Acarbose suppresses symptoms of mitochondrial disease in a mouse model of Leigh syndrome.

Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function, ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological ageing process. Rapamycin, a drug that increases lifespan and health during normative ageing, also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh syndrome. The Ndufs4 knockout (Ndufs4-/-) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh syndrome. Here we show that another drug that extends lifespan and delays normative ageing in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4-/- mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of inhibition of the mechanistic target of rapamycin. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4-/- mice. We find that acarbose remodels the intestinal microbiome and alters the production of short-chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression, while depletion of the endogenous microbiome in Ndufs4-/- mice appears to fully recapitulate the effects of acarbose on healthspan and lifespan in these animals. To our knowledge, this study provides the first evidence that alteration of the gut microbiome plays a significant role in severe mitochondrial disease and provides further support for the model that biological ageing and severe mitochondrial disorders share underlying common mechanisms.

Site Readiness Framework to Improve Health System Preparedness for a Potential New Alzheimer's Disease Treatment Paradigm.

New therapies that address the underlying pathophysiology of Alzheimer's Disease (AD), coupled with the growth of the AD population, will transform the AD care pathway and present significant challenges to health systems. We explored real-world challenges health systems may face in delivering potential new AD therapies with diverse stakeholders. Key challenges in care included integrating primary care providers into assessment and management, availability of memory care specialists, understanding payment and coverage issues and training mid-level providers to help coordinate care and serve as a shared resource across the system. This input informed a novel Site Readiness Framework for AD, comprising self-assessment exercises to identify health system capabilities and gaps and a framework of core strategies and responsive tools to help prepare to integrate new AD therapies. These resources may help health systems improve readiness to modify care pathways to integrate new therapies for AD.

A metabolomic endotype of bioenergetic dysfunction predicts mortality in critically ill patients with acute respiratory failure.

Acute respiratory failure (ARF) requiring mechanical ventilation, a complicating factor in sepsis and other disorders, is associated with high morbidity and mortality. Despite its severity and prevalence, treatment options are limited. In light of accumulating evidence that mitochondrial abnormalities are common in ARF, here we applied broad spectrum quantitative and semiquantitative metabolomic analyses of serum from ARF patients to detect bioenergetic dysfunction and determine its association with survival. Plasma samples from surviving and non-surviving patients (N = 15/group) were taken at day 1 and day 3 after admission to the medical intensive care unit and, in survivors, at hospital discharge. Significant differences between survivors and non-survivors (ANOVA, 5% FDR) include bioenergetically relevant intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, bile acids, and decreased acyl-glycerophosphocholines. Many metabolites associated with poor outcomes are substrates of NAD(P)-dependent enzymatic processes, while alterations in NAD cofactors rely on bioavailability of dietary B-vitamins thiamine, riboflavin and pyridoxine. Changes in the efficiency of the nicotinamide-derived cofactors' biosynthetic pathways also associate with alterations in glutathione-dependent drug metabolism characterized by substantial differences observed in the acetaminophen metabolome. Based on these findings, a four-feature model developed with semi-quantitative and quantitative metabolomic results predicted patient outcomes with high accuracy (AUROC = 0.91). Collectively, this metabolomic endotype points to a close association between mitochondrial and bioenergetic dysfunction and mortality in human ARF, thus pointing to new pharmacologic targets to reduce mortality in this condition.

Scanning Quadrupole Data-Independent Acquisition, Part B: Application to the Analysis of the Calcineurin-Interacting Proteins during Treatment of Aspergillus fumigatus with Azole and Echinocandin Antifungal Drugs.

Calcineurin is a critical cell-signaling protein that orchestrates growth, stress response, virulence, and antifungal drug resistance in several fungal pathogens. Blocking calcineurin signaling increases the efficacy of several currently available antifungals and suppresses drug resistance. We demonstrate the application of a novel scanning quadrupole DIA method for the analysis of changes in the proteins coimmunoprecipitated with calcineurin during therapeutic antifungal drug treatments of the deadly human fungal pathogen Aspergillus fumigatus. Our experimental design afforded an assessment of the precision of the method as demonstrated by peptide- and protein-centric analysis from eight replicates of the study pool QC samples. Two distinct classes of clinically relevant antifungal drugs that are guideline recommended for the treatment of invasive "aspergillosis" caused by Aspergillus fumigatus, the azoles (voriconazole) and the echinocandins (caspofungin and micafungin), which specifically target the fungal plasma membrane and the fungal cell wall, respectively, were chosen to distinguish variations occurring in the proteins coimmunoprecipitated with calcineurin. Novel potential interactors were identified in response to the different drug treatments that are indicative of the possible role for calcineurin in regulating these effectors. Notably, treatment with voriconazole showed increased immunoprecipitation of key proteins involved in membrane ergosterol biosynthesis with calcineurin. In contrast, echinocandin (caspofungin or micafungin) treatments caused increased immunoprecipitation of proteins involved in cell-wall biosynthesis and septation. Furthermore, abundant coimmunoprecipitation of ribosomal proteins with calcineurin occurred exclusively in echinocandins treatment, indicating reprogramming of cellular growth mechanisms during different antifungal drug treatments. While variations in the observed calcineurin immunoprecipitated proteins may also be due to changes in their expression levels under different drug treatments, this study suggests an important role for calcineurin-dependent cellular mechanisms in response to antifungal treatment of A. fumigatus that warrants future studies.

The relationship between maternal 25-hydroxyvitamin D status in pregnancy and childhood adiposity and allergy: an observational study.

BACKGROUND: Vitamin D insufficiency (defined as <75 nmol l-1) is widespread among pregnant women around the world and has been proposed to influence offspring outcomes in childhood and into adult life, including adiposity and allergy. Disorders, including asthma and eczema, are on the rise among children. Our aim was to investigate the relationship between maternal 25-hydroxyvitamin D status in pregnancy and offspring adiposity, asthma and eczema in childhood. SUBJECTS AND METHODS: Maternal 25-hydroxyvitamin D concentrations were analysed in serum samples collected at 15 weeks' gestation from 1710 participants of the prospective Screening for Pregnancy Endpoints cohort study. The offspring of 1208 mothers were followed up at age 5-6 years. Data collected included height, weight, percentage body fat (PBF, measured by bioimpedance) and history of asthma and eczema. Multivariable analysis controlled for maternal body mass index (BMI), age and sex of the child and season of serum sampling. RESULTS: Complete data were available for 922 mother-child pairs. Each 10 nmol l-1 increase in maternal 25-hydroxyvitamin D concentration at 15 weeks' gestation was associated with a decrease in offspring PBF of 0.2% (95% confidence interval 0.04-0.36%, P=0.01) after adjustment for confounders but was not related to child BMI z-score. Maternal mean (±s.d.) 25-hydroxyvitamin D concentration was similar in children who did and did not have asthma (71.7±26.1 vs 73.3±27.1 nmol l-1, P=0.5), severe asthma (68.6±28.6 vs 73.3±26.8 nmol l-1, P=0.2) and eczema (71.9±27.0 vs 73.2±27.0 nmol l-1, P=0.5). CONCLUSIONS: The finding of a relationship between maternal vitamin D status and adiposity in childhood is important, particularly because vitamin D insufficiency in pregnancy is highly prevalent. The association between maternal vitamin D supplementation in pregnancy and adiposity in the offspring merits examination in randomised controlled trials.

Identification of Altered Metabolomic Profiles Following a Panchakarma-based Ayurvedic Intervention in Healthy Subjects: The Self-Directed Biological Transformation Initiative (SBTI).

The effects of integrative medicine practices such as meditation and Ayurveda on human physiology are not fully understood. The aim of this study was to identify altered metabolomic profiles following an Ayurveda-based intervention. In the experimental group, 65 healthy male and female subjects participated in a 6-day Panchakarma-based Ayurvedic intervention which included herbs, vegetarian diet, meditation, yoga, and massage. A set of 12 plasma phosphatidylcholines decreased (adjusted p < 0.01) post-intervention in the experimental (n = 65) compared to control group (n = 54) after Bonferroni correction for multiple testing; within these compounds, the phosphatidylcholine with the greatest decrease in abundance was PC ae C36:4 (delta = -0.34). Application of a 10% FDR revealed an additional 57 metabolites that were differentially abundant between groups. Pathway analysis suggests that the intervention results in changes in metabolites across many pathways such as phospholipid biosynthesis, choline metabolism, and lipoprotein metabolism. The observed plasma metabolomic alterations may reflect a Panchakarma-induced modulation of metabotypes. Panchakarma promoted statistically significant changes in plasma levels of phosphatidylcholines, sphingomyelins and others in just 6 days. Forthcoming studies that integrate metabolomics with genomic, microbiome and physiological parameters may facilitate a broader systems-level understanding and mechanistic insights into these integrative practices that are employed to promote health and well-being.

British Dietetic Association systematic review and evidence-based practice guidelines for the dietary management of irritable bowel syndrome in adults (2016 update).

BACKGROUND: The first British Dietetic Association (BDA) guidelines for the dietary management of irritable bowel syndrome (IBS) in adults were published in 2012. Subsequently, there has been a wealth of new research. The aim of this work was to systematically review the evidence for the role of diet in the management of IBS and to update the guidelines. METHODS: Twelve questions relating to diet and IBS were defined based on review of the previous guideline questions, current evidence and clinical practice. Chosen topics were on healthy eating and lifestyle (alcohol, caffeine, spicy food, elimination diets, fat and fluid intakes and dietary habits), milk and dairy, dietary fibre, fermentable carbohydrates, gluten, probiotics and elimination diets/food hypersensitivity. Data sources were CINAHL, Cochrane Register of Controlled Trials, Embase, Medline, Scopus and Web of Science up to October 2015. Studies were assessed independently in duplicate using risk of bias tools specific to each included study based on inclusion and exclusion criteria for each question. National Health and Medical Research Council grading evidence levels were used to develop evidence statements and recommendations, in accordance with Practice-based Evidence in Nutrition Global protocol used by the BDA. RESULTS: Eighty-six studies were critically appraised to generate 46 evidence statements, 15 clinical recommendations and four research recommendations. The IBS dietary algorithm was simplified to first-line (healthy eating, provided by any healthcare professional) and second-line [low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) to be provided by dietitian] dietary advice. CONCLUSIONS: These guidelines provide updated comprehensive evidence-based details to achieve the successful dietary management of IBS in adults.

Arabis mosaic virus in Grapevines in New York State.

In a limited survey of commercial vineyards and a germplasm repository in Ontario County, NY, 20 vines of Vitis sp. were tested in fall and spring 2010 to 2012 for viruses using a double-antibody sandwich (DAS)-ELISA and macroarray with oligonucleotide probes for grapevine viruses ((3) and unpublished). The plants selected for analysis included those showing atypical growth including leaf deformation, yellowing, cupping or spotting, vein clearing, shortening of internodes, and reduced vigor. Arabis mosaic virus (ArMV; genus Nepovirus, family Secoviridae) was detected in leaf tissue and wood scrapings in two vines using the DAS-ELISA with antibodies from Bioreba (Reinach, Switzerland). The ArMV positive vines were from Vitis hybrid cultivars Noah and Geisenheim 26. ArMV was also detected in these two vines using the macroarray, with hybridization observed to 24 of 32 oligonucleotide probes specific to this virus. To confirm the identification of the virus, total RNAs were extracted from leaf tissues, hybridized with random hexamers, and reverse-transcribed using MMLV reverse transcriptase (Life Technologies, Grand Island, NY). Complementary DNAs were amplified by PCR using an IQ supermix (BioRad, Hercules, CA), and two sets of generic primers for nepoviruses (1,4). Thermocycler conditions were 94°C 5 min (1×); 94°C 30 s, 50°C 30 s, and 69°C 2 min (35×), and 72°C for 5 min. The PCR products were sequenced directly. Sequences from the 340-bp products obtained from cultivars Geisenheim 26 (GenBank Accession No. HE984333) and Noah (HE984334) using the Wei et al. primers (4) had 76 to 84% sequence identity to ArMV RNA1 GenBank accessions GQ369528 and AY303786. Sequences from the 301-bp products obtained from cultivars Geisenheim 26 (HE984335) and Noah (HE984336) using the Digiaro et al. primers (1) had 87 to 91% sequence identity to ArMV RNA2 GenBank accessions AY017339 and X81814. ArMV was mechanically transmitted from Geisenheim 26 to Nicotiana tabacum cultivar Xanthi NN. Inoculation gave rise to necrotic local lesions on the inoculated leaves of five plants in each of two experiments (10 of 10 plants total). The presence of ArMV in tobacco was confirmed by DAS-ELISA. Thus, the presence of ArMV in New York grapevines has been confirmed by the detection of the coat protein antigen, virus specific oligonucleotide probes, and the sequencing of portions of both genomic RNAs. There are limited reports of ArMV in North America and in grapevine in particular (2), but with a wide host range and seed and nematode transmissibility, ArMV has the ability to become more widespread among grapevine and other crops. References: (1) M. Digiaro, et al. J. Virol. Methods 141:34, 2007. (2) B. N. Milkus et al. Am. J. Enol. Vitic. 50:56, 1999. (3) J. Thompson et al. J. Virol. Methods 183:161, 2012. (4) T. Wei et al. J. Virol. Methods 153:16, 2008.

Antibiotic resistant Staphylococcus aureus in hospital wastewaters and sewage treatment plants with special reference to methicillin-resistant Staphylococcus aureus (MRSA).

AIMS: To investigate the presence of methicillin-resistant Staphylococcus aureus (MRSA) in untreated hospital wastewaters (UHWW), their transmission into the receiving sewage treatment plant (STP) and survival through the STP treatment. METHODS AND RESULTS: Over eight consecutive weeks of sampling, we isolated 224 Staph. aureus strains from UHWW-1, UHWW-2 and its receiving STP inlet (SI) and post-treatment outlet (SO). These strains were typed using the PhP typing method and RAPD-PCR and tested for their antibiotic resistance patterns. Resistance to cefoxitin and the presence of mecA gene identified MRSA isolates. In all, 11 common (C) and 156 single (S) PhP-RAPD types were found among isolates, with two multidrug resistant (MDR) C-types found in H2, SI and SO. These C-type strains also showed resistance to cefoxitin and vancomycin. The mean number of antibiotics to which the strains from UHWW were resistant (5.14 ± 2) was significantly higher than the STP isolates (2.9 ± 1.9) (P < 0.0001). Among the 131 (68%) MRSA strains, 24 were also vancomycin resistant. MDR strains (including MRSA) were more prevalent in hospital wastewaters than in the STP. CONCLUSION: This study provides evidence of the survival of MRSA strains in UHWWs and their transit to the STP and then through to the final treated effluent and chlorination stage. SIGNIFICANCE AND IMPACT OF THE STUDY: This preliminary study identifies the need to further investigate the load of MRSA in hospitals' wastewaters and possible their survival in STPs. From a public health point of view, this potential route of hospital MRSA dissemination is of great importance.

Effect of varying glucose and glucosamine concentration in vitro on mouse oocyte maturation and developmental competence.

The effects of hyper- and hypo-glycaemic conditions during the in vitro maturation of mouse cumulus-oocyte complexes on developmental competence were examined, with an emphasis on the role of the hexosamine biosynthesis pathway. A low (1 mM) glucose concentration achieved optimal oocyte competence (3-fold higher blastocyst development rate compared with high (30 mM) glucose, P<0.05). In addition, glucose supplementation during only the first hour after release from the follicle was necessary and sufficient to support oocyte maturation and embryo development to the blastocyst stage. Glucosamine (a known hyperglycaemic mimetic and specific activator of the hexosamine pathway) was able to substitute for glucose during this first hour, indicating that flux through the hexosamine pathway is essential for oocyte competence. In the absence of glucose throughout the maturation period, glucosamine was not able to increase developmental competence, and at higher concentrations (2.5 and 5 mM) had a detrimental effect on MII and blastocyst development rates, compared with controls (P<0.05). These experiments underscore the importance of glucose metabolic pathways during in vitro maturation and support the concept that excess flux through the hexosamine pathway has detrimental consequences.

Plasma proteomics of patients with non-valvular atrial fibrillation on chronic anti-coagulation with warfarin or a direct factor Xa inhibitor.

Plasma proteins mediate thrombogenesis, inflammation, endocardial injury and structural remodelling in atrial fibrillation (AF). We hypothesised that anti-coagulation with rivaroxaban, a direct factor Xa inhibitor, would differentially modulate biologically-relevant plasma proteins, compared with warfarin, a multi-coagulation protein antagonist. We performed unbiased liquid chromatography/tandem mass spectroscopy and candidate multiplexed protein immunoassays among Japanese subjects with non-valvular chronic AF who were randomly assigned to treatment with 24 weeks of rivaroxaban (n=93) or warfarin (n=94). Nine metaproteins, including fibulin-1 (p=0.0033), vitronectin (p=0.0010), haemoglobin α (p=0.0012), apolipoproteins C-II (p=0.0017) and H (p=0.0023), complement C5 precursor (p=0.0026), coagulation factor XIIIA (p=0.0026) and XIIIB (p=0.0032) subunits, and 10 candidate proteins, including thrombomodulin (p=0.0004), intercellular adhesion molecule-3 (p=0.0064), interleukin-8 (p=0.0007) and matrix metalloproteinase-3 (p=0.0003), were differentially expressed among patients with and without known clinical risk factors for stroke and bleeding in AF. Compared with warfarin, rivaroxaban treatment was associated with a greater increase in thrombomodulin (Δ 0.1 vs. 0.3 pg/ml, p=0.0026) and a trend towards a reduction in matrix metalloproteinase-9 (Δ 2.2 vs. -4.9 pg/ml, p=0.0757) over 24 weeks. Only modest correlations were observed between protein levels and prothrombin time, factor Xa activity and prothrombinase-induced clotting time. Plasma proteomics can identify distinct functional patterns of protein expression that report on known stroke and bleeding risk phenotypes in an ethnically-homogeneous AF population. The greater upregulation of thrombomodulin among patients randomised to rivaroxaban represents a proof-of-principle that pharmacoproteomics can be employed to discern novel effects of factor Xa inhibition beyond standard pharmacodynamic measures.

Dynamics of critical source areas: does connectivity explain chemistry?

Critical source area approaches to catchment management are increasingly being recognised as effective tools to mitigate sediment and nutrient transfers. These approaches often assume hydrological connectivity as a driver for environmental risk, however this assumption has rarely been tested. Using high resolution monitoring, 14 rainfall events of contrasting intensity were examined in detail for spatial and temporal dynamics of overland flow generation at a hydrologically isolated grassland hillslope in Co. Down, Northern Ireland. Interactions between overland flow connectivity and nutrient transfers were studied to test the critical source area hypothesis. While total and soluble phosphorus loads were found to be representative of the size of the overland flow contributing area (P=<0.05), the dynamics of concentrations throughout storm hydrographs were found to be complex and storm dependant. Near linear relationships were observed between the contributing area and total overland flow volumes (R(2)=0.86). Export coefficients (kg ha(-1)) calculated using plot size were found to under estimate annual losses of total phosphorus by a factor of 17, when compared to those calculated using the contributing area. This study shows that current critical source area definitions for implementing mitigation measures may be overlooking the importance of storm characteristics in determining nutrient transfers and hence may be insufficient in determining catchment scale risk.

What are the implications of variation in root hair length on tolerance to phosphorus deficiency in combination with water stress in barley (Hordeum vulgare)?

BACKGROUND AND AIMS: Phosphorus commonly limits crop yield and is frequently applied as fertilizer; however, supplies of quality rock phosphate for fertilizer production are diminishing. Plants have evolved many mechanisms to increase their P-fertilizer use efficiency, and an understanding of these traits could result in improved long-term sustainability of agriculture. Here a mutant population is utilized to assess the impact of root hair length on P acquisition and yield under P-deficient conditions alone or when combined with drought. METHODS: Mutants with various root hair phenotypes were grown in the glasshouse in pots filled with soil representing sufficient and deficient P treatments and, in one experiment, a range of water availability was also imposed. Plants were variously harvested at 7 d, 8 weeks and 14 weeks, and variables including root hair length, rhizosheath weight, biomass, P accumulation and yield were measured. KEY RESULTS: The results confirmed the robustness of the root hair phenotypes in soils and their relationship to rhizosheath production. The data demonstrated that root hair length is important for shoot P accumulation and biomass, while only the presence of root hairs is critical for yield. Root hair presence was also critical for tolerance to extreme combined P deficit and drought stress, with genotypes with no root hairs suffering extreme growth retardation in comparison with those with root hairs. CONCLUSIONS: The results suggest that although root hair length is not important for maintaining yield, the presence of root hairs is implicit to sustainable yield of barley under P-deficient conditions and when combined with extreme drought. Root hairs are a trait that should be maintained in future germplasm.

A biotin switch-based proteomics approach identifies 14-3-3ζ as a target of Sirt1 in the metabolic regulation of caspase-2.

While lysine acetylation in the nucleus is well characterized, comparatively little is known about its significance in cytoplasmic signaling. Here we show that inhibition of the Sirt1 deacetylase, which is primarily cytoplasmic in cancer cell lines, sensitizes these cells to caspase-2-dependent death. To identify relevant Sirt1 substrates, we developed a proteomics strategy, enabling the identification of a range of putative substrates, including 14-3-3ζ, a known direct regulator of caspase-2. We show here that inhibition of Sirtuin activity accelerates caspase activation and overrides caspase-2 suppression by nutrient abundance. Furthermore, 14-3-3ζ is acetylated prior to caspase activation, and supplementation of Xenopus egg extract with glucose-6-phosphate, which promotes caspase-2/14-3-3ζ binding, enhances 14-3-3ζ-directed Sirtuin activity. Conversely, inhibiting Sirtuin activity promotes14-3-3ζ dissociation from caspase-2 in both egg extract and human cultured cells. These data reveal a role for Sirt1 in modulating apoptotic sensitivity, in response to metabolic changes, by antagonizing 14-3-3ζ acetylation.

Disparity in the risk stratification of major surgery.

This case report illustrates the dilemma of risk prediction. In the objective documentation of peri-operative risk, cardiopulmonary testing offers a holistic assessment. At present, availability is limited and, as such, it is important to be mindful of the limitations of other more traditional forms of risk assessment.

Self-schema and social comparison explanations of body dissatisfaction: a laboratory investigation.

The current study was an investigation of the self-schema and social comparison theories of body dissatisfaction. The social comparison manipulation consisted of exposure to one of three levels of comparison figure: upward, downward, or no comparison. Two different imagery exercises served to prime either a participants' appearance self-schema, or a non-appearance schema. Participants completed state measures of body image and mood at pre- and posttest. Results indicated no significant interaction between priming and social comparison and no significant main effect for priming. However, there was a significant effect of social comparison, such that those in the downward comparison condition showed an increase in body satisfaction and positive mood. Results are discussed in the context of self-schema theory and social comparison, and suggestions are given for future research that might further shed light on these theoretical approaches for understanding body dissatisfaction.

Hidden magnetism and quantum criticality in the heavy fermion superconductor CeRhIn5.

With only a few exceptions that are well understood, conventional superconductivity does not coexist with long-range magnetic order (for example, ref. 1). Unconventional superconductivity, on the other hand, develops near a phase boundary separating magnetically ordered and magnetically disordered phases. A maximum in the superconducting transition temperature T(c) develops where this boundary extrapolates to zero Kelvin, suggesting that fluctuations associated with this magnetic quantum-critical point are essential for unconventional superconductivity. Invariably, though, unconventional superconductivity masks the magnetic phase boundary when T < T(c), preventing proof of a magnetic quantum-critical point. Here we report specific-heat measurements of the pressure-tuned unconventional superconductor CeRhIn5 in which we find a line of quantum-phase transitions induced inside the superconducting state by an applied magnetic field. This quantum-critical line separates a phase of coexisting antiferromagnetism and superconductivity from a purely unconventional superconducting phase, and terminates at a quantum tetracritical point where the magnetic field completely suppresses superconductivity. The T --> 0 K magnetic field-pressure phase diagram of CeRhIn5 is well described with a theoretical model developed to explain field-induced magnetism in the high-T(c) copper oxides, but in which a clear delineation of quantum-phase boundaries has not been possible. These experiments establish a common relationship among hidden magnetism, quantum criticality and unconventional superconductivity in copper oxides and heavy-electron systems such as CeRhIn5.

A two-stage design for a phase II clinical trial of coenzyme Q10 in ALS.

BACKGROUND: The combination of a small pool of patients at any given time with the availability of many potential neuroprotective agents to be tested in ALS requires efficient phase II trial designs. OBJECTIVE: To describe the design of the Clinical Trial of High Dose Coenzyme Q10 (CoQ10) in ALS (QALS study)--a phase II, randomized, placebo-controlled, double-blind, multicenter clinical trial. METHODS: The study design features two stages. The first stage (dose selection) identifies which of two doses of CoQ10 (1800 mg or 2700 mg) is preferred using a selection procedure rather than a formal hypothesis test. The second stage (early efficacy test) compares the preferred dose of CoQ10 against placebo using a non-superiority or futility design. Data from patients assigned to the preferred dose of CoQ10 in the first stage are also used in the second stage. The primary outcome measure is the decline in Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRSr) score from baseline to 9 months. RESULTS: The total sample size required is 185 patients, as compared to a much larger sample size estimated to be necessary using a conventional superiority design (total: 852 patients). The authors report a bias correction made necessary by the inclusion of patient data from the first stage in the second stage. CONCLUSIONS: Several features of the Clinical Trial of High Dose Coenzyme Q10 in ALS study design promote efficiency. These features may be beneficial in phase II trials in amyotrophic lateral sclerosis and other fields.