Maximizing the Yield of Small Samples in Prevention Research: A Review of General Strategies and Best Practices

The goal of this manuscript is describe strategies for maximizing the yield of data from small samples in prevention research. We begin by discussing what “small” means as a description of sample size in prevention research. We then present a series of practical strategies for getting the most out of data when sample size is small and constrained. Our focus is the prototypic between-group test for intervention effects; however, we touch on the circumstance in which intervention effects are qualified by one or more moderators. We conclude by highlighting the potential usefulness of graphical methods when sample size is too small for inferential statistical methods

Party finance reform as constitutional engineering? The effectiveness and unintended consequences of party finance reform in France and Britain

In both Britain and France, party funding was traditionally characterized by a laissez faire approach and a conspicuous lack of regulation. In France, this was tantamount to a 'legislative vacuum'. In the last two decades, however, both countries have sought to fundamentally reform their political finance regulation regimes. This prompted, in Britain, the Political Parties, Elections and Referendums Act 2000, and in France a bout of 'legislative incontinence' — profoundly transforming the political finance regime between 1988 and 1995. This article seeks to explore and compare the impacts of the reforms in each country in a bid to explain the unintended consequences of the alternative paths taken and the effectiveness of the new party finance regime in each country. It finds that constitutional engineering through party finance reform is a singularly inexact science, largely due to the imperfect nature of information, the limited predictability of cause and effect, and the constraining influence of non-party actors, such as the Constitutional Council in France, and the Electoral Commission in Britain

Severe Biallelic Loss-of-function Mutations in Nicotinamide Mononucleotide Adenylyltransferase 2 (NMNAT2) in Two Fetuses with Fetal Akinesia Deformation Sequence

The three nicotinamide mononucleotide adenylyltransferase (NMNAT) family members synthesize the electron carrier nicotinamide adenine dinucleotide (NAD+) and are essential for cellular metabolism. In mammalian axons, NMNAT activity appears to be required for axon survival and is predominantly provided by NMNAT2. NMNAT2 has recently been shown to also function as a chaperone to aid in the refolding of misfolded proteins. Nmnat2 deficiency in mice, or in its ortholog dNmnat in Drosophila, results in axon outgrowth and survival defects. Peripheral nerve axons in NMNAT2-deficient mice fail to extend and innervate targets, and skeletal muscle is severely underdeveloped. In addition, removing NMNAT2 from established axons initiates axon death by Wallerian degeneration. We report here on two stillborn siblings with fetal akinesia deformation sequence (FADS), severely reduced skeletal muscle mass and hydrops fetalis. Clinical exome sequencing identified compound heterozygous NMNAT2 variant alleles in both cases. Both protein variants are incapable of supporting axon survival in mouse primary neuron cultures when overexpressed. In vitro assays demonstrate altered protein stability and/or defects in NAD+ synthesis and chaperone functions. Thus, both patient NMNAT2 alleles are null or severely hypo-morphic. These data indicate a previously unknown role for NMNAT2 in human neurological development and provide the first direct molecular evidence to support the involvement of Wallerian degeneration in a human axonal disorder.Funding for the project comes from the NIH (R.W.S. R01NS085023; R.G.Z. R56NS095893), the UK Medical Research Council grant (J.G. MR/N004582/1), the John and Lucille van Geest Foundation (M.C.) and the Taishan Scholar Project of Shandong Province, China (R.G.Z.)

Consensus recommendations for the treatment and management of patients with Fabry disease on migalastat: a modified Delphi study

Objective: Fabry disease is a progressive disorder caused by deficiency of the α-galactosidase A enzyme (α-Gal A), leading to multisystemic organ damage with heterogenous clinical presentation. The addition of the oral chaperone therapy migalastat to the available treatment options for Fabry disease is not yet universally reflected in all treatment guidelines. These consensus recommendations are intended to provide guidance for the treatment and monitoring of patients with Fabry disease receiving migalastat. Methods: A modified Delphi process was conducted to determine consensus on treatment decisions and monitoring of patients with Fabry disease receiving migalastat. The multidisciplinary panel comprised 14 expert physicians across nine specialties and two patients with Fabry disease. Two rounds of Delphi surveys were completed and recommendations on the use of biomarkers, multidisciplinary monitoring, and treatment decisions were generated based on statements that reached consensus. Results: The expert panel reached consensus agreement on 49 of 54 statements, including 16 that reached consensus in round 1. Statements that reached consensus agreement are summarized in recommendations for migalastat treatment and monitoring, including baseline and follow-up assessments and frequency. All patients with Fabry disease and an amenable mutation may initiate migalastat treatment if they have evidence of Fabry-related symptoms and/or organ involvement. Treatment decisions should include holistic assessment of the patient, considering clinical symptoms and organ involvement as well as patient-reported outcomes and patient preference. The reliability of α-Gal A and globotriaosylsphingosine as pharmacodynamic response biomarkers remains unclear. Conclusion: These recommendations build on previously published guidelines to highlight the importance of holistic, multidisciplinary monitoring for patients with Fabry disease receiving migalastat, in addition to shared decision-making regarding treatments and monitoring throughout the patient journey. (Figure presented.)

Vitamin D and COVID-19: evidence and recommendations for supplementation

Vitamin D is a hormone that acts on many genes expressed by immune cells. Evidence linking vitamin D deficiency with COVID-19 severity is circumstantial but considerable—links with ethnicity, obesity, institutionalization; latitude and ultraviolet exposure; increased lung damage in experimental models; associations with COVID-19 severity in hospitalized patients. Vitamin D deficiency is common but readily preventable by supplementation that is very safe and cheap. A target blood level of at least 50 nmol l−1, as indicated by the US National Academy of Medicine and by the European Food Safety Authority, is supported by evidence. This would require supplementation with 800 IU/day (not 400 IU/day as currently recommended in UK) to bring most people up to target. Randomized placebo-controlled trials of vitamin D in the community are unlikely to complete until spring 2021—although we note the positive results from Spain of a randomized trial of 25-hydroxyvitamin D3 (25(OH)D3 or calcifediol) in hospitalized patients. We urge UK and other governments to recommend vitamin D supplementation at 800–1000 IU/day for all, making it clear that this is to help optimize immune health and not solely for bone and muscle health. This should be mandated for prescription in care homes, prisons and other institutions where people are likely to have been indoors for much of the summer. Adults likely to be deficient should consider taking a higher dose, e.g. 4000 IU/day for the first four weeks before reducing to 800 IU–1000 IU/day. People admitted to the hospital with COVID-19 should have their vitamin D status checked and/or supplemented and consideration should be given to testing high-dose calcifediol in the RECOVERY trial. We feel this should be pursued with great urgency. Vitamin D levels in the UK will be falling from October onwards as we head into winter. There seems nothing to lose and potentially much to gain

Intonation and Compensation of Fretted String Instruments

In this paper we present mathematical and physical models to be used in the analysis of the problem of intonation of musical instruments such as guitars, mandolins and the like, i.e., we study how to improve the tuning on these instruments. This analysis begins by designing the placement of frets on the fingerboard according to mathematical rules and the assumption of an ideal string, but becomes more complicated when one includes the effects of deformation of the string and inharmonicity due to other string characteristics. As a consequence of these factors, perfect intonation of all the notes on the instrument can never be achieved, but complex compensation procedures are introduced and studied to minimize the problem. To test the validity of these compensation procedures, we have performed extensive measurements using standard monochord sonometers and other basic acoustical devices, confirming the correctness of our theoretical models. In particular, these experimental activities can be easily integrated into standard acoustics courses and labs, and can become a more advanced version of basic experiments with monochords and sonometers.Comment: Improved version, with minor changes. 25 pages, including 6 figures and 2 tables. Accepted for publication in the American Journal of Physics (AJP

Together forever? Explaining exclusivity in party-firm relations

Parties and firms are the key actors of representative democracy and capitalism respectively and the dynamic of attachment between them is a central feature of any political economy. This is the first article to systematically analyse the exclusivity of party-firm relations. We consider exclusivity at a point in time and exclusivity over time. Does a firm have a relationship with only one party at a given point in time, or is it close to more than one party? Does a firm maintain a relationship with only one party over time, or does it switch between parties? Most important, how do patterns of exclusivity impact on a firm’s ability to lobby successfully? We propose a general theory, which explains patterns of party-firm relations by reference to the division of institutions and the type of party competition in a political system. A preliminary test of our theory with Polish survey data confirms our predictions, establishing a promising hypothesis for future research

Long-term multisystemic efficacy of migalastat on Fabry-associated clinical events, including renal, cardiac and cerebrovascular outcomes

BACKGROUND: Fabry disease is a rare, multisystemic disorder caused by GLA gene variants that lead to alpha galactosidase A deficiency, resulting in accumulation of glycosphingolipids and cellular dysfunction. Fabry-associated clinical events (FACEs) cause significant morbidity and mortality, yet the long-term effect of Fabry therapies on FACE incidence remains unclear. METHODS: This posthoc analysis evaluated incidence of FACEs (as a composite outcome and separately for renal, cardiac and cerebrovascular events) in 97 enzyme replacement therapy (ERT)-naïve and ERT-experienced adults with Fabry disease and amenable GLA variants who were treated with migalastat for up to 8.6 years (median: 5 years) in Phase III clinical trials of migalastat. Associations between baseline characteristics and incidence of FACEs were also evaluated. RESULTS: During long-term migalastat treatment, 17 patients (17.5%) experienced 22 FACEs and there were no deaths. The incidence rate of FACEs was 48.3 events per 1000 patient-years overall. Numerically higher incidence rates were observed in men versus women, patients aged >40 years versus younger patients, ERT-naïve versus ERT-experienced patients and men with the classic phenotype versus men and women with all other phenotypes. There was no statistically significant difference in time to first FACE when analysed by patient sex, phenotype, prior treatment status or age. Lower baseline estimated glomerular filtration rate (eGFR) was associated with an increased risk of FACEs across patient populations. CONCLUSIONS: The overall incidence of FACEs for patients during long-term treatment with migalastat compared favourably with historic reports involving ERT. Lower baseline eGFR was a significant predictor of FACEs