Current Practices and Challenges When Submitting Patient Experience Data for Regulatory Decisions by the US Food and Drug Administration: An Industry Survey.

OBJECTIVES: To understand industry practices and challenges when submitting patient experience data (PED) for regulatory decisions by the US Food and Drug Administration (FDA). METHODS: A two-part online survey related to collection, submission, and use of PED by FDA in regulatory decision-making (part 1) and a best-worst exercise for prioritizing potential PED initiatives (part 2) was completed by industry and contract research organization (CRO) members with ≥ 2 years of recent experience with patient-reported outcome (PRO), natural history study (NHS), or patient preference (PP) data; and direct experience with FDA filings including PED. RESULTS: A total of 50 eligible respondents (84% industry) completed part 1 of the survey, among which 46 completed part 2. Respondents mostly had PRO (86%) and PP (50%) experience. All indicated that FDA meetings should have a standing agenda item to discuss PED. Most (78%) reported meetings should occur before pivotal trials. A common challenge was justifying inclusion without knowing if and how data will be used. Most agreed that FDA and industry should co-develop the PED table in the FDA clinical review (74%), and the table should report reason(s) for not using PED (96%) in regulatory decision-making. Most important efforts to advance PED use in decision-making were a dedicated meeting pathway and expanded FDA guidance (51% each). CONCLUSIONS: FDA has policy targets expanding PED use, but challenges remain regarding pathways for PED submission and transparency in regulatory decision-making. Alignment on the use of existing meeting opportunities to discuss PED, co-development of the PED table, and expanded guidance are encouraged.

Comparing Outcomes of a Discrete Choice Experiment and Case 2 Best-Worst Scaling: An Application to Neuromuscular Disease Treatment.

BACKGROUND AND OBJECTIVES: Case 2 best-worst scaling (BWS-2) is an increasingly popular method to elicit patient preferences. Because BWS-2 potentially has a lower cognitive burden compared with discrete choice experiments, the aim of this study was to compare treatment preference weights and relative importance scores. METHODS: Patients with neuromuscular diseases completed an online survey at two different moments in time, completing one method per occasion. Patients were randomly assigned to either first a discrete choice experiment or BWS-2. Attributes included: muscle strength, energy endurance, balance, cognition, chance of blurry vision, and chance of liver damage. Multinomial logit was used to calculate overall relative importance scores and latent class logit was used to estimate heterogeneous preference weights and to calculate the relative importance scores of the attributes for each latent class. RESULTS: A total of 140 patients were included for analyses. Overall relative importance scores showed differences in attribute importance rankings between a discrete choice experiment and BWS-2. Latent class analyses indicated three latent classes for both methods, with a specific class in both the discrete choice experiment and BWS-2 in which (avoiding) liver damage was the most important attribute. Ex-post analyses showed that classes differed in sex, age, level of education, and disease status. The discrete choice experiment was easier to understand compared with BWS-2. CONCLUSIONS: This study showed that using a discrete choice experiment and BWS-2 leads to different outcomes, both in preference weights as well as in relative importance scores, which might have been caused by the different framing of risks in BWS-2. However, a latent class analysis revealed similar latent classes between methods. Careful consideration about method selection is required, while keeping the specific decision context in mind and pilot testing the methods.

Colorectal cancer screening preferences among physicians and individuals at average risk: A discrete choice experiment.

BACKGROUND: Guidelines include several options for average-risk colorectal cancer (CRC) screening that vary in aspects such as invasiveness, recommended frequency, and precision. Thus, patient and provider preferences can help identify an appropriate screening strategy. This study elicited CRC screening preferences of physicians and individuals at average risk for CRC (IAR). METHODS: IAR aged 45-75 years and licensed physicians (primary care or gastroenterology) completed an online discrete choice experiment (DCE). Participants were recruited from representative access panels in the US. Within the DCE, participants traded off preferences between screening type, screening frequency, true-positive, true-negative, and adenoma true positive (physicians only). A mixed logit model was used to obtain predicted choice probabilities for colonoscopy, multi-target stool DNA (mt-sDNA), fecal immunochemical test (FIT), and methylated septin 9 (mSEPT9) blood test. RESULTS: Preferences of IAR and physicians were affected by screening precision and screening type. IAR also valued more regular screening. Physicians preferred colonoscopy (96.8%) over mt-sDNA (2.8%; p < 0.001), FIT (0.3%; p < 0.001) and mSEPT9 blood test (0.1%; p < 0.01). IAR preferred mt-sDNA (38.8%) over colonoscopy (32.5%; p < 0.001), FIT (19.2%; p < 0.001), and mSEPT9 blood test (9.4%; p < 0.001). IAR naïve to screening preferred non-invasive screening (p < 0.001), while the opposite was found for those who previously underwent colonoscopy or sigmoidoscopy. CONCLUSIONS: While physicians overwhelmingly preferred colonoscopy, preferences of IAR were heterogenous, with mt-sDNA being most frequently preferred on average. Offering choices in addition to colonoscopy could improve CRC screening uptake among IAR. This study used a discrete choice experiment in the US to elicit preferences of physicians and individuals at average risk for colorectal cancer screening modalities and their characteristics.

Natural History of Leigh Syndrome: A Study of Disease Burden and Progression.

OBJECTIVE: This observational cohort study aims to quantify disease burden over time, establish disease progression rates, and identify factors that may determine the disease course of Leigh syndrome. METHODS: Seventy-two Leigh syndrome children who completed the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) at baseline at 3.7 years (interquartile range [IQR] = 2.0-7.6) and follow-up assessments at 7.5 years (IQR = 3.7-11.0) in clinics were enrolled. Eighty-two percent of this cohort had a confirmed genetic diagnosis, with pathogenic variants in the MT-ATP6 and SURF1 genes being the most common cause. The total NPMDS scores denoted mild (0-14), moderate (15-25), and severe (>25) disease burden. Detailed clinical, neuroradiological, and molecular genetic findings were also analyzed. RESULTS: The median total NPMDS scores rose significantly (Z = -6.9, p < 0.001), and the percentage of children with severe disease burden doubled (22% → 42%) over 2.6 years of follow-up. Poor function (especially mobility, self-care, communication, feeding, and education) and extrapyramidal features contributed significantly to the disease burden (τb  ≈ 0.45-0.68, p < 0.001). These children also deteriorated to wheelchair dependence (31% → 57%), exclusive enteral feeding (22% → 46%), and one-to-one assistance for self-care (25% → 43%) during the study period. Twelve children (17%) died after their last NPMDS scores were recorded. These children had higher follow-up NPMDS scores (disease burden; p < 0.001) and steeper increase in NPMDS score per annum (disease progression; p < 0.001). Other predictors of poor outcomes include SURF1 gene variants (p < 0.001) and bilateral caudate changes on neuroimaging (p < 0.01). INTERPRETATION: This study has objectively defined the disease burden and progression of Leigh syndrome. Our analysis has also uncovered potential influences on the trajectory of this neurodegenerative condition. ANN NEUROL 2022;91:117-130.

Use of hem-o-lok clips for laparoscopic appendectomy in children: retrospective analysis and comparison to ligature loop and endoscopic surgical stapler.

BACKGROUND: There are multiple techniques used for laparoscopic appendectomy (LA): ligature loop (LL), surgical stapler (SS) (Endopath Ets-Flex-Endoscopic Articulating Linear Cutter 33 mm Standard Ref Atb 35. Ethicon, Somerville, New Jersey, US), and hem-o-lok clips (HOL) (Weck Closure System. Triangle Park, NC, USA). The application of the LL usually demands dexterity and training, whilst using HOL may be more advantageous due to its simplicity in terms of application and its low cost in contrast with the SS. The objective of this study is to determine safety and efficacy of the different devices that can be used in the surgical procedure. METHODS: From June 2016 to December 2019, 253 consecutive children aged to 1 to 18 years were retrospectively reviewed. They were divided into three groups depending on the device used to secure the appendix: (I) in the first group, the base of the appendix was secured by double LL, (II) in the second group the base of the appendix was secured with SS, and (III) in the third group the base of the appendix was secured with two non-absorbable HOL. The data collected includes age, gender, operative time, device used to ligate the base of the appendix, previous tests (blood analysis, imaging), antibiotic prophylaxis administered, length of hospital stay, intraoperative and postoperative complications, shoulder pain and histological study of the specimen. RESULTS: There were 253 patients that underwent laparoscopic appendectomy during the study time, with a mean age of 10.3±4.1 in the LL group, 9.4±2.7 in the SS group and 10.4±3.3 in the HOL group, P=0.165. Distribution by gender was 77.8% for males in the LL group, 65.2% in the SS group and 61.3% in the HOL group, P=0.559. The mean surgical time with IQR in brackets was 60.0 (10.0) minutes (min), in the first group in which the base of the appendix was secured with LL, in the second group in which the base of the appendix was secured with SS 60.0 (15.0) min and finally in the third in which the base of the appendix was secured with HOL 40.0 (30.0) min, P<0.001. HOL clips have a significantly lower cost than their analogues. Specifically, 5 HOL clips have a cost of EUR 26.75, while three LL have a cost of EUR 53.70 and a single SS has a cost of EUR 276.58. Postoperative complications were found in 14.3% of the LL group, 9.8% in the SS group and 4.6% in the HOL group, P=0.137. Efficacy and safety in controlling the base of appendix were the same in all groups. CONCLUSIONS: The HOL are safe and reduce surgical costs during laparoscopic appendectomy in children.

Combinations of Legume Protein Hydrolysates Synergistically Inhibit Biological Markers Associated with Adipogenesis.

The objective was to investigate the anti-adipogenesis potential of selected legume protein hydrolysates (LPH) and combinations using biochemical assays and in silico predictions. Black bean, green pea, chickpea, lentil and fava bean protein isolates were hydrolyzed using alcalase (A) or pepsin/pancreatin (PP). The degree of hydrolysis ranged from 15.5% to 35.5% for A-LPH and PP-LPH, respectively. Antioxidant capacities ranged for ABTS•+ IC50 from 0.3 to 0.9 Trolox equivalents (TE) mg/mL, DPPH• IC50 from 0.7 to 13.5 TE mg/mL and nitric oxide (NO) inhibition IC50 from 0.3 to 1.3 mg/mL. LPH from PP-green pea, A-green pea and A-black bean inhibited pancreatic lipase (PL) (IC50 = 0.9 mg/mL, 2.2 mg/mL and 1.2 mg/mL, respectively) (p < 0.05). For HMG-CoA reductase (HMGR) inhibition, the LPH from A-chickpea (0.15 mg/mL), PP-lentil (1.2 mg/mL), A-green pea (1.4 mg/mL) and PP-green pea (1.5 mg/mL) were potent inhibitors. Combinations of PP-green pea + A-black bean (IC50 = 0.4 mg/mL), A-green pea + PP-green pea (IC50 = 0.9 mg/mL) and A-black bean + A-green pea (IC50 = 0.6 mg/mL) presented synergistic effects to inhibit PL. A-chickpea + PP-lentil (IC50 = 0.8 mg/mL) and PP-lentil + A-green pea (IC50 = 1.3 mg/mL) interacted additively to inhibit HMGR and synergistically in the combination of A-chickpea + PP-black bean (IC50 = 1.3 mg/mL) to block HMGR. Peptides FEDGLV and PYGVPVGVR inhibited PL and HMGR in silico, showing predicted binding energy interactions of -7.6 and -8.8 kcal/mol, respectively. Combinations of LPH from different legume protein sources could increase synergistically their anti-adipogenic potential.

Measuring the effects of exercise in neuromuscular disorders: a systematic review and meta-analyses.

Background: The benefit and safety of exercise training for patients with neuromuscular disorders (NMDs) has long been a contentious topic. This is, in part, due to recognised challenges associated with rare diseases including small and heterogenous patient populations. We performed a systematic review and meta-analyses to evaluate the effectiveness and safety of interventional exercise and establish minimal clinically important differences (MCID) in outcomes to facilitate clinical interpretation. Methods: We searched six databases from inception to Mar 2018. Aerobic, strength, and combined (aerobic and strength) intervention were eligible. Meta-analyses compared outcomes at baseline with those after at least six weeks (before-after exercise within individuals). A further meta-analysis compared outcomes before-after exercise between groups (exercise training versus usual care). Disease heterogeneity was explored using a random effect model. This study was registered (PROSPERO, CRD42018102183). An interactive database was developed to facilitate full interrogations of data. Results: We identified 130 articles describing 1,805 participants with 35 different forms of NMD. Of these studies, 76 were suitable for meta-analyses. Within group and between group meta-analyses detected an increase in peak aerobic capacity (p=0·04), and peak power (p=0·01). Six-minute walk test (p=0·04), sit-to-stand (STS) (repetitions) (p=0·03), STS (seconds) (p=0·04), rise from supine (p=0·008), SF-36 (p=0·0003), fatigue severity (p=<0·0001), citrate synthase (p=0·0002), central nuclei (p=0·04), type 1 (p=0·002) and type II muscle fibre area (p=0·003), were only able to detect change within group meta-analyses. Substantial I 2 statistic heterogeneity was revealed for STS (seconds) ( I²=58·5%; p=0·04) and citrate synthase ( I²=70·90%; p=0·002), otherwise heterogeneity for all outcomes was low. No study-related serious adverse events were reported nor significant increases in creatine kinase. Conclusions: Exercise training in patients with NMDs appears to cause no harm across a range of outcomes. With the emergence of new therapeutic strategies, defining MCID is vital in informing future clinical trial design.

Change over time in ability to perform activities of daily living in myotonic dystrophy type 1.

OBJECTIVE: The objective of this longitudinal, observational study was to investigate change over time in ability to perform activities of daily living in myotonic dystrophy type 1 (DM1). METHODS: Adults with genetically confirmed DM1 were recruited as part of the PhenoDM1 study in the UK. Data on activities of daily living were recorded through the DM1-ActivC at baseline and a follow-up visit after 12 (± 3) months. A subset of patients had advanced genetic testing to determine the size of the progenitor allele. RESULTS: Our sample comprised 150 patients with DM1 (mean age: 45 years; 52% female). Mean follow-up was 383 days. Mean DM1-ActivC total score at baseline was 71.24 (95% confidence interval 67.77-74.71) and at the follow-up visit 69.04 (65.54-72.54). Approximately 43% of patients had a lower score at the follow-up visit (indicating a decreased ability to perform activities of daily living), 24% a higher score (indicating an increased ability), and 33% the same score at baseline and follow-up. The mean annual change in the DM1-ActivC total score, estimated at - 2.06 (- 3.54 to - 0.59), was significantly related to patients' baseline score, but not sex, disease duration, timed test results, or cytosine-thymine-guanine repeat length. CONCLUSIONS: Change over time in ability to perform activities of daily living as recorded through the DM1-ActivC varies substantially between patients with DM1. Our data contribute to the understanding of the natural evolution of the disease, and should be helpful to inform the design of future trials based on the DM1-ActivC.

Activities of daily living in myotonic dystrophy type 1.

OBJECTIVES: The objective of this cross-sectional, observational study was to investigate performance of activities of daily living in patients with myotonic dystrophy type 1 (DM1). MATERIALS AND METHODS: Adults with genetically confirmed DM1 were recruited from Newcastle University (Newcastle upon Tyne, UK) and University College London Hospitals NHS Foundation Trust (London, UK). Data on activities of daily living were recorded through the DM1-ActivC (scale scores range between 0 and 100, where a higher/lower score indicates a higher/lower ability). RESULTS: Our sample comprised 192 patients with DM1 (mean age: 46 years; 51% female). Patients reported most difficulties with running, carrying and putting down heavy objects, and standing on one leg, and least difficulties with eating soup, washing upper body, and taking a shower. Irrespective of the disease duration (mean: 20 years), most patients were able to perform basic and instrumental activities of daily living (eg personal hygiene and grooming, showering, eating, cleaning and shopping), with the exception of functional mobility/transfer tasks (eg walking uphill and running). The mean DM1-ActivC total score was estimated at 71 (95% CI: 68-74). Estimated progenitor cytosine-thymine-guanine repeat length and age explained 27% of the variance in DM1-ActivC total scores (P < .001). CONCLUSIONS: We show that DM1 impairs performance of activities of daily living, in particular those requiring a high degree of muscle strength, stability and coordination. Yet, across the evolution of the disease, the majority of patients will still be able to independently perform most basic and instrumental activities of daily living.

Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort.

OBJECTIVE: To evaluate the role of genetic variation at the DMPK locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life-Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial. METHODS: We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats. RESULTS: We confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7-20.7, 2-tailed t test t = -3.7, p = 0.0019). CONCLUSIONS: Careful characterization of the DMPK CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining disease-specific outcome measures, and the basis of treatment response and stratification in DM1 trials.

Disease burden of myotonic dystrophy type 1.

OBJECTIVE: The objective of this cross-sectional, observational study was to investigate the disease burden of myotonic dystrophy type 1 (DM1), a disabling muscle disorder. METHODS: Adults with DM1 were recruited as part of the PhenoDM1 study from Newcastle University (Newcastle upon Tyne, UK). Disease burden data were recorded through the Individualized Neuromuscular Quality of Life (INQoL) questionnaire. Results were examined by sex and clinical variables [e.g. the six-minute walk test (6MWT), the Mini Mental State Examination, and estimated progenitor and modal allele CTG repeat length]. RESULTS: Our sample consisted of 60 patients with DM1 (mean age: 45 years; 45% female). Muscle weakness and fatigue constituted the two most common disease manifestations, reported by 93% and 90% of patients, respectively, followed by muscle locking (73%). Most patients (> 55%) reported feeling anxious/worried, depressed, frustrated, and/or having low confidence/self-esteem, 23% and 33% indicated substantial impairment of daily and leisure activities, respectively, and 47% did not work as a consequence of the disease. Estimated progenitor CTG length corrected by age correlated surprisingly well with INQoL scores. Differences by sex were generally minor. CONCLUSION: We show that DM1 is associated with a substantial disease burden resulting in impairment across many different domains of patients' lives, emphasizing the need for a holistic approach to medical management. Our results also show that the INQoL records relevant information about patients with DM1, but that further investigation of the psychometric properties of the scale is needed for meaningful interpretation of instrument scores.

Health-Related Quality of Life in Patients with Adult-Onset Myotonic Dystrophy Type 1: A Systematic Review.

BACKGROUND: Adult-onset myotonic dystrophy type 1 (DM1) is a chronic, multisystem disorder that leads to disability and premature death. OBJECTIVES: The objective of our study was to conduct a systematic literature review of the health-related quality of life (HRQoL) of patients with DM1. METHODS: We searched Embase, Web of Science, and PubMed for English language full-text articles reporting results from studies of HRQoL in patients with adult-onset DM1 published between 1 January 2000 and 21 February 2018. We excluded reviews, editorials, and studies reporting results for a sample with fewer than five patients (to allow for meaningful inference). RESULTS: The search identified 266 unique publications. Of these, 231 were excluded following title and abstract screening and 16 after full-text review, leaving 19 articles for data synthesis. We found 15 articles measuring the HRQoL of patients with adult-onset DM1 using the 36-Item Short Form Health Survey (SF-36), six using the Individualized Neuromuscular Quality of Life Questionnaire (INQoL), and one using Cantril's Ladder. Available evidence shows that patient HRQoL is impaired in DM1, mainly due to compromised physical health, but also reveals that substantial heterogeneity exists in estimates across studies. CONCLUSIONS: HRQoL in adult-onset DM1 has been extensively studied using the SF-36 and the INQoL, but current estimates are inconclusive, and little is known of the impact of the disease as measured using other instruments. Our data synthesis should help characterize the patient burden of DM1 and inform future studies of HRQoL in this indication.

Outcome measures for children with mitochondrial disease: consensus recommendations for future studies from a Delphi-based international workshop.

Although there are no effective disease-modifying therapies for mitochondrial diseases, an increasing number of trials are being conducted in this rare disease group. The use of sensitive and valid endpoints is essential to test the effectiveness of potential treatments. There is no consensus on which outcome measures to use in children with mitochondrial disease. The aims of this two-day Delphi-based workshop were to (i) define the protocol for an international, multi-centre natural history study in children with mitochondrial myopathy and (ii) to select appropriate outcome measures for a validation study in children with mitochondrial encephalopathy. We suggest two sets of outcome measures for a natural history study in children with mitochondrial myopathy and for a proposed validation study in children with mitochondrial encephalopathy.

Cognitive behavioural therapy with optional graded exercise therapy in patients with severe fatigue with myotonic dystrophy type 1: a multicentre, single-blind, randomised trial.

BACKGROUND: Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults and leads to severe fatigue, substantial physical functional impairment, and restricted social participation. In this study, we aimed to determine whether cognitive behavioural therapy optionally combined with graded exercise compared with standard care alone improved the health status of patients with myotonic dystrophy type 1. METHODS: We did a multicentre, single-blind, randomised trial, at four neuromuscular referral centres with experience in treating patients with myotonic dystrophy type 1 located in Paris (France), Munich (Germany), Nijmegen (Netherlands), and Newcastle (UK). Eligible participants were patients aged 18 years and older with a confirmed genetic diagnosis of myotonic dystrophy type 1, who were severely fatigued (ie, a score of ≥35 on the checklist-individual strength, subscale fatigue). We randomly assigned participants (1:1) to either cognitive behavioural therapy plus standard care and optional graded exercise or standard care alone. Randomisation was done via a central web-based system, stratified by study site. Cognitive behavioural therapy focused on addressing reduced patient initiative, increasing physical activity, optimising social interaction, regulating sleep-wake patterns, coping with pain, and addressing beliefs about fatigue and myotonic dystrophy type 1. Cognitive behavioural therapy was delivered over a 10-month period in 10-14 sessions. A graded exercise module could be added to cognitive behavioural therapy in Nijmegen and Newcastle. The primary outcome was the 10-month change from baseline in scores on the DM1-Activ-c scale, a measure of capacity for activity and social participation (score range 0-100). Statistical analysis of the primary outcome included all participants for whom data were available, using mixed-effects linear regression models with baseline scores as a covariate. Safety data were presented as descriptives. This trial is registered with ClinicalTrials.gov, number NCT02118779. FINDINGS: Between April 2, 2014, and May 29, 2015, we randomly assigned 255 patients to treatment: 128 to cognitive behavioural therapy plus standard care and 127 to standard care alone. 33 (26%) of 128 assigned to cognitive behavioural therapy also received the graded exercise module. Follow-up continued until Oct 17, 2016. The DM1-Activ-c score increased from a mean (SD) of 61·22 (17·35) points at baseline to 63·92 (17·41) at month 10 in the cognitive behavioural therapy group (adjusted mean difference 1·53, 95% CI -0·14 to 3·20), and decreased from 63·00 (17·35) to 60·79 (18·49) in the standard care group (-2·02, -4·02 to -0·01), with a mean difference between groups of 3·27 points (95% CI 0·93 to 5·62, p=0·007). 244 adverse events occurred in 65 (51%) patients in the cognitive behavioural therapy group and 155 in 63 (50%) patients in the standard care alone group, the most common of which were falls (155 events in 40 [31%] patients in the cognitive behavioural therapy group and 71 in 33 [26%] patients in the standard care alone group). 24 serious adverse events were recorded in 19 (15%) patients in the cognitive behavioural therapy group and 23 in 15 (12%) patients in the standard care alone group, the most common of which were gastrointestinal and cardiac. INTERPRETATION: Cognitive behavioural therapy increased the capacity for activity and social participation in patients with myotonic dystrophy type 1 at 10 months. With no curative treatment and few symptomatic treatments, cognitive behavioural therapy could be considered for use in severely fatigued patients with myotonic dystrophy type 1. FUNDING: The European Union Seventh Framework Programme.

Functional impairment in patients with myotonic dystrophy type 1 can be assessed by an ataxia rating scale (SARA).

Myotonic dystrophy type 1 (DM1) is not characterised by ataxia per se; however, DM1 and ataxia patients show similar disturbances in movement coordination often experiencing walking and balance difficulties, although caused by different underlying pathologies. This study aims to investigate the use of a scale previously described for the assessment and rating of ataxia (SARA) with the hypothesis that it could have utility in DM1 patients as a measure of disease severity and risk of falling. Data from 54 DM1 patients were pulled from the PHENO-DM1 natural history study for analysis. Mean SARA score in the DM1 population was 5.45 relative to the maximum score of eight. A flooring effect (score 0) was observed in mild cases within the sample. Inter-rater and test-retest reliability was high with intraclass coefficients (ICC) of 0.983 and 1.00, respectively. Internal consistency was acceptable as indicated by a Cronbach's alpha of 0.761. Component analysis revealed two principle components. SARA correlated with: (1) all measures of muscle function tested, including quantitative muscle testing of ankle dorsiflexion (r = -0.584*), the 6 min walk test (r = -0.739*), 10 m walk test (r = 0.741*), and the nine hole peg test (r = 0.602*) and (2) measures of disease severity/burden, such as MIRS (r = 0.718*), MDHI (r = 0.483*), and DM1-Activ (r = -0.749*) (*p < 0.001). The SARA score was predicted by an interaction between modal CTG repeat length and age at sampling (r = 0.678, p = 0.003). A score of eight or above predicted the use of a walking aid with a sensitivity of 100% and a specificity of 85.7%. We suggest that further research is warranted to ascertain whether SARA or components of SARA are useful outcome measures for clinical trials in DM1. As a tool, it can be used for gathering information about disease severity/burden and helping to identify patients in need of a walking aid, and can potentially be applied in both research and healthcare settings.

Nrf2 modulates cell proliferation and antioxidants defenses during liver regeneration induced by partial hepatectomy.

The objective was to determine the regulatory dynamic of Nrf2 during liver regeneration and the administration of EtOH and/or the G. schiedeanum extract. Male Wistar rats weighing 200-230 g were subjected to a 70% partial hepatectomy; they were then divided into three groups (groups 1-3). During the experiment, animals in Group 1 drank only water. The other two groups (2-3) received an intragastric dose of ethanol (1.5 g/kg BW, solution at 40% in isotonic saline solution). Additionally, rats in group 3 received a geranium extract daily at a dose of 300 mg/kg BW i.g. EtOh and/or Geranium schiedeanum was administered to rats with regenerating livers for 7 days. At the end of treatment, the activity was determined of the antioxidant enzymes, DNA concentration, TBARS, and TAC, in addition to the expression of Nrf-2, Cyclin D1, and Nqo1. EtOH increased ROS and Nrf-2, which activated the antioxidant defenses and delayed liver proliferation. On the other hand, Geranium schiedeanum exerted an antioxidant effect, diminishing ROS, but Nrf-2 expression increased, favoring liver proliferation through the increase of DNA concentration and the overexpression of Cyclin D1, however it did not activate the antioxidant defenses. In sum, it can be concluded that Nrf-2 possesses a regulatory dynamic that is evident in the presence of a toxic agent (EtOH) and/or a phytochemical agent with antioxidant capacity (Geranium schiedeanum) during liver regeneration.

[Spontaneous Non Ischaemic Blue Finger: A Rare and Benign Phenomenon]. / Dedo Azul Não-Isquémico Espontâneo: Um Fenómeno Raro e Benigno.

The spontaneous non-ischaemic blue finger is a rare and benign disorder, characterized by purple discoloration of a finger, with complete resolution. This article reports the case of a woman of 88 years, which after a few hours of stay in the emergency department developed without associated trauma, a purplish color of the 3rd finger of the right hand, with a palpable pulse and without temperature changes or pain. The etiological investigation was negative. The patient was assessed one week after the event and showed completeresolution. There are several diseases that share the same signs and symptoms, as such the diagnosis is based on the spontaneous violaceous color sparing the finger tip, and fast resolution without treatment. Though being a harmless phenomenon, it requires early assessment for timely differential diagnosis with severe pathologies.

O dedo azul não-isquémico espontâneo é uma entidade rara e benigna, caracterizada pela alteração da coloração isolada de um dedo, com aparecimento e resolução espontânea. Este artigo relata o caso de uma mulher de 88 anos, que após algumas horas de permanência no serviço de urgência desenvolveu, sem trauma associado uma coloração violácea do terceiro dedo da mão direita, com pulsos mantidos, sem alteração da temperatura e indolor. A pesquisa etiológica realizada foi negativa. A doente foi reavaliada uma semana após o evento e mostrava regressão total da lesão. Apesar de existirem várias patologias que partilham sinais e sintomassemelhantes, o diagnóstico baseia-se no aparecimento espontâneo, na coloração violácea característica que poupa a polpa do dedo, e na resolução rápida sem necessidade de tratamento. Mesmo sendo um fenómeno benigno necessita de avaliação precoce para que o diagnóstico diferencial com patologias mais graves seja feito atempadamente.

What is Known Regarding the Participation of Factor Nrf-2 in Liver Regeneration?

It has been known for years that, after chemical damage or surgical removal of its tissue, the liver initiates a series of changes that, taken together, are known as regeneration, which are focused on the recovery of lost or affected tissue in terms of the anatomical or functional aspect. The Nuclear factor-erythroid 2-related factor (Nrf-2) is a reduction-oxidation reaction (redox)-sensitive transcriptional factor, with the basic leucine Zipper domain (bZIP) motif, encoding the NFE2L2 gene. The Keap1-Nrf2-ARE pathway is transcendental in the regulation of various cellular processes, such as antioxidant defenses, redox equilibrium, the inflammatory process, the apoptotic processes, intermediate metabolism, detoxification, and cellular proliferation. Some reports have demonstrated the regulator role of Nrf-2 in the cellular cycle of the hepatocyte, as well as in the modulation of the antioxidant response and of apoptotic processes during liver regeneration. It has been reported that there is a delay in liver regeneration after Partial hepatectomy (PH) in the absence of Nrf-2, and similarly as a regulator of hepatic cytoprotection due to diverse chemical or biological agents, and in diseases such as hepatitis, fibrosis, cirrhosis, and liver cancer. This regulator/protector capacity is due to the modulation of the Antioxidant response elements (ARE). It is postulated that oxidative stress (OS) can participate in the initial stages of liver regeneration and that Nrf-2 can probably participate. Studies are lacking on the different initiation stages, maintenance, and the termination of liver regeneration alone or with ethanol.

Habilidades socio-cognitivas infantiles para resolver problemas junto a sus pares / Socio-cognitive skills children to solve problems with peers

Se presenta un estudio piloto cuyo propósito fue analizar la eficacia de un programa de intervención psico-educativo que promueva la resolución pacífica de los conflictos entre pares en la escuela. Los participantes fueron 117 niños y niñas de 9 a 11 años, de 4to y 5to año de primaria, quienes fueron evaluados según sus relaciones socio-afectivas en el aula, sus estatus grupales (popularidad, rechazo, aislamiento) y sus comportamientos. La intervención psico-educativa se realizó en las aulas durante tres meses en coordinación con los maestros. Los resultados mostraron que el entrenamiento en habilidades socio-cognitivas resultó efectivo para la disminución de las repuestas agresivas a través de la utilización alternativa de otras conductas y la anticipación para resolver conflictos interpersonales.

This pilot research aims firstly, to evaluate the group status (popularity, rejection, and isolation) related to dysfunctional behaviors, and secondly, to analyze the efficiency of an intervention program to promote the peaceful resolution of interpersonal problems. Socio-emotional relationship and behavior of 117 boys /girls aged between 9 to 11 year old of 4th and 5th grade were evaluated. A psycho-educational intervention program was implemented and assessed pre and post intervention. The results showed that the socio-cognitive skills training were effective to reduce the aggressive response through other alternative behaviors and the early decision process to solve peer conflicts.

Implante coclear en pacientes con hipoacusia súbita unilateral y acúfeno asociado / Cochlear implant in patients with sudden unilateral sensorineural hearing loss and associated tinnitus

Introducción y objetivos: Valorar la eficacia del implante coclear en pacientes con hipoacusia súbita unilateral y acúfeno incapacitante asociado. Métodos: Se han implantado 10 pacientes con hipoacusia súbita severa-profunda unilateral y acúfeno asociado, entre los cuales 4 son varones y 6 mujeres, con media de edad a la implantación de 42,7 años (rango: 34-62). Hemos evaluado la severidad del acúfeno mediante el Tinnitus Handicap Inventory (THI) en su versión validada al castellano y una escala analógica visual pre y postimplantación. Resultados: Se ha observado una supresión del acúfeno en dos pacientes. Siete pacientes han experimentado una mejoría del THI en distintos grados y no se han producido cambios en un paciente. No ha habido empeoramiento del acúfeno en ningún caso de la serie estudiada. Conclusiones: La reducción del acúfeno tras implantación coclear se puede deber a varios mecanismos, tales como la habituación, enmascaramiento acústico, estimulación directa del nervio coclear y reorganización de las áreas corticales. Aunque sean precisos más estudios, el implante coclear es un método efectivo para el tratamiento del acúfeno incapacitante en pacientes con hipoacusia súbita severa-profunda unilateral(AU)

Introduction and objectives: To assess the efficacy of cochlear implantation in patients with unilateral sudden sensorineural hearing loss and associated disabling tinnitus. Methods: Ten patients suffering from severe-to-profound sudden hearing loss and tinnitus in the affected ear received implants. The sample was comprised of 4 men and 6 women, with a mean age of 42.7 years (range 34-62) at implantation. The severity of the tinnitus was evaluated with the Spanish validated version of the Tinnitus Handicap Inventory (THI) and a visual analogue scale. These assessments were obtained before and after implantation. Results: Tinnitus suppression was observed in 2 patients. In 7 cases, we observed an improvement in the THI, in different degrees, and 1 patient remained without changes. Tinnitus worsening was not found in the series studied. Conclusions: Tinnitus reduction following cochlear implantation can be explained by several mechanisms, such as habituation, acoustic masking, direct stimulation of the cochlear nerve and reorganisation of cortical areas. Even though further research is required, cochlear implantation is an effective method for the treatment of disabling tinnitus in patients with severe-to-profound unilateral sudden sensorineural hearing loss(AU)