Demographic, clinical, and patient-reported outcome data from 2 global, phase 3 trials of chronic cough.

BACKGROUND: The current characterization of patients with refractory or unexplained chronic cough (RCC and UCC, respectively) primarily stems from relatively small clinical studies. OBJECTIVE: To report the baseline medical history and clinical characteristics of individuals with RCC or UCC who were enrolled in COUGH-1 and COUGH-2, 2 large, global, phase 3 trials of gefapixant, a P2 × 3-receptor antagonist. METHODS: Adults with a chronic cough lasting for more than 1 year, diagnosis of RCC or UCC, and score greater than 40 mm on a 100-mm cough severity visual analog scale at both screening and baseline were eligible for enrollment. Demographics, medical history, and cough characteristics were collected at baseline. Cough-related measures included objective cough frequency, cough severity visual analog scale, Leicester Cough Questionnaire, and Hull Airway Reflux Questionnaire. The data were summarized using descriptive statistics. RESULTS: Of 2044 participants, 75% were women; mean age was 58 years, and mean cough duration was approximately 11 years. Among all participants, 73% were previously diagnosed with asthma, gastroesophageal reflux disease, or upper airway cough syndrome. The mean Leicester Cough Questionnaire total score was 10.4, with domain scores reflecting impaired cough-specific quality of life across physical, psychological, and social domains. The mean Hull Airway Reflux Questionnaire score was 39.6, with some of the most burdensome reported items being consistent with features of cough-reflex hypersensitivity. Participant characteristics and cough burden were comparable across geographic regions. CONCLUSION: Participants with RCC or UCC had characteristics consistent with published demographics associated with chronic cough. These data reflect a global population with burdensome cough of long duration and substantial impairment to quality of life. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: COUGH-1, NCT03449134 (https://www. CLINICALTRIALS: gov/ct2/show/NCT03449134); COUGH-2, NCT03449147 (https://clinicaltrials.gov/ct2/show/NCT03449147).

The Efficacy and Safety of Gefapixant in a Phase 3b Trial of Patients with Recent-Onset Chronic Cough.

PURPOSE: We evaluated gefapixant, a P2X3 receptor antagonist, in participants with recent-onset (≤ 12 months) refractory chronic cough (RCC) or unexplained chronic cough (UCC). METHODS: Participants (≥ 18 years of age; ≥ 40 mm on a 100-mm cough severity visual analog scale [VAS] at screening and randomization) with chronic cough for < 12 months were enrolled in this phase 3b, double-blind, placebo-controlled, parallel group, multicenter study (NCT04193202). Participants were randomized 1:1 to gefapixant 45 mg BID or placebo for 12 weeks with a 2-week follow-up. The primary efficacy endpoint was change from baseline at Week 12 in Leicester Cough Questionnaire (LCQ) total score. Adverse events were monitored and evaluated. RESULTS: There were 415 participants randomized and treated (mean age 52.5 years; median [range] duration 7.5 [1-12] months): 209 received placebo and 206 received gefapixant 45 mg BID. A statistically significant treatment difference of 0.75 (95% CI: 0.06, 1.44; p = 0.034) for gefapixant vs. placebo was observed for change from baseline in LCQ total score at Week 12. The most common AE was dysgeusia (32% gefapixant vs. 3% placebo participants); serious AEs were rare (1.5% gefapixant vs. 1.9% placebo participants). CONCLUSION: Gefapixant 45 mg BID demonstrated significantly greater improvement in cough-specific health status from baseline compared to placebo, in participants with recent-onset chronic cough. The most common AEs were related to taste and serious AEs were rare.

Application of unsupervised deep learning algorithms for identification of specific clusters of chronic cough patients from EMR data.

BACKGROUND: Chronic cough affects approximately 10% of adults. The lack of ICD codes for chronic cough makes it challenging to apply supervised learning methods to predict the characteristics of chronic cough patients, thereby requiring the identification of chronic cough patients by other mechanisms. We developed a deep clustering algorithm with auto-encoder embedding (DCAE) to identify clusters of chronic cough patients based on data from a large cohort of 264,146 patients from the Electronic Medical Records (EMR) system. We constructed features using the diagnosis within the EMR, then built a clustering-oriented loss function directly on embedded features of the deep autoencoder to jointly perform feature refinement and cluster assignment. Lastly, we performed statistical analysis on the identified clusters to characterize the chronic cough patients compared to the non-chronic cough patients. RESULTS: The experimental results show that the DCAE model generated three chronic cough clusters and one non-chronic cough patient cluster. We found various diagnoses, medications, and lab tests highly associated with chronic cough patients by comparing the chronic cough cluster with the non-chronic cough cluster. Comparison of chronic cough clusters demonstrated that certain combinations of medications and diagnoses characterize some chronic cough clusters. CONCLUSIONS: To the best of our knowledge, this study is the first to test the potential of unsupervised deep learning methods for chronic cough investigation, which also shows a great advantage over existing algorithms for patient data clustering.

Validation and Meaningful Change Thresholds for an Objective Cough Frequency Measurement in Chronic Cough.

PURPOSE: Objective cough frequency is used to assess efficacy of chronic cough (CC) treatments. The objective of this study was to explore the relationship between objective cough frequency and cough-specific patient-reported outcomes (PROs) and estimate a clinically meaningful change threshold (MCT) for objective cough frequency. METHODS: Data collected in a phase 2b study in participants with refractory or unexplained CC were used to investigate the relationship between 24-h cough frequency (measured using an ambulatory cough monitor) and cough-specific PROs (i.e., cough severity visual analog scale, cough severity diary, Leicester Cough Questionnaire). Convergent validity was assessed using Spearman ρ. An MCT for 24-h cough frequency was estimated using the patient global impression of change (PGIC) scale as an anchor. RESULTS: Correlations between 24-h cough frequency and cough-specific PROs at baseline, Week 4, and Week 12 were significant (P < 0.0001) but low to moderate in strength (ρ = 0.30-0.58). Participants categorized as very much improved/much improved (i.e., PGIC of 1 or 2) or minimally improved (i.e., PGIC of 3) had mean 24-h cough frequency reductions of 55% and 30%, respectively. Receiver operating characteristic curve analysis suggested that a 24-h cough frequency reduction of 38% optimizes sensitivity and specificity for predicting a PGIC score of 1-3. CONCLUSION: Objective 24-h cough frequency is significantly associated with cough-specific PROs, but cough frequency and PROs most likely capture distinct aspects of CC. A ≥ 30% reduction in 24-h cough frequency is a reasonable MCT to define treatment response in CC clinical trials.

Improvements in Objective and Subjective Measures of Chronic Cough with Gefapixant: A Pooled Phase 3 Efficacy Analysis of Predefined Subgroups.

INTRODUCTION: In phase 3 trials (COUGH-1/COUGH-2), gefapixant 45 mg twice daily significantly reduced 24-h cough frequency vs placebo in refractory or unexplained chronic cough (RCC or UCC). METHODS: Here, the efficacy of gefapixant 45 mg vs placebo was evaluated across COUGH-1/COUGH-2 in predefined subgroups based on sex, region, age, cough duration, cough severity, cough frequency, and diagnosis (RCC, UCC). Awake cough frequency reductions at Week 12 and LCQ response rates (i.e., ≥ 1.3-point improvement) at Week 24 were assessed. RESULTS: Among 1360 participants analyzed, gefapixant 45 mg resulted in consistent awake cough frequency reductions overall and across predefined subgroups at Week 12. Gefapixant also resulted in improved LCQ scores across subgroups at Week 24; ≥ 70% of participants in each subgroup treated with gefapixant 45 mg had an LCQ response. CONCLUSION: These data suggest gefapixant 45 mg provides consistent objective and subjective efficacy across subgroups of individuals with RCC or UCC.

A phase 3, randomized, double-blind, clinical study to evaluate the long-term safety and efficacy of gefapixant in Japanese adult participants with refractory or unexplained chronic cough.

BACKGROUND: In two phase 3, global clinical trials (COUGH-1 and COUGH-2), the P2X3-receptor antagonist gefapixant significantly reduced objective 24-h cough frequency in participants with refractory or unexplained chronic cough (RCC or UCC) at a dosage of 45 mg twice daily (BID), with an acceptable safety profile. The primary objective of this phase 3, randomized, double-blind, parallel-group study was to assess the safety and tolerability of gefapixant in Japanese participants with RCC or UCC (ClinicalTrials.gov, NCT03696108; JAPIC-CTI, 184154). METHODS: Participants aged ≥20 years with chronic cough lasting ≥4 months and a diagnosis of RCC or UCC despite treatment in accordance with Japanese Respiratory Society guidelines were randomized 1:1 to receive gefapixant 15 or 45 mg BID for 52 weeks. The primary objective was to evaluate the safety and tolerability of gefapixant, including adverse events (AEs) and discontinuations due to AEs. Cough-specific quality of life was assessed using the Leicester Cough Questionnaire as a secondary objective. RESULTS: Of 169 randomized and treated participants, 63% were female and mean age was 58 years. Adverse events were reported by 79 (94%) and 82 (96%) participants in the 15- and 45-mg BID groups, respectively. Most treatment-related AEs were taste related. Discontinuations due to AEs occurred in 6 (7%) and 17 (20%) participants receiving gefapixant 15 or 45 mg BID, respectively. There were no serious treatment-related AEs or deaths. Leicester Cough Questionnaire total scores improved from baseline through Week 52. CONCLUSIONS: Gefapixant had an acceptable safety profile, with no serious treatment-related AEs in Japanese participants.

Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials.

BACKGROUND: Tildrakizumab is a high-affinity, humanised, IgG1 κ antibody targeting interleukin 23 p19 that represents an evolving treatment strategy in chronic plaque psoriasis. Previous research suggested clinical improvement with inhibition of interleukin 23 p19. We did two phase 3 trials to investigate whether tildrakizumab is superior to placebo and etanercept in the treatment of chronic plaque psoriasis. METHODS: We did two three-part, parallel group, double-blind, randomised controlled studies, reSURFACE 1 (at 118 sites in Australia, Canada, Japan, the UK, and the USA) and reSURFACE 2 (at 132 sites in Europe, Israel, and the USA). Participants aged 18 years or older with moderate-to-severe chronic plaque psoriasis (body surface area involvement ≥10%, Physician's Global Assessment [PGA] score ≥3, and Psoriasis Area and Severity Index [PASI] score ≥12) were randomised (via interactive voice and web response system) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo in reSURFACE 1 (2:2:1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2). Randomisation was done by region and stratified for bodyweight (≤90 kg or >90 kg) and previous exposure to biologics therapy for psoriasis. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Assigned medication was identical in appearance and packaging. Tildrakizumab was administered subcutaneously at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomised from placebo to tildrakizumab; etanercept was given twice weekly in part 1 of reSURFACE 2 and once weekly during part 2). The co-primary endpoints were the proportion of patients achieving PASI 75 and PGA response (score of 0 or 1 with ≥2 grade score reduction from baseline) at week 12. Safety was assessed in the all-participants-as-treated population, and efficacy in the full-analysis set. These trials are registered with ClinicalTrials.gov, numbers NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). These studies are completed, but extension studies are ongoing. FINDINGS: reSURFACE 1 ran from Dec 10, 2012, to Oct 28, 2015. reSURFACE 2 ran from Feb 12, 2013, to Sept 28, 2015. In reSURFACE 1, 772 patients were randomly assigned, 308 to tildrakizumab 200 mg, 309 to tildrakizumab 100 mg, and 155 to placebo. At week 12, 192 patients (62%) in the 200 mg group and 197 patients (64%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). 182 patients (59%) in the 200 mg group and 179 patients (58%) in the 100 mg group achieved PGA responses, compared with 11 patients (7%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). In reSURFACE 2, 1090 patients were randomly assigned, 314 to tildrakizumab 200 mg, 307 to tildrakizumab 100 mg, 156 to placebo, and 313 to etanercept. At week 12, 206 patients (66%) in the 200 mg group, and 188 patients (61%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group and 151 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p<0·0001 for 200 mg vs etanercept and p=0·0010 for 100 mg vs etanercept). 186 patients (59%) in the 200 mg group, and 168 patients (59%) [corrected] in the 100 mg group achieved a PGA response, compared with 7 patients (4%) in the placebo group and 149 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p=0·0031 for 200 mg vs etanercept and p=0·0663 for 100 mg vs etanercept). Serious adverse events were similar and low in all groups in both trials. One patient died in reSURFACE 2, in the tildrakizumab 100 mg group; the patient had alcoholic cardiomyopathy and steatohepatitis, and adjudication was unable to determine the cause of death. INTERPRETATION: In two phase 3 trials, tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated in the treatment of patients with moderate-to-severe chronic plaque psoriasis. FUNDING: Merck & Co.

Population pharmacokinetic analysis of the P2X3-receptor antagonist gefapixant.

Gefapixant, a P2X3-receptor antagonist, demonstrated objective and subjective efficacy in individuals with refractory or unexplained chronic cough. We report a population pharmacokinetic (PopPK) analysis that characterizes gefapixant pharmacokinetics (PKs), quantifies between- and within-participant variability, and evaluates the impact of intrinsic and extrinsic factors on gefapixant exposure. The PopPK model was initially developed using PK data from six phase I studies. Stepwise covariate method was utilized to identify covariates impacting PK parameters; the model was re-estimated and covariate effects were re-assessed after integrating PK data from three phase II and III studies. Simulations were conducted to evaluate the magnitude of covariate effects on gefapixant exposure. Of 1677 participants included in this data set, 1618 had evaluable PK records. Age, body weight, and sex had statistically significant, but not clinically relevant, effects on exposure. Degree of renal impairment (RI) had statistically significant and clinically relevant effects on exposure; exposure was 17% to 89% higher in those with versus without RI. Simulation results indicated that gefapixant 45 mg administered once daily to patients with severe RI has similar exposure to gefapixant 45 mg administered twice daily to patients with normal renal function. There were no significant effects of proton pump inhibitors or food. Of evaluated intrinsic and extrinsic factors, only RI had a clinically relevant effect on gefapixant exposure. Patients with mild or moderate RI do not require dosage adjustments; however, for patients with severe RI who are not on dialysis, gefapixant 45 mg once daily is recommended.

Leicester Cough Questionnaire validation and clinically important thresholds for change in refractory or unexplained chronic cough.

INTRODUCTION: The Leicester Cough Questionnaire (LCQ), a cough-specific quality-of-life measure, evaluates the impact of cough across physical, psychological, and social domains in patients with chronic cough (CC). This study assessed the psychometric properties of the LCQ. METHODS: Data from a phase IIb, randomized controlled trial of the P2X3-receptor antagonist gefapixant were analyzed (NCT02612610). Subjective [Cough Severity Diary, cough severity visual analogue scale, and patient global impression of change (PGIC)] and objective (awake and 24-h cough frequency) data were used to validate the LCQ for use in patients with refractory or unexplained CC (RCC and UCC, respectively). Psychometric analyses included confirmatory factor analyses, internal consistency and test-retest reliability, validity, responsiveness, and estimated within-patient thresholds for clinically meaningful change. RESULTS: Model-fit values for the proposed three-factor LCQ domains and most individual items were acceptable. Analyses suggest that a mean improvement ranging from 1.3 to 2.3 points for the LCQ total and ⩾0.8, ⩾0.9, and ⩾0.8 points for physical, psychological, and social domain scores, respectively, had the best sensitivity and/or specificity for predicting patient ratings of improvement on the PGIC. CONCLUSIONS: The LCQ is a valid and reliable measure to evaluate cough-specific quality of life and is a fit-for-purpose measure for use in patients with RCC or UCC. Although a single threshold for defining clinically meaningful change depends on the context of use, the results can help guide both treatment decisions and drug development. Therefore, clinicians may consider a ⩾1.3-point increase in the LCQ total score as clinically meaningful.

Applying interpretable deep learning models to identify chronic cough patients using EHR data.

BACKGROUND AND OBJECTIVE: Chronic cough (CC) affects approximately 10% of adults. Many disease states are associated with chronic cough, such as asthma, upper airway cough syndrome, bronchitis, and gastroesophageal reflux disease. The lack of an ICD code specific for chronic cough makes it challenging to identify such patients from electronic health records (EHRs). For clinical and research purposes, computational methods using EHR data are urgently needed to identify chronic cough cases. This research aims to investigate the data representations and deep learning algorithms for chronic cough prediction. METHODS: Utilizing real-world EHR data from a large academic healthcare system from October 2005 to September 2015, we investigated Natural Language Representation of the EHR data and systematically evaluated deep learning and traditional machine learning models to predict chronic cough patients. We built these machine learning models using structured data (medication and diagnosis) and unstructured data (clinical notes). RESULTS: The sensitivity and specificity of a transformer-based deep learning algorithm, specifically BERT with attention model, was 0.856 and 0.866, respectively, using structured data (medication and diagnosis). Sensitivity and specificity improved to 0.952 and 0.930 when we combined structured data with symptoms extracted from clinical notes. We further found that the attention mechanism of deep learning models can be used to extract important features that drive the prediction decisions. Compared with our previously published rule-based algorithm, the deep learning algorithm can identify more chronic cough patients with structured data. CONCLUSIONS: By applying deep learning models, chronic cough patients can be reliably identified for prospective or retrospective research through medication and diagnosis data, widely available in EHR and electronic claims data, thus improving the generalizability of the patient identification algorithm. Deep learning models can identify chronic cough patients with even higher sensitivity and specificity when structured and unstructured EHR data are utilized. We anticipate language-based data representation and deep learning models developed in this research could also be productively used for other disease prediction and case identification.

Design and rationale of two phase 3 randomised controlled trials (COUGH-1 and COUGH-2) of gefapixant, a P2X3 receptor antagonist, in refractory or unexplained chronic cough.

BACKGROUND: We present study designs, dose selection and preliminary patient characteristics from two phase 3 clinical trials of gefapixant, a P2X3 receptor antagonist, in refractory chronic cough (RCC) or unexplained chronic cough (UCC). METHODS: COUGH-1 (NCT03449134) and COUGH-2 (NCT03449147) are randomised, placebo-controlled, double-blind, parallel-group trials in subjects with RCC or UCC (age ≥18 years; cough duration ≥1 year; Cough Severity Visual Analogue Scale score ≥40 mm). The primary efficacy study periods are 12 weeks (40-week extension; COUGH-1) and 24 weeks (28-week extension; COUGH-2). Interventions include placebo, gefapixant 15 mg and gefapixant 45 mg (1:1:1 ratio). The primary efficacy endpoints are average 24-h cough frequency at Week 12 (COUGH-1) and Week 24 (COUGH-2). Awake cough frequency, patient-reported outcomes and responder analyses are secondary endpoints. RESULTS: The doses of 45 mg (to provide maximal efficacy and acceptable tolerability) and 15 mg (to provide acceptable efficacy and improved tolerability) were selected based on phase 1 and 2 studies. In COUGH-1, 730 participants have been randomised and treated; 74% are female with mean age of 59 years (39% over 65 years), and mean baseline duration of cough of 11.5 years. In COUGH-2, 1314 participants have been randomised and treated; 75% are female with mean age of 58 years (33% over 65 years), and mean baseline duration of cough of 11.1 years. CONCLUSIONS: These global studies include participants with baseline characteristics consistent with previous RCC and UCC studies and will inform the efficacy and safety profile of gefapixant in the treatment of patients with RCC and UCC.

Microbiological quality of saffron from the main producer countries.

A microbiological study of saffron spice was undertaken in the context of a European research project (Methodologies for Implementing International Standards for Saffron Purity and Quality, the acronym for which is SAFFIC), analyzing 79 samples obtained from the main producer countries, namely Greece, Iran, Italy, Morocco, and Spain. Current microbiological quality criteria are the same as for other spices, but saffron is added in minute quantities during the cooking process, so the health risk associated with microbial contamination might be lower. We did not detect Salmonella either by culture or by PCR methods in any sample, and Escherichia coli was only found in five samples. Enterobacteriaceae were frequently found (70.9% of the samples), but most of them belonged to species of probable environmental origin. Aerobic sporulated bacteria were also common, but only three samples contained Bacillus cereus at low levels (<200 CFU g(-1)). Clostridium perfringens counts were also very low, with only one sample reaching >100 CFU g(-1), an acceptable value. Overall, microbial contamination in saffron was markedly lower than it was in other spices.

Efficacy of an Intervention Program to Improve Employability of University Students.

In the current socioeconomic situation, the need to improve employability of potential workers is especially relevant. The aim of this study was to evaluate the efficacy of an intervention program focusing on improving employability of university students. To do this, a two-group study was designed: one group undertook the intervention program and the other group were used for comparison. Two measurements were taken at different times (pre-intervention and post-intervention). The sample consisted of 271 university students. The results show that the group that underwent the intervention program improved their perceived employability F(1, 269) = 17.49, p < .001; η2 = .06, openness to learning F(1, 269) = 4.24, p < .05; η2 = .02, self-efficacy for labor market insertion F(1, 269) = 75.70, p < .001; η2 = .22 and for teamwork F(1, 269) = 39.43, p < .001; η2 = .13, and their knowledge of employment resources F(1, 269) = 512.89, p < .001; η2 = .66 compared to the group that did not. Furthermore, there was a high level of satisfaction of participants with the intervention program.

Efectividad de la terapia láser combinada con la técnica convencional en pacientes con discromías dentales / Effectiveness of laser therapy combined with the conventional technique in patients with dental dischromya

Introducción: La discromía dental es una afectación estética, de causa multifactorial, caracterizada por el cambio de coloración de uno o varios dientes. Objetivo: Evaluar la efectividad de la terapia láser como fuente de luz y calor en pacientes con discromías dentales. Método: Se realizó un estudio cuasi experimental, de intervención terapéutica, en 24 pacientes con discromías dentales atendidos en la Clínica Estomatológica Provincial DocenteMártires del Moncada de Santiago de Cuba, desde julio de 2017 hasta julio de 2018. Los integrantes del estudio se asignaron de forma aleatoria a 2 grupos de tratamiento:a los pares (grupo de estudio) se les aplicó láser combinado con la técnica convencional de peróxido de hidrógeno;a los impares (grupo control), tratamiento convencional solamente.Se utilizaron las frecuencias absoluta y relativa como medidas de resumen, así como la prueba de X 2 de homogeneidad para la validación estadística, con un nivel de significación de 0,05. Resultados: Para los pacientes del grupo de estudio, la segunda y tercera sesiones fueron más efectivas. Al culminar el tratamiento, ambos resultaron efectivos, pero los que recibieron láser evolucionaron más rápidamente que los tratados solo con peróxido de hidrógeno. Conclusiones: El uso de la terapia láser y peróxido de hidrógeno fue efectivo en pacientes con discromías dentales y demostró que no provoca efectos adversos en los dientes tratados.

Introduction: The dental dischromya is an esthetic disorder, of multifactorial cause, characterized by the change of coloration of one or several teeth. Objective: To evaluate the effectiveness of laser therapy as a source of light and heat in patients with dental dischromya. Method: A quasi-experiment, of therapeutic intervention study, was carried out in 24 patients with dental dischromya assisted in Mártires del Moncada Teaching Provincial Stomatological Clinic in Santiago de Cuba, from July, 2017 to March, 2018. The members of the study were assigned at random with 2 treatment groups: a study group (pairs) to whom laser combined with the conventional technique of peroxide of hydrogen was applied; to odd number patients (control group), conventional treatment only. The absolute and relative frequencies were used as summary measures, as well as the chi-square test of homogeneity for the statistical validation, with a level of significance of 0.05. Results: For the patients of the study group, the second and third sessions were more effective. When culminating the treatment, both were effective, but those that received laser evolved more quickly than those treated with peroxide of hydrogen. Conclusions: The use of the laser therapy and peroxide of hydrogen was effective in patients with dental dischromya and it was demonstrated that doesn't cause adverse effects in the treated teeth.

Neurofibromatosis type 1 (NF1): Identification of eight unreported mutations in NF1 gene in Italian patients [corrected].

In the present study the entire NF1 coding region was analyzed for mutations in 132 unrelated Italian NF1 patients. Using PTT, SSCP, and DNA sequencing, we found 8 novel mutations. Clinical diagnosis of NF1 was established according to the NIH consensus criteria. We detected 59 truncated fragments, and 46 of them were characterized by SSCP and direct sequencing. Eight mutations represent novel changes that contribute to the germline mutational spectrum of the NF1 gene. In two patients, premature termination was due to substitutions at nucleotide c.3982C>T (Q1298X) and c.7411C>T (Q2471X), respectively. Two other mutations were caused by the deletions (1756delA, 4699delA), and two by the insertions (c.5266_5267insT, c.7464_7465insTCCA) of a small number of nucleotides. Lastly, we found 2 splice-site mutations (c.2252-2A>C, c.2251+1G>A).

Ten novel mutations in the human neurofibromatosis type 1 (NF1) gene in Italian patients.

The entire NF1 coding region was analyzed for mutations in a panel of 108 unrelated Italian NF1 patients. Using PTT, SSCP, and DNA sequencing, we found 10 mutations which have never been reported before. Clinical diagnosis of NF1 was established according to the NIH consensus criteria in 100 individuals, while 8 were young children with only multiple cafè-au-lait spots. We detected 46 truncated fragments, and 24 of them were fully characterized by SSCP and direct sequencing. Of the 24, 14 were known mutations (R304X, R681X, Q682X, R1306X, R1362X, R1513X, R1748X, Q1794X, R1947X, Y2264X, R2237X, 2674delA, 6789delTTAC, 2027insC). The other 10 mutations represent novel changes that contribute to the germline mutational spectrum of the NF1 gene (K810X, Q2595X, 6772delT, 7190delCT, 7331delA, 1021insTT, 3921insT, 4106insTA, 7149insC, 2033insCG / 2034delA). PTT in a large number of Italian NF1 patients supports the usefulness of this method for characterization of mutations in disorders where the responsible gene is very large and the disease-causing mutations often create a stop codon. In agreement with previous reports, no mutational hotspots within the NF1 gene were detected.

Diagnostico de hipobetalipoproteinemia en un nino de 8 años? / Diagnosis of hypobetalipoproteinemia in an 8-year-old child? / Diagnostico hipobetalipoproteinemia numa crianca de 8 anos?

La hipobetalipoproteinemia familiar es un trastorno hereditario autosomico dominante que afecta a las lipoproteinas que contienen Apo B, una proteina indispensable para el transporte de los quilomicrones en el intestino y que ademas participa en la sintesis y transporte de las VLDL en el higado. La concentracion de Apo B se usa junto con otras pruebas lipidicas para establecer el riesgo individual de un paciente de desarrollar enfermedad cardiovascular. Presentacion del caso: Paciente de 8 anos, varon, que acude a la consulta de Pediatria del Hospital Universitario Virgen Macarena de Sevilla con sintomas de dolor abdominal, deposiciones blandas y diarreicas, sobrepeso y unas quebradizas. El paciente fue derivado al laboratorio para su estudio con sospecha de hipobetalipoproteinemia. Se le solicito un hemograma, frotis sanguineo, pruebas de coagulacion, bioquimica general y estudio de riesgo vascular. Los datos del estudio bioquimico descartaron la celiaquia (IgA 174 mg/dL [100- 400 mg/dL] y antitransglutaminasa 5 U/mL [< 20]). Las determinaciones incluidas en el perfil de riesgo cardiovascular (RCV) fueron: colesterol total 83 mg/dL (45 mg/dL), c-LDL 32 mg/dL (< 160 mg/dL), colesterol no HDL 35 mg/dL, c-VLDL 3 mg/dL (< 40 mg/dL), trigliceridos 28 mg/dL, Apo-A1 112 mg/dL (119-240 mg/dL), Apo B-100 25 mg/dL (40-125 mg/dL), us-PCR 1,47 mg/dL (< 3 mg/dL), Lp (a) 2 mg/dL (< 30 mg/ dL), homocisteina 5,8 µmol/L (< 15 µmol/L), vitamina A 42 µg/dL (50-200 µg/ dL), vitamina E 1051 µg/dL (50-180 µg/dL) y 25-(OH) D 48,9 ng/mL (30-54 ng/mL) en intervalos de normalidad. El HLA-27 fue negativo. Tras encontrar hallazgos bioquimicos de bajas concentraciones de lipoproteinas con Apo B, se le solicito al paciente una prueba de saliva para realizacion de estudio genetico de LipochipR para mutaciones en el gen de Apo B y PCSK9. Se concluye que el paciente presento una disminucion de la concentracion de las lipoproteinas que contienen Apo B y trigliceridos. La sintomatologia de dolor abdominal y heces pastosas apoyaron el diagnostico clinico. La inexistencia de deficit vitaminico, retraso mental, acantocitosis y demas sintomatologia asociada, hizo pensar en una herencia heterocigota, que con las herramientas disponibles no se pudo describir geneticamente ya que LipochipR no detecta positividad para este paciente para una mutacion de cambio de aminoacidos en el gen y exon de Apo 26, PCSK9-7, PCSK9-4, PCSK9-10.

Familial hypobetalipoproteinemia is a dominant autosomal inherited disorder that affects lipoproteins containing Apo B. It is an essential protein for the transport of chylomicrons in the intestine and it is involved in the synthesis and transport of VLDL in the liver. This concentration is used along with other lipid tests to establish a patient's individual risk of developing cardiovascular disease. This is the case of an 8 year-old male patient who presented at the University Hospital Virgen Macarena in Seville with symptoms of abdominal pain, loose stools and diarrhea, overweight and broken nails. The patient was referred to the laboratory for examination with suspected hypobetalipoproteinemia. He was requested a complete blood count, blood smear, coagulation, biochemistry and vascular risk study. Biochemical data discarded celiac disease (IgA 174 mg/dL [100-400 mg/dL] y antitransglutaminase antibody 5 U/mL [< 20]). Determinations were RCV's profile: Total cholesterol 83 mg/dL (45 mg/dL), c-LDL 32 mg/dL (< 160 mg/dL), non-HDL cholesterol 35 mg/dL, c-VLDL 3 mg/dL (< 40 mg/dL), triglycerides 28 mg/dL, Apo-A1 112 mg/dL (119-240 mg/dL), Apo B-100 25 mg/dL (40-125 mg/dL), us-PCR 1,47 mg/dL (< 3 mg/dL), Lp (a) 2 mg/dL (< 30 mg/dL), Homocysteine 5,8 µmol/L (< 15 µmol/L), Vitamin A 42 µg/dL (50-200 µg/dL), Vitamine E 1051 µg/dL (50-180 µg/dL) and 25-(OH) D 48,9 ng/mL (30-54 ng/mL) in normal ranges. HLA-27 Negative. After biochemical findings of low concentrations of lipoproteins with Apo B100, the patient was requested a saliva test for genetic study conducting LipochipR for mutations of Apo B and PCSK9. It can be concluded that the patient had a decreased concentration of lipoproteins containing Apo-B and triglycerides. The symptoms of abdominal pain and tarry stools supported the clinical diagnosis. The lack of vitamin deficiency, mental retardation, acanthocytosis and other associated sintomatology, made it possible to consider it an heterozygous inheritance. which could not be genetically described with the tools available since LipochipR does not detect in this patient positivity for a mutation to the amino acid change in the gene and exon 26 of Apo, Apo 26, PCSK9-7, PCSK9- 4, PCSK9-10.

Hypobetalipoproteinemia familiar e um disturbio autossomico hereditario dominante que afeta as lipoproteinas contendo Apo--B, uma proteina essencial para o transporte de quilomicrons no intestino e esta envolvido na sintese e transporte de VLDL no figado. A concentracao de Apo-B e utilizada, juntamente com outros testes lipidicos, para estabelecer o risco individual de um paciente de desenvolver doencas cardiovasculares. O caso e o de um paciente de 8 anos, do sexo masculino, que se apresenta para consulta de Pediatria do Hospital Universitario Virgen Macarena, em Sevilha, com sintomas de dor abdominal, fezes brandas e diarreia, sobrepeso e unhas quebradicas. O paciente foi derivado ao laboratorio para exame com suspeita de hypobetalipoproteinemia. Foi pedido um hemograma completo, esfregaco de sangue, coagulacao, bioquimica geral e estudo de risco vascular. Os dados do estudo bioquimico descartaram a doenca celiaca (IgA 174 mg/dL [100-400 mg/dL] e Antitrasglutaminase 5 U/mL [<20]). As determinacoes incluidas no perfil de risco cardiovascular (RCV) foram colesterol total 83 mg/dL (45 mg/dL), LDL-C 32 mg/ dL (<160 mg/dL), colesterol nao-HDL de 35 mg/dL, VLDL-C 3 mg/dL (<40 mg/dL), triglicerideos de 28 mg/dL, Apo-A1 112 mg/ dL (119-240 mg/dL), Apo B-100-25 mg/dL (40-125 mg/dL), us-PCR 1,47 mg/dL (<3 mg/dL) de Lp (a) 2 mg/dL (<30 mg/dL), homocisteina de 5,8 µmol/L (<15 µmol/L), a vitamina A 42 µg/dL (50-200 µg/dL), vitamina E 1051 µg/dL (50-180 µg/dL) e 25- (OH) D 48,9 ng/mL (30-54 ng/mL) em intervalos de normalidade. O HLA-27 foi negativo. Depois de encontrar achados bioquimicos de baixas concentracoes de lipoproteinas com apo-B, foi solicitado ao paciente um teste de saliva para estudo genetico de LipochipR para mutacoes no gene de Apo-B e PCSK9. Conclui-se que o paciente apresentou uma diminuicao na concentracao das lipoproteinas contendo Apo-B e triglicerideos. Os sintomas de dor abdominal e fezes pastosas apoiaram o diagnostico clinico. A inexistencia de deficit vitaminico, retardo mental, acantocitose e outros sintomas associados fez pensar numa heranca heterozigotica, que com as ferramentas disponiveis nao se pode descrever geneticamente ja que LipochipR nao detecta positividade para este paciente para uma mutacao de mudanca de aminoacidos no gene e exon de Apo 26, PCSK9-7, PCSK9- 4, PCSK9-10.

Efficacy of an intervention program to improve employability of university students

In the current socioeconomic situation, the need to improve employability of potential workers is especially relevant. The aim of this study was to evaluate the efficacy of an intervention program focusing on improving employability of university students. To do this, a two-group study was designed: one group undertook the intervention program and the other group were used for comparison. Two measurements were taken at different times (pre-intervention and post-intervention). The sample consisted of 271 university students. The results show that the group that underwent the intervention program improved their perceived employability F(1, 269) = 17.49, p < .001; η2 = .06, openness to learning F(1, 269) = 4.24, p < .05; η2 = .02, self-efficacy for labor market insertion F(1, 269) = 75.70, p < .001; η2 = .22 and for teamwork F(1, 269) = 39.43, p < .001; η2 = .13, and their knowledge of employment resources F(1, 269) = 512.89, p < .001; η2 = .66 compared to the group that did not. Furthermore, there was a high level of satisfaction of participants with the intervention program (AU)

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