However, there was no covariation between corticospinal excitability and the type of DoC diagnosis (i.e., whether VS/UWS or MCS). Similarly, no covariation was detected with clinical changes between admission and discharge in clinical outcome measures. Both motor resonance and biological/non-biological motion discrimination correlated with the amplitude of the N20 somatosensory evoked potentials following the stimulation of the median nerve at the wrist (i.e., the temporal marker signalling the activation of the contralateral primary somatosensory cortex). Moreover, the startle-evoking stimulus produced an anomalous increase in corticospinal excitability, suggesting a functional dissociation between cortical and subcortical circuits in patients with DoC. Further work is needed to better comprehend the conditions in which corticospinal facilitation occurs and whether and how they may relate to individual clinical parameters.

Background: The purpose of this review is to clarify the natural course of Benign Paroxysmal Torticollis (BPT) and to update the relationship of this disorder with migraine. BPT belongs to a group of “episodic syndromes that may be associated with migraine” and is diagnosed when according to diagnostic criteria of the International Classification of Headache Disorders, 3rd edition. It is present in infants and young children and it is an underdiagnosed manifestation, because it is not well recognized and in most cases with a benign evolution, but requires careful differential diagnosis. It was first described by Snyder in 1969 as a movement disorder, a cervical dystonia consequent to labyrinthic disorder.Materials and methods: The PubMed and Web of Science databases were consulted from 1968 to 2024, according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines ,2020.( PRISMA)Results: 113 articles were identified, 86 selected and 20 considered for the purpose of this review. The clinical studies were considered in relation to evolution, cognitive and motor development, to genetic and not genetic etiology, to the relationship with migraine with and without aura, vestibular migraine, hemiplegic migraine, and paroxysmal vertigo.

The ultimate goal of our review is to draw clinician’s attention, especially of those who are managing pediatric patients with permanent, long-standing, ventriculoperitoneal or, less commonly, ventriculo-atrial shunts. This specific subgroup of patients may eventually suffer from severe, intractable headaches which may negatively impair their quality of daily living. In the absence of any other clinical condition that could be attributed as the cause of the headache, shunt overdrainage should not be overlooked but, on the contrary, should be seriously taken into consideration in the therapeutic armamentarium of such cases, that are difficult to be handled.

The gut-brain axis (GBA) represents a complex, bidirectional communication network that intri-cately connects the gastrointestinal tract with the central nervous system (CNS). Understanding and intervening in this axis opens a pathway for therapeutic advancements. In light of this, the current review assesses the effectiveness of neuromodulation techniques in treating neurological and gastrointestinal disorders by modulating the GBA, involving key elements such as gut micro-biota, neurotrophic factors, and proinflammatory cytokines. Through a comprehensive literature review encompassing PubMed, Google Scholar, Web of Science, and the Cochrane Library, and analyzing 182 relevant articles, this research highlights how neuromodulation can positively impact the management of functional gastrointestinal disorders (FGIDs), chronic pain, inflammation, and a range of GI disorders like Crohn's disease and ulcerative colitis. Despite existing challenges, the ability of neuromodulation to adjust disrupted neural pathways, alleviate pain, and mitigate in-flammation is significant in improving the quality of life for patients, thereby offering exciting prospects for future advancements in patient care.

Juvenile Polyposis Syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knockout on the development of intestinal polyps using Collaborative Cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knockout mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knockout males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knockout, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-Nearest Neighbours and Linear Regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides a comprehensive understanding of the intricate genetic interplay in the context of Smad4 knockout, offering valuable insights into potential therapeutic targets for juvenile polyposis and related diseases.

Exosome-based therapy has emerged as a promising strategy for addressing diverse disorders, indicating the need for further exploration of the potential therapeutic effects of the exosome cargos. This study introduces "enhanced exosomes," a novel type of exosomes developed through a novel cell culture system. These specific exosomes may become potent therapeutic agents for treating ovarian disorders. In this study, we conducted a comparative analysis of the protein and miRNA cargo compositions of enhanced exosomes and naïve exosomes. Our findings revealed distinct cargo compositions in enhanced exosomes, featuring upregulated proteins such as EFEMP1, HTRA1, PAM, RSU1, and SDF4, suggesting their potential for treating ovarian disorders. MicroRNA profiling revealed that miR-1-3p, miR-103a-3p, miR-122-5p, miR-1271-5p, miR-133a-3p, miR-184, miR-203a-3p, and miR-206 are key players in regulating ovarian cancer and chemosensitivity by affecting cell cycle progression, cell proliferation, and cell development. We examined polycystic ovary syndrome and premature ovarian insufficiency and identified altered expression of various miRNAs, such as miR-106a-5p, miR-130b-5p, and miR-130b-3p, for diagnostic insights. This study highlights the potential of enhanced exosomes as new therapeutic agents for women's reproductive health, offering a detailed understanding of the impact of their cargo on ovarian disorders.

Rett Syndrome (RTT) is a severe neurodevelopmental disorder predominately diagnosed in females and primarily caused by pathogenic variants in the X-linked gene Methyl-CpG Binding Protein 2 (MECP2). Most often, the disease causing MECP2 allele resides on the paternal X chromosome while a healthy copy is maintained on the maternal X chromosome with inactivation (XCI) resulting in mosaic expression of one allele in each cell. Preferential inactivation of the paternal X chromosome is theorized to result in reduced disease severity; however, establishing such a correlation is complicated by known MECP2 genotype effects and an age dependent increase in severity. To mitigate these confounding factors, we developed an age- and genotype-normalized measure of RTT severity by modeling longitudinal data collected in the US Rett Syndrome Natural History Study. This model accurately reflected individual increase in severity with age and preserved group-level genotype specific differences in severity allowing for the creation of a normalized clinical severity score. Applying this normalized score to a RTT XCI dataset revealed that XCI influence on disease severity depends on MECP2 genotype with a correlation between XCI and severity observed only in individuals with MECP2 variants associated with increased clinical severity. This normalized measure of RTT severity provides the opportunity for future discovery of additional factors contributing to disease severity that may be masked by age and genotype effects.

Furthermore, the nasal congestion typical of rhinitis can contribute to upper airway obstruction and sleep-disordered breathing. A vicious circle is created between asthma and sleep-disordered breathing: uncontrolled asthma and sleep-disordered breathing can worsen each other. In children with genetic obesity, despite alterations in the immune system, fewer allergies are found compared to the general population. The causes of this reduced allergenicity are unclear but probably involve genetic, immunological, and environmental factors. Further studies are needed to understand the mechanisms. The study emphasizes the importance of jointly evaluating and managing allergies, obesity, and sleep-disordered breathing in children, considering their close interconnection.

Mosquitoes are a family of the order Diptera, which includes more than 3500 species. Two groups able to suck human blood and transmit diseases: the anophelines and the culicines comprise several genera such as Culex, Aedes and Aedes communis (Ac). Previous study has demonstrated a significant relationship between Ac sensitization and either extract or single bee venom components suggesting a “bee-mosquito syndrome” occurrence. It is well known that CCD can interference with the measurement of quantitative IgE results. Hence, it has been hypnotized that the presence of sIgE to CCD could have a role in the Bee-Mosquito syndrome. Method Serum from 21 different Mosquito and Ape melifera allergic individuals were combined with extracts of Mosquito (in house) and Apis melifera. SDS-PAGE and Immunoblot (IB) were carried out without and with with CCD-Inhibitor. Results The data would suggest IgE binding to common bands between Culex male, Culex female and Aedes species mosquitos of approximate molecular weight ~21kDa, ~35kDa, ~40kDa and ~55kDa. Whilst IgE binding has been observed to protein bands from the Apis melifera extract, these bands do not align with any present in the mosquito extracts. The use of a CCD-Inhibitor results in differences in IgE binding. Specifically, bands that were previously observed in the Apis melifera venom sample without use of CCD-Inhibitor at 40kDa and 90kDa are no longer observed when CCD-Inhibitor is used. Two bands of the Apis melifera venom remain present between 15-20kDa. No major differences in banding pattern were observed for the mosquito samples with or without CCD-Inhibitor, although the blot appears cleaner with less background when CCD-Inhibitor is used. Conclusion Further experiments have to be done to determine whether the reactive bands from Apis melifera are unrelated proteins or whether the proteins are related homologues of varying molecular weight.

Prolylcarboxypeptidase (PRCP, PCP, Lysosomal Pro-X-carboxypeptidase, Angiotensinase C) controls angiotensin - and kinin- induced cell signaling. Elevation of PRCP appear to be activated in chronic inflammatory diseases (cardiovascular disease (CVD), diabetes) in proportion to severity. Vascular endothelial cell senescence and mitochondrial dysfunction have consistently been shown in models of CVD in aging. The cellular senescence, a driver of age-related dysfunction, can differentially alter the expression of lysosomal enzymes due to lysosomal membrane permeability. There is a lack of data demostrating the effect of age-related dysfunction on the expression and function of PRCP. To explore the changes in PRCP, PRCP-dependent prekallikrein (PK) pathway was charcterized in early – and late-passage human pulmonary artery endothelial cells (HPAECs). Detailed kinetic analysis of cells treated with high molecular weight kininogen (HK), a precursor of bradykinin (BK), and PK revealed a mechansim by which senescent HPAECs activate the generation of kallikrein upon the assembly of the HK-PK complex on HPAECs in parallel with an upregulation of PRCP and endothelial nitric oxide (NO) synthase (eNOS) and NO formation. The NO production and expression of both PRCP and eNOS increased in early-passage HPAECs while decreased in late-passage HPAECs. Low activity of PRCP in late passage HPAECs was associated with rapid decreased telomerase reverse transcriptase mRNA levels. We also found that, with an increase in the passage number of HPAECs, reduced PRCP altered respiration rate. These results indicated that aging dysregulates PRCP protein expression, and further studies will shed light into the complexity of PRCP-dependent signling pathway in aging.

Gardasil 4, a human papilloma virus vaccine, has been shown to protect against various cancers, including cervical cancer. Common side effects include injection site pain, fever, headaches, and muscle aches. In some individuals, the severe side effect of postural orthostatic tachycardia syndrome (POTS) has been reported. POTS is characterized by the abnormal response of lightheadedness, blurry vision, and dizziness while transitioning to an upright posture. POTS predominately affects women, with more than eighty-five (85) percent of POTS patients being female. POTS on average, takes five years and eleven months to receive the diagnosis. Additionally, ​A strong association between POTS and Ehlers Danlos Syndrome Type III (EDS) exists. Eighty (80) percent of patients with EDS have POTS. This severe side effect dictates that providers need to be aware of this strong association of HPV vaccinations and POTS. ​In this report we will present a case of a young women with a past medical history significant for EDS type III who was diagnosed with POTS after receiving Gardasil 4 vaccination. This case demonstrates the need for physicians to be aware of the association of POTS with EDS type III and HPV vaccination. Physician awareness of the associations, signs and symptoms of POTS and earlier testing at the first presentation of signs and symptoms will limit the negative impact on patient’s quality of life.

Previous investigations have illuminated the significant association between the gut microbiome and a broad spectrum of health conditions, including obesity, diabetes, cardiovascular diseases, and psychiatric disorders. Evidence from certain studies suggests that dysbiosis of the gut microbiota may play a role in the etiology of obesity and diabetes. Moreover, it is acknowledged that dietary habits, pharmacological interventions, psychological stress, and other exogenous factors can substantially influence the gut microbial composition. For instance, a diet rich in fiber has been demonstrated to increase the population of beneficial bacteria, whereas the consumption of antibiotics can reduce these advantageous microbial communities. In light of the established correlation between the gut microbiome and various pathologies, strategically altering the gut microbial profile represents an emerging therapeutic approach. This can be accomplished through the administration of probiotics or prebiotics, which aim to refine the gut microbiota and, consequently, mitigate the manifestations of associated diseases. The present manuscript evaluates recent literature on the relationship between gut microbiota and metabolic syndrome published over the past three years and anticipates future directions in this evolving field.

Objectives: Recently, desert dust in Europe has been recognized as a cardiovascular health problem. In Spain, desert dust inflows in recent years have been associated with worsening air quality. The present study examines whether desert dust events are related to the incidence of acute coronary syndrome (ACS) in patients under 55 years of age. Methods: Data from 2416 consecutive patients admitted to a tertiary hospital due to ACS were prospectively analyzed. A case-crossover time-stratified design using Poisson conditional regression models was applied to estimate the impact of desert dust events involving particulate matter concentrations of aerodynamic diameter < 10 μm (PM10) on the incidence of ACS. Results: Desert dust intrusion on days 0 to 5 after ACS onset showed no significant association with the incidence of ACS in patients under 55 years of age. The incidence rate ratios of PM10 concentrations 1, 2, 3, 3, 4 and 5 days before ACS onset (for changes of 10 µg/m3) were 1.02 (95% CI 0.97-1.1; p = 0.41), 1.01 (95% CI 0.96-1.07; p = 0.66), 0.99 (95% CI 0.94-1.05; p = 0.78), 0.96 (95% CI 0.9-1.02; p = 0.18) and 0.97 (95% CI 0.91-1.04; p = 0.41). Conclusions: Our findings suggest that desert dust is unlikely to be related to the incidence of premature coronary heart disease.

Objectives: To study sociodemographic and clinical variables including psychiatric comorbidities in patients with irritable bowel syndrome. Methods: A total of 150 patients were screened to select 100 patients for the study who were attending a medical gastroenterology clinic in a tertiary care centre in north India. Diagnosis of IBS was made using Rome IV criteria and severity of symptoms were assessed by the Irritable Bowel Syndrome Symptom Severity Scale (IBS-SSS). Clinical evaluation was done for screening of psychiatric comorbidities and diagnosis was made as per DSM 5. Depression, Anxiety and Stress Scale - 21 Items (DASS-21) and Somatic Symptom Scale–8 (SSS-8) were used to assess depression, anxiety, stress and somatic symptoms. Result: The mean age of cases was 35.6 years and majority were i.e., 38.0% in 18-29 years. Males were 62.0% and females were 38.0%. 61.0% of the cases were diagnosed with Moderate IBS. Evaluation on DASS-21 revealed 53.0% were in moderate category in depression, 43.0% were having moderate anxiety and 36.0% were having moderate stress. 48% cases were in high category in somatic symptom scale. Psychiatric comorbidities were present in 29.0% of cases. Depressive disorders were most common psychiatric comorbidity. Conclusion: Patients with IBS presenting to tertiary care centre in Northern India were mostly young males living in semi-urban area, belonging to hindu region, married and had a nuclear family. Patients with IBS commonly have associated psychiatric disorders; anxiety disorders and depression are most common.

The coronavirus pandemic was declared by the World Health Organization (WHO) in 2020, and a global genetic vaccination program has been rapidly implemented as a fundamental solution. However, many countries around the world have reported that so-called genetic vaccines, such as those using modified mRNA encoding the spike protein and lipid nanoparticles as the drug delivery system, have resulted in post-vaccination thrombosis and subsequent cardiovascular damage, as well as a wide variety of diseases involving all organs and systems, including the nervous system. In this article, based on these circumstances and the volume of evidence that has recently come to light, we call the attention of medical professionals to the various risks associated with blood transfusions using blood products derived from people who have suffered from long COVID and from genetic vaccine recipients, including those who have received mRNA vaccines, and we make proposals regarding specific tests, testing methods, and regulations to deal with these risks. We expect that this proposal will serve as a basis for discussion on how to address post-vaccination syndrome and its consequences following these genetic vaccination programs.

Background: The scaffold protein tyrosine kinase substrate 4 (TKS4) undergoes tyrosine phos-phorylation by the epidermal growth factor receptor (EGFR) pathway via Src kinase. The TKS4 deficiency in humans is responsible for the manifestation of a genetic disorder known as Frank-Ter Haar syndrome (FTHS). Based on our earlier investigation, the absence of TKS4 triggers migration, invasion, and epithelial-mesenchymal transition (EMT)-like phenomena while concurrently suppressing cell proliferation in HCT116 colorectal carcinoma cells. This indicates that TKS4 may play a unique role in the progression of cancer. In this study, we demonstrated that the enhancer of zeste homolog 2 (EZH2) and the histone methyltransferase of polycomb repressive complex 2 (PRC2) are involved in the migration, invasion, and EMT-like changes in TKS4-deficient cells (KO). EZH2 is responsible for the maintenance of the trimethylated lysine 27 on histone H3 (H3K27me3). Methods: We performed the transcriptome sequencing, chromatin immunoprecipitation, protein and RNA quantitative studies, cell mobility, invasion, and proliferation studies combined with/without EZH2 activity inhibitor 3-deazanoplanocine (DZNep) Results: We detected an elevation of global H3K27me3 levels in the TKS4 KO cells, which could be reduced with treatment with DZNep, an EZH2 inhibitor. Inhibition of EZH2 activity reversed the phenotypic effects of the knockout of TKS4, reducing the migration speed and wound healing capacity of the cells as well as decreasing the invasion capacity, while the decrease in cell prolif-eration became stronger. In addition, inhibition of EZH2 activity also reversed most epithelial and mesenchymal markers. We investigated the wider impact of TKS4 deletion on the gene expression profile of colorectal cancer cells using transcriptome sequencing of wild-type and TKS4 knockout cells, particularly before and after treatment with DZNep. Additionally, we observed changes in the expression of several protein-coding genes and long non-coding RNAs that showed a recovery in expression levels following EZH2 inhibition. Conclusions: Our results indicate that the removal of TKS4 causes a notable disruption in the gene expression pattern, leading to the disruption of several signal transduction pathways. Inhibiting the activity of EZH2 can restore most of these transcriptomics and phenotypic effects.

The most frequent cause of cardiac failure globally is ischemic heart disease, with chemothera-py-related cardiovascular side effects emerging as the second most frequent cause. Cancer therapy can result in acute cardiac events, such as coronary artery spasm, acute myocardial infarction, thromboembolism, myocarditis, bradycardia, tachyarrhythmias, atrio-ventricular blocks, QT pro-longation, torsades de pointes, pericardial effusion and hypotension, as well as chronic conditions, such as hypertension, systolic and diastolic left ventricular dysfunction presenting clinically as heart failure or cardiomyopathy. In cardio-oncology, when referring to cardiac toxicity and cardiovas-cular hypersensitivity, there is a great deal of misunderstanding. When a dose-related cardiovas-cular side effect continues even after the causative medication is stopped, it is referred to as cardi-otoxicity. A fibrotic response is the ultimate outcome of cardiac toxicity, which is defined as a dose-related cardiovascular adverse impact that lasts even after the causative treatment is stopped. Cardiotoxicity can occur after a single or brief exposure. On the other hand, the term cardiac or cardiovascular hypersensitivity describes an inflammatory reaction that is not dose-dependent, can occur at any point during therapy, even with very low medication dosages, and can show up as Kounis syndrome. It may also be accompanied by anti-drug antibodies and tryptase levels. In this comprehensive review, we present the current views on cardiac toxicity and cardiovascular hypersensitivity, together with the reviewed cardiac literature on the chemotherapeutic agents inducing hypersensitivity reactions. Cardiac hypersensitivity seems to be the pathophysiologic basis of coronary artery spasm, acute coronary syndromes such as Kounis syndrome and myocardi-tis caused by cancer therapy.

Background: In this investigation, we explored the effects of pharmacological cholinergic stimulation on cardiac function and renal inflammation following acute myocardial infarction (AMI) in spontaneously hypertensive rats (SHRs). Methods: Adult male SHRs were randomized into three experimental groups: sham-operated; AMI+Veh (infarcted, treated with vehicle); and AMI+PY (infarcted, treated with the cholinesterase inhibitor pyridostigmine bromide (PY) - 40 mg/kg, once daily for seven days). Rats were euthanized 7 or 30 days post-surgery. Clinical parameters were assessed on the day before euthanasia. Subsequent to euthanasia, blood samples were collected and renal tissues were harvested for histological and gene expression analyses aimed to evaluate inflammation and injury. Results: Seven days post-surgery, the AMI+PY group demonstrated improvements in left ventricular diastolic function and autonomic regulation, and a reduction in renal macrophage infiltration compared to the AMI+Veh group. Furthermore, there was a notable downregulation of pro-inflammatory gene expression and an upregulation of anti-inflammatory gene expression. Analysis 30 days post-surgery showed that PY treatment had a sustained positive effect on renal gene expression, correlated with a decrease in biomarkers indicative of subclinical kidney injury. Conclusion: Short-term cholinergic stimulation with PY provides both cardiac and renal protection by mitigating the inflammatory response after AMI.

Cerebellar ataxia, neuronopathy, and vestibular areflexia syndrome (CANVAS) is caused by biallelic pathogenic expansions, or compound heterozygosity with other pathogenic variants in the RFC1 gene. CANVAS is estimated to be underdiagnosed, both because of the lack of formal diagnostic criteria and molecular challenges that translate to lesser access and high cost of routine testing. Our aim was to address the need for making CANVAS genetic testing routine, by designing a streamlined two-step PCR consisting of a short-allele screening PCR and a confirmatory PCR with fragment capillary electrophoresis detection. Exome sequencing of RFC1 was additionally foreseen to resolve potential compound heterozygosity cases. Specificity of our approach was evaluated using ataxia patients with known non-CANVAS diagnoses, and optimized using Southern blot confirmed CANVAS patients. We evaluated our approach by testing patients consecutively referred for clinically suspected CANVAS using first the two-step PCR, followed by exome sequencing. Our approach was able to accurately identify negative and confirm positive cases in prospectively collected suspected CANVAS patients presenting with at least three typical clinical signs. The proposed testing approach provides an alternative method able to clearly distinguish between CANVAS negative and positive cases and can be easily incorporated into the genetic diagnostic laboratory workflow.

Lynch syndrome (LS) is an inherited cancer predisposition disorder associated with an elevated risk of various epithelial cancers. Despite sharing the same pathogenic variant (PV), Lynch syn-drome variant heterozygotes (LSVH) exhibit considerable phenotypic variability in cancer risk. The role of Human Leukocyte Antigen (HLA) in modifying cancer risk prompted our investiga-tion into whether HLA variations act as genetic modifiers influencing age at cancer diagnosis in a unique cohort of LSVH carrying a PV in the hMLH1 gene in South Africa. Within our extensive LS cohort, 426 individuals carried the same hMLH1 PV (MLH1:c.1528C>T). We selected 100 indi-viduals with the greatest diversity in age at cancer diagnosis and the oldest unaffected individu-als for high-throughput HLA genotyping of 12 HLA class I and II loci using next-generation se-quencing. Statistical analyses employed Kaplan-Meier survival analyses with Logrank tests and Cox proportional hazards. Following the robust application of statistical correction methods, six HLA alleles (3.2%) were significantly associated with a young age at cancer diagnosis. Notably, HLA-B*15:17 and HLA-DPB1*55:01 correlated significantly with very young colorectal cancer (CRC) diagnosis (Mean age: 21y [17-25]; HR = 71.59; q

Throughout this paper the effects of injuries on athletes are highlighted in different aspects. Exertional compartment syndrome is a specific injury related to athletes that is thoroughly explored in this paper through an analysis of the anatomy, symptoms, diagnosis and treatments of the syndrome. Exertional compartment syndrome is an exercise-induced muscle and nerve condition that causes pain, swelling as well as disability in the affected muscles of the lower leg. This syndrome commonly develops in young athletes involved in sports with excessive running and repetitive impact such as track and field, soccer, basketball and lacrosse. Exertional compartment syndrome is commonly misdiagnosed as other less severe injuries such as shin splints, which is symptomatic of pain along the tibia bone of the lower leg caused by overuse. The misdiagnosis of exertional compartment syndrome allows the syndrome to worsen and intensify resulting in the only effective treatment to be fasciotomy, a surgical procedure to release the pressure within the compartment of the lower leg. There is no definitive protocol developed for patients after fasciotomy is performed. Athletes experiencing similar symptoms after surgery are usually treated for their symptoms rather than the syndrome as a whole, which does not have a high degree of success. The development of a definitive protocol utilizing the techniques of manual therapy, mobility stretching and corrective strength training can improve the adverse effects of exertional compartment syndrome as well as restore functionality to the athlete. Raising awareness of this syndrome in athletics will be effective in treating the athlete early on in order to avoid severe effects and invasive procedures.

Populational aging is marked by chronic non-communicable diseases, such as metabolic syndrome (MetS). IL-10 and IL-1β are pleiotropic cytokines with multiple biological effects linked to metabolic disorders. This cross-sectional study assessed 193 participants' IL-10 and IL-1β serum levels regarding their role in developing MetS, clinical characteristics, and their IL1B rs1143627 and IL10 rs1800890 variants' genotype frequencies in a population over 60. IL-10 levels correlated weakly with HDL levels and fat mass and inversely with triglycerides, glucose, glycated hemoglobin, and estimated average blood glucose levels. IL-10 levels were also indirectly influenced by the patient's T2DM duration, lean mass amount, and bone mineral content. Participants with altered HDL, elevated serum glucose, raised HbA1c levels, or those over 80 had reduced serum IL-10 levels compared to those with normal levels or other age groups, respectively. Women also had higher serum IL-10 levels than men. Dissimilarity, IL-1β levels correlated directly only with the number of total leukocytes and segmented neutrophils, showing only significant variations with self-reported alcohol consumption. Our study also found that those with the IL10 AA genotype (lower IL-10 levels) had a significantly higher risk of developing MetS. These findings may help direct future research and more targeted therapeutic approaches in older adults.

Background Although the management of the majority of patients with IBS is dealt with by General Practitioners, randomized clinical trials and treatment guidelines are developed mostly in academic settings. Probiotics are one of the most investigated treatment modality for this condition. Scarce information is available as regards GPs attitude in this regard. Methods A literature search was performed to identify papers specifically dealing with probiotic treatment of IBS in the general practice setting. Moreover, the preliminary results of a survey on this topic conducted by the authors among general practitioners in a province in northern Italy are reported. Results Five papers specifically addressing probiotic treatment of IBS in general practice were found. The response rate varied from 4 to 100%. The prescription rate of probiotics by GPs in IBS varied from <10 to 46%, regardless of the patients’ bowel habits. Physicians’ satisfaction with this treatment varied from 20 to 93%. The variability of these results probably depends on factors such as differences in the interpretation of the available data on probiotics use in IBS and traditional/ cultural differences. Moreover, compliance with patient satisfaction, may play a role. Conclusions The reported data on the treatment of IBS with probiotics in general practice is scarce and inhomogeneous, thus it does not allow firm conclusions. It is suggested that the involvement in research on the use of probiotics in IBS of physicians working in general practice would be useful in order to pursue more reliable and useful results, since the majority of the IBS population is followed in general practice and may differ from the one represented in academic clinical trials.

Infection with human immunodeficiency virus (HIV) and induced acquired immune deficiency syndrome (AIDS) represent one of the greatest health burdens worldwide. The complex pathophysiological pathways that link highly active antiretroviral therapy (HAART) and HIV infection per se with dyslipidemia make the management of lipid disorders and the subsequent increase in cardiovascular risk essential for the treatment of people living with HIV (PLHIV). Amongst the HAART regimens, darunavir and atazanavir in terms of protease inhibitors, tenofovir disoproxil fumarate, nevirapine or rilpivirine in terms of nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors respectively, and especially integrase inhibitors, have demonstrated the most favorable lipid profile emerging as sustainable options in HAART substitution. To this day, statins remain the cornerstone pharmacotherapy for dyslipidemia in PLHIV, although important drug-drug interactions with different HAART agents should be taken into account upon treatment initiation. For those intolerant or not meeting therapeutic goals, the addition of ezetimibe, PCSK9, bempedoic acid, fibrates or fish oils should also be considered. This review summarizes the current literature on the multifactorial etiology and intricate pathophysiology of hyperlipidemia in PLHIV, with an emphasis on the role of different HAART agents, while also providing valuable insights into potential switching strategies and therapeutic options.

Background: As a relatively high number of ST-segment elevation myocardial infarction (STEMI) patients develop major adverse cardiovascular events (MACE) following percutaneous coronary intervention (PCI), our aim was to determine the significance, and possible predictive value of QRS complex width and ST-segment elevation. Methods: Our patient sample included 200 PCI-treated STEMI patients, which were divided into two groups, based on the duration of symptoms: (I) less than 6 hours, and (II) 6-12 hours. For every patient, ECG was performed at 6 different time points. Long-term follow-up lasted 6 years from the STEMI onset. Statistical analysis was performed. Results: The mean age was 60.6±11.39 years, and 142 were male. Wider QRS complex, more pronounced ST-segment elevation, and more frequently absent ST-segment resolution were more common in the second group. Presentation of MACE was more frequent in this group. An increase of pre-PCI QRS complex width by 1 msec increases the risk of 6-year MACE by 3%, and an increase in pre-PCI ST-segment elevation by 1mm increases the risk of 6-year MACE by 3.26 times. Conclusion: To the best of our understanding, this study represents a pioneer research that utilized these ECG elements in the context of predicting a 6-year MACE. A wider QRS complex and a more pronounced ST-segment elevation were associated with longer total ischemic time. More research is needed to confirm these findings.

Systemic lupus erythematosus (SLE) is a prevalent autoimmune condition, yet its alignment with a specific host immunological pathway remains unclear. The THαβ host immunological pathway, recognized for its defense against viruses and prions, has recently emerged as a response to DNA, RNA, and protein pathogens. SLE patients often produce anti-double strand DNA antibodies and anti-nuclear antibodies, suggesting a potential association with the THαβ host immune reaction. Throughout the course of SLE, elevated levels of type 1 interferons, type 3 interferons, interleukin-10, IgG1, and IgA1 are commonly observed. These cytokines and antibody isotypes are indicative of the THαβ host immunological pathway. Similarly, Myasthenia gravis, Grave’s disease, Graft versus host disease, autoimmune hemolytic anemia, immune thrombocytopenia, dermatomyositis, and Sjogren’s syndrome are also linked to THαβ-related type 2 hypersensitivities. Considering the potential association of these diseases with dysregulated THαβ immune responses, therapeutic strategies such as anti-interleukin-10 or anti-interferons α/β could be explored to manage these disorders effectively.

Turner syndrome (TS) is caused by a complete or partial absence of an X or Y chromosome, including chromosomal mosaicism, affecting 1 in 2,500 female live births. Sister chromatid exchange (SCE) is used as a sensitive indicator of spontaneous chromosome instability. Cells from mosaic patients constitute useful material for SCE evaluations as they grow under the influence of the same genetic background and endogenous and exogenous factors. We evaluated proliferation dynamics and SCE frequencies of 45,X and 46,XN cells of 17 mosaic TS patients. In two participants, 45,X cells exhibited a proliferative disadvantage in relation to 46,XN cells after 72h of cultivation. The analysis of mean PI showed significant differences between 45,X and 46,XN lineages; however there were no intraindividual differences. On the other hand, mean SCE frequencies showed no differences between the two lineages, but there were intraindividual differences in 5 patients. The absence of mean SCE frequency differences between 45,X and 46,XN lineages may indicate that both were equally unstable, as more than 70% of the 46,XN lineages had an anomalous karyotype. However, 46,XN had a higher mean PI, suggesting that the amount of cells with a karyotype distinct from 45,X may increase with time in mosaic TS women.

Background: DICER1, cancer predisposition syndrome (CPS), seems to escape timely diagnosis in pediatric patients. Case report 1: A 16-year-old female patient was referred to the endocrinology ward due to a large goiter. Her medical history indicated normal sexual maturation, with menarche occurring at 13.5 years. Over the past 2.5 years, she developed pronounced androgenic symptoms, including a deepened male voice, facial, back and neckline acne, hirsutism, and menstrual irregularities leading to secondary amenorrhoea. A thyroid ultrasound identified a multinodular goiter with cystic-solid lesions containing calcifi-cations. An abdominal ultrasound identified a 5.7x6.9 cm solid mass in the right adnexal region, displacing the uterus to the left. Histopathological examination confirmed a Sertoli-Leydig cell tumor. The patient was subjected to total thyroidectomy. Histopathology revealed benign follicular cell-derived neoplasms. Thyroid follicular nodular disease was diagnosed bilaterally. DNA analysis using NGS, confirmed by the Sanger method, revealed a pathogenic heterozygotic variant c.2953>T [p.Gln985*] in exon 18 of DICER1 gene. Case report 2: A 12-year-old male patient was admitted to the pediatric surgery unit due to a 33 ml goiter. A month prior to admission, the patient discovered a palpable nodule in his neck, accompanied by hoarseness. An ultrasound revealed a multinodular goiter. Molecular analysis revealed a pathogenic heterozygotic variant c.2782C>T [p.Gln928Ter] in exon 17 of DICER1 gene. Subsequently, a total thyroidectomy was performed, and histopathological examination revealed thyroid follicular nodu-lar disease bilaterally. Conclusion: Multinodular goiter, although rare in pediatric population, when accompanied by characteristic ultrasound and histopathological features, and by additional features such as androgen excess, warrants exclusion of DICER1 syndrome.

Coccomyxa subellipsoidea KJ (C-KJ) is a green alga with unique immunoregulatory characteristics. Here, we investigated the mechanism underlying the modification of T cell function by C-KJ components. The water-soluble extract of C-KJ was fractionated into protein (P) and sugar (S) fractions [acidic (AS), basic (BS), and neutral (NS)]. These fractions were used for the treatment of peripheral blood mononuclear cells stimulated with toxic shock syndrome toxin-1. Transcriptome analysis revealed that both P and AS enhanced the expression of the genes encoding metallothionein (MT) family proteins, inflammatory factors, and T helper (Th) 17 cytokine and suppressed that of those encoding Th2 cytokines in stimulated T cells. The kinetics of MT1 and MT2A gene expression showed a transient increase in MT1 and maintenance of MT2A mRNA after T cell stimulation in the presence of AS. The kinetics of Th17-related cytokine secretion in the early period were comparable to those of MT2A mRNA. Furthermore, our findings revealed that static, a STAT-3 inhibitor, significantly suppressed MT2A gene expression. These findings suggest that the expression of MTs is involved in the immune regulatory function of C-KJ components, which is partially regulated by Th17 responses, and may help develop innovative immunoregulatory drugs or functional foods.

Etiological factors involved in myelodysplastic syndrome (MDS) include immunologic, oxidative stress, and inflammatory factors, among others, and these are targets for microRNAs (miRNs). Here, we evaluated whether some miRNs may affect the tumor development comparing untreated and 5-azacitidine (5-AZA) MDS-treated patients. Peripheral blood samples were collected from 20 controls and 24 MDS patients, and selected miRNs related to redox balance and inflammation, including miR-18a, miR-21, miR-34a and miR-146a, were isolated and measured by quantitative real-time polymerase chain reaction (qRTPCR). A differential expression profile of miRNs was detected in untreated MDS patients and 5-AZA group. MiR-18a, miR-21, miR-34a and miR-146a were significantly overexpressed in untreated MDS, compared to controls. However, we did not observe any miRNs profile alteration during the progression of the disease. On the other hand, 5-AZA treatment tends to restore miRNs expression levels. Relating to prognostic risk factors, high risk MDS groups (high IPSS-R, high cytogenetic risk, high molecular risk (HMR) mutations tended to be related with higher expression levels of miR-18a and miR-34a. Higher miRNs expression is correlated with lower glutathione peroxidase activity, while they are related with a higher profile of pro-inflammatory cytokines (IL-2, IL-6, IL-8, TNF-α). Although our study was limited by the low number of MDS patients included, we identified miRNs deregulation involved in the MDS development, that could regulate redox sensors and inflammatory responses. Finally, 5-AZA treatment is related with lower miRNs expression levels in MDS patients.

Objectives: Metabolic interactions amongst mutated genes in myelodysplastic syndrome (MDS) offer promising avenues for novel anticancer treatments. Our comprehensive study delves into these mutational and transcriptomic landscapes, pinpointing hallmark gene mutations and deregulated gene expression that could influence MDS patients’ metabolomes. Methods: The study utilized a retrospective, cross-sectional approach, employing mutational data on the cBio Cancer Genomics Portal conducted and reported by the University of Tokyo in 2011 and multi-center MDS cohorts regulated by Wellcome Trust Sanger Institute, United Kingdom, all in 2020. For transcriptomic data, we selected three publicly accessible independent cohorts on the Gene Expression Omnibus (GEO) database (GSE114922 in Wellcome Trust Centre for Human Genetics, United Kingdome, GSE63569 in University of Oxford, United Kingdome, and GSE183328 in CIMA, Spain) held in 2015, 2018, and 2022, respectively. To compile clinical, mutational, and transcriptomic data on MDS patients from multiple datasets and studies. This meta-analysis included genomic data derived from cellular genomics sources to assess mutations in specific genes, alongside an examination of transcriptomic data from three separate datasets that have been previously published. Results: DNMT3A presented a 20% mutation frequency, playing a pivotal role in MDS metabolomics. The DNMT3A gene mutations displayed significant mutual exclusivity with the SRSF2, ASXL1, JAK2, and TP53 genes. The mutational analysis also showed that the gene expression landscape in MDS is associated with alterations to DNA methylation pathways. Conclusion: This analysis suggests a potential therapeutic niche. Identifying signature genes in MDS that have metabolic and methylation affiliations could illuminate the disease's intricate biology and inspire novel treatments.

Aim: To analyze a single center's experience with Short Bowel Syndrome/ Chronic Intestinal Failure (SBS/CIF) in adult patients treated with Home Parenteral Nutrition (HPN). Materials and methods: In the last thirty years, 13 patients with SBS/CIF were included in an HPN program. Results: Between 1992 and 2023, 13 patients were included in an HPN program. The primary underlying pathology was acute mesenteric ischemia. The median age of the starting HPN was 44 years old. Most are submitted to several surgeries of extensive intestinal resection with posterior intestinal reconstruction. Five of the 13 patients have died while on HPN for a median of 42 months. The causes of death HPN-related were catheter sepsis, endocarditis with cardiac failure, or hepatic failure. One patient died due to underlying pathology: pelvic abscesses and bleeding related to radiotherapy. Eight patients remain alive with a median time of HPN of 173 months. During the HPN support, the most frequent complications were venous catheter infection and venous territory thrombosis. None of the eight patients alive have hepatic failure. Two patients recently started teduglutide, with good tolerance, and need reduction of HPN support. All these eight patients have a satisfactory quality of life (parenteral support needs range between five to two nutrition bags per week). Conclusion: HPN remains the gold standard of SBS/CIF treatment, although Teduglutide may reduce HPN needs and HPN complications and provide a better quality of life. An HPN multidisciplinary healthcare group support is essential to ensure these patients' survival and quality of life. Keywords Short bowel Syndrome, Chronic Intestinal failure, Home Parenteral Nutrition, Teduglutide, Complications of Parenteral Support.

Molecular analysis of growing teratoma syndrome has not been extensively studied. Here, we report a 14-year-old boy with a growing mass during treatment for a mixed germ cell tumor of the pineal region. Tumor markers were negative; thus, growing teratoma syndrome was suspected. A radical resection via the occipital transtentorial approach was performed, and histopathological examination revealed a teratoma with malignant features. Methylation classifier analysis confirmed the diagnosis of teratoma, and DMRT1 loss and 12p gain were identified by copy number variation analysis, potentially elucidating the cause of growth and malignant transformation of the teratoma. The patient remains in remission after intense chemoradiation treatment as a high-risk germ cell tumor.

(1) Background: Sudden Infant Death Syndrome (SIDS) represents unexplained and sudden deaths during the sleep of infants under one year of age, despite thorough investigation. Screening for prolonged QTc or Long QT Syndrome (LQTS) should be conducted on all newborns to reduce the incidence of SIDS. Neonatal electrocardiogram (ECG) could identify congenital heart defects (CHD) early, especially those not detected at birth. Infants with prolonged QT intervals typically undergo genetic analysis for Long QT Syndrome; (2) Methods: The study involved infants aged 20-40 days, born clinically healthy, with initial ECG screening. Infants with prenatal diagnoses or signs/symptoms of CHD identified immediately after birth, as well as those who underwent ECG or echocardiogram for other clinical or historical indications, were excluded from the study. The data were analyzed using SPSS version 22.0; (3) Results: Of the 42,200 infants involved, 2,245 were enrolled, with 39.9% being males. Subsequently, 164 children (37.8% males) with prolonged QT intervals underwent further diagnostic investigations. Genetic mutations were identified in 11 out of 18 tested children. The most common mutations were LQT1 (54.5%), LQT2 (36.4%), and LQT3 (1 patient). Medications used included propranolol (39.8%), nadolol (22.2%), inderal (11.1%), metoprolol (11.1%), and no treatment (16.7%). The most common abnormalities were focal right bundle branch block (54.5%), left axis deviation (9.2%), and nonspecific ventricular repolarization abnormalities (7.1%). Multiple anomalies were found in 0.47% of children with focal right bundle branch block. Structural abnormalities were associated with specific features in 267 patients (11.9%), primarily isolated patent foramen ovale (PFO) at 61.4%; (4) Conclusions: The screening has proven effective in early diagnosing Long QT Syndrome and other cardiac rhythm anomalies, with additional benefits in detecting mutations and/or QTc prolongations in family members. Identifying other ECG abnormalities and congenital heart malformations further enhances the benefits of the screening.

Burning mouth syndrome (BMS) is a chronic oral pain disorder. There is a theory that BMS is nociplastic pain. Standard treatment for BMS has not yet been established. Kampo medicine is a traditional oriental medicine. The purpose of this study is to evaluate the effectiveness of rikkosan—a traditional Japanese herbal medicine (Kampo)—in the treatment of BMS. A single-center retrospective study was conducted in 20 patients who were diagnosed with BMS and treated with rikkosan alone (7.5 g) three times daily for approximately 4 weeks. They were treated with rikkosan alone approximately 4 weeks (29.5 ± 6.5 days) for the initial treatment. They had an average age of 63 years and 90% were being treated for other illnesses, but their medication status was the same during this study period, except for rikkosan. No side effects were observed in patients. Numerical rating scale (NRS) or visual analogue scale (VAS)/10 scores decreased significantly between the time of the initiation of rikkosan and the one-month after (-2.1 ± 1.2, p < 0.05). Rikkosan has a short-term effect of reducing NRS by two levels in BMS patients.

Study design: Technical note. Objectives: To present a novel technique of treatment for patient with basilar invagination. Background : Basilar invagination (BI) is considered a congenital condition and can compress the cervicomedullary junction, causing neurologic deficit. Severe neurological deficit due to BI should be treated surgically. However, there is controversy regarding whether an anterior or posterior approach should be used. Anterior approach is optimal for decompression of cervicomedullary junction, but this approach has high complication rates. Posterior reduction has a high risk of occipital screws backout and/or instrument failure. Materials and Methods : A 15-year-old boy with severe myelopathy was referred to our hospital. He had neck pain, muscle weakness of bilateral upper limbs, gait disturbance appeared 3 months before he visited our hospital, he drops a cup several times recently. In the examination, he had hyperreflexia of upper and lower limbs and muscle weakness of bilateral arms (MMT 4), hypoesthesis was observed bilaterally below elbow and both legs. He also had clumsiness of bilateral hands, mild urinary and bowel incontinence, and spastic gait. His 10 second grip and release test was 16 in both hands. His grip power was 20 kg in right and 17 kg in left. Radiograms showed severe BI and spinal cord was severely compressed with odontoid process.. Results : The patinet underwent posterior surgery with C-arm free technique. All screws including occipital screws were inserted adequate position under navigation guidance. Reduction was achieved with skull rotation and distraction. A follow-up at one year we have these results : Manual muscle testing results and sensory function tests showed almost full recovery, bilateral arms (MMT 5) ,walking smoothly. Cervical Japanese orthopedic association score of the patient has improved from 9/17 to 16/17. Post-operative images showed an excellent spinal cord decompression, and no major or severe complications has occured . Conclusions/Level of Evidence : Basilar invagination with Klippel-Feil syndrome is relatively rare condition. Posterior approach and occipito-cervical fixation for BI treatment with navigation technique is a safe method to treat severe myelopaty with reducible odontoid. This novel navigation technique provides an excellent results for a patient with BI. Level V.

Cornelia de Lange syndrome (CdLS) is a complex genetic disorder with a distinct set of facial features, growth limitations, and limb anomalies. Its clinical spectrum is broad and presents significant challenges in pediatric diagnosis and management. The variable presentation of the disorder, due to cohesin complex mutations, requires extensive research to refine care and improve outcomes. This article provides a case series review of pediatric CdLS patients, alongside a comprehensive literature review, exploring clinical variability and the relationship between genotypic changes and phenotypic outcomes. It also discusses the evolution of diagnostic and therapeutic techniques, with an emphasis on innovations in genetic testing, including the detection of mosaicism and novel genetic variations. The aim is to synthesise case studies with current research to advance our understanding of CdLS and the effectiveness of management strategies in pediatric healthcare. This work highlights the need for an integrated, evidence-based approach to diagnosis and treatment, and aims to fill existing research gaps and advocate for holistic care protocols and tailored treatment plans for CdLS patients, ultimately improving their quality of life.

Heel pain in the “funnel-shaped” space between the calcaneus, talus, and talocalcaneonavicular and subtalar joints may be representative of Sinus Tarsi syndrome. The pain is often characterized by a burning, numbness, or tingling sensation that can stem from strains and tears on the ligaments in that area. Injury treatment typically includes balance training, muscle exercises, bracing, foot orthosis, and non-steroidal anti-inflammatory drugs (NSAIDs). This study presents Wharton Jelly (WJ) tissue allografts as an alternative intervention for patients who fail standard-care treatments. WJ targets tissue defects, unlike other therapies, which aim to reduce swelling and symptomatic pain. This study includes five female patients who have previously failed standard-of-care treatment. Each received extracorporeal pulse-activated therapy (EPAT), WJ, laser therapy, and an orthotic. After an average of 80 days, the cohort had an overall 85.29% improvement in pain. The study's limitations include a small cohort size and a non-blinded design. Given the significant improvement in pain, WJ tissue allograft, combined with other techniques, presents an optimal patient care plan for tissue defects associated with Sinus Tarsi syndrome when standard-of-care treatments fail. These results provide evidence for a more extensive, randomized study to define dosage protocols further and confirm safety and efficacy.

Introduction: The academic landscape is increasingly recognizing the complex interplay of personal and professional responsibilities on scholarly productivity. For women scholars, particularly those with significant parenting duties, this balance is even more precarious. This study aims to explore how family responsibilities, personal vulnerabilities, and motivational theories such as Imposter Syndrome and Self-Determination Theory (SDT) influence the motivation to publish scholarly work. Understanding these dynamics is crucial for developing supportive mechanisms that can enhance academic productivity and personal fulfilment. Methods: Utilizing a Qualitative Evidence Synthesis (QES) framework, this study will systematically review and synthesize qualitative research on women scholars' experiences in academia, focusing on the challenges and motivators related to publishing. Data sources will include academic databases, grey literature, and first-hand narratives. Thematic analysis will be employed to identify key themes and patterns across the collected data. Results/Findings: Preliminary findings suggest that the dual demands of parenting—especially in extreme cases such as assuming responsibility for seven children—and academic work significantly impact women scholars' publishing activities. Personal vulnerabilities, including imposter syndrome and low self-efficacy, further exacerbate these challenges. However, the data also highlight resilience strategies and the potential for intrinsic and extrinsic motivational factors to mitigate these effects. Discussion: The study underscores the nuanced impact of familial and personal factors on academic motivation. The preliminary findings suggest that addressing imposter syndrome and enhancing self-determination could be pivotal in supporting women scholars. The role of institutional policies and academic culture in either exacerbating or alleviating these challenges is also discussed. Significance: By elucidating the specific challenges and motivators for women scholars in publishing, this study will contribute to the development of targeted interventions and policies that support work-life integration and promote academic productivity. The insights that will be gained could inform mentorship programs, institutional support systems, and policy reforms aimed at fostering a more inclusive and supportive academic environment.

Myelodysplastic neoplasm (MDS) is a heterogenous clonal disorder of hemopoietic stem cells charac-terized by cytomorphologic dysplasia, ineffective hematopoiesis, peripheral cytopenias and risk of pro-gression to Acute Myeloid Leukemia (AML). Our understanding of this disease has continued to evolve over the last century. More recently prognostication and treatment are determined by cytogenetic and molecular data. Specific genetic abnormalities such as 5q deletion (del 5q), TP53 inactivation and SF3B1 mutation, are increasingly associated with disease phenotype and outcomes, as reflected in the recently updated 5th edition of the World Health Organization Classification of Hematolymphoid Tumors (WHO5) and International Consensus Classification 2022 (ICC 2022) classifications. Treatments are in-creasingly being tailored for patient specific phenotypes, and trials exploring the efficacy of targeted treatments are ongoing in this era of precision medicine.

Background: The workplace burnout syndrome is often associated with particular aspects of certain job positions, especially those which entail working with people with special needs. The burnout syndrome in healthcare jobs is a serious problem which has grown into an epidemic among healthcare workers and associates. Objectives: The aim of this research is to assess the presence of stress and burnout syndrome at work with healthcare workers, expert workers, professional associates and associates in social service institutions in Belgrade. Material and Methods: This research has been conducted in the form of a cross-sectional study of a representative sample in social institutions in Belgrade. It has been conducted from March to the end of June of 2023. The sample of the study had 491 participants. The questionnaires used were a structured instrument with social-demographic and social-economic characteristics, workplace characteristics, life style characteristics, and the following questionnaires: DASS-21, Copenhagen, Brief Resilience Scale, and Brief Resilient Coping Scale. Results: The end results indicate the following to be significant risk factors for the occurrence of workplace burnout syndrome: overtime (OR=2.62; CI=1.50-4.56), BRS average score (OR=0.28; CI=0.17-0.44), DASS21 D heightened depression (OR=2.09; CI=1.1-4.04), DASS21 A heightened anxiety (OR=2.38; CI=1.34-4.21), DASS21 S heightened stress (OR=2.08; CI=1.11-3.89). The only protective risk factor which stood out was the self-assessment of health levels (OR=0.60; CI=0.42-0.85). Conclusion: Overtime is a significant predictor of workplace burnout. Apart from it, other significant predictors of workplace burnout were heightened depression, anxiety, and stress levels.

Chronic fatigue syndrome (CFS) is a disease in which fatigue that interferes with daily life persists for six months or longer. The number of patients with CFS is increasing, as CFS-like symptoms have been reported to occur in the sequelae of both COVID-19 infection and the SARS-CoV-2 vaccine, both of which have become significant issues in recent years. While the pathogenesis mechanism is not yet fully understood, research suggests that oxidative stress (OS) may play a role in the development of CFS. In this paper, we discuss the antioxidant potential of the antioxidant formulation Twendee M® (TwM) and the results of a questionnaire that monitored changes in symptoms before and after TwM in a total of 23 men and women diagnosed with CFS. TwM is a supplement containing 15 different ingredients, and has a strong antioxidant capacity that cannot be achieved with a single antioxidant ingredient. The results of the questionnaire showed that TwM significantly improved all of the major symptoms of CFS, including fatigue, muscle pain, joint pain, sleep disturbance, decreased memory and concentration, and headache. TwM was shown to alleviate various symptoms of CFS and improve quality of life.

A rare genetic disorder caused by col18.a1 mutations, inherited mostly in autosomal recessive and rarely in autosomal dominant pattern, giving rise to ocular abnormalities and other associated disorders, the condition is referred to as Knobloch syndrome. This paper overviews the anterior and posterior ocular symptoms in Knobloch patients, thus demonstrating the major findings in Knobloch cases including the mutational analysis which discusses the proteins involved and exon number on which mutations are detected. Animal modeling done by knocking out col18.a1 has also been discussed to determine the functions of this gene which have been identified based on anomalies found in knock-out mice.

Research on microglia in Down syndrome (DS) has shown that microglial activation, increased inflammatory gene expression, and oxidative stress occur at different ages in DS brains. However, most studies resulted in simplistic definitions of microglia as quiescent or active, ignoring potential intermediate states. However, a recent work on microglial cells in young DS brains indicated that those evolve through different intermediate activation phenotypes before reaching a full activated state. Here we used single nucleus RNA sequencing, to examine how trisomy affects microglial states in the Ts65Dn mouse model of DS. Despite no substantial changes in the proportion of glial populations, differential expression analysis revealed cell type-specific gene expression changes, most notably in astroglia, microglia, and oligodendroglia. Focusing on microglia, we identified differential expression of genes associated with different microglial states, including disease-associated microglia (DAMs), activated response microglia (ARMs), and human Alzheimer’s disease microglia (HAMs), in trisomic microglia. Furthermore, pseudotime analysis reveals a unique reactivity profile in Ts65Dn microglia, with fewer in a homeostatic state and more in an intermediate aberrantly reactive state than in euploid microglia. This comprehensive understanding of microglial transcriptional dynamics sheds light on potential pathogenetic mechanisms but also possible avenues for therapy for neurodevelopmental disorders.

Acute peritonitis is a severe complication of abdominal surgery with a high mortality rate. Intes-tinal insufficiency syndrome (IIS) is a key factor in the progression of peritonitis, contributing significantly to morbidity and mortality. The most characteristic and rapid manifestation of IIS is the development of intestinal paresis. Intestinal paresis is a condition characterized by inhibi-tion of intestinal motility, with the inability to evacuate intestinal contents. Intestinal paresis is caused by a cascade of neuroreflex and humoral reactions that lead to severe microcirculatory and metabolic disturbances. In the absence of adequate treatment, IIS can progress to enteritis, a state of complete intestinal insufficiency, with the inability to absorb nutrients and water.

Background: Auriculotherapy is a widely used approach for alleviating discomfort in patients experiencing pain, itchiness, sleep disturbances, and heightened anxiety. This method is also applicable to patients dealing with significant burn scars, who often encounter similar symptoms. Employed as an adjuvant therapy, auriculotherapy demonstrates potential in mitigating these clinical manifestations among individuals with major burn scars. These symptoms are known to be influenced by the autonomic nervous system. Objectives: Despite the absence of current data elucidating the impact of auriculotherapy on the autonomic nervous system, we embarked on an analysis of our heart rate variability (HRV) data to evaluate autonomic system functionality before and after the administration of auriculotherapy. Methods: Paired-samples t-tests and linear regression analysis of HRV variables and correlations with TBSA before and after auriculotherapy of a cohort of 31 survivors from 2016 Formosa Color Dust Explosion was carried out. Results: Significant change of specific HRV variables were found before and after auriculotherapy, and significantly negative correlations was revealed between TBSA and pre-SD prior to auriculotherapy. Conclusion: Our study showed that auriculotherapy may, at least in part, restore the equilibrium of autonomic nervous system and improve HRV parameters.

Movement disorders can be associated with various drugs and systemic diseases, posing diagnostic challenges for clinicians. This review explores the spectrum of movement disorders associated with pharmacological agents and medical conditions. Drug-induced movement disorders encompass a broad range of conditions resulting from exposure to medications that affect several neurotransmitters. Neuroleptic medications can lead to tardive dyskinesia, characterized by involuntary, repetitive movements. Antipsychotics and antiemetics, including metoclopramide, may induce acute dystonic reactions. Other drugs, such as dopamine receptor-blocking agents, can contribute to drug-induced parkinsonism. Beyond medications, movement disorders can also arise secondary to systemic diseases. Metabolic disorders like Wilson's disease, characterized by copper accumulation, may manifest as chorea or dystonia. Inflammatory conditions such as rheumatoid arthritis and systemic lupus erythematosus can result in secondary movement disorders due to autoimmune-mediated processes affecting the central nervous system. Movement disorders linked to drugs or systemic diseases often necessitate a thorough clinical evaluation, including detailed medication histories and comprehensive systemic assessments. Neuroimaging, laboratory investigations, and, in some cases, cerebrospinal fluid analyses and electrodiagnostic studies help in establishing accurate diagnoses. Management involves addressing the underlying cause, modifying medications, and employing symptomatic treatments.

Intellectual disability with speech delay and behavioural abnormalities as well as hypotonia, seizures, feeding difficulties and cra-niofacial dysmorphism are the main symptoms associated with pathogenic variants of ZMYND11 gene. The range of clinical mani-festations of ZMYND phenotype is constantly being expanded by new cases described in the literature. Here, we present 2 previ-ously unreported paediatric patients with neurodevelopmental features diagnosed with missense variants in ZMYND11 gene. It should be noted that one of the individuals manifested with hyperinsulinemic hypoglycaemia (HH), a symptom that was not de-scribed before in published works. Although the reason for the occurrence of HH in our proband is not clear, it is likely that it broadens the spectrum of symptoms characteristic of ZMYND11 syndrome. Thus, this paper contributes to extending the range of possible manifestations of ZMYND disease and further supports its association with neurodevelopmental challenges.

Punica granatum L., commonly known as pomegranate, is a typical fruit of Asia, Mediterranean countries, Middle East and USA areas. While in the ancient time pomegranate was considered an ornamental plant, nowadays numerous scientific studies have highlighted its antioxidant and anti-radical activities, up to consider pomegranate as a “superfood”. Pomegranate presents a high content of natural bioactive compounds (NBCs) and its consumption appears to exert numerous healthy beneficial effects, in particular, in several pathological conditions, namely in patients affected by metabolic syndrome, cancer, nephrolithiasis, urinary tract infections and neurodegenerative diseases. Moreover, recent studies pointed out the possible beneficial action of pomegranate on oral health. For these reasons, the utility of pomegranate in internal medicine and in dentistry represents a promising field, as it could permit the development of innovative natural adjuvant therapies, able to empower the standard pharmaceutical therapies.

Background: Survival and outcome of extremely preterm (EP) infants have improved due to changes in the management of stabilization at birth and respiratory distress syndrome. Methods: In a retrospective study conducted at an academic perinatal level III center in Romania, we compared the effects of different protocols on the early outcomes of EP infants of two different periods (2008-2012 vs. 2018 vs. 2022). Two subgroups were studied in each period, based on gestational age (GA), 22-25 weeks, and 26-28 weeks, excluding those with significant congenital anomalies or missing data. Results: 270 EP infants were included in the study (121/149), with a mean GA 26.1±1.6/26.7±1.1 weeks. Significant improvements were found during period II regarding initial FiO2 (40% vs. 100%; &lt;0.001), nCPAP (55.7% vs. 19.0%; p&lt;0.001) at birth, early rescue surfactant administration (65.8% vs. 34.7%; p&lt;0.001), need of mechanical ventilation (58.4% vs. 98.3%; p&lt;0.001). Survival rates of EP infants significantly improved from 41.3% to 72.5%, particularly in the 26-28 weeks subgroup (63.8% to 83%). The frequency of severe IVH decreased in period II from 30.6% to 14.1%, while the rates of BPD were lower in period II (23.4% vs. 36.6%; p=0.045), in the 26-28 weeks subgroup. We found improvements but no significant differences in NEC, sepsis, PVL, ROP, or PDA frequencies. Conclusions: Using updated guidelines and protocols is crucial for improving outcomes.

. The Tau protein is associated with microtubule function in the neuron and is crucial for normal axonal transport. In several different neurodegenerative disorders, Tau misfolding leads to hyper-phosphorylation (p-Tau) and intracellular p-Tau aggregates known as neurofibrillary tangles (NFTs). This is particularly evident in individuals with Down syndrome (DS), who develop Alzheimer’s disease-like (AD) neuropathology early in life with almost complete penetrance, associated with the development of dementia symptoms in their 40s or 50s. Our previous findings have shown that certain forms of p-Tau are present already in childhood in individuals with DS in neuron-derived exosomes, suggesting an early phosphorylation profile in this population that could influence the development of AD pathology. Misfolded p-Tau isoforms are known to be seeding competent and may be responsible for spreading AD pathology in different regions of the brain. This review is focused on the accumulation of p-Tau in the brain of individuals with DS and potential consequences for brain function.

Chronic Fatigue Syndrome (CFS) can be triggered by different factors and create a complex health situation. In the last decades incidence has been increasing. This situation is a clear example of how humans, viruses, and the environment are all connected. In the 90s cases related to CFS, com-plaints about a feeling of chronic fatigue, inability for everyday tasks, dull pain, cephalalgia, de-pression, anxiety, poor concentration. Clinical tests for EBV, HHV, CMV, IgG, IgM, T4 and T8 subsets were tested, along with hormones and hemogram tests. Most of the cases were women. The timeline of the medical history showed also myomas, breast lumps, premenstrual syndrome previously to CFS development. The nature of these conditions promoted the idea of a possible common link among them and CFS. Some cases also suffered from allergies, food intolerances, candidiasis, intestinal impairment, thyroid implications, endometriosis. As an initial working hypothesis, The Liver Link (TLL) was proposed in order to understand those different conditions affecting body, mind and emotional wellbeing. Considering liver implication can make a differ-ence in treatment and recovery. Low grade inflammatory conditions are related to Th2 predom-inance and liver functions. Functional disharmonies are very important because they usually still do not appear in any conventional tests. In 2002, TLL was presented as a framework to explain the concomitance of CFS and other conditions and the relationship with some viruses such as EBV, HHV, CMV, as a lecture in a congress at the University of Westminster (London). When SARS-CoV-2 outbroke, TLL helped to warn about the post-covid syndrome more likely to occur in specific individuals.

Abstract Background: Metabolic syndrome (MetS) is a complex disorder characterized by insulin resistance (IR), central obesity, atherogenic dyslipidemia and higher glucose levels. It increases the risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM), imposing an economic burden on the healthcare system. However, the historical origins of MetS as well as the development and evolution of its definitions have not been conclusively documented in the literature. Aim: This study seeks to enhance the understanding of the developmental trends of MetS during the preceding two decades, placing particular emphasis on the definition, diagnosis and prevalence. Methods: An extensive search was performed from 1920 to 2023 across prominent scientific research engines, including Scopus, PubMed, MDPI, and others. Results: Despite advancements, many aspects of MetS remain inadequately understood. As the understanding of the nature and pathophysiology of MetS progresses, the development and refinement of its diagnostic criteria, and assessment and treatment guidelines will continue. Additionally, there exists significant variation in the global prevalence of metabolic syndrome, ranging from 14 to 39%. This prevalence is projected to increase due to the adoption of less healthy dietary patterns and sedentary lifestyles. The observed disparities in metabolic syndrome prevalence can be attributed to multiple factors, including demographic characteristics. Furthermore, the lack of a standardized definition across studies also contributes to the variation in reported prevalence rates. Conclusion: Further studies focusing on the standardization of the MetS definition across different research are crucial. The establishment of consistent criteria would enhance the reliability and validity of research findings, enabling more meaningful comparisons and interpretations.

Long COVID–19 syndrome is another vicious feature of COVID-19 infection, the mechanism remains unidentified. Several observational studies suggest that vaccinations might have protective and therapeutic effect on long COVID-19 and our study aimed to assess the influence of vaccination on COVID-19 patients. We performed an observational cohort study from October 2020 to July 2022, which included 503 patients (291 males and 212 females) with a median age of 65. They were hospitalized due to COVID-19 pneumonia and had persistent symptoms (after 1 month of COVID-19 infection. The clinical and demographic data including vaccination status collected during hospitalization and regular visits at the Community Healthcare Center dr. Adolf Drolc Maribor were analyzed. More non-vaccinated patients acquired long COVID-19 than vaccinated. Patients with type 2 diabetes suffered from long COVID-19 in a smaller percentage than patients without diabetes. Gender, inhalational therapy due to chronic pulmonary disease and the number of complications have significantly influenced long COVID-19 development and the mostly vaccinated patients were older and with asthma/COPD. Our study confirmed that vaccination is a safe and effective measure to prevent the severe progression of acute disease and to lower the incidence of developing long COVID.

Understanding the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that herpesviruses' infection of endothelial cells (ECs) may underlie ME/CFS symptomatology. We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment – symptoms consistent with ME/CFS and Long COVID. The paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation. We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within ECs of ME/CFS patients. This review offers a conceptual advance by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research towards potentially unexplored avenues in understanding and treating this complex syndrome.

Cirrhosis is a chronic disease with multiple etiologies, multiple manifestations, and multi-organ involvement. Affects about 200 million people worldwide. Its main complication is Portal hypertension (PHT). Cirrhotic cardiomyopathy is a consequence of PHT, with heart failure (HF) being the main manifestation. On the other hand, for people with cardiopathy due to other reasons beyond cirrhosis, the presence of the last could act as a trigger to acute HF. Finally, when HF and cirrhosis coexist, the renal system suffers the most, originating from type-5 cardio-renal syndrome, a complex entity with many challenges in diagnosis and treatment. This entity was recently defined and there is a lack of data on the epidemiology of this syndrome. A 77-year-old woman, with cardiovascular risk factors; heart failure with reduced ejection fraction (HFrEF), secondary ischemic and valvular cardiopathy, chronic Kidney disease (CKD), and stable decompensated cirrhosis, went to the emergency department after progressive abdominal perimeter augmentation, legs’ edema and hematochezia. It was assumed acute decompensated cirrhosis and acute decompensated chronic kidney disease, had triggered digestive bleeding and the patient stayed hospitalized. Intravenous diuretic therapy was started but, the ascites and kidney function got worse, the Nt pro-BNP grew until 1125000 pg/ml, and a transthoracic echocardiography showed important signs of congestion, isolated right ventricular dysfunction, with normal cardiac output. After teamwork’s discussion, a type-5 cardio-renal syndrome was assumed deciding not to act on tricuspid regurgitation due to the maladaptive RV remodeling. Hepatorenal syndrome treatment was begun (oral terlipressin and intravenous albumin), followed by decongestion therapy, resulting in a marked improvement in clinical presentation. The kidney, heart, and liver recovered to these basal states. With this clinical case, the authors want to show how multidisciplinary management is important to face tricuspid regurgitation and right ventricular dysfunction.

Serine peptidase CLPP is conserved among bacteria, chloroplasts, and mitochondria. In humans and mice, its loss causes Perrault syndrome with growth deficit, infertility, deafness, and ataxia. In the filamentous fungus Podospora anserina, CLPP-loss leads to longevity. CLPP substrates are selected by CLPX, an AAA+ unfoldase. CLPX is known to target delta-amino-levulinic-acid synthase (ALAS) to promote pyridoxal-phosphate (PLP) binding. CLPX may influence cofactor association with other enzymes. Here, the evaluation of P. anserina metabolomics highlighted arginine/histidine reduction. In Mus musculus cerebellum, reductions of Arginine/Histidine and Citrulline occurred with concomitant accumulation of heme-precursor protoporphyrin-IX. This suggests that increased biosynthesis of 5-carbon (C5) chain deltaALA consumes not only C4 succinyl-CoA with C1 glycine but also specific C5 delta amino-acids. As responsible enzymes for these converse effects, elevated abundance of CLPX and ALAS is paralleled by elevation of OAT (PLP-dependent, ornithine-delta-aminotransferase). Possibly as consequence of altered C1 metabolism, CLPP-null cells in P. anserina proteome profiles showed strong accumulation of a methyltransferase and two mitoribosomal large subunit factors. Reduced Histidine levels may explain previously observed metal interaction problems. As main nitrogen-storing metabolite, deficient Arginine would affect the urea cycle and polyamine synthesis. Supplementation of Arginine and Histidine might rescue growth deficits of CLPP-mutant patients.

Abstract: (1) Background: Post-COVID syndrome is defined as symptoms that occur simultane-ously with or after COVID-19 infection, last for 12 weeks, and are not due to another diagnosis. Limited data are available on people’s long-term quality of life (QoL) following COVID-19 infection. The aim of this cross-sectional study was to investigate long-term QoL after COVID-19 among employees of the St. Josef Hospital in Paderborn, Germany, and to identify risk factors. (2) Methods: A monocentric, cross-sectional study was conducted using the validated and digitized WHOQOL-BREF questionnaire via Netigate® between 10/2022 and 02/2023. Data on QoL and global health status were collected in the following four domains: physical health, mental health, social relationships, and environment. (3) Results: The response rate was 73.84% (923/1250). Furthermore, 63.45% of hospital staff respondents reported at least one persistent symptom after COVID-19 infection, leading to significant differences in QoL. Pre-existing conditions, persistent symptoms, and disability after COVID-19 infection, as well as high BMI, no partnership, and low educational level were found to significantly contribute to long-term low QoL. (4) Conclusions: Obesity, lack of partnership, and a low level of education were independent risk factors for lower QoL post-COVID-19 infection in this cohort of hospital staff. Further multicenter studies are re-quired to validate the incidence and their suitability as independent risk factors for post-COVID syndrome.

Vasculitis diseases include Kawasaki Disease (KD), Kawasaki Disease Shock Syndrome (KDSS), Multisystem Inflammatory Syndromes (MIS), Henoch-Schönlein purpura (HS) or IgA Vasculitis, and additional vasculitis diseases. These diseases are often preceded by infections or immunizations. Disease incidence rates are higher in children than adults. These diseases have been extensively studied, but understanding of the disease etiology remains to be established. Many studies have failed to demonstrate an association between these vasculitis diseases and vaccination. Here, the Vaccine Adverse Event Reporting System (VAERS) is used to demonstrate that, in certain rare cases, the number of cases of KD, MIS, and HS is higher than background following vaccination. These rare cases are predicted to occur in individuals with genetic risk factors who produce antibody titer levels above primary immune response level. Herein, the model of humoral immune response antibodies bound to antigens (pathogen or vaccine) creating immune complexes is proposed. These immune complexes are proposed to bind Fc receptors on immune cells and platelets resulting in cell activation and release of inflammatory molecules including histamine and serotonin. Immune complexes and inflammatory molecules including serotonin and histamine likely trigger vasculitis. Elevated serotonin and likely histamine drive initial vasoconstrictions disrupting blood flow. Increased blood flow pressure from cardiac capillary vasoconstrictions is predicted to trigger coronary artery aneurysms in some patients. For KDSS and MIS patients, these cardiac capillary vasoconstrictions are predicted to result in ischemia followed by ventricular dysfunction. Ongoing ischemia can result in long-term cardiac damage. Cases associated with pathogens are likely to have persistent infections triggering disease onset.

Current research suggests that polycystic ovary syndrome (PCOS) might originate in utero and implicates the placenta in its pathogenesis. Kisspeptin (KISS1) and neurokinin B (NKB) are produced by the placenta in high amounts, and they have been implicated in several pregnancy complications associated with placental dysfunction. However, their placental expression has not been studied in PCOS. We isolated mRNA after delivery from the placentae of 31 PCOS and 37 control women with term, uncomplicated, singleton pregnancies. The expression of KISS1, NKB, and neurokinin receptors 1, 2, and 3 was analyzed with real-time polymerase chain reaction, using β-actin as the reference gene. Maternal serum and umbilical cord levels of total testosterone, sex hormone binding globulin (SHBG), free androgen index (FAI), androstenedione, dehydroepiandrosterone sulfate (DHEAS), Anti-Mullerian hormone (AMH), and estradiol were also assessed. NKB placental mRNA expression was higher in PCOS versus controls in pregnancies with female offspring. NKB expression depended on fetal gender, being higher in pregnancies with male fetuses. NKB was positively correlated with umbilical cord FAI and AMH, and KISS1 with cord testosterone and FAI; there was also a strong positive correlation between NKB and KISS1 expression. Women with PCOS had higher serum AMH and FAI and lower SHBG than controls. Our findings indicate that NKB might be involved in PCOS-related placental dysfunction, and warrant further investigation. Studies assessing the placental expression of NKB should take fetal gender into consideration.

It is currently believed that the cause of superior mesenteric artery syndrome (SMAS) is compression of the duodenum in the angle between the aorta and superior mesenteric artery (SMA). It is recognized that a decrease in aortomesenteric angle (AMA) <25° and intervascular distance < 8 mm, caused by fat loss, is characteristic of SMAS. Based on these statements, surgeons operate on patients with symptoms of dyspepsia only based on a reduction of AMA. This study is devoted to the analysis of the literature, including four own studies on this issue. Results: Measurement of the length of the constriction in the third part of the duodenum on radiograms from available sources showed that its true length ranged from 2.5 to 4.2 (3.30±0.15) cm and began a few centimeters cranial to the AMA. Therefore, it could not have been caused by compression in the AMA. In terms of length (3.20±0.15 cm) and location, this constriction corresponded to Ochsner’s sphincter, which normally short-term contracts to prevent the penetration of an acid bolus into the jejunum. Conscientious studies have shown that AMA is proportional to BMI, i.e., a decrease in AMA is observed in all thin people. An analysis of 211 cases of SMAS made it possible to differentiate two types of diseases. In 101 patients, the disease occurred acutely 1–53 (8.2 ± 1.9) days after stressful situations, accompanied by a catabolic reaction and hypersecretion of hydrochloric acid. In 110 patients, SMAS developed 3-72 (17.2±3.2) months after the diagnosis of acid-dependent diseases. Conclusion: The analysis of the literature led to the conclusion that hypersecretion of hydrochloric acid causes damage to the upper level of the digestive system, including duodenal dyskinesia. One of the manifestations of duodenal dyskinesia is an increase in tone and hypertrophy of the Ochsner’s sphincter. The clinic of the disease depends on the varying degree of Ochsner’s sphincter dyskinesia. In severe cases, partial or complete intestinal obstruction. New ideas about the etiology and pathogenesis of the so-called SMAS have made it possible to propose a tactic for the diagnosis and treatment of Ochsner’s sphincter dyskinesia, where there is no place for surgical treatment.

Antiphospholipid antibody syndrome (APS) is an autoimmune disorder characterised by thrombosis and the presence of antiphospholipid antibodies (aPL): lupus anticoagulant and/or IgG/IgM anti-β2-glycoprotein I and anticardiolipin antibodies. APS carries significant morbidity for a relatively young patient population from recurrent thrombosis in any vascular bed (arterial, venous or microvascular), often despite current standard of care, which is anticoagulation with vitamin K antagonists (VKA). Platelets have established roles in thrombosis at any site, and platelet hyperreactivity is clearly demonstrated in the pathophysiology of APS. Together with excess thrombin generation, platelet activation and aggregation are the common end result of all the pathophysiological pathways leading to thrombosis in APS. However, antiplatelet therapies play little role in APS, reserved as a possible option of low dose aspirin in addition to VKA in arterial or refractory thrombosis. This review outlines the current evidence and mechanisms for excessive platelet activation in APS, how it plays a central role in APS-related thrombosis, what evidence for antiplatelets is available in clinical outcomes studies and potential future avenues to define how to target platelet hyperreactivity better with minimal impact on haemostasis.

Hepatic vein outflow obstruction causes congestion of the liver, leading to necrosis, fibrosis, and portal hypertension (PH). Transjugular intrahepatic portosystemic shunt (TIPS) reduces congestion and PH by providing artificial outflow. The aim of the study was to investigate fibrosis progression in patients with Budd-Chiari syndrome (BCS) and TIPS using transient elastography (TE). From 2010 to 2022, 25 patients received 80 TEs using FibroScan® (3.2±2.1 per patient). TIPS function was assessed using Doppler ultrasound or radiological intervention. At the time of TE examination, 21 patients had patent shunts. Four patients had occluded shunts but normal pressure gradients during the intervention. The first TE measurement performed 9.8±6.8 years after the BCS diagnosis showed stiffness values of 24.6±11.5 kPa. A second or last measurement performed 7.0±2.9 years after the first measurement showed similar stiffness values of 24.1±15.7 kPa (p=0.943). Except for three patients, the liver stiffness was always >12 kPa, indicating advanced fibrosis. Stiffness values obtained <5 years (n=8, 23,8±9,2 kPa) or >5 years after the BCS diagnosis (24,9±12,7 kPa) did not differ (p=0.907). In addition, stiffness was not related to the interval between BCS and TIPS implantation (p=0.999). One patient received liver transplantation, and two patients died from non-hepatic causes. Most patients develop mild to moderate cirrhosis, possibly during the early phase of the disease. Timing of TIPS did not influence fibrosis progression. This and the release of portal hypertension may argue in favor of a generous TIPS implantation practice in patients with BCS.

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder. Diagnosis can take a long time, especially in the presence of confounding factors, and it is, at least in part, of exclusion. AOSD is generally mild, however a small percentage of patients can develop a fearsome as well potentially fatal complication, the macrophage activation syndrome (MAS), which is also referred to as hemophagocytic lymphohistocytosis (HLH). This condition is correlated with a cytokine storm production and monocyte/macrophage overactivation, and typically occurs with rash, pyrexia, pancytopenia, hepatosplenomegaly and systemic involvement. Exitus occurs in approximately 10% of cases. The Histiocyte Society, which is a nonprofit organization committed to improving the lives of patients with histiocytic disorders, currently suggests etoposide in combination with dexamethasone for the treatment of HLH/MAS, although a multidisciplinary collaboration using the resources and expertise of several specialists (e.g. rheumatologist, infectiologist, critical care medicine specialist) is always recommended. Hereby we propose the detailed description of the clinical case of a previously healthy young woman in which MAS was the dramatic onset manifestation of AOSD and whose diagnosis posed a real clinical challenge.

Neuromyelitis optica spectrum disorder (NMOSD), previously known as Devic disease or neuromyelitis optica (NMO), represents inflammatory conditions affecting the central nervous system. These disorders are characterized by severe immune-mediated demyelination and axonal damage, with a predilection for targeting optic nerves and the spinal cord. Key clinical features of NMOSD encompass acute episodes of bilateral or rapid sequential optic neuritis and transverse myelitis, typically exhibiting a relapsing course. These attacks endure for several days, and recovery varies, spanning from weeks to months. In this report, we present the case of a 35-year-old individual who initially complained of urinary retention, followed by decreasing vision in the left eye and subsequently in the right eye. These visual symptoms were succeeded by weakness in the right upper and lower limbs.

This narrative review delves into the evolving landscape of fertility preservation techniques with a particular focus on their use in patients undergoing oncology treatment that carries a risk of ovarian insufficiency. Advances in established methods such as cryopreservation of oocytes and embryos are highlighted and the increasing use of gonadotropin-releasing hormone (GnRH) agonists is discussed. The review also addresses the complexities and controversies associated with these approaches, such as the 'flare-up' effect associated with GnRH agonists and the potential of GnRH antagonists to reduce the risk of ovarian hyperstimulation syndrome. Despite advances in fertility preservation, the report highlights the challenges we face, including the need for personalized treatment protocols and management of associated risks. It calls for continued research and collaboration between healthcare professionals to refine these techniques and ultimately improve reproductive outcomes for patients facing the prospect of fertility-impairing treatment.

A monolayer of endothelial cells (ECs) lines the lumen of blood vessels and as such provides a semi-selective barrier between the blood and the interstitial space. Compromise of the lung EC barrier due to inflammatory or toxic events may results in pulmonary edema, which is a cardinal feature of acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS). The EC functions are controlled, at least in part, via epigenetic mechanisms mediated by histone deacetylases (HDACs). Zinc-dependent HDACs represent the largest group of HDACs and are activated by Zn2+. Members of this HDAC group are involved in the epigenetic regulation primarily via modifying the structure of chromatin upon removal of acetyl groups from histones. In addition, they can deacetylate many non-histone histone proteins, including those located in extra nuclear compartments. Recently, the therapeutic potential of inhibiting zinc-dependent HDACs for EC barrier preservation has gained momentum. However, the role of specific HDAC subtypes in EC barrier regulation remains largely unknown. This review aims to provide an update on the role of zinc-dependent HDACs in endothelial dysfunction and its related diseases. We will broadly focus on biological contributions, signaling pathways and transcriptional roles of HDACs in endothelial pathobiology associated mainly with lung diseases and we will discuss the potential of their inhibitors for lung injury prevention.

COVID-19 was an inflammatory pneumonia caused by a respiratory infection with a coronavirus named SARS-CoV-2. Severely ill COVID-19 patients could die of acute pulmonary and systemic inflammation. Thus, there was a theory that long COVID-19 shared many similarities with systemic autoimmune diseases. There was also a theory that the SARS-CoV-2 virus could infect many cell- and tissue-types distributed throughout multiple organ systems of the body. I aim to review the above theories using unbiased high-throughput datasets cataloguing gene expression. Studies reviewed used the technology of next generation sequencing, either as bulk tissue RNA sequencing, or as single-cell RNAs sequencing; ingenious methods for signal deconvolution were then used to identify individual cell types. Datasets reviewed suggested that severe COVID-19 induced expression of genes associated with pro-inflammatory signaling, tissue development or remodeling, scarring, or cell death. The datasets also provided evidence for several inflammatory syndromes associated with COVID-19, such as neuronal COVID, acute respiratory disease syndrome, vascular inflammation, or multisystem inflammatory syndrome. Indeed, inflammatory signal during severe COVID-19 was reported in many cell types, for example in structural cells, in infiltrating immune cells, in the vascular system, or in circulating cells in the blood. There was also frequently a change in proportions of immune cell-types in the blood, epithelial cells in the lungs, or among infiltrating immune cells.

Polycystic Ovary Syndrome (PCOS) is a highly prevalent endocrine-metabolic disorder in women of reproductive age. Diagnosis of this syndrome relies on criteria established by the Rotterdam Consensus, with PCOS phenotypes being crucial for distinguishing potential complications, treatment approaches, and timing. The aim of this study is to characterize the biodemographic, clinical, metabolic, and reproductive variables and their association with PCOS phenotypes in a population from the Ecuadorian Andes. Methodology: A cross-sectional study was conducted with a non-random consecutive sample of 92 women attending the gynecology and endocrinology outpatient clinic at the Technical University of Loja Hospital (UTPL)-Santa Inés, Loja, Ecuador, between January 2022 and July 2023.Results: The average age was 22±3.4 years, predominantly mestizo, urban, single, with higher education and a medium-high socioeconomic status. Oligo-amenorrhea and acne appear strongly associated with phenotypes A and B, while hirsutism and polycystic ovaries on ultrasound show a weaker association with these phenotypes. Alopecia is more prevalent in phenotypes C and D. Triglyceride levels and BMI have a strong association with phenotypes A and B. Total testosterone levels, 17 OH progesterone, LH, and free androgen index show a moderate association with phenotypes A and B, while other reproductive variables exhibit weak associations. Conclusions: Classical phenotypes A and B of PCOS are most common in Andean Ecuadorian women, carrying higher risks of insulin resistance, anovulation, metabolic disorders, and elevated triglycerides compared to phenotypes C and D. Ethnic diversity and sociocultural habits influence the prevalence and clinical manifestations of phenotypes.

Background: Quality of life (QoL) in IC/BPS patients is an evidence gap in guidelines, because studies are limited and outdated. Therefore, guidelines might not reflect the current situation accurately, and no possible improvements in QoL of these patients. Secondly, guidelines suggest multimodal approach in therapy, however unknown is how the efficacy of these therapies are perceived by the patient themselves. The aim of this study is to investigate the perception of IC/BPS patients on their QoL and to determine which treatments they received and how they evaluate the efficacy of these various (alternative) therapies.Methods: Quantitative retrospective database study in IC/BPS patients, compiled of existing patient survey data (n=217) from July 2021. Results: The QoL of patients is affected significantly by IC/BPS. This is evident from the substantial self-reported impact by patients, the various affected domains on EQ-5D 5L. The QoL was not negatively affected by delayed diagnosis, but there were differences between female and males. Secondly, there was the wide array of (alternative) treatments utilized, although some have doubtful results and high dropout rates. Conclusion: QoL is considerably impaired in IC/BPS patients. Coagulation therapy and intravesical GAG therapy were most appreciated treatments. The diverse responses and adherence to various treatments warrant a personalized approach (phenotype-oriented therapy). To achieve improvement in the QoL, it is important to incorporate the patient’s perspective in treatment guidelines.

Richard Peto’s Paradox, first described in 1975 from an epidemiological perspective, established an inverse correlation between the probability of developing cancer in multicellular organisms and the number of cells. Larger animals exhibit fewer tumors compared to smaller ones, though exceptions exist. Mice are more susceptible to cancer than humans, while elephants and whales demonstrate significantly lower cancer prevalence rates than humans. How nature and evolution have addressed the issue of cancer in the animal kingdom remains largely unexplored. In the field of medicine, much attention has been devoted to cancer predisposing genes, as they offer avenues for intervention, including blocking, downregulating, early diagnosis, and targeted treatment. Predisposing genes also tend to manifest clinically earlier and more aggressively, making them easier to identify. However, despite significant strides in modern medicine, the role of protective genes lags behind. Identifying genes with a mild predisposing effect poses a significant challenge. Consequently, comprehending the protective function conferred by genes becomes even more elusive, and their very existence is subject to questioning. While the role of variable expressivity and penetrance defects of the same variant in a family is well-documented for many hereditary cancer syndromes, attempts to delineate the function of protective/modifier alleles have been restricted to a few instances. In this review, we endeavor to elucidate the role of protective genes observed in the animal kingdom and within certain genetic syndromes that appear to act as cancer-resistant/repressor alleles. The ultimate goal is to discern why individuals, like Winston Churchill, managed to live up to 91 years of age, despite engaging in minimal physical activity, consuming large quantities of alcohol daily, and not abstaining from smoking.

Both scleroderma and immunoglobulin G4-related disease (IgG4-RD) are systemic fibro-inflammatory diseases characterised by lymphoplasmacytic infiltrates. IgG4-RD and systemic Sclerosis (SSc) may share common pathophysiological mechanisms, but no examples of co-occurrence of the diseases have been found. Autologous haematopoietic stem cell transplantation (AHSCT) is implemented in selected rapidly progressive SSc with high risk of organ failure. However, existing guidelines are based on clinical trials that do not represent the entire patient population and exclude critically ill patients with no therapeutic alternatives. Examples of AHSCT in IgG4-RD are absent. We report the case of AHSCT in a female patient with overlapping progressive diffuse SSc and sinonasal IgG4-RD. Despite immunosuppressive therapy, IgG4-RD developed and clinically manifested shortly before AHSCT. Lacking therapeutic alternatives, after 11 years of SSc therapy, the 44-year-old successfully underwent AHSCT. The 63-month follow-up showed regression of symptoms. Only after surgical treatment (bilateral ethmoidectomy, sphenoidotomy, intranasal buccal antrostomy) the initially progressive clinical course of IgG4-RD remained indolent.

Different nutraceuticals are often considered by parents of infants and children with abdominal pain and disorders of the gut-brain interaction. Herb extracts and natural compounds have long been used in traditional medicine, but clinical pediatric trials are very limited. This narrative review based on relevant studies identified through Pubmed-Medline literature search updated to October 2023, focused on the effect of nutraceuticals in infantile colic, functional abdominal pain and irritable bowel syndrome in children and adolescents. Significant reduction of colic episodes and crying time was reported in two studies on fennel (seeds oil or tea), in three studies on different multiple herbal extracts (all including fennel), in one study on Mentha piperita, and in at least two double-blind randomized controlled studies on Lactobacillus reuteri DSM 17938 and Bifidobacterium lactis BB-12 (108 CFU/day for at least 21 days) in breast-fed infants. Compared to placebo, in children with functional abdominal pain or irritable bowel syndrome a significant reduction of pain was reported in two studies supplementing peppermint oil capsules or psyllium fibers, in one study on corn fiber cookies or partial hydrolysed guar gum or a specific multiple herbal extract (STW-5) or vitamin D supplementation. To date, there is a moderate certainty of evidence with a weak grade of recommendation for Lactobacillus reuteri DSM 17938 (108 CFU/day) for reducing pain intensity in children with functional abdominal pain and for Lactobacillus rhamnosus GG (1-3 x109 CFU twice daily) for reducing pain frequency and intensity in children with IBS. Further large and well-designed pediatric studies are needed to prove efficacy and safety of different herbal extracts and prolonged use of studied products in infants and children with pain disorders of the gut-brain interaction.

A number of epidemiological studies have implicated elevated iron levels with higher risks of cardiometabolic diseases, including the metabolic syndrome (MetS). MetS is a pathologic clustering of metabolic derangements characterized by central obesity, insulin resistance, hypertension, and dyslipidemia, which can all lead to increased cardiovascular disease morbidity and mortality. However, it remains unclear whether a causal association exists between higher iron status and MetS and its associated risk components. Using the data from the Taiwan Biobank (TWB) (19,012 males; 42,340 females) and of the European Whites from the UK Biobank (UKB) (128,549 males; 142,817 females), we first constructed ethnic- and sex-specific hemoglobin-polygenic risk scores (Hb-PRS) as instrumental variable (IV) for iron status with the Hb-associated SNPs we previously identified from genome-wide association studies (GWAS). We then conducted Mendelian randomization (MR) analyses to elucidate the causal role of elevated iron (either Hb-PRS quintiles or continuous Hb-PRS) on various metabolic components. MR-Egger regressions determined the potential pleiotropic effects of the constructed Hb-PRSs, while the causal relationship of Hb-PRS with anemia served as a control in the analyses. The mean Hb concentration range corresponding to the Hb-PRS quintiles is relatively narrow in both UKB (14.91-15.21 g/dL for males and 13.39-13.71 g/dL for females) and TWB (14.79-15.28 g/dL for males and 12.78-13.21 g/dL for females). In these windows of Hb-PRSs, we found differential associations of Hb-PRS with diabetes (T2D) or hyperglycemia (HGY) as compared to other MetS components. The highest quintiles of Hb-PRSs were causally associated with greater risks of hypertension (HTN) and hypertriglyceridemia (DLP) (i.e., [Taiwanese HC males: Q5 vs. Q1 ORHTN = 1.10 (1.00–1.21), p = 0.0473, Q4 vs. Q1 ORDLP = 1.10 (1.00–1.22), p = 0.0485; European White males: ORHTN = 1.05 (1.01–1.09), p = 0.0194, ORDLP = 1.04 (1.00–1.08), p = 0.0468]). Interestingly, we obtained a consistent negative causal association between increasing Hb-PRS quintiles and T2D or HGY risk across all sex subgroups (i.e., [Taiwanese HC females: ORHGY = 0.89 (0.84–0.95), 0.88 (0.83–0.94), 0.87 (0.82–0.93), 0.86 (0.81–0.92) from Q2 to Q5; European White females: ORHGY = 0.92 (0.87–0.98), 0.91 (0.86–0.97), 0.93 (0.87–0.98), 0.87 (0.82–0.93) from Q2 to Q5; all p &lt; 0.05]. The positive causal relationships between Hb-PRSs and diastolic blood pressure (DBP) and triglycerides (TG) but inverse causal association with glucose (GLU) and glycated hemoglobin (HbA1c) further corroborated such findings. There is, however, a lack of causal association with central obesity (CO), while a U-shaped type of causality was observed for gout (GT) or hyperuricemia (HUA). Sensitivity analyses, which excluded subjects based on self-reports of health conditions or medications and hospital episode statistics data, revealed similar results. Our MR studies confirm a modest causal relationship between propensity of elevated iron status and increased risk of HTN and DLP. We have further observed that modestly lower iron levels causally contribute to the development of T2D. Further validation and elucidation of the underlying biological mechanisms are highly warranted.

In the contest of childhood epilepsies, the concept of continuous spike-waves during slow sleep (CSWS) includes several childhood-onset heterogeneous conditions, sharing an electroencephalogram (EEG) characterized by a high frequency of paroxysmal abnormalities during sleep which are attributed negative effects on the cognitive development and behavior of the child. These negative effects may have the characteristics of a clear regression or of a slowdown in development. Seizures are very often present, but not constantly. The above makes it clear why CSWS have been included in epileptic encephalopathies, in which by definition the frequent EEG paroxysmal abnormalities have an unfavorable impact on the cognitive functions, including socio-communicative skills causing autistic features, even regardless of the presence of clinically overt seizures. Although several decades have passed since the original descriptions of the electroclinical condition of CSWS, there are still many areas that are little known and deserve to be further studied, including the EEG diagnostic criteria, the most effective electrophysiological parameter for monitoring the evolution, the role of the thalamus in the CSWS pathogenesis, the long-term evolution, the nosographic location of Landau-Kleffner syndrome, the standardized neuropsychological and behavioral assessment, the pharmacological and non-pharmacological therapies.

Introduction: On March 11, 2020, the World Health Organization (WHO) declared Coronavirus disease 2019 (COVID-19) as a pandemic. The spread of the Delta variant of coronavirus started in June 2021 and accounted for the fifth peak of COVID-19 in Iran in July 2021. According to reports from other countries, vaccination protects against severe diseases caused by COVID-19, including the Delta variant. Studies have also shown that vaccination provides strong protection against SARS-CoV-2 infection, COVID-19-related hospitalization, and mortality. This retrospective cohort study was designed based on the medical care monitoring center (MCMC) database of Sayyad Shirazi Hospital.Methods: The following patient data were extracted for this study: demographic characteristics, signs and symptoms, ICU admission, need for aggressive oxygen therapy, including intubation, mortality, and vaccination status. Results: Being vaccinated was associated with a 4.14-fold increase in survival (adjusted OR=4.14; 95% CI: 2.22 to 7.69; P<0.01), and individuals in a younger age group demonstrated a 5.58-fold higher likelihood of surviving (adjusted OR=5.58; 95% CI: 4.25 to 8.14; P<0.01). The risk of severe COVID-19 was significantly lower in vaccinated individuals, showing a 3.12-fold decrease in risk (adjusted OR=3.12; 95% CI: 2.06 to 4.72; P<0.01), and in younger age groups, the risk exhibited a 3.28-fold decrease (adjusted OR=3.28; 95% CI: 2.66 to 4.04; P<0.01).Conclusion: The present results suggest that receiving at least one dose of COVID-19 vaccine had a significant relationship with decreased COVID-19 severity and mortality in vaccinated patients compared to unvaccinated patients.

Brown-Séquard Syndrome (BSS) is a rare spinal cord injury characterized by asymmetrical motor and sensory dysfunction. Trauma to the spinal cord, particularly the hemi section, is the primary cause. Diagnosis involves a thorough medical history, physical examination, and imaging studies. Treatment focuses on stabilization, rehabilitation, and potential emerging therapies. This article provides a comprehensive overview of BSS, including its causes, symptoms, diagnosis, and treatment.

Electrical storm (ES) is defined as the presence of at least three episodes of sustained ventricular tachycardia or ventricular fibrillation within 24 hours. This patient had a previously known arterial hypertension, type II diabetes mellitus, and chronic kidney disease and has presented to the Emergency Department (ED) with symptoms of retrosternal chest pain lasting for several hours prior. The initial 12-lead electrocardiogram revealed ST segment elevation in the anterior leads (V1-V6). Emergent coronary angiography revealed an acute occlusion of the proximal left anterior descending artery (pLAD) and percutaneous coronary intervention was performed with successful implantation of one drug-eluting stent in the pLAD. On the day 8 of hospitalization, patient developed a refractory ES for which he received 50 DC shocks and did not respond to multiple lines of antiarrhythmic medications. Due to a failure of medical therapy, we decided to implant a temporary pacemaker and initiate ventricular overdrive pacing (VOP) that was successful in terminating ES. Following electrical stabilization, the patient underwent a successful ICD implantation. This case demonstrates that VOP can contribute to hemodynamic and electrical stabilization of a patient that suffers from refractory ES and this treatment modality might serve as a temporary bridge to ICD implantation.