Spina bifida and cardiorespiratory profile: the impact of leisure sport activities on physical fitness.

PURPOSE: The aim of the present study is to evaluate a population of young patients affected by Spina Bifida (SB) to describe their cardiorespiratory function and bone mineral density profile, analyzing any differences between people performing and those who do not perform sports activity. The study also aimed to rule out possible congenital heart disease associated with spina bifida, considering the common origin of certain cardiac structures with those found to be altered in SB patients. METHODS: Thirty-four young patients, aged between 12 and 22 years, diagnosed with spinal dysraphism (SD), have been clinically described and, in order to evaluate their physical fitness, functional capacity and bone mass, almost all of them underwent a complete cardiorespiratory assessment, including electrocardiogram (ECG), echocardiogram, Cardiopulmonary Exercise Test (CPET), body composition analysis using bioimpedance analysis (BIA) and Dual Energy X-ray Absorptiometry (DEXA), as well as the estimation of bone mineral density (BMD) with Computerized Bone Mineralometry (CBM). RESULTS: Collected data demonstrated that only 35% of the subjects practiced physical activity during the week. BMI and percentage FM values were pathological in at least 50% of the population. On cardiological investigations (ECG and echocardiogram), no significant alterations were found. In all patients who performed CPET (79.4%), pathological values of the main functional capacity parameters were revealed, especially peak oxygen consumption (VO2 peak), even when corrected for BCM or FFM estimated at BIA and DEXA, respectively. In the CBM analysis, out of 27 patients in whom the femoral T-score was evaluated, a condition of osteopenia was revealed in 40.7% of the patients (11/27) and osteoporosis in 18.5% (5/27); out of 27 patients in whom the lumbar T-score was evaluated, 37% of the patients showed osteopenia (10/27) and 29.6% osteoporosis (8/27). When the comparison between exercising and non-exercising patients was performed, the only statistically significant difference that emerged was the median lumbar T-score value, which appeared lower in the group not performing physical activity (p = 0,009). CONCLUSIONS: The extensive cardiorespiratory evaluation, including CPET, of our cohort of spina bifida patients showed altered values of the main parameters related to cardiorespiratory fitness and is the only study in the literature that analysed bone mineralization values in physically active and sedentary spina bifida patients and demonstrated a statistically significant difference. Furthermore, it is the only study to date that investigated the possible association of congenital heart diseases with SD, without demonstrating the existence of pathological conditions.

A dynamic power prior approach to non-inferiority trials for normal means.

Non-inferiority trials compare new experimental therapies to standard ones (active control). In these experiments, historical information on the control treatment is often available. This makes Bayesian methodology appealing since it allows a natural way to exploit information from past studies. In the present paper, we suggest the use of previous data for constructing the prior distribution of the control effect parameter. Specifically, we consider a dynamic power prior that possibly allows to discount the level of borrowing in the presence of heterogeneity between past and current control data. The discount parameter of the prior is based on the Hellinger distance between the posterior distributions of the control parameter based, respectively, on historical and current data. We develop the methodology for comparing normal means and we handle the unknown variance assumption using MCMC. We also provide a simulation study to analyze the proposed test in terms of frequentist size and power, as it is usually requested by regulatory agencies. Finally, we investigate comparisons with some existing methods and we illustrate an application to a real case study.

Pathogenesis of rheumatoid arthritis: one year in review 2023.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by local and systemic inflammation. The complex interplay between immune cells and soluble mediators leads to the induction and perpetuation of aberrant inflammatory and autoimmune responses. The research carried out in the last year in the field of RA enabled the identification of new mechanisms involved in the pathogenesis of the disease and therefore unmasked new potential therapeutic targets. In this review article we summarised the new insights into RA pathogenesis from original research articles published in the last year.

Monocyte-to-lymphocyte, neutrophil-to-lymphocyte and neutrophil-to-monocyte plus lymphocyte ratios in children with active tuberculosis: A multicentre study.

AIM: Higher number of monocytes and neutrophils may correlate with active tuberculosis (TB) in children. However, the few paediatric studies available are limited by the small numbers of children with TB disease or infection included. METHODS: We calculated the monocyte-to-lymphocyte-ratio (MLR), neutrophil-to-lymphocyte-ratio (NLR) and neutrophil-to-monocyte-plus-lymphocyte-ratio (NMLR) in children with active TB, latent TB infection (LTBI), other infectious and non-infectious conditions and healthy children evaluated in two referral centres in Rome. RESULTS: Overall, 649 children were included (41.8% females, mean age of 5.74 years). MLR, NLR and NMLR values were always significantly higher in patients with TB compared with the other groups (p < 0.001). Considering the entire population with the outcome of TB diagnosis, NMLR, with a cut-off of 1.2, had a sensitivity of 63% and a specificity of 76% (AUC: 0.71 [0.64-0.78]); NLR, with a cut-off of 1.5, had a sensitivity of 61% and a specificity of 79% (AUC: 0.72 [0.65-0.79]); MLR, considering a cut-off of 0.2, was less sensitive (56%) but more specific (82%) with a similar AUC (0.72 [0.65-0.79]). CONCLUSION: Our study provides further evidence that MLR, NLR and NMLR can serve as first level diagnostics to support the clinical suspicion of TB in children.

Profiling the Urobiota in a Pediatric Population with Neurogenic Bladder Secondary to Spinal Dysraphism.

The human bladder has been long thought to be sterile until that, only in the last decade, advances in molecular biology have shown that the human urinary tract is populated with microorganisms. The relationship between the urobiota and the development of urinary tract disorders is now of great interest. Patients with spina bifida (SB) can be born with (or develop over time) neurological deficits due to damaged nerves that originate in the lower part of the spinal cord, including the neurogenic bladder. This condition represents a predisposing factor for urinary tract infections so that the most frequently used approach to treat patients with neurogenic bladder is based on clean intermittent catheterization (CIC). In this study, we analyzed the urobiota composition in a pediatric cohort of patients with SB compared to healthy controls, as well as the urobiota characteristics based on whether patients received CIC or not.

Pathogenesis of rheumatoid arthritis: one year in review 2022.

The mechanisms underlying the pathogenesis of rheumatoid arthritis (RA) involve different components of the immune system. In subjects with genetic predisposition to develop RA, a tight interaction between cells and mediators of the innate and adaptive immune system leads to the amplification and perpetuation of inflammation and tissue remodelling. The research carried out in the last year in the field of RA has improved the current knowledge on the pathogenesis of the disease, and is potentially useful to develop new therapeutic approaches. Thus, in this review we provide an overview on the new insights into RA pathogenesis, resulting from a literature search of the data published in the last year.

Pulmonary artery sling in a 22-month-old boy with 18q deletion syndrome: A rare but possible association.

The 18q deletion syndrome is a rare genetic condition characterized by a large variability in clinical phenotype and severity. Congenital heart diseases have been described by several previous reports, most commonly including pulmonary valve anomalies and septal defects. We describe a new case of a 22-month-old boy affected by 18q del syndrome found to have a symptomatic pulmonary artery sling. This study reports a new case of pulmonary artery sling associated with 18q del syndrome, providing an alert for pediatric cardiologists about less common cardiovascular anomalies, which can easily be missed, allowing for early diagnosis and appropriate care.

The impact of constant antibiotic prophylaxis in children affected by spinal dysraphism performing clean intermittent catheterization: a 2-year monocentric retrospective analysis.

INTRODUCTION: Spinal dysraphism (SD) is a general term used to refer to developmental abnormalities of the spine that involves many clinical conditions including myelomeningocele (MMC). In these patients, neurogenic bladder (NB) is a common and predisposing factor for renal damage; the most frequently used approach to manage this situation is based on clean intermittent catheterization (CIC) and anticholinergic drugs. Urinary tract infections (UTIs) are a significant concern for these patients, and antibiotic prophylaxis is frequently used even if it is still a debated topic of literature. The purpose of this paper is to investigate the role and the real effectiveness of antibiotic prophylaxis in the reduction of incidence of UTIs in patients with spina bifida performing CIC. METHODS: We collected data of all patients performing CIC, who did their last follow-up visit in the period between January 2019 and January 2021, followed at the children multidisciplinary Spina Bifida Center of A. Gemelli Hospital in Rome. Data collected included age at referral, gender, type of SD lesion, serum creatinine and cystatin C levels, the use of anticholinergic medications, antibiotic prophylaxis and type of prophylaxis (oral/endovesical), age of starting prophylaxis with its duration/adherence, number of CIC/day and its duration, episodes of UTIs in the 2 years prior to the last follow-up, and presence and grade of vesical-ureteric reflux (VUR) on cystourethrogram. RESULTS: A total of 121 patients with SD performing CIC was included in the study; 66 (54%) presented ≥ 1 episode of UTIs in the last two years and 55 (46%) none. During the study period, 85 (70%) patients received antibiotic prophylaxis (ABP group) and 36 (30%) did not (NABP group): no statistically significative difference in terms of UTI development was observed between the two groups (p = 0.17). We also evaluated compliance to the therapy; 71 patients (59%) took antibiotic prophylaxis constantly (CABP group) and 50 (41%) did not do antibiotic prophylaxis constantly or did not do antibiotic prophylaxis at all (NCABP group): we observed a statistically significative difference in terms of UTIs with a 2.2 times higher risk of development at least one episode of UTIs in NCABP group. CONCLUSION: In conclusion, antibiotic prophylaxis performed constantly, without interruption, is associated with a lower risk of developing urinary tract infections and consequently to develop renal failure in adulthood.

Adherence to the Mediterranean diet and the impact on clinical features in primary Sjögren's syndrome.

OBJECTIVES: The relationship between dietary patterns, including the Mediterranean diet, and rheumatic and musculoskeletal diseases (RMDs) has been increasingly assessed but data on patients with established primary Sjögren's syndrome (pSS) is lacking. The aim of the study was to explore the adherence to the Mediterranean diet and its relationship with metabolic and inflammatory features in a cohort of patients with pSS. METHODS: Demographic, clinical and serological data, including anthropometric parameters and cardiovascular (CV) disease risk factors/events among others were collected from 91 pSS patients. Adherence to the Mediterranean diet over the previous 12 months was assessed with the 14-item PREvencion con DIeta MEDiterranea (PREDIMED) tool and the 28-item Mediterranean Lifestyle (MEDLIFE) index. RESULTS: According to the PREDIMED score 29 (31%) patients had a good adherence to the Mediterranean Diet, 57 (61%) a medium adherence and only 7 (8%) a poor adherence. No difference could be identified across groups with regard to demographic data, disease activity, CV risk factors or other parameters. With regard to the MEDLIFE, the total of blocks 1 and 2, that are related to Mediterranean foods and dietary habits, did not correlate with the total of block 3 (related to other healthy habits such as physical activity), meaning that the patients adhering the most to the Mediterranean Diet not necessarily had an overall healthy lifestyle. The PREDIMED score was inversely correlated with disease activity, as measured by ESSDAI (Spearman's rho=-0.27, p=0.009) and ClinESSDAI (Spearman's rho=-0.26, p=0.01). Fish consumption was associated with lower prevalence of hypertension. CONCLUSIONS: Adherence to the Mediterranean diet, with particular attention to fish consumption, may be beneficial on various domains in pSS, such as the CV system and the inflammatory environment, and as such should be recommended to patients with this disease.

Metformin Induces Apoptosis and Alters Cellular Responses to Oxidative Stress in Ht29 Colon Cancer Cells: Preliminary Findings.

Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anti-cancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared to the untreated group with a follow-up of 1 month. In our study, HT29 cells were treated with graded concentrations of metformin, 10 mM/25 mM/50 mM for 24/48 h. We performed immunofluorescence experiments by means of confocal microscopy and western blot analysis to evaluate a panel of factors involved in apoptotic/autophagic processes and oxidative stress response. Moreover, HT29 cells treated with metformin were analyzed by a flow cytometry assay to detect the cell apoptotic rate. The results demonstrate that metformin exerts growth inhibitory effects on cultured HT29 cells by increasing both apoptosis and autophagy; moreover, it affects the survival of cultured cells inhibiting the transcriptional activation of Nuclear factor E2-related factor 2 (NRF-2) and nuclear factor-kappa B (NF-κB). The effects of metformin on HT29 cells were dose- and time-dependent. These results are very intriguing since metformin is emerging as a multi-faceted drug: It has a good safety profile and is associated with low cost and might be a promising candidate for the prevention or the treatment of colorectal cancer.

Role of the Vanins-Myeloperoxidase Axis in Colorectal Carcinogenesis.

The presence of chronic inflammation in the colonic mucosa leads to an increased risk of cancer. Among proteins involved in the regulation of mucosal inflammation and that may contribute both to structural damage of the intestinal mucosa and to intestinal carcinogenesis, there are myeloperoxidase (MPO) and vanins. The infiltration of colonic mucosa by neutrophils may promote carcinogenesis through MPO, a key enzyme contained in the lysosomes of neutrophils that regulates local inflammation and the generation of reactive oxygen species (ROS) and mutagenic species. The human vanin gene family consists of three genes: vanin-1, vanin-2 and vanin-3. All vanin molecules are pantetheinases, that hydrolyze pantetheine into pantothenic acid (vitamin B5), and cysteamine, a sulfhydryl compound. Vanin-1 loss confers an increased resistance to stress and acute intestinal inflammation, while vanin-2 regulates adhesion and transmigration of activated neutrophils. The metabolic product of these enzymes has a prominent role in the inflammation processes by affecting glutathione levels, inducing ulcers through a reduction in mucosal blood flow and oxygenation, decreasing local defense mechanisms, and in carcinogenesis by damaging DNA and regulating pathways involved in cell apoptosis, metabolism and growth, as Nrf2 and HIF-1α.

Palladium-Catalyzed Intramolecular Carbene Insertion into C(sp(3) )-H Bonds.

A palladium-catalyzed carbene insertion into C(sp(3) )-H bonds leading to pyrrolidines was developed. The coupling reaction can be catalyzed by both Pd(0) and Pd(II) , is regioselective, and shows a broad functional group tolerance. This reaction is the first example of palladium-catalyzed C(sp(3) )-C(sp(3) ) bond assembly starting from diazocarbonyl compounds. DFT calculations revealed that this direct C(sp(3) )-H bond functionalization reaction involves an unprecedented concerted metalation-deprotonation step.

Chemerin/chemR23 axis in inflammation onset and resolution.

Chemerin is an adipokine secreted by adipocytes and associated with obesity, insulin resistance and metabolic syndrome. Different chemerin fragments with pro- or anti-inflammatory action can be produced, depending on the class of proteases predominating in the microenvironment. Chemerin binds to three receptors, especially to chemR23, expressed on various cells, as dendritic cells, macrophages and natural killer cells, regulating chemotaxis towards the site of inflammation and activation status. Recently, the chemerin/chemR23 axis has attracted particular attention for the multiple roles related to the control of inflammation, metabolism and cancerogenesis in different organs and systems as lung (allergy and cancer), skin (psoriasis, lupus, cancer, wound repair), cardiovascular system (lipid profile and atherosclerosis), reproductive apparatus (polycystic ovary syndrome, follicular homoeostasis), and digestive tract (inflammatory bowel diseases and cancer). This pathway may regulate immune responses by contributing both to the pathogenesis of inflammatory diseases and to the resolution of acute inflammation. Thus, chemerin-derived peptides or other substances that may affect the chemerin/chemR23 axis could be used in the future for the treatment of many diseases, including cancer at different sites.

Up-regulation of the chemo-attractive receptor ChemR23 and occurrence of apoptosis in human chondrocytes isolated from fractured calcaneal osteochondral fragments.

To study the expression level of a panel of pro/anti-apoptotic factors and inflammation-related receptors in chondral fragments from patients undergoing surgical treatment for intra-articular calcaneal fractures, cartilage fragments were retrieved from calcaneal fractures of 20 patients subjected to surgical treatment. Primary cultures were performed using chondral fragments from fractured and control patients. Chondrocyte cultures from each patient of the fractured and control groups were subjected to immunofluorescence staining and quantitatively analyzed under confocal microscopy. Proteins extracted from the cultured chondrocytes taken from the fractured and control groups were processed for Western blot experiments and densitometric analysis. The percentage of apoptotic cells was determined using the cleaved PARP-1 antibody. The proportion of labelled cells was 35% for fractured specimens, compared with 7% for control samples. Quantification of caspase-3 active and Bcl-2 proteins in chondrocyte cultures showed a significant increase of the apoptotic process in fractured specimens compared with control ones. Fractured chondrocytes were positively stained for ChemR23 with statistically significant differences with respect to control samples. Densitometric evaluation of the immunoreactive bands confirmed these observations. Human articular chondrocytes obtained from patients with intra-articular calcaneal fractures express higher levels of pivotal pro-apoptotic factors, and of the chemo-attractive receptor ChemR23, compared with control cultures. On the basis of these observations, the authors hypothesize that consistent prolonged chondrocyte death, associated with the persistence of high levels of pro-inflammatory factors, could enhance the deterioration of cartilage tissue with consequent development of post-traumatic arthritis following intra-articular bone fracture.

Procalcitonin and Presepsin as Markers of Infectious Respiratory Diseases in Children: A Scoping Review of the Literature.

INTRODUCTION: Procalcitonin and presepsin have been suggested to be able to discriminate bacterial and viral infections, also in children. This scoping review aims to better explore the available evidence around the potential role of these biomarkers in the subgroup of children with respiratory infectious diseases. METHODS: We performed a systematic scoping review of studies published until March 2023 in the following bibliographic databases: PubMed, EMBASE, Cochrane and SCOPUS. RESULTS: In children with bacterial infection, procalcitonin values ranged from 0.5 ng/mL to 8.31 ng/dL, while in those hospitalized in an intensive care unit ranged from 0.6 ng/dL to 452.8 ng/dL with PCR from 2 ng/dL to 51.7 ng/dL. In children with viral infections, procalcitonin value values ranged from 0.2 ng/dL to 0.84 ng/dL, while in those hospitalized in an intensive care unit ranged from 0.61 ng/dL to 46.6 ng/dL. No studies on presepsin in children with respiratory infections were retrieved. CONCLUSIONS: Although the available literature is highly heterogeneous, evidence does not suggest a role of procalcitonin in accurately differentiating bacterial and viral infections in children with respiratory infections. In future, new approaches based on multiple markers may better help determine which febrile children require antibiotics.

Cardiopulmonary Exercise Testing in Children With Long COVID: A Case-controlled Study.

BACKGROUND: Cardiopulmonary exercise testing (CPET) is a noninvasive and nonexpensive diagnostic tool, that provides a comprehensive evaluation of the pulmonary, cardiovascular, and skeletal muscle systems' integrated reactions to exercise. CPET has been extensively used in adults with Long COVID (LC), while the evidence about its role in children with this condition is scarce. METHODS: Prospective, case-controlled observational study. Children with LC and a control group of healthy children underwent CPET. CPET findings were compared within the 2 groups, and within the LC groups according to main clusters of persisting symptoms. RESULTS: Sixty-one children with LC and 29 healthy controls were included. Overall, 90.2% of LC patients (55 of 61) had a pathologic test vs 10.3% (3/29) of the healthy control. Children with LC presented a statistically significant higher probability of having abnormal values of peak VO2 (P = 0.001), AT% pred (P <0.001), VO2/HR % (P = 0.03), VO2 work slope (P = 0.002), VE/VCO2 slope (P = 0.01). The mean VO2 peak was 30.17 (±6.85) in LC and 34.37 (±6.55) in healthy patients (P = 0.007). CONCLUSIONS: Compared with healthy controls, children with LC have objective impaired functional capacity (expressed by a low VO2 peak), signs of deconditioning and cardiogenic inefficiency when assessed with CPET. As such, CPET should be routinely used in clinical practice to objectify and phenotype the functional limitations of children with LC, and to follow-up them.

Persisting Gastrointestinal Symptoms in Children with SARS-CoV-2: Temporal Evolution over 18 Months and Possible Role of Lactoferrin.

BACKGROUND AND AIM: Persisting gastrointestinal symptoms are reported to be relatively common in children with long COVID; however, their detailed characterization and long-term outcomes have not yet been described. METHODS: We performed a retrospective study aiming to investigate the temporal evolution of gastrointestinal symptoms in children with SARS-CoV-2, from acute infection to 18-months follow-up. To further investigate possible therapeutic strategies, we evaluated the role of lactoferrin in improving gastrointestinal symptoms in these children, compared with those not treated. RESULTS: A total of 1224 patients (47.7% females) were included. Of these participants, 246 (19.8%) were vaccinated and 143 (11.5%) presented with comorbidities. A total of 175 patients (14.1%) presented gastrointestinal symptoms during acute infection, 54 (4.4%) at three months, 23 (1.9%) at six months, 6 (3.3%) at twelve months, and 2 (2.3%) at eighteen months follow-up. At six months follow-up, children who were treated with 3 months oral lactoferrin had less persisting symptoms compared to those who did not receive lactoferrin, although this difference was not statistically significant (three patients (25%) in the lactoferrin group vs. fourteen patients (33.3%) not treated, p = 0.73), probably due to the low number of patients with persisting GI symptoms. CONCLUSIONS: GI symptoms are relatively common during acute SARS-CoV-2 infection in children, and a non-negligible proportion of these children reported persisting symptoms for up to 12-18 months after the acute infection. In addition, we found a trend even if statistically nonsignificant toward faster improvement of persisting gastrointestinal symptoms in children with long COVID treated with lactoferrin. Despite the limitations relating to the present study's design, given the significant burden of gastrointestinal symptoms in children with long COVID, our findings provide the basis to perform a prospective, placebo-controlled study.