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Background: Bacterial meningitis (BM) in infants is a serious condition that can lead to significant complications. Lumbar puncture (LP) is essential to provide diagnoses, however false negatives may result if LP is performed after the starting of antibiotic therapy. Methods: We conducted a retrospective analysis of infants of any gestational age with BM within their first 90 days of life and admitted to the Neonatal Intensive Care Unit of Modena Policlinico between 1 January 2011, and 31 December 2023. Results: A total of 44 episodes of meningitis were confirmed in 40 infants, diagnosed by positive cerebrospinal fluid cultures (n = 37), polymerase chain reaction testing (n = 4), or both methods (n = 3). Three out of forty infants (8%) experienced a relapse of meningitis. Most episodes (31/44, 70%) occurred in preterm infants. The incidence of early-onset meningitis was lower than that of late-onset (0.18 vs. 0.94 cases per 1000 births, respectively), with Gram-positive accounting for most cases (27/44, 61%). LP was performed prior to antibiotic administration in most episodes (30/44, 68%). Two preterm infants (5%) died from meningitis-related complications. Forty-two episodes occurred among thirty-eight surviving infants; brain lesions were detected through brain ultrasound or MRI in nine out of forty-two episodes (21%). Conclusions: Preterm infants have higher rates of BM, brain lesions or case fatalities. Early diagnosis and prompt antibiotic treatment are critical to improve outcomes.

Background: There are wide variations in antibiotic use in neonatal intensive care units (NICUs). Limited data are available on antimicrobial stewardship (AS) programs and long-term maintenance of AS interventions in preterm very-low-birth-weight (VLBW) infants. Methods: We extended a single-centre observational study carried out in an Italian NICU. Three periods were compared: I. “baseline” (2011–2012), II. “intervention” (2016–2017), and III. “maintenance” (2020–2021). Intensive training of medical and nursing staff on AS occurred between periods I and II. AS protocols and algorithms were maintained and implemented between periods II and III. Results: There were 111, 119, and 100 VLBW infants in periods I, II, and III, respectively. In the “intervention period”, there was a reduction in antibiotic use, reported as days of antibiotic therapy per 1000 patient days (215 vs. 302, p < 0.01). In the “maintenance period”, the number of culture-proven sepsis increased. Nevertheless, antibiotic exposure of uninfected VLBW infants was lower, while no sepsis-related deaths occurred. Our restriction was mostly directed at shortening antibiotic regimens with a policy of 48 h rule-out sepsis (median days of early empiric antibiotics: 6 vs. 3 vs. 2 in periods I, II, and III, respectively, p < 0.001). Moreover, antibiotics administered for so-called culture-negative sepsis were reduced (22% vs. 11% vs. 6%, p = 0.002), especially in infants with a birth weight between 1000 and 1499 g. Conclusions: AS is feasible in preterm VLBW infants, and antibiotic use can be safely reduced. AS interventions, namely, the shortening of antibiotic courses in uninfected infants, can be sustained over time with periodic clinical audits and daily discussion of antimicrobial therapies among staff members.

Background: Centrally inserted central catheters (CICCs) are increasingly used in neonatal care. CICCs have garnered attention and adoption owing to their advantageous features. Therefore, achieving clinical competence in ultrasound-guided CICC insertion in term and preterm infants is of paramount importance for neonatologists. A safe clinical training program should include theoretical teaching and clinical practice, simulation and supervised CICC insertions. Methods: We planned a training program for neonatologists for ultrasound-guided CICCs placement at our level III neonatal intensive care unit (NICU) in Modena, Italy. In this single-centre prospective observational study, we present the preliminary results of a 12-month training period. Two paediatric anaesthesiologists participated as trainers, and a multidisciplinary team was established for continuing education, consisting of neonatologists, nurses, and anaesthesiologists. We detail the features of our training program and present the modalities of CICC placement in newborns. Results: The success rate of procedures was 100%. In 80.5% of cases, the insertion was obtained at the first ultrasound-guided venipuncture. No procedure-related complications occurred in neonates (median gestational age 36 weeks, IQR 26–40; median birth weight 1200 g, IQR 622–2930). Three of the six neonatologists (50%) who participated in the clinical training program have achieved good clinical competence. One of them has acquired the necessary skills to in turn supervise other colleagues. Conclusions: Our ongoing clinical training program was safe and effective. Conducting the program within the NICU contributes to the implementation of medical and nursing skills of the entire staff.

Background. Lysosomal acid alpha-glucosidase (GAA) deficiency, also known as Pompe disease, is an autosomal recessive disorder that leads to the accumulation of glycogen in lysosomes and cytoplasm, resulting in tissue destruction. Infantile-onset GAA deficiency is characterized by cardiomyopathy and severe generalized hypotonia. Without treatment, most patients die within the first two years of life. The demonstration of reduced GAA activity, followed by sequencing of the GAA gene, confirms the disease. GAA deficiency is currently treated with enzyme replacement therapy (ERT) with improved clinical outcomes and survival. Case Presentation. We describe the case of DGAA in two siblings, in which the diagnostic time point, treatment, and outcomes were completely different. The girl was diagnosed with DGAA at the age of 6 months during investigations for poor weight gain and excessive sleepiness. The finding of severe cardiomyopathy through EKG and echocardiography led to the suspicion of storage disease, and the GAA deficiency was later confirmed by genetic analysis. The girl died of complications due to the clinical picture before starting ERT. Conversely, her younger brother had the opportunity to receive an early diagnosis and the rapid onset of ERT. He is showing a regression of cardiac hypertrophy. Conclusion. The advent of ERT improved clinical outcomes and survival in infantile-onset PD. Its impact on cardiac function is still under study, but different reports in the literature have shown encouraging data. Early recognition of DGAA and prompt initiation of ERT is therefore crucial to prevent the progression of the disease and improve the outcomes.

Objective: To investigate the impact of timing, in vitro activity and appropriateness of empirical antimicrobials on the outcome of late-onset sepsis among preterm very low birth weight infants that are at high risk of developing meningitis. Study design: This retrospective study included 83 LOS episodes in 73 very low birth weight infants born at ≤32 weeks’ gestation with positive blood and/or cerebrospinal fluid culture or polymerase chain reaction at >72 h of age. To define the appropriateness of empirical antimicrobials we considered both their in vitro activity and their ideal delivery through the blood-brain barrier when meningitis was confirmed or not ruled out through a lumbar puncture. The primary outcome was sepsis-related mortality. The secondary outcome was the development of brain lesions. Timing, in vitro activity and appropriateness of empirical antimicrobials, were compared between fatal and non-fatal episodes. Uni- and multi-variable analyses were carried out for the primary outcome. Results: Time to antibiotics and in vitro activity of empirical antimicrobials were similar between fatal and non-fatal cases. By contrast, empirical antimicrobials were appropriate in a lower proportion of fatal episodes of late-onset sepsis (4/17, 24%) compared to non-fatal episodes (39/66, 59%). After adjusting for Gram-negative vs. Gram-positive pathogen and for other supportive measures (time to volume administration), inappropriate empirical antimicrobials remained associated with mortality (aOR, 10.3; 95% CI, 1.4–76.8, p = 0.023), while timing to first antibiotics was not (aOR 0.9; 95% CI, 0.7–1.2, p = 0.408; AUC = 0.88). The association between appropriate antimicrobials and brain sequelae was also significant (p = 0.024). Conclusions: The risk of sepsis-related mortality and brain sequelae in preterm very low birth weight infants is significantly associated with the appropriateness (rather than the timing and the in vitro activity) of empirical antimicrobials. Until meningitis is ruled out through lumbar puncture, septic very low birth weight infants at high risk of mortality should receive empiric antimicrobials with high delivery through the blood-brain barrier.

The use of umbilical venous catheters (UVCs) has become the standard of care in the neonatal intensive care unit (NICU) to administer fluids, medications and parenteral nutrition. However, it is well known that UVCs can lead to some serious complications, both mechanical and infective, including CLABSI (Central Line-Associated Bloodstream Infections). Most authors recommend removing UVC within a maximum of 14 days from its placement. However, the last Infusion Therapy Standards of Practice (INS) guidelines recommends limiting the UVC dwell time to 7 to 10 days, to reduce risks of infectious and thrombotic complications. These guidelines also suggest as an infection prevention strategy to remove UVC after 4 days, followed by the insertion of a PICC if a central line is still needed. Nevertheless, the maximum UVC dwell time to reduce the risk of CLABSI is still controversial, as well as the time of its replacement with a PICC. In this study we reviewed a total of 177 articles, found by using the PubMed database with the following search strings: “UVC AND neonates”, “(neonate* OR newborn*) AND (UVC OR central catheter*) AND (infection*)”. We also analyze the INS guidelines to provide the reader an updated overview on this topic. The purpose of this review is to give updated information on CVCs infectious risks by examining the literature in this field. These data could help clinicians in deciding the best time to remove or to replace the UVC with a PICC, to reduce CLABSIs risk. Despite the lack of strong evidence, the risk of CLABSI seems to be minimized when UVC is removed/replaced within 7 days from insertion and this indication is emerging from more recent and larger studies.

Abstract Background The optimal management of PDA in very low birth weight (VLBW) infants is still controversial. Aim of our study was to investigate the management of PDA in the Italian neonatal intensive care units (NICU). Methods We conducted an on-line survey study from June to September 2017. A 50-items questionnaire was developed by the Italian Neonatal Cardiology Study Group and was sent to Italian NICUs. Results The overall response rate was 72%. Diagnosis of PDA was done by neonatologists, cardiologists or both (62, 12 and 28% respectively). PDA significance was assessed by a comprehensive approach in all centers, although we found a heterogeneous combination of parameters and cut-offs used. None used prophylactic treatment. 19% of centers treated PDA in the first 24 h, 60% after the first 24 h, following screening echocardiography or clinical symptoms, 18% after the first 72 h and 2% after the first week. In the first course of treatment ibuprofen, indomethacin and paracetamol were used in 87, 6 and 7% of centers respectively. Median of surgical ligation was 3% (1–6%). Conclusions Significant variations exist in the management of PDA in Italy. Conservative strategy and targeted treatment to infants older than 24 h with echocardiographic signs of hemodynamic significance seemed to be the most adopted approach.

Abstract Background Neonatologist performed echocardiography (NPE) has increasingly been used to assess the hemodynamic status in neonates. Aim of this survey was to investigate the utilization of NPE in Italian neonatal intensive care units (NICUs). Methods We conducted an on-line survey from June to September 2017. A questionnaire was developed by the Italian neonatal cardiology study group and was sent to each Italian NICU. Results The response rate was 77%. In 94% of Italian NICUs functional echocardiography was used by neonatologists, cardiologists or both (57, 15 and 28% respectively). All the respondents used NPE in neonates with patent ductus arteriosus and persistent pulmonary hypertension, 93% in neonates with hypotension or shock, 85% in neonates with perinatal asphyxia, 78% in suspicion of cardiac tamponade, and 73% for line positioning. In 30% of center, there was no NPE protocol. Structural echocardiography in stable and critically ill neonates was performed exclusively by neonatologists in 46 and 36% of center respectively. Conclusions NPE is widely used in Italian NICUs by neonatologists. Structural echocardiography is frequently performed by neonatologists. Institutional protocols for NPE are lacking. There is an urgent need of a formal training process and accreditation to standardize the use of NPE.

Mucopolysaccharidosis are genetic disorders due to deficiency of lysosomal enzymes, resulting in abnormal glycosaminoglycans accumulation in several tissues. Heart involvement tends to be progressive and worsens with age. We describe the first case of mucopolysaccharidosis type I presenting with noncompaction/dilated-mixed cardiomyopathy and heart failure within neonatal period, which responded successfully to specific metabolic treatment. Cardiac function recovered after enzyme replacement therapy and hematopoietic stem cell transplantation, adding to the existing knowledge of the disease.

In 2013 we presented results showing that at the histological level lifelong increased physical activity promotes reinnervation of muscle fibers in aging muscles. Indeed, in muscle biopsies from 70-year old men with a lifelong history of high-level physical activity, we observed a considerable increase in fiber-type groupings (F-TG), almost exclusively of the slow type. Slow-type transformation by denervation-reinnervation in senior sportsmen seems to fluctuate from those with scarce fiber-type transformation and groupings to almost fully transformed muscle, going through a process in which isolated fibers co-expressing fast and slow Myosin Heavy Chains (MHCs) seems to fill the gaps. Taken together, our results suggest that, beyond the direct effects of aging on the muscle fibers, changes occurring in skeletal muscle tissue appear to be largely, although not solely, a result of sparse denervation-reinnervation. The lifelong exercise allows the body to adapt to the consequences of the age-related denervation and to preserve muscle structure and function by saving otherwise lost muscle fibers through recruitment to different, mainly slow, motor units. These beneficial effects of high-level life-long exercise on motoneurons, specifically on the slow type motoneurones that are those with higher daily activity, and on muscle fibers, serve to maintain size, structure and function of muscles, delaying the functional decline and loss of independence that are commonly seen in late aging. Several studies of independent reserchers with independent analyses confirmed and cited our 2013 results. Thus, the results we presented in our paper in 2013 seem to have held up rather well.

Despite the ravages of long term denervation there is structural and ultrastructural evidence for survival of muscle fibers in mammals, with some fibers surviving at least ten months in rodents and 3-6 years in humans. Further, in rodents there is evidence that muscle fibers may regenerate even after repeated damage in the absence of the nerve, and that this potential is maintained for several months after denervation. While in animal models permanently denervated muscle sooner or later loses the ability to contract, the muscles may maintain their size and ability to function if electrically stimulated soon after denervation. Whether in mammals, humans included, this is a result of persistent de novo formation of muscle fibers is an open issue we would like to explore in this review. During the past decade, we have studied muscle biopsies from the quadriceps muscle of Spinal Cord Injury (SCI) patients suffering with Conus and Cauda Equina syndrome, a condition that fully and irreversibly disconnects skeletal muscle fibers from their damaged innervating motor neurons. We have demonstrated that human denervated muscle fibers survive years of denervation and can be rescued from severe atrophy by home-based Functional Electrical Stimulation (h-bFES). Using immunohistochemistry with both non-stimulated and the h-bFES stimulated human muscle biopsies, we have observed the persistent presence of muscle fibers which are positive to labeling by an antibody which specifically recognizes the embryonic myosin heavy chain (MHCemb). Relative to the total number of fibers present, only a small percentage of these MHCemb positive fibers are detected, suggesting that they are regenerating muscle fibers and not pre-existing myofibers re-expressing embryonic isoforms. Although embryonic isoforms of acetylcholine receptors are known to be re-expressed and to spread from the end-plate to the sarcolemma of muscle fibers in early phases of muscle denervation, we suggest that the MHCemb positive muscle fibers we observe result from the activation, proliferation and fusion of satellite cells, the myogenic precursors present under the basal lamina of the muscle fibers. Using morphological features and molecular biomarkers, we show that severely atrophic muscle fibers, with a peculiar cluster reorganization of myonuclei, are present in rodent muscle seven-months after neurectomy and in human muscles 30-months after complete Conus-Cauda Equina Syndrome and that these are structurally distinct from early myotubes. Beyond reviewing evidence from rodent and human studies, we add some ultrastructural evidence of muscle fiber regeneration in long-term denervated human muscles and discuss the options to substantially increase the regenerative potential of severely denervated human muscles not having been treated with h-bFES. Some of the mandatory procedures, are ready to be translated from animal experiments to clinical studies to meet the needs of persons with longterm irreversible muscle denervation. An European Project, the trial Rise4EU (Rise for You, a personalized treatment for recovery of function of denervated muscle in long-term stable SCI) will hopefully follow.

Aging is a multifactorial process that is characterized by decline in muscle mass and performance. Several factors, including reduced exercise, poor nutrition and modified hormonal metabolism, are responsible for changes in the rates of protein synthesis and degradation that drive skeletal muscle mass reduction with a consequent decline of force generation and mobility functional performances. Seniors with normal life style were enrolled: two groups in Vienna (n=32) and two groups in Bratislava: (n=19). All subjects were healthy and declared not to have any specific physical/disease problems. The two Vienna groups of seniors exercised for 10 weeks with two different types of training (leg press at the hospital or home-based functional electrical stimulation, h-b FES). Demografic data (age, height and weight) were recorded before and after the training period and before and after the training period the patients were submitted to mobility functional analyses and muscle biopsies. The mobility functional analyses were: 1. gait speed (10m test fastest speed, in m/s); 2. time which the subject needed to rise from a chair for five times (5x Chair-Rise, in s); 3. Timed –Up-Go- Test, in s; 4. Stair-Test, in s; 5. isometric measurement of quadriceps force (Torque/kg, in Nm/kg); and 6. Dynamic Balance in mm. Preliminary analyses of muscle biopsies from quadriceps in some of the Vienna and Bratislava patients present morphometric results consistent with their functional behaviors. The statistically significant improvements in functional testings here reported demonstrates the effectiveness of h-b FES, and strongly support h-b FES, as a safe home-based method to improve contractility and performances of ageing muscles.

The induction of exercise-induced apoptosis in not actively involved in exercise organs, such as kidney could be a result of oxidative stress. Metallothionein (MT) exerts a protective effect in the cell against oxidative stress and apoptosis. We have previously demonstrated an increased incidence of apoptosis in distal tubular cells and collecting ducts in rat kidney after acute exercise. The present study was designed to test the hypothesis that MT may play a protective role in rat renal tubules against exercise-induced apoptosis after the acute exercise and regular training. Male Wistar rats were divided into control, acute exercised and 8-wk regularly trained groups. The kidneys were removed after a rest period of 6 h and 96 h. The ultrastructure of renal tubular cells was examined by electron microscopy. Apoptosis was detected in paraffin sections by the TUNEL technique. Expression of MT was examined by immunohistochemistry. The level of lipid peroxidation (thiobarbituric acid reactive substances - TBARS) was assayed in renal tissue homogenates. After acute exercise, the occurrence of apoptosis was restricted to distal tubules and collecting ducts of rat kidney, whereas the proximal tubules remained unaffected. The 8-wk training did not result in increased apoptosis in tubular cell. MT expression was confined exclusively to proximal tubules in all groups. However, it was significantly increased in acutely exercised animals, as compared to control and trained rats. After the 8-wk training, MT expression remained unaltered as compared to the control group. TBARS levels were significantly increased after acute exercise, while after regular training they remained unchanged. A significant correlation between TBARS level and MT expression was demonstrated. The findings could suggest a protective role of MT against oxidative stress and apoptosis in proximal tubular cells.

It has long been recognized that histological changes observed in aging muscle suggest that denervation contributes to muscle deterioration and that disuse accelerates the process while running activity, sustained for decades, protects against age-related loss of motor units. Here we show at the histological level that lifelong increased physical activity promotes reinnervation of muscle fibers. In muscle biopsies from 70-year old men with a lifelong history of high-level physical activity, we observed a considerable increase in fiber-type groupings (almost exclusively of the slow type) in comparison to sedentary seniors, revealing a large population of reinnervated muscle fibers in the sportsmen. Slow-type transformation by reinnervation in senior sportsmen seems to be a clinically relevant mechanism: the muscle biopsies fluctuate from those with scarce fiber-type transformation and groupings to almost fully transformed muscle, going through a process in which isolated fibers co-expressing fast and slow MHCs seems to fill the gaps. Taken together, our results suggest that, beyond the direct effects of aging on the muscle fibers, changes occurring in skeletal muscle tissue appear to be largely, although not solely, a result of sparse denervation. Our data suggest that lifelong exercise allows the body to adapt to the consequences of the age-related denervation and to preserve muscle structure and function by saving otherwise lost muscle fibers through recruitment to different, mainly slow, motor units. These beneficial effects on motoneurons and, subsequently on muscle fibers, serve to maintain size, structure and function of muscle fibers, delaying the functional decline and loss of independence that are commonly seen in late aging.

Contrary to general believe, in one case of 18month cauda equina lesion four-month electrical stimulation of thigh muscles (impulse energy 1.92 Joule) increased stimulation frequency from 2 to 20 Hz, i. e., up to tetanic contractions. After 2 years of treatment, CT-cross sectional area of quadriceps improved 58.3% (right) and 44.4% (left) with increased muscle density. Mean myofiber size was 37.2 ± 24.8 µm (right) and 40.5 ± 24.9 µm (left). Improvement of stimulated knee torque, from zero to 12.0 Nm and 10.5 Nm, respectively, enabled to stand up trials. Surviving myofibers undergo re-growth (they show the chess board appearance of normal muscle), and dying myofibers continuously regenerate (up to 3% are embryonic myosin positive 3-year post-FES). Regeneration events are essential components of the FES rehabilitation protocol due to superior excitability of regenerated myofibers in comparison to long-term denervated, degenerated myofibers, which were almost not excitable before FES training.