Implementing carrier screening for cystic fibrosis outside the clinic: ethical analysis in the light of the personalist view

Background. Cystic Fibrosis (CF) is an autosomal recessive genetic disease. Two models for screening CF are normally used: newborn screening and population-based CF carrier screening. In turn, there are three main models of population-based CF carrier screening: prenatal carrier screening, preconception carrier screening, and carrier screening outside clinical settings. Aim. To evaluate, in the light of the personalist view, the use of carrier screenings for CF outside the clinic, i.e. in non-clinical settings, such as school and workplaces.Methods. Analysis has been carried out according to the “Perso-nalist approach” (also called “Triangular model”), an ethical method for performing ethical analysis within HTA process. It includes factual, anthropological and ethical data in a ‘‘triangular’’ normative reflection process.Findings. Implementing carrier screening for cystic fibrosis outside the clinical settings allows acquisition of knowledge for informing reproductive choices, that can be considered as valuable; benefit-risk ratio seems to be not much favorable; autonomous and responsible decisions can be taken only under certain conditions; economic ad-vantage is difficult to determine; therefore, from a personalist view, implementing carrier screenings outside the clinic seems not to be ethically justified. Conclusion. In accordance with the personalist perspective, public health programs providing carrier screenings outside the clinic should not be implemented

Preventive Newborn Male Circumcision: What Is the Child's Best Interest?

Preventive newborn male circumcision has been at the center of scientific debate for many years. The reason for promoting preventive newborn male circumcision, is the reduction of the incidence of UTIs (in the first six months of life), penile cancer, transmission of STDs/HIV infection/AIDS. However preventive interventions in the newborn involving violations of bodily integrity elicit several ethical questions. In this article, we reviewed the literature regarding circumcision, the prevention of UTIs, penile cancer, transmission of STDs/HIV infection/AIDS and complications of this practice in the neonatal period. The very limited reduction of incidence of UTIs and the uncertain preventive role of newborn male circumcision towards penile cancer, STDs/HIV infection and AIDS, makes it difficult to justify male circumcision in newborns. Moreover, the challenge in obtaining a unanimous opinion on newborn male circumcision derives from the fact that, as a preventive intervention, it requires evaluation criteria that are not comparable to those of therapeutic treatments. Since preventive male circumcision determines permanent alteration of the body, some authors believe that it can be used only in subjects that are capable of giving their valid consent. In the case of a newborn, the ″child's best interest″ should be used as a standard, but preventive newborn male circumcision does not satisfy it

Reactive oxygen-related diseases: therapeutic targets and emerging clinical indications

SIGNIFICANCE Enhanced levels of reactive oxygen species (ROS) have been associated with different disease states. Most attempts to validate and exploit these associations by chronic antioxidant therapies have provided disappointing results. Hence, the clinical relevance of ROS is still largely unclear. RECENT ADVANCES We are now beginning to understand the reasons for these failures, which reside in the many important physiological roles of ROS in cell signaling. To exploit ROS therapeutically, it would be essential to define and treat the disease-relevant ROS at the right moment and leave physiological ROS formation intact. This breakthrough seems now within reach. CRITICAL ISSUES Rather than antioxidants, a new generation of protein targets for classical pharmacological agents includes ROS-forming or toxifying enzymes or proteins that are oxidatively damaged and can be functionally repaired. FUTURE DIRECTIONS Linking these target proteins in future to specific disease states and providing in each case proof of principle will be essential for translating the oxidative stress concept into the clinic. Antioxid. Redox Signal. 23, 1171-1185

Associations of physical activity with body weight and fat in men and women

OBJECTIVE: Increasing physical activity is strongly advocated as a key public health strategy for weight gain prevention. We investigated associations of leisure-time physical activity (LTPA) and occupational/domestic physical activity with body mass index (BMI) and a skinfold-derived index of body fat (sum of six skinfolds), among normal-weight and overweight men and women.DESIGN: Analyses of cross-sectional self-report and measured anthropometric data.SUBJECTS: A total of 1302 men and women, aged 18-78 y, who were part of a randomly selected sample and who agreed to participate in a physical health assessment.MEASUREMENTS: Self-report measures of physical activity, measured height and weight, and a skinfold-derived index of body fatness.RESULTS: Higher levels of LTPA were positively associated with the likelihood of being in the normal BMI and lower body fat range for women, but few or no associations were found for men. No associations were found between measures of occupational/domestic activity and BMI or body fat for men or women.CONCLUSION: By using a skinfold sum as a more direct measure of adiposity, this study extends and confirms the previous research that has shown an association between BMI and LTPA. Our results suggest gender differences in the relationship of leisure-time physical activity with body fatness. These findings, in conjunction with a better understanding of the causes of such differences, will have important public health implications for the development and targeting of weight gain prevention strategies.<br /

Eating episode frequency and fruit and vegetable consumption among Italian university students

Objective. To analyze breakfast consumption, regularity of meals, fruit and vegetable consumption in the Italian university student population on a national level. Design. Descriptive analysis evaluating data taken from the Sportello Salute Giovani (SSG) questionnaire. Participants. 12 000 university students who self-administered a confidential survey. 8292 questionnaires were analyzed. Variables measured. Age; sex; self-reported economic status; BMI; number of breakfast and portions of vegetables and portions of fruit usually consumed per week; number of eating episodes per day; intended weight loss. Analysis. Descriptive and logistic regression analyses were conducted. Gender and age differences were tested by c2 and Mann-Whitney tests. Results. 15.8% of males and 26.3% of females declared to consume at least one portion of fruit every day. Similar results were found for vegetable consumption. Age does not influence fruit or vegetables consumption, frequency of eating episodes or breakfast habit. Both a regular breakfast and a higher number of eating episodes are significantly associated both with a higher frequency of fruit and vegetables intake. Conclusions and implications. This study underlines the need to promote nutritional education campaigns to increase adherence to nutritional guidelines

A Functional Variant of the Dimethylarginine Dimethylaminohydrolase-2 Gene Is Associated with Insulin Sensitivity

Background: Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase, which was associated with insulin resistance. Dimethylarginine dimethylaminohydrolase (DDAH) is the major determinant of plasma ADMA. Examining data from the DIAGRAM+ (Diabetes Genetics Replication And Meta-analysis), we identified a variant (rs9267551) in the DDAH2 gene nominally associated with type 2 diabetes (P =3610 25). Methodology/Principal Findings: initially, we assessed the functional impact of rs9267551 in human endothelial cells (HUVECs), observing that the G allele had a lower transcriptional activity resulting in reduced expression of DDAH2 and decreased NO production in primary HUVECs naturally carrying it. We then proceeded to investigate whether this variant is associated with insulin sensitivity in vivo. To this end, two cohorts of nondiabetic subjects of European ancestry were studied. In sample 1 (n = 958) insulin sensitivity was determined by the insulin sensitivity index (ISI), while in sample 2 (n = 527) it was measured with a euglycemic-hyperinsulinemic clamp. In sample 1, carriers of the GG genotype had lower ISI than carriers of the C allele (67633 vs.79644; P = 0.003 after adjusting for age, gender, and BMI). ADMA levels were higher in subjects carrying the GG genotype than in carriers of the C allele (0.6860.14 vs. 0.5760.14 mmol/l; P = 0.04). In sample 2, glucose disposal was lower in GG carriers as compared with C carriers (9.364.1 vs. 11.064.2 mg6Kg 21 free fat mass6min 21; P = 0.009)

A Prognostic Model for Estimating the Time to Virologic Failure in HIV-1 Infected Patients Undergoing a New Combination Antiretroviral Therapy Regimen

<p>Abstract</p> <p>Background</p> <p>HIV-1 genotypic susceptibility scores (GSSs) were proven to be significant prognostic factors of fixed time-point virologic outcomes after combination antiretroviral therapy (cART) switch/initiation. However, their relative-hazard for the time to virologic failure has not been thoroughly investigated, and an expert system that is able to predict how long a new cART regimen will remain effective has never been designed.</p> <p>Methods</p> <p>We analyzed patients of the Italian ARCA cohort starting a new cART from 1999 onwards either after virologic failure or as treatment-naïve. The time to virologic failure was the endpoint, from the 90^thday after treatment start, defined as the first HIV-1 RNA > 400 copies/ml, censoring at last available HIV-1 RNA before treatment discontinuation. We assessed the relative hazard/importance of GSSs according to distinct interpretation systems (Rega, ANRS and HIVdb) and other covariates by means of Cox regression and random survival forests (RSF). Prediction models were validated via the bootstrap and c-index measure.</p> <p>Results</p> <p>The dataset included 2337 regimens from 2182 patients, of which 733 were previously treatment-naïve. We observed 1067 virologic failures over 2820 persons-years. Multivariable analysis revealed that low GSSs of cART were independently associated with the hazard of a virologic failure, along with several other covariates. Evaluation of predictive performance yielded a modest ability of the Cox regression to predict the virologic endpoint (c-index≈0.70), while RSF showed a better performance (c-index≈0.73, p < 0.0001 vs. Cox regression). Variable importance according to RSF was concordant with the Cox hazards.</p> <p>Conclusions</p> <p>GSSs of cART and several other covariates were investigated using linear and non-linear survival analysis. RSF models are a promising approach for the development of a reliable system that predicts time to virologic failure better than Cox regression. Such models might represent a significant improvement over the current methods for monitoring and optimization of cART.</p

Communicating simply, but not too simply: Reporting of participants and speech and language interventions for aphasia after stroke

Purpose: Speech and language pathology (SLP) for aphasia is a complex intervention delivered to a heterogeneous population within diverse settings. Simplistic descriptions of participants and interventions in research hinder replication, interpretation of results, guideline and research developments through secondary data analyses. This study aimed to describe the availability of participant and intervention descriptors in existing aphasia research datasets. Method: We systematically identified aphasia research datasets containing ≥10 participants with information on time since stroke and language ability. We extracted participant and SLP intervention descriptions and considered the availability of data compared to historical and current reporting standards. We developed an extension to the Template for Intervention Description and Replication checklist to support meaningful classification and synthesis of the SLP interventions to support secondary data analysis. Result: Of 11, 314 identified records we screened 1131 full texts and received 75 dataset contributions. We extracted data from 99 additional public domain datasets. Participant age (97.1%) and sex (90.8%) were commonly available. Prior stroke (25.8%), living context (12.1%) and socio-economic status (2.3%) were rarely available. Therapy impairment target, frequency and duration were most commonly available but predominately described at group level. Home practice (46.3%) and tailoring (functional relevance 46.3%) were inconsistently available. Conclusion : Gaps in the availability of participant and intervention details were significant, hampering clinical implementation of evidence into practice and development of our field of research. Improvements in the quality and consistency of participant and intervention data reported in aphasia research are required to maximise clinical implementation, replication in research and the generation of insights from secondary data analysis

Utilising a systematic review-based approach to create a database of individual participant data for meta- and network meta-analyses: the RELEASE database of aphasia after stroke

Background: Collation of aphasia research data across settings, countries and study designs using big data principles will support analyses across different language modalities, levels of impairment, and therapy interventions in this heterogeneous population. Big data approaches in aphasia research may support vital analyses, which are unachievable within individual trial datasets. However, we lack insight into the requirements for a systematically created database, the feasibility and challenges and potential utility of the type of data collated. Aim: To report the development, preparation and establishment of an internationally agreed aphasia after stroke research database of individual participant data (IPD) to facilitate planned aphasia research analyses. Methods: Data were collated by systematically identifying existing, eligible studies in any language (≥10 IPD, data on time since stroke, and language performance) and included sourcing from relevant aphasia research networks. We invited electronic contributions and also extracted IPD from the public domain. Data were assessed for completeness, validity of value-ranges within variables, and described according to pre-defined categories of demographic data, therapy descriptions, and language domain measurements. We cleaned, clarified, imputed and standardised relevant data in collaboration with the original study investigators. We presented participant, language, stroke, and therapy data characteristics of the final database using summary statistics. Results: From 5256 screened records, 698 datasets were potentially eligible for inclusion; 174 datasets (5928 IPD) from 28 countries were included, 47/174 RCT datasets (1778 IPD) and 91/174 (2834 IPD) included a speech and language therapy (SLT) intervention. Participants’ median age was 63 years (interquartile range [53, 72]), 3407 (61.4%) were male and median recruitment time was 321 days (IQR 30, 1156) after stroke. IPD were available for aphasia severity or ability overall (n = 2699; 80 datasets), naming (n = 2886; 75 datasets), auditory comprehension (n = 2750; 71 datasets), functional communication (n = 1591; 29 datasets), reading (n = 770; 12 datasets) and writing (n = 724; 13 datasets). Information on SLT interventions were described by theoretical approach, therapy target, mode of delivery, setting and provider. Therapy regimen was described according to intensity (1882 IPD; 60 datasets), frequency (2057 IPD; 66 datasets), duration (1960 IPD; 64 datasets) and dosage (1978 IPD; 62 datasets). Discussion: Our international IPD archive demonstrates the application of big data principles in the context of aphasia research; our rigorous methodology for data acquisition and cleaning can serve as a template for the establishment of similar databases in other research areas

Complex speech-language therapy interventions for stroke-related aphasia: The RELEASE study incorporating a systematic review and individual participant data network meta-analysis

Background: People with language problems following stroke (aphasia) benefit from speech and language therapy. Optimising speech and language therapy for aphasia recovery is a research priority. Objectives: The objectives were to explore patterns and predictors of language and communication recovery, optimum speech and language therapy intervention provision, and whether or not effectiveness varies by participant subgroup or language domain. Design: This research comprised a systematic review, a meta-analysis and a network meta-analysis of individual participant data. Setting: Participant data were collected in research and clinical settings. Interventions: The intervention under investigation was speech and language therapy for aphasia after stroke. Main outcome measures: The main outcome measures were absolute changes in language scores from baseline on overall language ability, auditory comprehension, spoken language, reading comprehension, writing and functional communication. Data sources and participants: Electronic databases were systematically searched, including MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature, Linguistic and Language Behavior Abstracts and SpeechBITE (searched from inception to 2015). The results were screened for eligibility, and published and unpublished data sets (randomised controlled trials, non-randomised controlled trials, cohort studies, case series, registries) with at least 10 individual participant data reporting aphasia duration and severity were identified. Existing collaborators and primary researchers named in identified records were invited to contribute electronic data sets. Individual participant data in the public domain were extracted. Review methods: Data on demographics, speech and language therapy interventions, outcomes and quality criteria were independently extracted by two reviewers, or available as individual participant data data sets. Meta-analysis and network meta-analysis were used to generate hypotheses. Results: We retrieved 5928 individual participant data from 174 data sets across 28 countries, comprising 75 electronic (3940 individual participant data), 47 randomised controlled trial (1778 individual participant data) and 91 speech and language therapy intervention (2746 individual participant data) data sets. The median participant age was 63 years (interquartile range 53-72 years). We identified 53 unavailable, but potentially eligible, randomised controlled trials (46 of these appeared to include speech and language therapy). Relevant individual participant data were filtered into each analysis. Statistically significant predictors of recovery included age (functional communication, individual participant data: 532, n = 14 randomised controlled trials) and sex (overall language ability, individual participant data: 482, n = 11 randomised controlled trials; functional communication, individual participant data: 532, n = 14 randomised controlled trials). Older age and being a longer time since aphasia onset predicted poorer recovery. A negative relationship between baseline severity score and change from baseline (p < 0.0001) may reflect the reduced improvement possible from high baseline scores. The frequency, duration, intensity and dosage of speech and language therapy were variously associated with auditory comprehension, naming and functional communication recovery. There were insufficient data to examine spontaneous recovery. The greatest overall gains in language ability [14.95 points (95% confidence interval 8.7 to 21.2 points) on the Western Aphasia Battery-Aphasia Quotient] and functional communication [0.78 points (95% confidence interval 0.48 to 1.1 points) on the Aachen Aphasia Test-Spontaneous Communication] were associated with receiving speech and language therapy 4 to 5 days weekly; for auditory comprehension [5.86 points (95% confidence interval 1.6 to 10.0 points) on the Aachen Aphasia Test-Token Test], the greatest gains were associated with receiving speech and language therapy 3 to 4 days weekly. The greatest overall gains in language ability [15.9 points (95% confidence interval 8.0 to 23.6 points) on the Western Aphasia Battery-Aphasia Quotient] and functional communication [0.77 points (95% confidence interval 0.36 to 1.2 points) on the Aachen Aphasia Test-Spontaneous Communication] were associated with speech and language therapy participation from 2 to 4 (and more than 9) hours weekly, whereas the highest auditory comprehension gains [7.3 points (95% confidence interval 4.1 to 10.5 points) on the Aachen Aphasia Test-Token Test] were associated with speech and language therapy participation in excess of 9 hours weekly (with similar gains notes for 4 hours weekly). While clinically similar gains were made alongside different speech and language therapy intensities, the greatest overall gains in language ability [18.37 points (95% confidence interval 10.58 to 26.16 points) on the Western Aphasia Battery-Aphasia Quotient] and auditory comprehension [5.23 points (95% confidence interval 1.51 to 8.95 points) on the Aachen Aphasia Test-Token Test] were associated with 20-50 hours of speech and language therapy. Network meta-analyses on naming and the duration of speech and language therapy interventions across language outcomes were unstable. Relative variance was acceptable (< 30%). Subgroups may benefit from specific interventions. Limitations: Data sets were graded as being at a low risk of bias but were predominantly based on highly selected research participants, assessments and interventions, thereby limiting generalisability. Conclusions: Frequency, intensity and dosage were associated with language gains from baseline, but varied by domain and subgroup