Linkage analysis of the dominant distal myopathy we previously identified in a large Australian family demonstrated one significant linkage region located on chromosome 7 and encompassing 18.6 Mbp ...and 151 genes. The strongest candidate gene was FLNC because filamin C, the encoded protein, is muscle-specific and associated with myofibrillar myopathy. Sequencing of FLNC cDNA identified a c.752T>C (p.Met251Thr) mutation in the N-terminal actin-binding domain (ABD); this mutation segregated with the disease and was absent in 200 controls. We identified an Italian family with the same phenotype and found a c.577G>A (p.Ala193Thr) filamin C ABD mutation that segregated with the disease. Filamin C ABD mutations have not been described, although filamin A and filamin B ABD mutations cause multiple musculoskeletal disorders. The distal myopathy phenotype and muscle pathology in the two families differ from myofibrillar myopathies caused by filamin C rod and dimerization domain mutations because of the distinct involvement of hand muscles and lack of pathological protein aggregation. Thus, like the position of FLNA and B mutations, the position of the FLNC mutation determines disease phenotype. The two filamin C ABD mutations increase actin-binding affinity in a manner similar to filamin A and filamin B ABD mutations. Cell-culture expression of the c.752T>C (p.Met251)Thr mutant filamin C ABD demonstrated reduced nuclear localization as did mutant filamin A and filamin B ABDs. Expression of both filamin C ABD mutants as full-length proteins induced increased aggregation of filamin. We conclude filamin C ABD mutations cause a recognizable distal myopathy, most likely through increased actin affinity, similar to the pathological mechanism of filamin A and filamin B ABD mutations.
The practice of induced molting involves the restriction of light, feed removal and optionally water for 5–14 days. However, there is growing concern regarding feed removal and animal welfare issues. ...With this in mind, alternative diets have been developed to produce similar molting effects as that of feed deprivation. Alfalfa, which largely consists of insoluble fiber, can be used as a molting diet. In this study, heterophil and lymphocyte counts, serum chemistry, and organ weight parameters were evaluated in hens that were deprived of feed or fed alfalfa during a nine day induced molt. Full-fed hens were used as the control. Blood serum parameters assessed included calcium, magnesium, glucose, total protein, ketone bodies, uric acid, and cholesterol. White blood cells were counted and categorized by cell type. On the ninth day of the trial, the hens were euthanized and the liver, spleen, heart, intestine, pancreas, ovary, oviduct, and kidney were collected and weighed. On day 8 birds molted with alfalfa or by feed deprivation had significantly higher (
P
<
0.05) levels of ketone bodies and cholesterol and lower levels of calcium, and magnesium compared to the full-fed hens while birds molted by feed deprivation exhibited significantly lower levels of uric acid. Birds molted by both methods exhibited significant reductions in ovary, oviduct, liver and pancreas weights and increased spleen weights when compared to the non-molted hens. On days 0, 2, and 6 there were no significant differences (
P
>
0.05) in either heterophil or lymphocyte percentages. However, heterophil percentages were higher in feed withdrawal birds than full-fed birds on day 4 but lymphocyte percentages were higher in full-fed birds compared to feed withdrawal birds. On day 8 of the induced molt lymphocyte percentages were higher from full-fed birds when compared to feed withdrawal birds but no significant differences were detectable for heterophil percentages. Based on reproductive organ weight loss and changes in serum and immunological responses of birds during molt, it appears that alfalfa meal can be an effective molt induction alternative.
As part of the Eastern Lake Survey in U.S.A. (see preceding abstracts), a study was carried out on 252 selected lakes in the southern Blue Ridge province (Southern Appalachians) and Fla., to quantify ...the number of acidic lakes and lakes with low acid-neutralizing capacity. None of the lakes in the southern Blue Ridge were acidic and only 1.4 per cent had low acid-neutralizing capacity. By contrast, 22 per cent of the lakes in Fla., were acidic and 35.3 per cent had a low acid-neutralizing capacity. The southern Blue Ridge lakes showed a high degree of chemical homogeneity, while lakes in Fla., were chemically heterogeneous, indicating that these 2 areas should be regarded as distinct regions.
•A multilevel process theory of gameful experience is developed and presented.•The term gamefulness is replaced with three more precisely defined constructs.•Gameful design, gameful systems, and ...gameful experiences are carefully defined.•This theory links these constructs causally whereas previously they were confounded.•This theory thus serves as a unifying foundation for future work on gamification.
Gamefulness is commonly cited as the primary goal of gamification, a family of approaches employed in education, business, healthcare, government, and elsewhere. However, gamefulness is defined imprecisely across the literature. To address this, we present a theory of gamefulness that splits gamefulness into more specific constructs and outlines their effects in a process model.
We integrate extant literature from psychology, human-computer interaction, and other fields to define gameful design, systems, and experiences. Most critically, we argue that gameful experience is the core focal construct of this theory and define it as an interactive state occurring when a person perceives non-trivial achievable goals created externally, is motivated to pursue them under an arbitrary set of behavioral rules, and evaluates that motivation as voluntary.
We present six resulting propositions: (1) gameful systems lead to gameful experiences, (2) gameful systems impact psychological characteristics, (3) effective gameful design leads to gameful systems, (4) effective gameful systems lead to behavioral change, (5) appropriate behavioral change causes the distal outcomes gamification designers target, and (6) individual differences moderate the effectiveness of gameful systems.
Gameful experience theory provides researchers with a unified foundation to study gamification from any social scientific lens.
We obtained data on lecture practices from 100 of the 110 university-affiliated anesthesiology residency programs certified in the United States in 1988. Of these residency programs, 36% had a ...majority of their lectures before the operating room schedule began, 57% had no lectures at all in this early time slot, and 78% had morning lectures at least once a week in conjunction with a delayed operating room start. Seventy-one percent of programs had one or more afternoon lectures each week. An attendance of more than 80% was reported in 66% of the programs for morning lectures and in 50% of the programs for afternoon lectures, which is a significant difference. Aggregate pass rates on the American Board of Anesthesiology written examinations in 1987 and 1988 correlated significantly with morning-lecture attendance, but not with afternoon-lecture attendance, number of lecture days per week, or mandatory lecture attendance. These findings suggest the need for further study and definition of the role of lectures in resident education in anesthesiology.
The addition of O2 to gas mixtures in time projection chambers containing CS2 has recently been shown to produce multiple negative ions that travel at slightly different velocities. This allows a ...measurement of the absolute position of ionising events in the z (drift) direction. In this work, we apply the z-fiducialisation technique to a directional dark matter search. We present results from a 46.3 live-day source-free exposure of the DRIFT-IId detector run in this new mode. With full-volume fiducialisation, we have achieved the first background-free operation of a directional detector. The resulting exclusion curve for spin-dependent WIMP-proton interactions reaches 1.1 pb at 100 GeV/c2, a factor of 2 better than our previous work. We describe the automated analysis used here, and argue that detector upgrades, implemented after the acquisition of these data, will bring an additional factor of ≳3 improvement in the near future.
Atracurium, a nondepolarizing muscle relaxant, does not depend on the liver for clearance, but its principal metabolite, laudanosine, is eliminated primarily by the liver and is potentially ...neurotoxic. We measured atracurium and laudanosine levels in 15 adult patients during the three stages of liver transplantation to assess the effect of major impairment of liver function. Atracurium was given in a bolus dose of 0.5 mg/kg followed by continuous infusion at a rate adjusted to maintain 95-99% of total neuromuscular block, as judged by train of four response to facial nerve stimulation. Atracurium levels remained constant at 1.4-1.8 micrograms/mL during the 180-min preanhepatic and 75-min anhepatic stages but decreased to a mean of 1.0 microgram/mL by the end of the 180-min postanhepatic stage. In contrast, laudanosine levels increased during each stage, being 0.40 +/- 0.18, 0.50 +/- 0.22, and 0.43 +/- 0.16 micrograms/mL after the preanhepatic, anhepatic, and postanhepatic stages, respectively. The highest individual value recorded was 1.02 microgram/mL. We conclude that, despite increases in laudanosine levels during each stage of liver transplantation in patients receiving atracurium, those levels are only about one-tenth of the maximum values previously reported in humans.
Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative syndrome. In up to 20% of cases, a family history is observed. Although Mendelian disease gene variants are found in ...apparently sporadic ALS, genetic testing is usually restricted to those with a family history or younger patients with sporadic disease. With the advent of therapies targeting genetic ALS, it is important that everyone treatable is identified. We therefore sought to determine the probability of a clinically actionable ALS genetic test result by age of onset, globally, but using the UK as an exemplar. Blood-derived DNA was sequenced for ALS genes, and the probability of a clinically actionable genetic test result estimated. For a UK subset, age- and sex-specific population incidence rates were used to determine the number of such results missed by restricting testing by age of onset according to UK's National Genomic Test Directory criteria. There were 6274 people with sporadic ALS, 1551 from the UK. The proportion with a clinically actionable genetic test result ranged between 0.21 95% confidence interval (CI) 0.18-0.25 in the youngest age group to 0.15 (95% CI 0.13-0.17) in the oldest age group for a full gene panel. For the UK, the equivalent proportions were 0.23 (95% CI 0.13-0.33) in the youngest age group to 0.17 (95% CI 0.13-0.21) in the oldest age group. By limiting testing in those without a family history to people with onset below 40 years, 115 of 117 (98% of all, 95% CI 96%-101%) clinically actionable test results were missed. There is a significant probability of a clinically actionable genetic test result in people with apparently sporadic ALS at all ages. Although some countries limit testing by age, doing so results in a significant number of missed pathogenic test results. Age of onset and family history should not be a barrier to genetic testing in ALS.
Aims
To identify simple insulin regimens for people with Type 2 diabetes mellitus that can be accepted and implemented earlier in primary and specialist care, taking into consideration each ...individual's needs and capabilities.
Methods
Using randomized clinical trials identified by a search of the PubMed database, as well as systematic reviews, meta‐analyses and proof‐of‐concept studies, this review addresses topics of interest related to the progressive intensification of a basal insulin regimen to a basal‐plus regimen (one basal insulin injection plus stepwise addition of one to three preprandial short‐acting insulin injections/day) vs a basal‐bolus regimen (basal insulin plus three short‐acting insulin injections per day) in people with Type 2 diabetes. The review explores approaches that can be used to define the meal for first prandial injection with basal‐plus regimens, differences among insulin titration algorithms, and the importance of self‐motivation and autonomy in achieving optimum glycaemic control.
Results
A basal‐plus regimen can provide glycaemic control equivalent to that obtained with a full basal‐bolus regimen, with fewer injections of prandial insulin. The first critical step is to optimize basal insulin dosing to reach a fasting glucose concentration of ~6.7 mmol/l; this allows ~40% of patients with baseline HbA1c >75 mmol/mol (9%) to be controlled with only one basal insulin injection per day.
Conclusions
Compared with a basal‐bolus regimen, a basal‐plus insulin regimen is as effective but more practical, and has the best chance of acceptance and success in the real world.
What's new?
Insulin initiation and intensification in people with Type 2 diabetes mellitus are often delayed, increasing the risk of complications.
Simplified regimens may lead to greater acceptance and earlier implementation of insulin therapy.
This evidence‐based review shows that a basal‐plus insulin regimen can provide glycaemic control equivalent to that obtained with a full basal‐bolus regimen, with fewer injections of prandial insulin.
A basal‐plus insulin regimen may therefore have a better chance of acceptance and success in the real world than a full basal‐bolus regimen through improved glycaemic control and consequent reduction in the risk of complications of diabetes.
Abstract
With the advent of gene therapies for amyotrophic lateral sclerosis (ALS), there is a surge in gene testing for this disease. Although there is ample experience with gene testing for ...C9orf72, SOD1, FUS and TARDBP in familial ALS, large studies exploring genetic variation in all ALS-associated genes in sporadic ALS (sALS) are still scarce. Gene testing in a diagnostic setting is challenging, given the complex genetic architecture of sALS, for which there are genetic variants with large and small effect sizes. Guidelines for the interpretation of genetic variants in gene panels and for counselling of patients are lacking.
We aimed to provide a thorough characterization of genetic variability in ALS genes by applying the American College of Medical Genetics and Genomics (ACMG) criteria on whole genome sequencing data from a large cohort of 6013 sporadic ALS patients and 2411 matched controls from Project MinE.
We studied genetic variation in 90 ALS-associated genes and applied customized ACMG-criteria to identify pathogenic and likely pathogenic variants. Variants of unknown significance were collected as well. In addition, we determined the length of repeat expansions in C9orf72, ATXN1, ATXN2 and NIPA1 using the ExpansionHunter tool.
We found C9orf72 repeat expansions in 5.21% of sALS patients. In 50 ALS-associated genes, we did not identify any pathogenic or likely pathogenic variants. In 5.89%, a pathogenic or likely pathogenic variant was found, most commonly in SOD1, TARDBP, FUS, NEK1, OPTN or TBK1. Significantly more cases carried at least one pathogenic or likely pathogenic variant compared to controls (odds ratio 1.75; P-value 1.64 × 10−5). Isolated risk factors in ATXN1, ATXN2, NIPA1 and/or UNC13A were detected in 17.33% of cases. In 71.83%, we did not find any genetic clues. A combination of variants was found in 2.88%.
This study provides an inventory of pathogenic and likely pathogenic genetic variation in a large cohort of sALS patients. Overall, we identified pathogenic and likely pathogenic variants in 11.13% of ALS patients in 38 known ALS genes. In line with the oligogenic hypothesis, we found significantly more combinations of variants in cases compared to controls. Many variants of unknown significance may contribute to ALS risk, but diagnostic algorithms to reliably identify and weigh them are lacking. This work can serve as a resource for counselling and for the assembly of gene panels for ALS. Further characterization of the genetic architecture of sALS is necessary given the growing interest in gene testing in ALS.
The development of gene therapies for amyotrophic lateral sclerosis (ALS) has led to increased interest in genetic testing, including for patients with the sporadic form of the disease. Van Daele et al. characterize variability in ALS-associated genes, and search for likely pathogenic variants, in more than 6000 patients with sporadic ALS.
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