Glucose self-monitoring in non-insulin-treated patients with type 2 diabetes in primary care settings: A randomized trial

IMPORTANCE The value of self-monitoring of blood glucose (SMBG) levels in patients with non-insulin-treated type 2 diabetes has been debated. OBJECTIVE To compare 3 approaches of SMBG for effects on hemoglobin A1c levels and health-related quality of life (HRQOL) among people with non-insulin-treated type 2 diabetes in primary care practice. DESIGN, SETTING, AND PARTICIPANTS The Monitor Trial studywas a pragmatic, open-label randomized trial conducted in 15 primary care practices in central North Carolina. Participants were randomized between January 2014 and July 2015. Eligible patients with type 2 non-insulin-treated diabetes were: older than 30 years, established with a primary care physician at a participating practice, had glycemic control (hemoglobin A1c) levels higher than 6.5%but lower than 9.5%within the 6 months preceding screening, as obtained from the electronic medical record, and willing to comply with the results of random assignment into a study group. Of the 1032 assessed for eligibility, 450 were randomized. INTERVENTIONS No SMBG, once-daily SMBG, and once-daily SMBG with enhanced patient feedback including automatic tailored messages delivered via the meter. MAIN OUTCOMES AND MEASURES Coprimary outcomes included hemoglobin A1c levels and HRQOL at 52 weeks. RESULTS A total of 450 patients were randomized and 418 (92.9%) completed the final visit. There were no significant differences in hemoglobin A1c levels across all 3 groups (P = .74; estimated adjusted mean hemoglobin A1c difference, SMBG with messaging vs no SMBG, -0.09%; 95%CI, -0.31% to 0.14%; SMBG vs no SMBG, -0.05%; 95%CI, -0.27%to 0.17%). There were also no significant differences found in HRQOL. There were no notable differences in key adverse events including hypoglycemia frequency, health care utilization, or insulin initiation. CONCLUSIONS AND RELEVANCE In patients with non-insulin-treated type 2 diabetes, we observed no clinically or statistically significant differences at 1 year in glycemic control or HRQOL between patients who performed SMBG compared with those who did not perform SMBG. The addition of this type of tailored feedback provided through messaging via ameter did not provide any advantage in glycemic control

Mapping interactions with the chaperone network reveals factors that protect against tau aggregation.

A network of molecular chaperones is known to bind proteins ('clients') and balance their folding, function and turnover. However, it is often unclear which chaperones are critical for selective recognition of individual clients. It is also not clear why these key chaperones might fail in protein-aggregation diseases. Here, we utilized human microtubule-associated protein tau (MAPT or tau) as a model client to survey interactions between ~30 purified chaperones and ~20 disease-associated tau variants (~600 combinations). From this large-scale analysis, we identified human DnaJA2 as an unexpected, but potent, inhibitor of tau aggregation. DnaJA2 levels were correlated with tau pathology in human brains, supporting the idea that it is an important regulator of tau homeostasis. Of note, we found that some disease-associated tau variants were relatively immune to interactions with chaperones, suggesting a model in which avoiding physical recognition by chaperone networks may contribute to disease

Multi-disciplinary team directed analysis of whole genome sequencing reveals pathogenic non-coding variants in molecularly undiagnosed inherited retinal dystrophies

PURPOSE: To identify, using genome sequencing (GS), likely pathogenic non-coding variants in inherited retinal dystrophy (IRD) genes Methods: Patients with IRD were recruited to the study and underwent comprehensive ophthalmological evaluation and GS. The results of GS were investigated through virtual gene panel analysis and plausible pathogenic variants and clinical phenotype evaluated by multi-disciplinary team (MDT) discussion. For unsolved patients in whom a specific gene was suspected to harbour a missed pathogenic variant, targeted re-analysis of non-coding regions was performed on GS data. Candidate variants were functionally tested including by mRNA analysis, minigene and luciferase reporter assays. RESULTS: Previously unreported, likely pathogenic, non-coding variants, in 7 genes (PRPF31, NDP, IFT140, CRB1, USH2A, BBS10, and GUCY2D), were identified in 11 patients. These were shown to lead to mis-splicing (PRPF31, IFT140, CRB1, USH2A) or altered transcription levels (BBS10, GUCY2D). CONCLUSION: MDT-led, phenotype driven, non-coding variant re-analysis of GS is effective in identifying missing causative alleles

Constraints to Economic Development and Growth in the Middle East and North Africa

When comparing the speed and extent of economic development in different geographic regions of the world over the past 20 years, the under-average performance of Arab countries in general and Arab Mediterranean countries in particular is striking. This is despite an overall favorable geo-strategic situation at the crossroads of three continents, with excellent connections to sea and waterways and in direct proximity to the European Union, one of the world’s economic hubs. It is also despite the minor importance of negative factors such as a high-burden diseases or high levels of ethnic fractionalization. In this paper, I focus on identifying the most important constraints on Arab Mediterranean economic development. I use state-of-the-art econometric tools to quantify constraints that have been identified through economic theory and studies of the political economy characteristics of the region. The empirical results offer support for the central hypothesis that limited technological capacities and political economy structures are the primary constraints on economic development. With a view to international structural adjustment efforts, my findings imply that the limited success of the Euro-Mediterranean policy to stimulate the economic development of the Arab Mediterranean countries might be because structural adjustment efforts do not tackle—or at least do not sufficiently tackle— these constraints.Vergleicht man Geschwindigkeit und Umfang der wirtschaftlichen Entwicklung der verschiedenen Weltregionen in den vergangenen zwanzig Jahren, so fällt insbesondere das unterdurchschnittliche Abschneiden der arabischen Länder im Allgemeinen und der arabischen Mittlemeerländer im Besonderen ins Auge, und dies trotz einer insgesamt vorteilhaften geographischen Lage im Schnittpunkt dreier Kontinente mit exzellenten Anschlussmöglichkeiten an See- und Wasserwege, trotz der direkten Nachbarschaft zum Weltwirtschaftsdrehkreuz Europäische Union und trotz der relativ geringen Bedeutung wichtiger entwicklungshemmender Faktoren, beispielsweise ethnische Zersplitterung oder massive Ausbreitung von Krankheiten wie AIDS oder Malaria. In diesem Aufsatz wird versucht, von den unterschiedlichen Hemmfaktoren wirtschaftlicher Entwicklung, die in der wirtschaftstheoretischen Literatur und/oder in MENARegionalstudien diskutiert werden, diejenigen herauszuarbeiten, die wirtschaftliche Entwicklung am stärksten behindern oder möglicherweise stärker als andere. Dabei benutze ich modernste ökonometrische Verfahren, um den Einfluss der verschiedenen erklärenden Variablen zu quantifizieren. Die Ergebnisse stützen die Eingangshypothese, dass insbesondere mangelnde technologische Kapazitäten und Fähigkeiten sowie regionalspezifische politökonomische Strukturen die wirtschaftliche Entwicklung in den arabischen Mittelmeerländern behindern

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care — Preliminary Report

BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection. METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis. RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives. CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.)

C9orf72-mediated ALS and FTD: multiple pathways to disease

The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression