Chemical Characterization, Phenolic Compounds Quantification, and Assessment of Antioxidant and Anti-Acetylcholinesterase Activities of Byrsonima sericea DC fruits.

Byrsonima sericea is a species native to Brazil that is widely used in traditional medicine. The seed ethanol extract (SEE) had the highest content of total phenols (179.35 mg GAE g-1 extract) and flavonoids (10.42 mg QE g-1 extract) and was the most active in relation to antioxidant activity (DPPH: IC50 =4.25 µg mL-1 and ABTS: IC50 =4.82 µg mL-1 ). The peel/pulp ethanol extract (PEE) had the best anticholinesterase activity (IC50 =6.02 µg mL-1 ). Chromatographic investigation identified gallic acid, isoquercitrin, quercetin and amentoflavone in SEE, and gallic acid, isoquercitrin, quercetin and rutin in PEE. Six fatty acid methyl esters and seven triterpenes were identified, highlighting oleic acid in the seed hexane extract (61.85 %) and in the peel/pulp hexane extract (52.61 %), and betulin in the peel/pulp hexane extract (5.25 %). The substances and biological activities identified in B. sericea characterize this fruit as a functional food for future studies.

The meaning in loss protocol: A clinical trial of online grief therapy.

For a minority of the bereaved, the loss of a significant other can trigger an overwhelming emotional reaction and impaired functioning across life domains, known as prolonged grief disorder (PGD). Hence, ongoing efforts have been made to refine existing treatments to increase their efficacy and to accommodate the idiosyncrasies of grief reactions. This study presents the results of an open clinical trial of the feasibility and effectiveness of the Meaning in Loss (MIL) protocol in an online format. The brief intervention of 12 to 16 sessions combines constructivist and narrative strategies to explore and work through impediments to meaning reconstruction in loss. The sample included 25 participants diagnosed with PGD who were treated by six therapists. Baseline and post-therapy comparisons showed a significant improvement in all clinical measures (grief symptomatology, depression and general distress) and an increase of meaning making regarding the loss. Meaning making was found to be a prospective mediator of symptomatic improvement in grief across the course of therapy. These findings suggest the effectiveness of the MIL protocol in decreasing grief specific and associated symptomatology and argue for the relevance of further controlled evaluations of its efficacy. Moreover, results confirm previous findings that meaning making is a relevant factor in the evolution of grief reactions, including in the context of psychotherapy.

Chest Computed Tomography for Lymphoma Staging: A Wasted Opportunity for Cardiovascular Risk Stratification?

AIM: Patients with a lymphoma diagnosis undergo non-gated chest computed tomography (CT) scans as part of cancer diagnosis or staging. Although coronary artery calcification (CAC) is traditionally evaluated on dedicated cardiac CT, CAC can also be detected on standard chest CT. This exploratory study aimed to determine the prognostic value of CAC detected on non-gated chest CT and to report its use on clinical practice. METHOD: Consecutive patients with a lymphoma diagnosis who performed non-contrasted non-gated chest CT for cancer diagnosis or staging were included and retrospectively evaluated. Coronary artery calcification was evaluated by quantitative (Agatston score) and qualitative (visual) assessment. RESULTS: Fifty-seven patients were included in this study (mean age 61±15 years; 58% male). Coronary artery calcification was identified in 22 patients (39%), most of them with multi-vessel involvement. Coronary artery calcification was qualitatively classified as mild, moderate and severe in 11%, 19% and 9% patients, respectively. This study suggested that moderate or severe CAC was an independent predictor of all-cause mortality (odds ratio 3, 95% confidence interval 2-11; p=0.04) after adjusting for cardiovascular risk factors and lymphoma staging. Regarding quantitative evaluation, a higher CAC score was also associated with higher mortality. While significant CAC was identified in 22 patients, it was only reported in four patients. CONCLUSIONS: The preliminary findings of this hypothesis-generating study support the investigation of CAC identified by chest CT for diagnosis/staging of cancer as a risk modifier in the global risk assessment of patients with lymphoma. The unrecognition and underreporting of this finding may represent a wasted opportunity to detect subclinical coronary atherosclerosis in these patients and may help in guiding preventive cardiology care.

A phase 1/2, open-label, multicenter study of isatuximab in combination with cemiplimab in patients with lymphoma.

Patients with relapsed or refractory lymphoma have limited treatment options, requiring newer regimens. In this Phase 1/2 study (NCT03769181), we assessed the safety, efficacy, and pharmacokinetics of isatuximab (Isa, anti-CD38 antibody) in combination with cemiplimab (Cemi, anti-programmed death-1 [PD-1] receptor antibody; Isa + Cemi) in patients with classic Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma (PTCL). In Phase 1, we characterized the safety and tolerability of Isa + Cemi with planned dose de-escalation to determine the recommended Phase 2 dose (RP2D). Six patients in each cohort were treated with a starting dose of Isa + Cemi to determine the RP2D. In Phase 2, the primary endpoints were complete response in Cohort A1 (cHL anti-PD-1/programmed death-ligand 1 [PD-L1] naïve), and objective response rate in Cohorts A2 (cHL anti-PD-1/PD-L1 progressors), B (DLBCL), and C (PTCL). An interim analysis was performed when the first 18 (Cohort A1), 12 (Cohort A2), 17 (Cohort B), and 11 (Cohort C) patients in Phase 2 had been treated and followed up for 24 weeks. Isa + Cemi demonstrated a manageable safety profile with no new safety signals. No dose-limiting toxicities were observed at the starting dose; thus, the starting dose of each drug was confirmed as the RP2D. Based on the Lugano 2014 criteria, 55.6% (Cohort A1), 33.3% (Cohort A2), 5.9% (Cohort B), and 9.1% (Cohort C) of patients achieved a complete or partial response. Pharmacokinetic analyses suggested no effect of Cemi on Isa exposure. Modest clinical efficacy was observed in patients with cHL regardless of prior anti-PD-1/PD-L1 exposure. In DLBCL or PTCL cohorts, interim efficacy analysis results did not meet prespecified criteria to continue enrollment in Phase 2 Stage 2. Isa + Cemi did not have a synergistic effect in these patient populations.

Acute kidney injury in critically ill children: predictive value of renal arterial Doppler assessment.

BACKGROUND: Renal resistive index (RRI) and renal pulsatility index (RPI) are Doppler-based variables proposed to assess renal perfusion at the bedside in critically ill patients. This study aimed to assess the accuracy of such variables to predict acute kidney injury (AKI) in mechanically ventilated children. METHODS: Consecutive children aged <14 years underwent kidney Doppler ultrasound examination within 24 h of invasive mechanical ventilation. Renal resistive index (RRI) and renal pulsatility index (RPI) were measured. The primary outcome was severe AKI (KDIGO stage 2 or 3) on day 3. RESULTS: On day 3, 22 patients were classified as having AKI, of which 12 were severe. RRI could effectively predict severe AKI (area under the ROC curve [AUC] = 0.94) as well as RPI (AUC = 0.86). The optimal cut-off for RRI was 0.85 (sensitivity, 91.7%; specificity, 84.7%; PPV, 50.0%; and NPV, 98.4%). Similar results were obtained when the accuracy to predict AKI on day 5 was assessed. Significant correlations were observed between RRI and estimated glomerular filtration rate at enrollment (ρ = -0.495) and on day 3 (ρ = -0.467). CONCLUSIONS: Renal Doppler ultrasound may be a promising tool to predict AKI in critically ill children under invasive mechanical ventilation. IMPACT: Early recognition of acute kidney injury (AKI) is essential to promptly initiate supportive care aimed at restoring renal perfusion, which may prevent or attenuate acute tubular necrosis. Renal arterial Doppler-based parameters are rapid, noninvasive, and repeatable variables that may be promising for the prediction of AKI in children. To the best of our knowledge, this is the first study to evaluate the use of renal Doppler-based variables to predict AKI in critically ill children. The present study found that Doppler-based variables could accurately predict the occurrence of severe AKI and were correlated with urinary output and diuretic use.

Prevalence of vitamin A deficiency in women of childbearing age in Brazil: a systematic review and meta-analysis.

Vitamin A is an essential micronutrient, especially during pregnancy. We aimed to assess the prevalence of vitamin A deficiency in Brazilian women of childbearing age. We conducted a systematic review with meta-analysis of studies that assessed vitamin A deficiency in women of childbearing age following the registered protocol (CRD42020171856). Independent peer researchers selected the studies retrieved from MEDLINE, Embase, Scopus and other sources. Data from the eligible studies were extracted in pairs and assessed for methodological quality. The prevalence of vitamin A deficiency (< 0·70 µmol/l or <0·20 µg/dl) and 95 % CI was combined by meta-analysis, and heterogeneity was estimated by I2. Out of 3610 screened records, thirty-two studies were included, which assessed 12 577 women from 1965 to 2017, mostly in maternity hospitals. Main limitations of the studies were in sample frame (30/32) and sampling method (29/32). Deficiency occurred in 13 % (95 % CI 9·4, 17·2 %; I² = 97 %) of all women and was higher in pregnant women (16·1 %; 95 % CI 5·6, 30·6 %; I² = 98 %) than non-pregnant women (12·3 %; 95 % CI 8·4, 16·8 %; I² = 96 %). The prevalence increased according to the decade, from 9·5 % (95 % CI 1·9­21·6 %; I² = 98 %) up to 1990, 10·8 % (95 % CI 7·9, 14·2 %; I² = 86 %) in the 2000s and 17·8 % (95 % CI 8·7, 29·0 %; I² = 98 %) in the 2010s. Over 10 % of Brazilian women in childbearing age were deficient in vitamin A. Higher prevalence was observed in pregnant women, and deficiency seemed to be increasing over the decades. Low representativeness of the studies, mainly based on convenience sampling that included pregnant, postpartum, lactating and non-pregnant women, as well as high heterogeneity, limits the findings.

Emotional processing during the therapy for complicated grief.

OBJECTIVE: Prior research, mainly conducted on depression, observed that clients' improved capability to process their emotions predicted better therapeutic outcomes. The current comparative study aimed to investigate whether emotional processing was related to therapeutic change in complicated grief. METHOD: We analyzed two contrasting cases (good or poor outcome) treated with grief constructivist therapy. In both cases we investigated the association of emotional processing (Experiencing Scale) to (1) therapeutic outcome (Inventory of Complicated Grief), and (2) change in the type of grief-related emotions (Emotions Episodes). RESULTS: The session-by-session growth of clients' emotional processing and the change of grief-related emotions were qualitatively explored throughout both cases. Compared with the poor outcome case, the good outcome case achieved more improvement in the ability to process emotions. Such improvement occurred alongside a deeper change in the type of grief-related emotions aroused, from maladaptive to more adaptive responses. CONCLUSION: Our findings suggest that a higher emotional processing capability may be associated with the transformation of grief-related maladaptive emotions and with the improvement of complicated grief condition.

Leadership, adequate staffing and material resources, and collegial nurse-physician relationships promote better patients, professionals and institutions outcomes.

AIM: To test a theoretical model aiming to understand which characteristics of the professional nursing practice environment most affect patients, professionals and institution outcomes. DESIGN: A cross-sectional and correlational study, using a structural equation model. METHODS: One thousand seven hundred and seventy-three staff nurses were recruited using convenience sampling in five Brazilian hospitals from November 2017 to July 2018. Structural equation modelling was used to assess the relationship between the characteristics of the nursing work environment and patients (climate of safety and quality of care), nursing professionals (job satisfaction and emotional exhaustion) and institutions (intention to leave the job) outcomes. The model was tested using the partial least squares method, considering the bootstrapping technique to estimate the results. The path coefficients and their respective 95% confidence intervals were calculated. The quality of fit of the structural model was assessed by calculating the coefficient of determination (R2 ), the predictive validity coefficient (Q2 ) and the effect size (f2 ). RESULTS: The characteristics that most affected the outcomes for patients were Nurse manager ability, leadership and support of nurses (λ=0.27), and Staffing and resource adequacy (λ=0.26); for nursing professionals, Staffing and resource adequacy (λ=-0.19), and Collegial nurse-physician relations (λ=0.19); and for institutions, Nurse manager ability, leadership and support of nurses (λ=-0.10), and Collegial nurse-physician relations (λ=-0.10). CONCLUSION: The characteristics of the professional nursing practice environment that most contribute to achieving better outcomes include nurse manager ability, leadership and support of nurses, staffing and resource adequacy, and collegial nurse-physician relations. IMPACT: This study allowed us to assess which strategies should be prioritized in the professional nursing practice environment to achieve better results. Thus, investment in the training of leadership, in the adequacy of resources, and in physician-nurse relations will bring better results for patients, nursing professionals, and institutions.

Fatigue performance of adhesively luted glass or polycrystalline CAD-CAM monolithic crowns.

STATEMENT OF PROBLEM: Data comparing the fatigue performance of adhesively luted glass or polycrystalline ceramic systems for computer-aided design and computer-aided manufacturing (CAD-CAM) are scarce. PURPOSE: The purpose of this in vitro study was to evaluate and compare the fatigue performance of monolithic crowns manufactured from glass or polycrystalline CAD-CAM ceramic systems adhesively luted to a dentin analog. MATERIALS AND METHODS: Fifty-four pairs of standardized preparations of dentin analog (NEMA Grade G10) and simplified ceramic crowns of 1.5-mm thickness were obtained with 3 ceramic materials: lithium disilicate (LD) glass-ceramic (IPS e.max CAD); zirconia-reinforced lithium silicate (ZLS) glass-ceramic (Vita Suprinity); and translucent yttrium fully stabilized polycrystalline zirconia (Trans YZ) (Prettau Anterior). The simplified crowns (n=15) were adhesively cemented onto the preparations and subjected to step-stress fatigue test (initial load of 400 N, 20 Hz, 10 000 cycles, followed by 100-N increment steps until failure). Collected data (fatigue failure load [FFL] and cycles for failure [CFF]) were submitted to survival analysis with the Kaplan-Meier and Mantel-Cox post hoc tests (α=.05) and to Weibull analysis (Weibull modulus and its respective 95% confidence interval). Failed crowns were submitted to fractography analysis. The surface characteristics of the internal surface (roughness, fractal dimension) of additional crowns were accessed, and the occlusal cement thickness obtained in each luted system was measured. RESULTS: Trans YZ crowns presented the highest values of FFL, CFF, and survival rates, followed by ZLS and LD (mean FFL: 1740 N>1187 N>987 N; mean CFF: 149 000>92 613>73 667). Weibull modulus and cement thickness were similar for all tested materials. LD presented the roughest internal surface, followed by ZLS (mean Ra: 226 nm>169 nm>93 nm). The LD and ZLS internal surfaces also showed higher fractal dimension, pointing to a more complex surface topography (mean fractal dimension: 2.242=2.238>2.147). CONCLUSIONS: CAD-CAM monolithic crowns of Trans YZ show the best fatigue performance. In addition, ZLS crowns also showed better performance than LD crowns.

Bond strength and quality of bond interface of multifilament fiberglass posts luted onto flat-oval root canals without additional dentin wear after biomechanical preparation.

STATEMENT OF PROBLEM: An intraradicular retainer formed by multiple independent glass fiber filaments was developed aiming to allow better adaptation in flattened root canals; however, the performance of the new posts is unclear. PURPOSE: The purpose of this in vitro study was to compare the bond strength (BS) and adhesive interface quality achieved in flattened root canals restored with conventional glass fiber posts (CFPs) and multifilament glass fiber posts (MFPs). MATERIAL AND METHODS: The distal roots of mandibular molars with long oval root canals were endodontically treated, and the obturation material was removed and assigned to 2 groups (n=11) according to the type of retainer used: CFP (WhitePostDC#0.5; FGM) or MFP (CometTail#4; Synca). The posts were cemented with self-adhesive resin cement. The specimens were sectioned (2 slices per third). The most cervical slice in each third was used to evaluate the BS, while the adhesive interface in the apical slices was analyzed by scanning electron microscopy. BS data were analyzed by using a multilevel generalized linear model, and adhesive interface SEM data were analyzed by using a multilevel ordinal logistic regression model (α=.05). RESULTS: Multilevel regression showed a statistically significant difference for the "type of retainer" factor (P=.001; CFP 2.61 ±1.30>MFP 1.59 ±1.54). No statistically significant differences were found for the "root thirds" factor (P=.346) or for the interaction of both factors (P=.114). The failure pattern was predominantly mixed or adhesive for CFP and adhesive to dentin for MFP. A better adaptation of the restorative material was observed in the cervical third for CFP and in the apical third for MFP (P<.001). CONCLUSIONS: MFP resulted in lower BS values than CFP, with a higher prevalence of adhesive failures to dentin and better adaptation of the adhesive interface in the apical third.

Relational schemas as mediators of innovative moments in symptom improvement in major depression.

OBJECTIVES: Innovative moments (IMs) are exceptions to the maladaptive framework of meaning that typically motivates clients to seek psychotherapy, and previous studies have shown that IMs are associated with psychotherapy outcomes. While IMs are exceptions that occur at the level of the therapeutic conversation, relational schemas are more stable patterns, and their increased flexibility may facilitate change during psychotherapy. With this in mind, we tested the hypothesis that IMs contribute to outcomes by improving the flexibility of relational schemas. METHOD: The Core Conflictual Relationship Theme (CCRT) was used to assess relational schemas. IMs were evaluated using the Innovative Moments Coding System. The sample included 22 clients diagnosed with major depressive disorder. The flexibility of the three components of the CCRT (Wishes, responses of the self (RS), and responses of others (RO)) were tested as mediators between IMs and outcomes. RESULTS: The flexibility of the RS was a mediator between IMs and outcomes, but Wishes and RO were not. CONCLUSION: These findings align with previous research showing that RS is the component most open to change, whereas the other components seem less sensitive to change during brief therapy. Clinical or methodological significance of this article: This study shows the mediation role of relational schemas in the association between in-session events (innovative moments (IMs)) and the symptoms improvement. It contributes to the literature that emphasizes the importance of relational schemas in psychotherapy by using a mediation model, which has rarely been tested.

Low potassium and high sodium intakes: a double health threat to Cape Verdeans.

BACKGROUND: Cape Verde presents a high rate of cardiovascular diseases. Low potassium and high sodium intakes are related to cardiovascular diseases. However, studies regarding these two micronutrients continue to be rare in African urban settings. This work aims to estimate potassium and sodium intakes and to analyse the self-reported salt intake by gender and by type of urban area in the city of Praia - the capital of Cape Verde. METHODS: In the first stage (n = 1912), an intra-urban study was designed in two types of urban areas (formal and informal), using a sampling strategy based on random selection of geographical coordinates, in order to apply a questionnaire. In a second stage, a 24-h dietary recall and anthropometric measurements were performed by local nutritionists. Potassium and sodium intakes were estimated for 599 participants (149 men and 450 women). Non-parametric methods (including quantile regression) were used in the statistical analysis. RESULTS: In informal areas, a higher percentage of women reported having hypertension (31.0%) compared to formal areas (19.7%). Based on 24-h dietary recall, median potassium intake for men was 2924.2 mg/day and for women and 2562.6 mg/day. Almost 70.0% of men and 80.0% of women ingested less than the recommended 3510 mg/day of potassium. In informal areas, men and women presented high medians of sodium intakes compared to formal areas (men: 4131.2 vs 3014.6 mg/day and women: 3243.4 vs 2522.4 mg/day). On the other hand, the percentage of participants exceeding 2000 mg/day for sodium was high (≥70.8%), even for participants that self-reported low-salt intake. Quantile regression models revealed effects of the type of urban area and gender in the potassium and sodium intakes, at least, in some quartiles, accounting for age, academic qualifications, and professional situation. CONCLUSIONS: A low potassium intake and a high sodium intake were found in Praia. Thus, efficient health education campaigns and health promotion are needed and should be tailored considering gender and urban areas.

Nursing practice environment, job outcomes and safety climate: a structural equation modelling analysis.

AIM: To assess correlations between the characteristics of the nursing practice environment, job outcomes and safety climate. BACKGROUND: The nursing practice environment is critical to the well-being of professionals and to patient safety, as highlighted by national and international studies; however, there is a lack of evidence regarding this theme in paediatric units. METHODS: A cross-sectional study, in two paediatric hospitals in Brazil, was conducted from December 2013 to February 2014. For data collection, we used the Nursing Work Index - Revised, Safety Attitudes Questionnaire - Short Form 2006 and the Maslach Burnout Inventory, and for analysis Spearman's correlation coefficient and structural equation modelling were used. RESULTS: Two hundred and sixty-seven professional nurses participated in the study. Autonomy, control over the work environment and the relationship between nursing and medical staff are factors associated with job outcomes and safety climate and can be considered their predictors. CONCLUSIONS: Professional nurses with greater autonomy, good working relationships and control over their work environment have lower levels of emotional exhaustion, higher job satisfaction, less intention of leaving the job and the safety climate is positive. IMPLICATIONS FOR NURSING MANAGEMENT: Initiatives to improve the professional practice environment can improve the safety of paediatric patients and the well-being of professional nurses.

Three narrative-based coding systems: Innovative moments, ambivalence and ambivalence resolution.

Narrative and dialogical perspectives suggest that personal meaning systems' flexibility is an important resource for change in psychotherapy. Drawn from these theoretical backgrounds, a research program focused on the identification of Innovative Moments (IMs)-exceptions to the inflexible meaning systems present in psychopathological suffering-has been carried out. For this purpose, three process-oriented coding systems were developed: The IMs Coding System, the Ambivalence Coding System, and the Ambivalence Resolution Coding System. They allow, respectively, for the study of change, ambivalence, and ambivalence resolution in therapy. This paper presents these coding systems, the main findings that resulted from their application to different samples and therapeutic models, the main current and future lines of research, as well as the clinical applications of this research program.

Rare sequelae in the permanent successor due to trauma in the primary incisor: a case report.

Severe dental trauma-such as intrusion or avulsion-to the primary dentition in infants and toddlers may cause developmental disturbances in the permanent successor. In this case, a 9-year-old boy was referred for treatment due to the absence of his permanent maxillary right central incisor. The mother reported avulsion of the corresponding primary tooth when the patient was 2 years old. The radiographic examination revealed impaction and root dilaceration of the permanent tooth; therefore, the treatment plan was tooth extraction. The extracted tooth presented multiple abnormalities, including enamel discoloration, enamel hypoplasia, root dilaceration, and root duplication. Several factors need to be considered when treatment of traumatic sequelae to a permanent successor is planned, including the age of the patient, the developmental stage of the permanent successor at the time of trauma, and the type of trauma to the primary tooth.

Ambivalence in grief therapy: The interplay between change and self-stability.

This article explores the role of ambivalence in grief therapy within a narrative framework. From this perspective, change starts with the occurrence of innovative moments, which can be nullified by reaffirmation of the problematic self-narrative as a sign of ambivalence. This study analyzed ambivalence in six complicated grief cases using the "Return to the Problem Coding System." Markers of ambivalence emerged in all cases, with a decreasing profile in cases with greater symptomatic improvement, suggesting an association between clinical change and ambivalence evolution in therapy. Addressing ambivalence may bring to light important aspects of client's self-reconstruction after a major loss.

Nursing work environment, patient safety and quality of care in pediatric hospital. / Ambiente de trabalho da enfermagem, segurança do paciente e qualidade do cuidado em hospital pediátrico.

Objectives To describe the characteristics of the nursing work environment, safety attitudes, quality of care, measured by the nursing staff of the pediatric units, as well as to analyze the evolution of quality of care and hospital indicators. Methods Descriptive study with 136 nursing professionals at a paediatric hospital, conducted through personal and professional characterization form, Nursing Work Index - Revised, Safety Attitudes Questionnaire - Short Form 2006 and quality indicators. Results The professionals perceive the environment as favourable to professional practice, and consider good quality care that is also observed by reducing the incidence of adverse events and decreased length of stay. The domain job satisfaction was considered favourable to patient safety. Conclusions The work environment is favourable to nursing practice, the professionals nursing approve the quality of care and the indicators tended reducing adverse events and length of stay.

Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.

Lateral meningocele syndrome (LMS, OMIM%130720), also known as Lehman syndrome, is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele-related neurologic dysfunction. The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine. Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis may be present. Lateral meningocele syndrome has phenotypic overlap with Hajdu-Cheney syndrome. We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating NOTCH3 mutations. In an additional unrelated individual Sanger sequencing revealed a deleterious variant in the same exon 33. In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients. One had a 26 bp deletion (c.6461_6486del, p.G2154fsTer78), two carried the same single base pair insertion (c.6692_93insC, p.P2231fsTer11), and three individuals had a nonsense point mutation at c.6247A > T (pK2083*), c.6663C > G (p.Y2221*) or c.6732C > A, (p.Y2244*). All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline-glutamate-serine-threonine rich PEST domain. Our results suggest that mutant mRNA products escape nonsense mediated decay. The truncated NOTCH3 may cause gain-of-function through decreased clearance of the active intracellular product, resembling NOTCH2 mutations in the clinically related Hajdu-Cheney syndrome and contrasting the NOTCH3 missense mutations causing CADASIL.

Increasing use of non-invasive ventilation in asthma: a long-term analysis of the Portuguese national hospitalization database.

OBJECTIVES: To describe the use and outcomes of non-invasive positive pressure ventilation (NPPV) and invasive ventilation (IV) in adults hospitalized for acute asthma exacerbations in Portugal. METHODS: We analyzed the hospitalizations of adults with a principal diagnosis of asthma in mainland Portugal between 2000 and 2010. The data source was the national hospitalizations database, which includes administrative and clinical data produced by physicians trained in coding. RESULTS: Ventilation support was used in 5.1% (n = 747) of the 14,515 hospitalizations with a principal diagnosis of asthma: NPPV in 1.7% (n = 241) and IV in 3.5% (n = 506); NPPV use increased from 1% in 2000 to 3.3% in 2010. In patients with asthma, the ratio of NPPV use to IV use increased from 0.27 to 1.06. This increase was observed even after exclusion of secondary diagnoses in which NPPV is frequently used. The mortality rate was 1.5% for all asthma hospitalizations: 2.5% when NPPV was used and 15.8% for those requiring IV. CONCLUSIONS: The use of ventilation support in asthma remained stable over time; however, the use of non-invasive ventilation has increased. Still, we do not have good data regarding the effectiveness of non-invasive ventilation when treating asthma exacerbations. Therefore, additional studies are much needed and should assess physiologic and clinical variables that might affect the effectiveness of non-invasive ventilation in patients with asthma exacerbations.