Variance-balanced designs under interference for dependent observations

It is shown that variance-balanced designs can be obtained from Type I orthogonal arrays for many general models with two kinds of treatment effects, including ones for interference, with general dependence structures. These designs can be used to obtain optimal and efficient designs. Some examples and design comparisons are given. (C) 2002 Elsevier B.V. All rights reserved.

Advantage of single-trial models for response to selection in wheat breeding multi-environment trials

An investigation was conducted to evaluate the impact of experimental designs and spatial analyses (single-trial models) of the response to selection for grain yield in the northern grains region of Australia (Queensland and northern New South Wales). Two sets of multi-environment experiments were considered. One set, based on 33 trials conducted from 1994 to 1996, was used to represent the testing system of the wheat breeding program and is referred to as the multi-environment trial (MET). The second set, based on 47 trials conducted from 1986 to 1993, sampled a more diverse set of years and management regimes and was used to represent the target population of environments (TPE). There were 18 genotypes in common between the MET and TPE sets of trials. From indirect selection theory, the phenotypic correlation coefficient between the MET and TPE single-trial adjusted genotype means [r(p(MT))] was used to determine the effect of the single-trial model on the expected indirect response to selection for grain yield in the TPE based on selection in the MET. Five single-trial models were considered: randomised complete block (RCB), incomplete block (IB), spatial analysis (SS), spatial analysis with a measurement error (SSM) and a combination of spatial analysis and experimental design information to identify the preferred (PF) model. Bootstrap-resampling methodology was used to construct multiple MET data sets, ranging in size from 2 to 20 environments per MET sample. The size and environmental composition of the MET and the single-trial model influenced the r(p(MT)). On average, the PF model resulted in a higher r(p(MT)) than the IB, SS and SSM models, which were in turn superior to the RCB model for MET sizes based on fewer than ten environments. For METs based on ten or more environments, the r(p(MT)) was similar for all single-trial models.

Some results on the design of field experiments for comparing unreplicated treatments

In early generation variety trials, large numbers of new breeders' lines need to be compared, and usually there is little seed available for each new line. A so-called unreplicated trial has each new line on just one plot at a site, but includes several (often around five) replicated check or control (or standard) varieties. The total proportion of check plots is usually between 10% and 20%. The aim of the trial is to choose some good performing lines (usually around 1/3 of those tested) to go on for further testing, rather than precise estimation of their mean yield. Now that spatial analyses of data from field experiments are becoming more common, there is interest in an efficient layout of an experiment given a proposed spatial analysis. Some possible design criteria are discussed, and efficient layouts under spatial dependence are considered.

Effectiveness of Community versus Hospital Eye Service follow-up for patients with neovascular age-related macular degeneration with quiescent disease (ECHoES): a virtual non-inferiority trial

OBJECTIVES: To compare the ability of ophthalmologists versus optometrists to correctly classify retinal lesions due to neovascular age-related macular degeneration (nAMD).

DESIGN: Randomised balanced incomplete block trial. Optometrists in the community and ophthalmologists in the Hospital Eye Service classified lesions from vignettes comprising clinical information, colour fundus photographs and optical coherence tomographic images. Participants' classifications were validated against experts' classifications (reference standard).

SETTING: Internet-based application.

PARTICIPANTS: Ophthalmologists with experience in the age-related macular degeneration service; fully qualified optometrists not participating in nAMD shared care.

INTERVENTIONS: The trial emulated a conventional trial comparing optometrists' and ophthalmologists' decision-making, but vignettes, not patients, were assessed. Therefore, there were no interventions and the trial was virtual. Participants received training before assessing vignettes.

MAIN OUTCOME MEASURES: Primary outcome-correct classification of the activity status of a lesion based on a vignette, compared with a reference standard. Secondary outcomes-potentially sight-threatening errors, judgements about specific lesion components and participants' confidence in their decisions.

RESULTS: In total, 155 participants registered for the trial; 96 (48 in each group) completed all assessments and formed the analysis population. Optometrists and ophthalmologists achieved 1702/2016 (84.4%) and 1722/2016 (85.4%) correct classifications, respectively (OR 0.91, 95% CI 0.66 to 1.25; p=0.543). Optometrists' decision-making was non-inferior to ophthalmologists' with respect to the prespecified limit of 10% absolute difference (0.298 on the odds scale). Optometrists and ophthalmologists made similar numbers of sight-threatening errors (57/994 (5.7%) vs 62/994 (6.2%), OR 0.93, 95% CI 0.55 to 1.57; p=0.789). Ophthalmologists assessed lesion components as present less often than optometrists and were more confident about their classifications than optometrists.

CONCLUSIONS: Optometrists' ability to make nAMD retreatment decisions from vignettes is not inferior to ophthalmologists' ability. Shared care with optometrists monitoring quiescent nAMD lesions has the potential to reduce workload in hospitals.

TRIAL REGISTRATION NUMBER: ISRCTN07479761; pre-results registration.

New electrocardiographic criteria for discriminating between Brugada types 2 and 3 patterns and incomplete right bundle branch block.

OBJECTIVES: The aim of this study was to evaluate new electrocardiographic (ECG) criteria for discriminating between incomplete right bundle branch block (RBBB) and the Brugada types 2 and 3 ECG patterns. BACKGROUND: Brugada syndrome can manifest as either type 2 or type 3 pattern. The latter should be distinguished from incomplete RBBB, present in 3% of the population. METHODS: Thirty-eight patients with either type 2 or type 3 Brugada pattern that were referred for an antiarrhythmic drug challenge (AAD) were included. Before AAD, 2 angles were measured from ECG leads V(1) and/or V(2) showing incomplete RBBB: 1) α, the angle between a vertical line and the downslope of the r'-wave, and 2) β, the angle between the upslope of the S-wave and the downslope of the r'-wave. Baseline angle values, alone or combined with QRS duration, were compared between patients with negative and positive results on AAD. Receiver-operating characteristic curves were constructed to identify optimal discriminative cutoff values. RESULTS: The mean β angle was significantly smaller in the 14 patients with negative results on AAD compared to the 24 patients with positive results on AAD (36 ± 20° vs. 62 ± 20°, p < 0.01). Its optimal cutoff value was 58°, which yielded a positive predictive value of 73% and a negative predictive value of 87% for conversion to type 1 pattern on AAD; α was slightly less sensitive and specific compared with β. When the angles were combined with QRS duration, it tended to improve discrimination. CONCLUSIONS: In patients with suspected Brugada syndrome, simple ECG criteria can enable discrimination between incomplete RBBB and types 2 and 3 Brugada patterns.

A new electrocardiographic criteria for discriminating between Brugada types 2 and 3 patterns and incomplete right bundle branch block

Le syndrome de Brugada, une affection rythmique du sujet jeune potentiellement fatale, se manifeste sur l'ECG par un bloc de branche droit (BBD) complet, avec sus-décalage majeur du segment ST et inversion des ondes Τ de V1 à V3 appelé pattern de type 1. Cette présentation peut être intermittente. Les manifestations incomplètes du syndrome de Brugada sont appelées patterns de types 2 ou 3, et sont caractérisées par un BBD incomplet et un sus-décalage ST plus ou moins prononcé dans les dérivations V-, et V2 de l'ECG. Cette description, cependant, est aussi celle du BBD incomplet fréquemment rencontré chez les sujets jeunes, de moins de 40 ans, et présent dans 3% de la population. Bo nombre de ces sujets sont donc référés pour une recherche de syndrome de Brugada. Le but de cette thèse est donc d'évaluer de nouveaux critères permettant de discriminer les BBD incomplets, banals, des sujets porteurs d'un syndrome de Brugada de types 2 ou 3. Trente-huit patients avec un pattern de Brugada de types 2 et 3, référés pour un test médicamenteux utilisant un antiarythmique révélant un pattern de type 1 chez les sujets porteurs, ont été inclus dans l'étude. Avant le test médicamenteux, deux angles ont été mesurés sur les dérivations Vi et/ou V2 : a, l'angle entre une ligne verticale et la descente de l'onde r', et β, l'angle entre la montée de l'onde S et la descente de l'onde r'. Les mesure à l'état basai des deux angles, seules ou combinées avec la durée du QRS, on été comparées entre les patients avec une épreuve pharmacologique positive et ceux dont l'épreuve s'est révélée négative (i.e. servant de groupe contrôle car porteur d'un véritable BBD incomplet). Des courbes ROC ont été établies afin de déterminer les valeurs d'angles les plus discriminantes. La moyenne des angles β était significativement plus petite chez les 14 patients avec un test pharmacologique négatif comparé aux 24 patients avec un test positif. La valeur optimale pour l'angle β était de 58°, ce qui donnait une valeur prédictive positive de 73% et une valeur prédictive négative de 97% pour une conversion en pattern de type 1 lors du test pharmacologique. L'angle α était un peu moins sensible et spécifique que β. Quand les angles étaient combinés à la durée du QRS, on observait une discrète amélioration de la discrimination entre les deux populations. Notre travail permet donc, chez des patients suspects d'un syndrome de Brugada, de discriminer entre un BBD incomplet et les patterns de Brugada types 2 et 3 en utilisant un critère simple basé sur l'ECG de surface potentiellement applicable au lit du patient

Isolated congenital atrioventricular block diagnosed in utero: natural history and outcome.

BACKGROUND: Isolated congenital atrioventricular block (CAVB) diagnosed in utero is associated with a high morbidity and mortality. Prognosis is especially poor when heart rate drops below 55 beats per minute (bpm) and when fetal hydrops develops. We describe the natural history and outcome of 24 infants with isolated CAVB diagnosed in utero, review the literature, and assess the risk factors that could predict outcome. METHODS: This was a retrospective multicenter study of 24 patients with isolated CAVB diagnosed in utero. RESULTS: CAVB was detected at a mean gestational age (GA) of 24.7 +/- 5.1 weeks. Ten fetuses initially presented with complete heart block. Low heart rate or incomplete heart block was the first documentation of bradyarrhythmia in the other 14 fetuses. In 11 of them, CAVB developed during pregnancy after a median time of 3 (range 1-16) weeks. Fetal hydrops developed in 10 of 24 (42%) fetuses at a mean GA of 27.6 +/- 5.1 weeks. Hydropic fetuses showed lower heart rates during pregnancy (47 +/- 10 bpm) than non-hydropic fetuses (57 +/- 10 bpm). There were three intrauterine deaths; all were hydropic and female. Nine viable females and 12 males were born at a mean GA of 37.1 +/- 6.1 weeks with an average birth weight of 3097 +/- 852 g. Fifteen CAVB patients required pacemaker (PM) intervention, 10 of them immediately after birth. Dilated cardiomyopathy (DCM) developed in three infants of whom two died of congestive heart failure, shortly after the diagnosis was made; one is still alive. Mortality before or after birth was 21%, and was associated with heart rates below 50 bpm and development of fetal hydrops. Poor outcome, defined as death, PM implantation, or development of DCM, occurred in 83% of cases and was associated with heart rates below 60 bpm during pregnancy. CONCLUSIONS: Isolated CAVB diagnosed in utero is associated with high morbidity and mortality. Patients who develop fetal hydrops show lower heart rates during pregnancy than patients who do not. A fetal heart rate below 50 bpm and development of fetal hydrops is associated with increased mortality. Rates below 60 bpm are associated with PM requirement and/or DCM.

Casein Kinase 1γ Ensures Monopolar Growth Polarity under Incomplete DNA Replication Downstream of Cds1 and Calcineurin in Fission Yeast.

Cell polarity is essential for various cellular functions during both proliferative and developmental stages, and it displays dynamic alterations in response to intracellular and extracellular cues. However, the molecular mechanisms underlying spatiotemporal control of polarity transition are poorly understood. Here, we show that fission yeast Cki3 (a casein kinase 1γ homolog) is a critical regulator to ensure persistent monopolar growth during S phase. Unlike the wild type, cki3 mutant cells undergo bipolar growth when S phase is blocked, a condition known to delay transition from monopolar to bipolar growth (termed NETO [new end takeoff]). Consistent with this role, Cki3 kinase activity is substantially increased, and cells lose their viability in the absence of Cki3 upon an S-phase block. Cki3 acts downstream of the checkpoint kinase Cds1/Chk2 and calcineurin, and the latter physically interacts with Cki3. Autophosphorylation in the C terminus is inhibitory toward Cki3 kinase activity, and calcineurin is responsible for its dephosphorylation. Cki3 localizes to the plasma membrane, and this localization requires the palmitoyltransferase complex Erf2-Erf4. Membrane localization is needed not only for proper NETO timing but also for Cki3 kinase activity. We propose that Cki3 acts as a critical inhibitor of cell polarity transition under S-phase arrest.

Length of the Mitral Isthmus But Not Anatomical Location of Ablation Line Predicts Bidirectional Mitral Isthmus Block in Patients Undergoing Catheter Ablation of Persistent Atrial Fibrillation: A Randomized Controlled Trial.

INTRODUCTION: Mitral isthmus (MI) ablation is an effective option in patients undergoing ablation for persistent atrial fibrillation (AF). Achieving bidirectional conduction block across the MI is challenging, and predictors of MI ablation success remain incompletely understood. We sought to determine the impact of anatomical location of the ablation line on the efficacy of MI ablation. METHODS AND RESULTS: A total of 40 consecutive patients (87% male; 54 ± 10 years) undergoing stepwise AF ablation were included. MI ablation was performed in sinus rhythm. MI ablation was performed from the left inferior PV to either the posterior (group 1) or the anterolateral (group 2) mitral annulus depending on randomization. The length of the MI line (measured with the 3D mapping system) and the amplitude of the EGMs at 3 positions on the MI were measured in each patient. MI block was achieved in 14/19 (74%) patients in group 1 and 15/21 (71%) patients in group 2 (P = NS). Total MI radiofrequency time (18 ± 7 min vs. 17 ± 8 min; P = NS) was similar between groups. Patients with incomplete MI block had a longer MI length (34 ± 6 mm vs. 24 ± 5 mm; P < 0.001), a higher bipolar voltage along the MI (1.75 ± 0.74 mV vs. 1.05 ± 0.69 mV; P < 0.01), and a longer history of continuous AF (19 ± 17 months vs. 10 ± 10 months; P < 0.05). In multivariate analysis, decreased length of the MI was an independent predictor of successful MI block (OR 1.5; 95% CI 1.1-2.1; P < 0.05). CONCLUSIONS: Increased length but not anatomical location of the MI predicts failure to achieve bidirectional MI block during ablation of persistent AF.

Minimal local anesthetic volume for peripheral nerve block: a new ultrasound-guided, nerve dimension-based method

BACKGROUND AND OBJECTIVES: Nerve blocks using local anesthetics are widely used. High volumes are usually injected, which may predispose patients to associated adverse events. Introduction of ultrasound guidance facilitates the reduction of volume, but the minimal effective volume is unknown. In this study, we estimated the 50% effective dose (ED50) and 95% effective dose (ED95) volume of 1% mepivacaine relative to the cross-sectional area of the nerve for an adequate sensory block. METHODS: To reduce the number of healthy volunteers, we used a volume reduction protocol using the up-and-down procedure according to the Dixon average method. The ulnar nerve was scanned at the proximal forearm, and the cross-sectional area was measured by ultrasound. In the first volunteer, a volume of 0.4 mL/mm of nerve cross-sectional area was injected under ultrasound guidance in close proximity to and around the nerve using a multiple injection technique. The volume in the next volunteer was reduced by 0.04 mL/mm in case of complete blockade and augmented by the same amount in case of incomplete sensory blockade within 20 mins. After 3 up-and-down cycles, ED50 and ED95 were estimated. Volunteers and physicians performing the block were blinded to the volume used. RESULTS: A total 17 of volunteers were investigated. The ED50 volume was 0.08 mL/mm (SD, 0.01 mL/mm), and the ED95 volume was 0.11 mL/mm (SD, 0.03 mL/mm). The mean cross-sectional area of the nerves was 6.2 mm (1.0 mm). CONCLUSIONS: Based on the ultrasound measured cross-sectional area and using ultrasound guidance, a mean volume of 0.7 mL represents the ED95 dose of 1% mepivacaine to block the ulnar nerve at the proximal forearm.

Length of the Mitral Isthmus But Not Anatomical Location of Ablation Line Predicts Bidirectional Mitral Isthmus Block in Patients Undergoing Catheter Ablation of Persistent Atrial Fibrillation: A Randomized Controlled Trial

INTRODUCTION Mitral isthmus (MI) ablation is an effective option in patients undergoing ablation for persistent atrial fibrillation (AF). Achieving bidirectional conduction block across the MI is challenging, and predictors of MI ablation success remain incompletely understood. We sought to determine the impact of anatomical location of the ablation line on the efficacy of MI ablation. METHODS AND RESULTS A total of 40 consecutive patients (87% male; 54 ± 10 years) undergoing stepwise AF ablation were included. MI ablation was performed in sinus rhythm. MI ablation was performed from the left inferior PV to either the posterior (group 1) or the anterolateral (group 2) mitral annulus depending on randomization. The length of the MI line (measured with the 3D mapping system) and the amplitude of the EGMs at 3 positions on the MI were measured in each patient. MI block was achieved in 14/19 (74%) patients in group 1 and 15/21 (71%) patients in group 2 (P = NS). Total MI radiofrequency time (18 ± 7 min vs. 17 ± 8 min; P = NS) was similar between groups. Patients with incomplete MI block had a longer MI length (34 ± 6 mm vs. 24 ± 5 mm; P < 0.001), a higher bipolar voltage along the MI (1.75 ± 0.74 mV vs. 1.05 ± 0.69 mV; P < 0.01), and a longer history of continuous AF (19 ± 17 months vs. 10 ± 10 months; P < 0.05). In multivariate analysis, decreased length of the MI was an independent predictor of successful MI block (OR 1.5; 95% CI 1.1-2.1; P < 0.05). CONCLUSIONS Increased length but not anatomical location of the MI predicts failure to achieve bidirectional MI block during ablation of persistent AF.

Heads buried in the sand: member states block solutions to the refugee crisis. EPC Commentary, 15 September 2015

Yesterday’s meeting of Interior Ministers demonstrated that the EU’s asylum and immigration policy remains incomplete. This is mainly due to the member states’ inability to plan ahead, their reluctance to adopt binding common rules – considered as a violation of their sovereignty – and their central position in the implementation of EU rules.

Recursive Methods for Construction of Balanced N-ary Block Designs

2000 Mathematics Subject Classification: Primary 05B05; secondary 62K10.

Synthesis and structural characterization of block and random low molecular weight copolymers composed of L-lactic acid and isosorbide succinate moieties

Isosorbide succinate moieties were incorporated into poly(L-lactide) (PLLA) backbone in order to obtain a new class of biodegradable polymer with enhanced properties. This paper describes the synthesis and characterization of four types of low molecular weight copolymers. Copolymer I was obtained from monomer mixtures of L-lactide, isosorbide, and succinic anhydride; II from oligo(L-lactide) (PLLA), isosorbide, and succinic anhydride; III from oligo(isosorbide succinate) (PIS) and L-lactide; and IV from transesterification reactions between PLLA and PIS. MALDI-TOFMS and 13C-NMR analyses gave evidence that co-oligomerization was successfully attained in all cases. The data suggested that the product I is a random co-oligomer and the products II-IV are block co-oligomers.

Universal and nonuniversal contributions to block-block entanglement in many-fermion systems

We calculate the entanglement entropy of blocks of size x embedded in a larger system of size L, by means of a combination of analytical and numerical techniques. The complete entanglement entropy in this case is a sum of three terms. One is a universal x- and L-dependent term, first predicted by Calabrese and Cardy, the second is a nonuniversal term arising from the thermodynamic limit, and the third is a finite size correction. We give an explicit expression for the second, nonuniversal, term for the one-dimensional Hubbard model, and numerically assess the importance of all three contributions by comparing to the entropy obtained from fully numerical diagonalization of the many-body Hamiltonian. We find that finite-size corrections are very small. The universal Calabrese-Cardy term is equally small for small blocks, but becomes larger for x > 1. In all investigated situations, however, the by far dominating contribution is the nonuniversal term stemming from the thermodynamic limit.