Acute chest syndrome in children with sickle cell disease: Data from a national AIEOP cohort identify priority areas of intervention in a hub-and-spoke system.

Acute chest syndrome (ACS) is a frequent cause of hospitalization in sickle cell disease (SCD). Despite advances in acute care, many settings still lack knowledge about ACS best practices. After the AIEOP Guidelines were published in 2012, suggesting standardized management in Italy, a retrospective study was performed to assess the diagnostic and therapeutic pathways of ACS in children. From 2013 to 2018, 208 ACS episodes were presented by 122/583 kids in 11 centres. 73 were male, mean age 10.9 years, 85% African, 92% HbSS or Sß°. In our hub-and-spoke system, a good adherence to Guidelines was documented, but discrepancies between reference centres and general hospitals were noted. Improvement is needed for timely transfer to reference centres, use of incentive spirometry, oxygen therapy and pain management.

Artificial intelligence for predictive biomarker discovery in immuno-oncology: a systematic review.

BACKGROUND: The widespread use of immune checkpoint inhibitors (ICIs) has revolutionised treatment of multiple cancer types. However, selecting patients who may benefit from ICI remains challenging. Artificial intelligence (AI) approaches allow exploitation of high-dimension oncological data in research and development of precision immuno-oncology. MATERIALS AND METHODS: We conducted a systematic literature review of peer-reviewed original articles studying the ICI efficacy prediction in cancer patients across five data modalities: genomics (including genomics, transcriptomics, and epigenomics), radiomics, digital pathology (pathomics), and real-world and multimodality data. RESULTS: A total of 90 studies were included in this systematic review, with 80% published in 2021-2022. Among them, 37 studies included genomic, 20 radiomic, 8 pathomic, 20 real-world, and 5 multimodal data. Standard machine learning (ML) methods were used in 72% of studies, deep learning (DL) methods in 22%, and both in 6%. The most frequently studied cancer type was non-small-cell lung cancer (36%), followed by melanoma (16%), while 25% included pan-cancer studies. No prospective study design incorporated AI-based methodologies from the outset; rather, all implemented AI as a post hoc analysis. Novel biomarkers for ICI in radiomics and pathomics were identified using AI approaches, and molecular biomarkers have expanded past genomics into transcriptomics and epigenomics. Finally, complex algorithms and new types of AI-based markers, such as meta-biomarkers, are emerging by integrating multimodal/multi-omics data. CONCLUSION: AI-based methods have expanded the horizon for biomarker discovery, demonstrating the power of integrating multimodal data from existing datasets to discover new meta-biomarkers. While most of the included studies showed promise for AI-based prediction of benefit from immunotherapy, none provided high-level evidence for immediate practice change. A priori planned prospective trial designs are needed to cover all lifecycle steps of these software biomarkers, from development and validation to integration into clinical practice.

Efficacy and safety of ramucirumab plus carboplatin and paclitaxel in untreated metastatic thymic carcinoma: RELEVENT phase II trial (NCT03921671).

BACKGROUND: Thymic carcinoma (TC) is a rare tumor with aggressive behavior. Chemotherapy with carboplatin plus paclitaxel represents the treatment of choice for advanced disease. Antiangiogenic drugs, including ramucirumab, have shown activity in previously treated patients. RELEVENT trial was designed to evaluate the activity and safety of ramucirumab plus chemotherapy as first-line treatment in advanced TC. PATIENTS AND METHODS: This phase II trial was conducted within the Italian TYME network. Eligible patients had treatment naive advanced TC. They received ramucirumab, carboplatin and paclitaxel for 6 cycles, followed by ramucirumab maintenance until disease progression or intolerable toxicity. Primary endpoint was ORR according to RECIST v1.1 as assessed by the investigator. Secondary endpoints were PFS, OS and safety. Centralized radiologic review was performed. RESULTS: From 11/2018 to 06/2023, 52 patients were screened, 35 were enrolled. Median age was 60.8 years, 71.4% of patients were male and 85.7% had Masaoka-Koga stage IVB. ECOG PS was 0 in 68.5%, 1 in 31.4% patients. At the present analysis carried out some months later the interim analysis (earlier than expected) on 35 patients, ORR was 80.0% [95%CI 63.1-91.6]. At the centralized radiological review of 33/35 evaluable patients, ORR was 57.6% [95%CI 39.2-74.5]. After a median follow-up of 31.6 months, median PFS was 18.1 [95%CI 10.8-52.3] and median OS 43.8 [95%CI 31.9-NR] months. Thirty-two out of 35 patients (91.4%) experienced at least one treatment-related adverse event (AE), of which 48.6% were AE≥G3. CONCLUSIONS: In previously untreated advanced TC, the addition of ramucirumab to carboplatin and paclitaxel showed the highest activity compared to historical controls, with a manageable safety profile. Despite the small number of patients, given the rarity of the disease, the trial results support the consideration of this combination as first-line treatment in TC.

Diagnosis and management of acquired aplastic anemia in childhood. Guidelines from the Marrow Failure Study Group of the Pediatric Haemato-Oncology Italian Association (AIEOP).

Acquired aplastic anemia (AA) is a rare heterogeneous disorder characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2-3 per million population per year in the Western world, but 3 times higher in East Asia. Survival in severe aplastic anemia (SAA) has improved significantly due to advances in hematopoietic stem cell transplantation (HSCT), immunosuppressive therapy, biologic agents, and supportive care. In SAA, HSCT from a matched sibling donor (MSD) is the first-line treatment. If a MSD is not available, options include immunosuppressive therapy (IST), matched unrelated donor, or haploidentical HSCT. The purpose of this guideline is to provide health care professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary evidence-based document prepared by a group of pediatric hematologists of the Bone Marrow Failure Study Group of the Italian Association of Pediatric Hemato-Oncology (AIEOP) was discussed, modified and approved during a series of consensus conferences that started online during COVID 19 and continued in the following years, according to procedures previously validated by the AIEOP Board of Directors.

Quality of care and clinical inertia in the management of cardiovascular risk factors in patients with type 1 and type 2 diabetes: data from AMD annals.

BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality among patients with diabetes, and for this reason, all guidelines for CV risk management provide the same targets in controlling traditional CV risk factors in patients with type 1 or type 2 diabetes at equal CV risk class. Aim of our study was to evaluate and compare CV risk management in patients with type 1 and type 2 diabetes included in AMD Annals Database paying particular attention to indicators of clinical inertia. METHODS: This was a multicenter, observational, retrospective study of AMD Annals Database during year 2022. Patients with diabetes were stratified on the basis of their cardiovascular risk, according to ESC-EASD guidelines. The proportion of patients not treated with lipid-lowering despite LDL cholesterol > to 100 mg/dl or the proportion of patients not treated with antihypertensive drug despite BP > 140/90 mmhg and proportion of patients with proteinuria not treated with angiotensin converting enzyme inhibitors or angiotensinogen receptor blockers (ACE/ARBs) were considered indicators of clinical inertia. The proportion of patients reaching at the same time HbA1c < 7% LDL < 70 mg/dl and BP < 130/80 mmhg were considered to have good multifactorial control. Overall quality of health care was evaluated by the Q-score. RESULTS: Using the inclusion criteria and stratifying patients by ESC/EASD Cardiovascular Risk categories, we included in the analysis 118.442 patients at High Cardiovascular risk and 416.246 patients at Very High Cardiovascular risk. The proportion of patients with good multifactorial risk factor control was extremely low in both T1D and T2D patients in each risk class. At equal risk class, the patients with T1D had lower proportion of subjects reaching HbA1c, LDL, or Blood Pressure targets. Indicators of clinical inertia were significantly higher compared with patients with T2D at equal risk class. Data regarding patients with albuminuria not treated with RAAS inhibitors were available only for those at Very High risk and showed that the proportion of patients not treated was again significantly higher in patients with T1DM. CONCLUSIONS: In conclusion, this study provides evidence of wide undertreatment of traditional cardiovascular risk factors among patients with diabetes included in AMD Annals Database. Undertreatment seems to be more pronounced in individuals with T1D compared to those with T2D and is frequently due to clinical inertia.

Effectiveness of oral semaglutide on glucose control and body weight up to 18 months: a multicenter retrospective real-world study.

AIM: Oral semaglutide, an innovative orally administered GLP-1 receptor agonist for type 2 diabetes (T2D) management was herein evaluated for its effectiveness in a multi-center retrospective real-world study. METHODS: We included new-users of oral semaglutide from 18 specialist care centres and collected retrospective data on baseline clinical characteristics. Updated values of HbA1c and body weight were analyzed using the mixed model for repeated measures. RESULTS: The study included 166 individuals with T2D, predominantly men (64.5%), with a mean age of 64.4 years and a mean diabetes duration of 10.1 years. In the majority of patients (68.3%) oral semaglutide was used as a second-line drug, mostly with metformin. At baseline, mean BMI was 28.9 kg/m2 and HbA1c was 7.5%. During the 18-month observation period, oral semaglutide demonstrated significant reductions in HbA1c, with a maximum change of - 0.9%, and 42.1% of patients achieved HbA1c values below 7.0%. Additionally, there was a substantial reduction in body weight, with an estimated change of - 3.4 kg at 18 months, and 30.3% of patients experienced a 5% or greater reduction in baseline body weight. Only 24.2% of patients reached the 14 mg dose. Subgroup analysis revealed that baseline HbA1c > 7%, persistence on drug, not being on a prior therapy with DPP-4 inhibitors, and loosing 5% or more the initial body weight were associated with greater HbA1c reductions. CONCLUSION: This study supports oral semaglutide as an effective option for T2D treatment, offering improved glucose control and weight management in a real-world setting.

Temporal trends in the starting of insulin therapy in type 2 diabetes in Italy: data from the AMD Annals initiative.

AIMS: Opportunities and needs for starting insulin therapy in Type 2 diabetes (T2D) have changed overtime. We evaluated clinical characteristics of T2D subjects undergoing the first insulin prescription during a 15-year-observation period in the large cohort of the AMD Annals Initiative in Italy. METHODS: Data on clinical and laboratory variables, complications and concomitant therapies and the effects on glucose control after 12 months were evaluated in T2D patients starting basal insulin as add-on to oral/non-insulin injectable agents, and in those starting fast-acting in add-on to basal insulin therapy in three 5-year periods (2005-2019). RESULTS: We evaluated data from 171.688 T2D subjects who intensified therapy with basal insulin and 137.225 T2D patients who started fast-acting insulin. Overall, intensification with insulin occurred progressively earlier over time in subjects with shorter disease duration. Moreover, the percentage of subjects with HbA1c levels > 8% at the time of basal insulin initiation progressively decreased. The same trend was observed for fast-acting formulations. Clinical characteristics of subjects starting insulin did not change in the three study-periods, although all major risk factors improved overtime. After 12 months from the starting of basal or fast-acting insulin therapy, mean HbA1c levels decreased in all the three investigated time-periods, although mean HbA1c levels remained above the recommended target. CONCLUSIONS: In this large cohort of T2D subjects, a progressively earlier start of insulin treatment was observed during a long observation period, suggesting a more proactive prescriptive approach. However, after 12 months from insulin prescription, in many patients, HbA1c levels were still out-of-target.

Sex- and gender-differences in chronic long-term complications of type 1 and type 2 diabetes mellitus in Italy.

AIMS: This review summarizes the contribution of Italian diabetologists devoted to a better understanding of the complex relationship linking sex/gender and long-term complications of type 1 (T1DM) and type 2 diabetes (T2DM) over the last fifteen years. DATA SYNTHESIS: Microvascular and macrovascular complications of diabetes show sex- and gender-related differences, involving pathophysiological mechanisms, epidemiological features and clinical presentation, due to the interaction between biological and psychosocial factors. These differences greatly impact on the progression of diabetes and its long-term complications, especially in the cardiovascular, renal and liver districts. CONCLUSION: A better knowledge of such sex- and gender-related characteristics is required for a more precise patient phenotypization, and for the choice of a personalized antihyperglycemic treatment. Despite such mounting evidence, current diabetes clinical guidelines do not as yet adequately consider sex/gender differences.

Role of Wnt-signaling inhibitors DKK-1 and sclerostin in bone fragility associated with Turner syndrome.

PURPOSE: Girls affected with Turner syndrome (TS) present with low bone mineral density (BMD) and osteopenia/osteoporosis. Thus, they have an increased risk to develop fractures compared to normal population. The aim of this study was to deepen the pathophysiology of skeletal fragility in TS subjects by evaluating the serum levels of Dickkopf-1 (DKK-1) and sclerostin, main regulators of bone mass, as well as the percentage of circulating osteoblast precursors (OCPs). METHODS: Thirty-four TS girls and 24 controls were recruited. All subjects underwent anthropometric measures (height, weight, body mass index-BMI). A peripheral venous blood sample was collected to determine serum levels of active intact parathyroid hormone (PTH), 25-OH vitamin D, calcium, phosphorus, bone alkaline phosphatase (bALP), osteocalcin, sclerostin, DKK-1, RANKL and OPG. OCPs were detected by flow cytometry. In TS subjects bone mineralization was measured at lumbar spine by dual energy X-ray absorptiometry (DXA). RESULTS: bALP, 25-OH Vitamin D, and osteocalcin levels were significant lower in TS subjects than in the controls. Statistically significant higher levels of sclerostin, DKK-1 and RANKL were measured in patients compared with the controls. The percentage of OCPs did not show significant differences between patients and controls. Sclerostin and DKK-1 levels were related with anthropometric parameters, bone metabolism markers, HRT, rhGH therapy, RANKL and lumbar BMAD-Z-score. CONCLUSION: TS patients showed higher levels of sclerostin and DKK-1 than controls which can be related to HRT, and to reduced bone formation markers as well as the increased bone resorption activity.

Sensation Seeking and Adolescent Drinking: Do Protective Behavioral Strategies Lower Risk?

Using a cross-sectional design, we examined protective behavioral strategies (PBS) as a moderator of the relationship between sensation seeking and hazardous drinking and alcohol-related consequences among high school seniors (N = 212). Hierarchical regression analyses indicated sensation seeking was a significant predictor of binge drinking (ß = .65, p < .001), pre-partying (ß = .71, p < .001), gaming (ß = .75, p < .001), and alcohol-related consequences (ß = .69, p < .001). Further, PBS moderated these relationships such that among high sensation seeking adolescents, PBS use was associated with better outcomes, including lower levels of binge drinking (ß = -.37, p < .01), pre-partying (ß = -.44, p < .01), gaming (ß = -.31, p < .05), and alcohol-related consequences (ß = -.53, p < .001). We discuss counseling implications, including assessment and harm reduction strategies focusing on PBS to reduce hazardous drinking among high sensation seeking adolescents.

Focal lesions induce large-scale percolation of sleep-like intracerebral activity in awake humans.

Focal cortical lesions are known to result in large-scale functional alterations involving distant areas; however, little is known about the electrophysiological mechanisms underlying these network effects. Here, we addressed this issue by analysing the short and long distance intracranial effects of controlled structural lesions in humans. The changes in Stereo-Electroencephalographic (SEEG) activity after Radiofrequency-Thermocoagulation (RFTC) recorded in 21 epileptic subjects were assessed with respect to baseline resting wakefulness and sleep activity. In addition, Cortico-Cortical Evoked Potentials (CCEPs) recorded before the lesion were employed to interpret these changes with respect to individual long-range connectivity patterns. We found that small structural ablations lead to the generation and large-scale propagation of sleep-like slow waves within the awake brain. These slow waves match those recorded in the same subjects during sleep, are prevalent in perilesional areas, but can percolate up to distances of 60 mm through specific long-range connections, as predicted by CCEPs. Given the known impact of slow waves on information processing and cortical plasticity, demonstrating their intrusion and percolation within the awake brain add key elements to our understanding of network dysfunction after cortical injuries.

MosquirixTM malaria vaccine: an evaluation of patients' willingness to pay in Cameroon.

OBJECTIVES: The purpose of this study was to determine the average price that a patient living in Cameroon would be willing to pay for the MosquirixTM vaccine and the factors influencing the proposed price. STUDY DESIGN: Cross-sectional study Methods: Data were collected using a semi-open questionnaire in 5 hospitals in Cameroon. This study included all persons over 18 years who came for consultation in one of the 5 selected hospitals during the study period (from 02th to 14th April 2018 and from 02th to 22th July 2018). The factors associated with the price of the vaccine proposed by the patient were determined by linear multiple regression analysis. The average price was determined based on the patient's income and the percentage of that income proposed for the purchase of the vaccine. RESULTS: We collected data from 1,187 participants aged 18 to 80 years. The average price that Cameroonian patients were willing to pay for the MosquirixTM vaccine was 1,514±475 XAF (2.3±0.73 Euro). The minimum and maximum purchase price of the vaccine were 1,178 XAF (1.8 Euro) and 1,850 XAF (2.8 Euro) respectively. We also noted that patients were willing to spend an average of 1.34% of their income on the vaccine. This percentage of income was significantly (lt;0.001) associated with the respondents' income, the fact that they had been consulted at least once for malaria in the 12 months preceding the survey (lt;0.001) and the fact that the respondent had at least one under- five year child (lt;0.001). CONCLUSION: Factors associated with the average price are elements that should be strongly considered by policy makers to introduce this vaccine in Cameroon. This pilot study can serve as a framework for a potential national population-based study.

Absolute basophil count is associated with time to recurrence in patients with high-grade T1 bladder cancer receiving bacillus Calmette-Guérin after transurethral resection of the bladder tumor.

BACKGROUND: Basophils, eosinophils and monocytes may be involved in BCG-induced immune responses and be associated with outcomes of bladder cancer patients receiving intravesical BCG. Our objective was to explore the association of baseline counts of basophils, eosinophils and monocytes with outcomes of patients with high-grade T1 bladder cancer receiving a standard course of intravesical BCG. METHODS: We retrospectively reviewed medical records of patients with primary T1 HG/G3 bladder cancer. After re-TURBT, patients were treated with a 6-week course of intravesical BCG induction followed by intravesical BCG every week for 3 weeks given at 3, 6, 12, 18, 24, 30 and 36 months from initiation of therapy The analysis of potential risk factors for recurrence, muscle invasion and cancer-specific and overall survival was performed using univariable Cox regression models. Those factors that presented, at univariate analysis, an association with the event at a liberal p < 0.1, have been selected for the development of a multivariable model. RESULTS: A total of 1045 patients with primary T1 HG/G3 were included. A total of 678 (64.9%) recurrences, 303 (29.0%) progressions and 150 (14.3%) deaths were observed during follow-up. Multivariate analysis showed that logarithmic transformation of basophils count was associated with a 30% increment in the hazard of recurrence per unit increase of logarithmic basophils count (HR 1.30; 95% confidence interval 1.09-1.54; p = 0.0026). Basophil count modeled by quartiles was also significantly associated with time to recurrence [second vs. lower quartile HR 1.42 (1.12-1.79); p = 0.003, third vs. lower quartile HR 1.26 (1.01-1.57); p = 0.041; upper vs. lower quartile HR 1.36 (1.1-1.68); p = 0.005]. The limitations of a retrospective study are applicable. CONCLUSION: Baseline basophil count may predict recurrence in BCG-treated HG/G3 T1 bladder cancer patients. External validation is warranted.

Ontogenetic allometry and architectural properties of the paravertebral and hindlimb musculature in Eastern cottontail rabbits (Sylvilagus floridanus): functional implications for developmental changes in locomotor performance.

Due to small body size, an immature musculoskeletal system, and other growth-related limits on performance, juvenile mammals frequently experience a greater risk of predation than their adult counterparts. As a result, behaviorally precocious juveniles are hypothesized to exhibit musculoskeletal advantages that permit them to accelerate rapidly and evade predation. This hypothesis was tested through detailed quantitative evaluation of muscle growth in wild Eastern cottontail rabbits (Sylvilagus floridanus). Cottontail rabbits experience high rates of mortality during the first year of life, suggesting that selection might act to improve performance in growing juveniles. Therefore, it was predicted that muscle properties associated with force and power capacity should be enhanced in juvenile rabbits to facilitate enhanced locomotor performance. We quantified muscle architecture from 24 paravertebral and hindlimb muscles across ontogeny in a sample of n = 29 rabbits and evaluated the body mass scaling of muscle mass (MM), physiological cross-sectional area (PCSA), isometric force (Fmax ), and instantaneous power (Pinst ), along with several dimensionless architectural indices. In contrast to our hypothesis, MM and PCSA for most muscles change with positive allometry during growth by scaling at Mb1.3 and Mb1.1 , respectively, whereas Fmax and Pinst generally scale indistinguishably from isometry, as do the architectural indices tested. However, scaling patterns indicate that the digital flexors and ankle extensors of juvenile S. floridanus have greater capacities for force and power, respectively, than those in adults, suggesting these muscle properties may be a part of several compensatory features that promote enhanced acceleration performance in young rabbits. Overall, our study implies that body size constraints place larger, more mature rabbits at a disadvantage during acceleration, and that adults must develop hypertrophied muscles in order to maintain mechanical similarity in force and power capacities across development. These findings challenge the accepted understanding that juvenile animals are at a performance detriment relative to adults. Instead, for prey-predator interactions necessitating short intervals of high force and power generation relative to body mass, as demonstrated by rapid acceleration of cottontail rabbits fleeing predators, it may be the adults that struggle to keep pace with juveniles.

Increased fibulin-1 plasma levels in polycystic ovary syndrome (PCOS) patients: possible contribution to the link between PCOS and cardiovascular risk.

PURPOSE: To investigate a possible relation between fibulin-1 plasma levels and PCOS. DESIGN: ELISA quantitative determination of human fibulin-1. METHODS: 50 women with PCOS and 40 control patients who attended the Unit of Human Reproductive Pathophysiology, Università Cattolica del Sacro Cuore, Rome, were enrolled. Ultrasonographic pelvic examinations, hormonal profile assays, oral tolerance test OGTT, lipid profile and ELISA quantitative determination of human fibulin-1 were performed. RESULTS: Fibulin-1 levels were found to be statistically significantly higher in PCOS patients than in matched control women. No statistically significant positive correlation was found between fibulin-1 and AUCi, HOMA-IR, total cholesterol, LDL, AMH, androstenedione and FAI, whereas a statistically significant positive correlation was found between fibulin-1 and 17OHP (p = 0.016) in the PCOS group. However, multivariable linear regression analysis showed that 17 OH P did not independently predict fibulin-1 levels (p = 0.089). CONCLUSIONS: Our data could contribute to explain the hypothesized increased cardiovascular risk and vascular damage in patients with PCOS. A better understanding of the cellular and molecular mechanisms involved in cardiometabolic disorders associated with PCOS is mandatory to identify new therapeutic strategies to eventually prevent the progression of cardiovascular diseases in these patients.

High rate of detection of ultrasound signs of prostatitis in patients with HPV-DNA persistence on semen: role of ultrasound in HPV-related male accessory gland infection.

BACKGROUND: Papillomavirus (HPV) often occurs in the semen of patients with male accessory gland infection (MAGI). Ultrasound (US) evaluation has been suggested as a promising diagnostic tool for patients with HPV-related MAGI. No data on the spontaneous clearance of HPV-DNA have been reported so far in HPV-related MAGI. PURPOSE: The primary aim of the study was to assess the percentage of early HPV-DNA spontaneous clearance in patients with prostatitis. The secondary aim was to evaluate the frequency of spontaneous clearance of HPV-DNA among patients with prostatitis associated with the presence or absence of US abnormalities. METHODS: Patients with inflammatory MAGI and at least one suspicious criterion for HPV infection underwent semen HPV-DNA detection and prostate US. The presence of HPV-DNA was further investigated after a 6-month-long follow-up. MAIN RESULTS: Eighty patients satisfied the inclusion criteria and were recruited in the study. 69% of patients (55/80) showed HPV-DNA persistence in the semen. Among them, 82% (45/55) was positive for US signs of prostatitis, while they occurred only in 12% (3/25) of those patients with no sign of HPV-DNA persistence (p < 0.001). All patients with persistent high-risk HPV genotype (n = 30) showed at least two US signs of prostatitis. In 73% of patients (22/30), E6 and E7 mRNAs were detected. CONCLUSION: US signs of prostatitis more frequently occurred in patients with evidence of HPV-DNA persistence on semen, especially in those with high-risk genotypes. This highlights the importance of US in the framework of HPV-related MAGI.

Yogurt is tolerated by the majority of children with IgE-mediated cow's milk allergy.

BACKGROUND: Children with IgE-mediated cow's milk allergy (IgE-CMA) with gastrointestinal symptoms tolerate yogurt at 100%. Yogurt tolerance in children with IgE-CMA with urticaria and anaphylaxis was 7%. METHODS: We enrolled children with IgE-CMA with cutaneous, respiratory, gastrointestinal and anaphylactic symptoms. All performed prick by prick (PbP) and oral food challenge (OFC) with yogurt. Some children performed also an OFC with CM mixed with wheat flour and baked, baked liquid CM, parmesan. RESULTS: 34 children were enrolled, 31/34 (91%) with systemic adverse reaction after ingestion of CM (systemic CMA), 3/34 (9%) with isolated contact urticaria (ICU CMA). PbP with yogurt was negative only in one patient. OFC with yogurt was passed (that is, the OFC was negative) by 20/31 (64%) of the children with systemic CMA. 10/11 (91%) of the patients who failed OFC (that is, the OFC was positive) with yogurt were positive to SPT with casein vs. 8/20 (40%) of the patients who passed it (p=0.018). None of the 19 children who passed OFC with yogurt failed all OFC with processed CM forms other than yogurt that tested vs. 4/8 among those who failed OFC with yogurt (p=0.006). The rub test with yogurt was negative in 1/3 (33%) of the patients with ICU CMA. CONCLUSIONS: The results of our study are placed alongside others already present in the literature and concerning other methods of processing CM proteins and help to reduce the dietary restrictions of the majority of children with systemic IgE-CMA.

Multiple time courses of somatosensory responses in human cortex.

Here we show how anatomical and functional data recorded from patients undergoing stereo-EEG can be used to decompose the cortical processing following nerve stimulation in different stages characterized by specific topography and time course. Tibial, median and trigeminal nerves were stimulated in 96 patients, and the increase in gamma power was evaluated over 11878 cortical sites. All three nerve datasets exhibited similar clusters of time courses: phasic, delayed/prolonged and tonic, which differed in topography, temporal organization and degree of spatial overlap. Strong phasic responses of the three nerves followed the classical somatotopic organization of SI, with no overlap in either time or space. Delayed responses presented overlaps between pairs of body parts in both time and space, and were confined to the dorsal motor cortices. Finally, tonic responses occurred in the perisylvian region including posterior insular cortex and were evoked by the stimulation of all three nerves, lacking any spatial and temporal specificity. These data indicate that the somatosensory processing following nerve stimulation is a multi-stage hierarchical process common to all three nerves, with the different stages likely subserving different functions. While phasic responses represent the neural basis of tactile perception, multi-nerve tonic responses may represent the neural signature of processes sustaining the capacity to become aware of tactile stimuli.

Assessing the effects of habitat patches ensuring propagule supply and different costs inclusion in marine spatial planning through multivariate analyses.

Marine Protected Areas are considered key tools for conservation of coastal ecosystems. However, many reserves are characterized by several problems mainly related to inadequate zonings that often do not protect high biodiversity and propagule supply areas precluding, at the same time, economic important zones for local interests. The Gulf of Naples is here employed as a study area to assess the effects of inclusion of different conservation features and costs in reserve design process. In particular eight scenarios are developed using graph theory to identify propagule source patches and fishing and exploitation activities as costs-in-use for local population. Scenarios elaborated by MARXAN, software commonly used for marine conservation planning, are compared using multivariate analyses (MDS, PERMANOVA and PERMDISP) in order to assess input data having greatest effects on protected areas selection. MARXAN is heuristic software able to give a number of different correct results, all of them near to the best solution. Its outputs show that the most important areas to be protected, in order to ensure long-term habitat life and adequate propagule supply, are mainly located around the Gulf islands. In addition through statistical analyses it allowed us to prove that different choices on conservation features lead to statistically different scenarios. The presence of propagule supply patches forces MARXAN to select almost the same areas to protect decreasingly different MARXAN results and, thus, choices for reserves area selection. The multivariate analyses applied here to marine spatial planning proved to be very helpful allowing to identify i) how different scenario input data affect MARXAN and ii) what features have to be taken into account in study areas characterized by peculiar biological and economic interests.

In vitro evaluation of different antimicrobial combinations against carbapenemase-producing Klebsiella pneumoniae: the activity of the double-carbapenem regimen is related to meropenem MIC value.

Objectives and methods: We evaluated the in vitro activity of different antimicrobial combinations with and without colistin against 39 carbapenem-resistant Klebsiella pneumoniae (CR-Kp) strains (colistin + meropenem/doripenem, colistin + tigecycline, colistin + rifampicin, gentamicin + meropenem, gentamicin + tigecycline and the double-carbapenem regimen meropenem + ertapenem) using the chequerboard method. The triple combination colistin + meropenem + tigecycline was also tested. In addition, killing studies were performed for meropenem + ertapenem. Results: Gentamicin-based combinations showed a high level of synergy. Meropenem + ertapenem was synergic in 12/39 (30.7%) of the strains, whereas based on killing studies 1 × MIC meropenem + 1 × MIC ertapenem and 2 × MIC meropenem + 1 × MIC ertapenem combinations were bactericidal and synergic at 24 h [mean area under the bactericidal curve (AUBC) 54.9 ±âŸ26.1 and 44.2 ±âŸ15.3 compared with 1 × MIC meropenem (134.5 ±âŸ40.1) and 2 × MIC meropenem (126.4 ±âŸ5.4), respectively, P < 0.0001]. When the results were stratified according to meropenem MIC, we found that the degree of synergy significantly increased for isolates with lower meropenem (and not ertapenem) MICs, up to an MIC of 128 mg/L. Among colistin-containing combinations, synergy was observed in 18/39 (46.1%), 33/34 (97%), 24/39 (61.5%) and 17/39 (43.5%) of the strains for colistin + meropenem, colistin + rifampicin, colistin + tigecycline and colistin + doripenem, respectively, including colistin-resistant strains. Colistin + meropenem + tigecycline at subinhibitory concentrations resulted in the absence of growth of 37/39 strains (94.8%). Conclusions: Our in vitro data suggest that colistin might be a valid therapeutic option against CR-Kp, even in the presence of colistin resistance, whereas the double-carbapenem regimen represents a viable option when colistin is not recommended, especially if the meropenem MIC is ≤ 128 mg/L. Since traditional antimicrobial susceptibility reports are not sufficiently informative for clinicians, synergy testing as well as actual meropenem MIC evaluation should always be performed in the case of CR-Kp infections.