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Background: Maternal phenylketonuria (mPKU) is a pathologic condition occurring in the fetus of a mother with PKU that is caused by prolonged elevated intrauterine blood phenylalanine (Phe) levels, which can lead to congenital abnormalities and mental retardation of newborns. Management of PKU during pregnancy can be challenging as protein substitutes may exacerbate nausea, vomiting, and gastrointestinal symptoms. Aim: To report the successful management of four PKU pregnant women. Methods: The patients were administered with prolonged-release amino acid supplementation and were recommended to follow a strict diet. Blood Phe concentration, adherence to diet, and occurrence of adverse events were monitored. Results: All patients achieved safe levels of blood Phe concentration (120-360 µmol/L) since preconception and during pregnancy (mean Phe concentration values of 143.34 ± 137.59, 226.48 ± 194.57, 186.68 ± 133.67, and 187.47 ± 42.59 µmol/L). During the first trimester of pregnancy, all patients manifested gastrointestinal symptoms such as nausea, gastrointestinal reflux, and abdominal bloating, which were managed by either changing protein substitute or extending the time window between different meals and amino acid mixtures administration. The four women continued their pregnancies without experiencing further complications and delivered neonates with normal growth parameters and no malformations. Conclusion: Findings of this case series suggest that the intake of a prolonged-release amino acid mixture in granules is well tolerated by pregnant PKU patients, eventually leading to good metabolic control and fetal growth within normal ranges., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: To achieve a normal nutritional status, patients suffering from phenylketonuria (PKU) are typically prescribed amino acid (AA) supplements with low or no phenylalanine (Phe) content. Studies evaluating patient preferences regarding the intake modalities of AA supplements are limited. This study aimed to collect real-world data regarding prescription adherence and intake modalities of AA supplements reported by PKU patients while monitoring metabolic control., Methods: This cross-sectional study included 33 PKU patients (16 female and 17 male) with a mean age of 27.2 years. Questionnaires were provided to assess information on AA supplement intake, such as prescription adherence rate, frequency and timing of administration, supplement formulation, and combination with food or drinks. Plasma phenylalanine levels were monitored during the study period., Results: 51.5% ( n = 17) of patients reported to lay within an adherence range of 75-100%. The majority of patients consumed AA supplements twice daily, with breakfast (87.9%) and afternoon snacks (51.5%). Powder supplements were most commonly used (72.7%) and often combined with milk and/or fruit juices (45.4%)., Conclusions: Despite the known concerns related to treatment compliance among PKU adolescents and adults, most of the study participants reported a high level of adherence to AA supplement prescription. The personalized dietary regimens followed by the patients included in the current study represent a treatment approach that might be worth trying in non-compliant patients.

Many inherited metabolic disorders (IMDs), including disorders of amino acid, fatty acid, and carbohydrate metabolism, are treated with a dietary reduction or exclusion of certain macronutrients, putting one at risk of a reduced intake of micronutrients. In this review, we aim to provide available evidence on the most common micronutrient deficits related to specific dietary approaches and on the management of their deficiency, in the meanwhile discussing the main critical points of each nutritional supplementation. The emerging concepts are that a great heterogeneity in clinical practice exists, as well as no univocal evidence on the most common micronutrient abnormalities. In phenylketonuria, for example, micronutrients are recommended to be supplemented through protein substitutes; however, not all formulas are equally supplemented and some of them are not added with micronutrients. Data on pyridoxine and riboflavin status in these patients are particularly scarce. In long-chain fatty acid oxidation disorders, no specific recommendations on micronutrient supplementation are available. Regarding carbohydrate metabolism disorders, the difficult-to-ascertain sugar content in supplementation formulas is still a matter of concern. A ketogenic diet may predispose one to both oligoelement deficits and their overload, and therefore deserves specific formulations. In conclusion, our overview points out the lack of unanimous approaches to micronutrient deficiencies, the need for specific formulations for IMDs, and the necessity of high-quality studies, particularly for some under-investigated deficits.

Co-moments of asset returns play a major role in financial contagion during crises. We study the properties of a particular specification of the generalized bivariate normal distribution which allows for co-volatility and co-skewness. With this probability distribution, formulae for single-name and exchange options can be evaluated quickly since they are based on one-dimensional integrals. We provide a very precise approximation formula for spread option prices and derive the corresponding greeks. We perform a day-to-day re-estimation of the probability distribution on a dataset of WTI vs Brent spread options, showing the ability of this specification to capture the salient empirical features observed in the market. Finally, we show the impact of co-movements on portfolio risk management., (© The Author(s) 2022.)

Background: Vaccines for COVID-19 have had a significant impact on the spread of COVID-19 infection, reducing the incidence and mortality of the infection in several countries. However, hesitancy toward this vaccine is a global health issue for the general population The Vaccine acceptance rate among patients affected with inherited metabolic disorders (IMD), as well as safety profile, has not been described., Methods: We conducted a cross-sectional study, based on a telephone survey, investigating the COVID-19 vaccination rate, the incidence and type of adverse effects (AEs), the reasons for vaccine refusal and the effects on the underlying disease in a cohort of IMD patients followed at a single center and invited directly to vaccination by specialistic team., Results: Seventy-four patients were included in the study, the median age was 23.4 years (min 12.1-max 61.7), 47% ( n = 85) were females and 61% (107) were affected from impaired metabolism of phenylalanine. By October 2021, 94% ( n = 163) of them had received at least one dose of the vaccine, which was, in 98% of cases, mRNA-based vaccine, given at the referral hospital in 65% of cases. Overall, 72% of patients with IMD reported AE to the vaccine: 60% after the first dose, 81% after the second. The highest rate of adverse events at the first dose was reported in patients with amino acids related disorders other than impaired phenylalanine metabolism (PKU/HPA) (88%). For the second dose, the PKU/HPA group reported the highest rate of AEs (89% of cases). There was no effect on the underlying disease or acute decompensation after the vaccine. Eleven patients (6%) were not vaccinated because they considered it dangerous., Conclusion: Among individuals with IMD, the vaccination rate was high, the incidence and severity of AEs were comparable to those in the general population with no effects on the disease. Direct contact with the specialist medical team, has proven to reassure patients and effectively contrast hesitancy.

There is a lack of evidence on the impact on body composition of high protein intake and types of protein substitutes in PKU patients—particularly in adolescents, who are more inclined to dietary transgressions. In this observational, cross-sectional study, PKU patients were observed during prepubertal age (p) or after the pubertal spurt (P), assessing body composition and bone quality and correlating these parameters with dietary compliance and types of protein substitutes. Anthropometric and dietary data were evaluated together with bioelectrical impedance analysis (BIA), quantitative ultrasound (QUS) and branched-chain amino acids (BCAAs). A total of 36 patients (16 males, 17 prepubertal and 19 post-pubertal; mean ± SD age 11.4 ± 3.9 years) were included. A higher BMI was observed in adolescents (p-value: 0.018). The BIA revealed a significant increase in total body water (TBW) and muscle mass (MM) in P subjects either compliant (p-value: 0.001) or non-compliant with the diet (p-value: 0.001). MM content correlated with increased Phe intake (r = 0.63; p < 0.001). In the subgroup of five patients taking L-AAs and glycomacropeptides (GMPs), BCAA values tended to be lower than those taking only L-AA mixtures, with a significant trend for valine. Maintenance of body composition parameters within the normal range—for both fat and muscle mass—and levels of BCAAs can be helpful in reducing the risk of becoming overweight in adulthood. Further studies are needed to confirm these findings.

Studies on Hyperphenylalaninemia (HPA) patients are scarce and primarily focused on neurocognitive outcomes compared to PKU patients. In this study, we characterized the food habits and lifestyle of HPA patients compared with healthy peers. We performed a cross-sectional survey of a cohort of 30 patients (13 males, median age/range: 7.9; 2.2-16.7 years) and 28 controls (8 males, median age/range: 7.9; 2.1-16.7 years). Anthropometric parameters, food and nutrient intakes, and level of physical activity were assessed. Food neophobia, eating disorders, and body image perception was investigated by specific tests. Patients showed greater selectivity in the choice of foods than controls, preferring products with lower protein content ( p -value: 0.03) and avoiding associating multiple protein and carbohydrate sources. A comparable tendency to distrust new foods emerged without elements suggestive of eating disorders. Patients had higher image dissatisfaction than peers ( p -value: 0.01). This group of patients manifested more selective eating habits and worse body image acceptance. A regular evaluation of these aspects in these patients may result in a more effective follow-up of this disorder. More studies are needed to confirm these findings.

Background: Autophagic vacuolar myopathies (AVMs) are an emerging group of heterogeneous myopathies sharing histopathological features on muscle pathology, in which autophagic vacuoles are the pathognomonic morphologic hallmarks. Glycogen storage disease type II (GSDII) caused by lysosomal acid α-glucosidase (GAA) deficiency is the best-characterised AVM., Aims: This study aimed to investigate the mutational profiling of seven neuromuscular outpatients sharing clinical, myopathological and biochemical findings with AVMs., Methods: We applied a diagnostic protocol, recently published by our research group for suspected late-onset GSDII (LO-GSDII), including counting PAS-positive lymphocytes on blood smears, dried blood spot (DBS)-GAA, muscle biopsy histological and immunofluorescence studies, GAA activity assay and expression studies on muscle homogenate, GAA sequencing, GAA multiplex ligation-dependent probe amplification (MLPA) and whole exome sequencing (WES)., Results: The patients had a limb girdle-like muscular pattern with persistent hyperCKaemia; vacuolated PAS-positive lymphocytes, glycogen accumulation and impaired autophagy at muscle biopsy. Decreased GAA activity was also measured. While GAA sequencing identified no pathogenic mutations, WES approach allowed us to identify for each patient an unexpected mutational pattern in genes cooperating in lysosomal-autophagic machinery, some of which have never been linked to human diseases., Conclusions: Our data suggest that reduced GAA activity may occur in any condition of impaired autophagy and that WES approach is advisable in all genetically undefined cases of autophagic myopathy. Therefore, deficiency of GAA activity and PAS-positive lymphocytes should be considered as AVM markers together with LC3/p62-positive autophagic vacuoles., (© 2021 British Neuropathological Society.)

Objectives: Because it is involved in calcium homeostasis, vitamin D is a prohormone with many implications for health, especially bone health. Hypovitaminosis D is considered pandemic worldwide, with important health health consequences. The aim of our study was to evaluate vitamin D levels in children living in a southern region of Italy with high exposure to sunlight for at least 5 mo a year along with contributing factors., Methods: A total of 1484 children and adolescents (age 0.02-17.74 y) living in the Apulia region (Southern Italy) were studied. Serum 25-hydroxyvitamin D (25[OH]D) concentrations were assessed and vitamin status defined as follows: deficiency with serum 25(OH)D < 20 ng/mL, insufficiency from 20 to 29.9 ng/mL, and sufficiency with serum 25(OH)D from 30 to 100 ng/mL., Results: The median serum 25(OH)D levels were 20.2 ng/mL (interquartile range, 14.5-26.4 ng/mL): 48.9% of the overall population had 25(OH)D < 20 ng/mL and only 15% had sufficient 25(OH)D values. There was an inverse association between blood levels of 25(OH)D and age (P < 0.001, ρ: -0.113). Significant 25(OH)D variations were recorded according to the season in which blood samples were drawn, but even during summer only 32.6% of analyzed children had sufficient 25(OH)D levels., Conclusions: More than 80% of our population had 25(OH)D less than sufficiency cutoff levels. Results highlight a high prevalence of 25(OH)D deficiency in our area, even during summer. It is important to establish screening, supplementation guidelines, and pediatric cutoff levels to optimize vitamin D status in children, taking into account age, nutritional status, and seasonality., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The aim of this study is to investigate the relationship between delirium and symptom expression in advanced cancer patients admitted to palliative care services. This is a secondary analysis of a consecutive sample of advanced cancer patients who were admitted to home care and hospices, and prospectively assessed for a period of 10 months. The Edmonton Symptom Assessment Scale (ESAS) and the MDAS (Memorial Delirium Assessment Scale) were measured at admission (T0) and after seven days of home care or hospice care (T7). Of the eight hundred and forty-eight patients screened in the period, 585 were not considered in the analysis for various reasons. The mean age was 72.1 years (SD 13.7), and 146 patients were males (55.5%). The mean Karnofsky status recorded at T0 is 34.1 (SD = 6.69). The mean duration palliative care assistance is 38.4 days (SD = 48, range 2-220). Of 263 patients who had a MDAS available at T0, 110 patients (41.8%) had a diagnosis of delirium. Of them, 167 patients had complete data regarding MDAS measurement, either at T0 and T7. A larger number of patients (n 167, 63.5%) had delirium after a week of palliative care. Patients with delirium are likely to be older, to have a lower Karnofsky level at T0, and to be home care patients. At T0, weakness, nausea, drowsiness, lack of appetite, and well-being are associated with delirium. At T7, weakness, poor appetite, and poor well-being are significantly associated with delirium. 27% of patients who had a normal cognitive status at T0 developed delirium at T7. In patients with delirium, an improvement in the cognitive status corresponds to a significant improvement in weakness, depression, and appetite. Conversely, the occurrence of delirium in patients who had a normal cognitive status at admission significantly increases the level depression, while the level of weakness and appetite decrease. Symptom expression is amplified in patients with delirium admitted to home care or hospices, while patients without delirium can be more responsive to palliative treatments with a significant decrease in intensity of ESAS items.

Aim: The aim of this study was to assess the prevalence of delirium in advanced cancer patients admitted to different palliative care services in Italy and possible related factors. The secondary outcome was to assess the changes of delirium after 1 week of palliative care., Methods: A consecutive sample of patients was screened for delirium in period of 1 year in seven palliative care services. General data, including primary tumor, age, gender, concomitant disease, palliative prognostic score (PaP), and Karnofsky status, were collected. Possible causes or factors associated with delirium were looked for. The Edmonton Symptom Assessment Scale was used to assess physical and psychological symptoms and the Memorial Delirium Assessment Scale (MDAS) to assess the cognitive status of patients, at admission (T0) and 1 week after palliative care (T7)., Results: Of 848 patients screened, 263 patients were evaluated. Sixty-six patients had only the initial evaluation. The mean Karnofsky status was 34.1 (SD = 6.69); the mean PaP score at admission was 6.9 (SD = 3.97). The mean duration of palliative care assistance, equivalent to survival, was 38.4 days (SD = 48, range 2-220). The mean MDAS values at admission and after 1 week of palliative care were 6.9 (SD = 6.71) and 8.8 (SD = 8.26), respectively. One hundred ten patients (41.8%) and 167 patients (67.3%) had MDAS values ≥ 7 at admission and after 1 week of palliative care, respectively. Age, dehydration, cachexia, chemotherapy in the last three months, and intensity of drowsiness and dyspnea were independently associated with a MDAS > 7. A worsening of drowsiness, the use of opioids, and the use of corticosteroids were independently associated with changes of MDAS from T0 to T7., Conclusion: Although the prevalence of delirium seems to be similar to that reported in other acute settings, delirium tended to worsen or poorly responded to a palliative care treatment. Some clinical factors were independently associated with delirium. This information is relevant for decision-making when delirium does not change despite a traditional intervention. Continuous assessment of delirium should be performed in these settings to detect deterioration of cognitive function. Further studies should elucidate whether an earlier approach to palliative care would decrease the prevalence of delirium at a late stage of disease.

Goals: We assessed the efficacy of a probiotic mixture of Bifidobacterium infantis M-63, breve M-16V, and longum BB536 in improving abdominal pain (AP) and quality of life (QoL) in children with irritable bowel syndrome (IBS) and functional dyspepsia (FD)., Background: AP-associated functional gastrointestinal disorders, particularly IBS and FD, are common in pediatrics, and no well-established treatment is currently available. Although probiotics have shown promising results in adults, data in children are heterogeneous., Study: Forty-eight children with IBS (median age, 11.2 y; range, 8 to 17.9 y) and 25 with FD (age, 11.6 y; range, 8 to 16.6 y) were randomized to receive either a mixture of 3 Bifidobacteria or a placebo for 6 weeks. After a 2-week "washout" period, each patient was switched to the other group and followed up for further 6 weeks. At baseline and follow-up, patients completed a symptom diary and a QoL questionnaire. AP resolution represented the primary outcome parameter., Results: In IBS, but not in FD, Bifidobacteria determined a complete resolution of AP in a significantly higher proportion of children, when compared with placebo (P=0.006), and significantly improved AP frequency (P=0.02). The proportion of IBS children with an improvement in QoL was significantly higher after probiotics than after placebo (48% vs. 17%, P=0.001), but this finding was not confirmed in FD., Conclusions: In children with IBS a mixture of Bifidobacterium infantis M-63, breve M-16V, and longum BB536 is associated with improvement in AP and QoL. These findings were not confirmed in FD subjects. Trial identifier: NCT02566876 (http://www.clinicaltrial.gov).

Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1-16 years who had developed SDNS in the previous 6-12 months and were maintained in remission with high prednisone doses (≥0.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m(2); intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m(2) per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for ≥1 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6-13.5 years]) were enrolled and followed for ≤60 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS., (Copyright © 2015 by the American Society of Nephrology.)

Context: Although there are increasing numbers of studies of outcomes of high-fidelity patient simulators, few contrast their instruction with that provided by equivalent low-fidelity, inexpensive simulators. Further, examination of decays in learning and application (transfer) to real patient problems is rare. In this study, we compared the effects of training using a high-fidelity heart sound simulator (Harvey) and a low-fidelity simulator (a CD) on recognition of both simulated heart sounds and those in actual patients., Methods: A pilot study with 10 students was conducted to show the feasibility of the methods and some evidence of modality-specific learning (the Harvey-trained group scored 72% correct on Harvey and 36% correct on CD test examples; the CD-trained group scored 60% correct on both CD and Harvey test examples). A main study was then initiated involving 37 Year 3 medical students from the University of Leeds. They received 1 hour of common instruction, after which one group received 3 hours of specific instruction on Harvey. The second group received 3 hours of instruction using a CD. Six weeks later, both groups were tested blind with real patients with stable heart sounds. Stations were observed by an examiner who scored communication skills and examination skills using 5-point scales., Results: The Harvey-trained group was slightly but not significantly better than the CD-trained group at identifying heart sounds (3.11 versus 2.47, respectively; P = 0.06). However, there was no difference between the Harvey and CD-trained groups in diagnosis (2.94 versus 2.84, respectively), communication skills (18.9 versus 19.6, respectively) or examination skills (17.4 versus 17.5, respectively)., Conclusions: The study found little evidence that students trained with a high-fidelity simulator were more able to transfer skills to real patients than a control group. Although there was some suggestion that the Harvey-trained group was better at recognising heart sounds, there was no difference between groups in diagnostic accuracy or clinical skills.

From September 1986 to April 1988, all consecutive patients with histologically proven (pathologic review mandatory) malignant mesothelioma, measurable disease, age less than 75 years, Karnofsky performance status equal to or greater than 40, and no previous chemotherapy were treated with epirubicin at the dosage of 75 mg/m2 i.v. every 3 weeks. Of the 23 patients who entered the study, 2 were retrospectively found not to have malignant mesothelioma. In the 21 eligible patients (all evaluable), no complete remission, 1 partial remission, 11 stable diseases and 9 progressions were noted. Toxicity was very mild. Median survival was 7.5 months. At the dosage used, epirubicin proved to be of little value in the management of these patients. Whether higher doses are more effective, as has been noted in other tumors, remains to be ascertained.