Rate Modulated Pacing Based on Right Ventricular dP/dt: Quantitative Analysis of Chronotropic Response

Right ventricular contractility increases in response to catecholamine stimulation and greater ventricular preload, factors that increase with exercise workload. Thus, the maximum systolic dP/dt may be a potentially useful sensor to control the pacing rate of a permanent pacing system. The present study was designed to test the long-term performance of a permanent pacemaker that modulates pacing rate based on right ventricular dP/dt and to quantitatively analyze the chronotropic response characteristics of this sensor in a group of patients with widely varying structural heart diseases and degrees of hemodynamic impairment. A permanent pacing system incorporating a high fidelity pressure sensor in the lead for measurement of right ventricular dP/dt was implanted in 13 patients with atrial arrhythmias and AV block, including individuals with coronary artery disease, hypertension, severe obstructive pulmonary disease with prior pneumonectomy, atrial septal defect, dilated cardiomyopathy, restrictive cardiomyopathy, and mitral stenosis. Patients underwent paired treadmill exercise testing in the VVI and VVIR pacing modes with measurement of expired gas exchange and quantitative analysis of chronotropic response using the concept of metabolic reserve. The peak right ventricular dP/dt ranged from 238–891 mmHg/sec with a pulse pressure that ranged from 19–41 mmHg. There was a positive correlation between the right ventricular dP/dt and pulse pressure (r = 0.70, P = 0.012). The maximum pacing rate and VO_2max were 72 ± 6 beats/min and 12.61 ± 4.0 cc O₂/kg per minute during VVI pacing and increased to 124 ± 18 beats/min and 15.89 ± 5.9 cc 0₂/kg per minute in the VVIR pacing mode (P < 0.0003 and P < 0.002, respectively). The integrated area under the normalized rate response curve was 96.7 ± 45.7% of expected during exercise and 100.1 ± 43.4% of expected during recovery. One patient demonstrated an anomalous increase in pacing rate in response to a change in posture to the left lateral decubitus position. Thus, the peak positive right ventricular dP/dt is an effective rate control parameter for permanent pacing systems. The chronotropic response was proportional to metabolic workload during treadmill exercise in this study population with widely varying forms of structural heart disease.     

Integrating climate change adaptation into public health practice: using adaptive management to increase adaptive capacity and build resilience

Background: Climate change is expected to have a range of health impacts, some of which are already apparent. Public health adaptation is imperative, but there has been little discussion of how to increase adaptive capacity and resilience in public health systems.Objectives: We explored possible explanations for the lack of work on adaptive capacity, outline climate–health challenges that may lie outside public health’s coping range, and consider changes in practice that could increase public health’s adaptive capacity.Methods: We conducted a substantive, interdisciplinary literature review focused on climate change adaptation in public health, social learning, and management of socioeconomic systems exhibiting dynamic complexity.Discussion: There are two competing views of how public health should engage climate change adaptation. Perspectives differ on whether climate change will primarily amplify existing hazards, requiring enhancement of existing public health functions, or present categorically distinct threats requiring innovative management strategies. In some contexts, distinctly climate-sensitive health threats may overwhelm public health’s adaptive capacity. Addressing these threats will require increased emphasis on institutional learning, innovative management strategies, and new and improved tools. Adaptive management, an iterative framework that embraces uncertainty, uses modeling, and integrates learning, may be a useful approach. We illustrate its application to extreme heat in an urban setting.Conclusions: Increasing public health capacity will be necessary for certain climate–health threats. Focusing efforts to increase adaptive capacity in specific areas, promoting institutional learning, embracing adaptive management, and developing tools to facilitate these processes are important priorities and can improve the resilience of local public health systems to climate change.     

A trivariate continual reassessment method for phase I/II trials of toxicity,efficacy, and surrogate efficacy

Recently, many Bayesian methods have been developed for dose finding when simultaneously modeling both toxicity and efficacy outcomes in a blended phase I/II fashion. A further challenge arises when all the true efficacy data cannot be obtained quickly after the treatment so that surrogate markers are instead used (e.g., in cancer trials). We propose a framework to jointly model the probabilities of toxicity, efficacy, and surrogate efficacy given a particular dose. Our trivariate binary model is specified as a composition of two bivariate binary submodels. In particular, we extend the bivariate continual reassessment method (CRM), as well as utilize a particular Gumbel copula. The resulting trivariate algorithm utilizes all the available data at any given time point and can flexibly stop the trial early for either toxicity or efficacy. Our simulation studies demonstrate that our proposed method can successfully improve dosage targeting efficiency and guard against excess toxicity over a variety of true model settings and degrees of surrogacy. Copyright © 2012 John Wiley & Sons, Ltd.     

Impact of Adaptive Rate Pacing Controlled by a Right Ventricular Impedance Sensor on Cardiac Output in Response to Exercise

COOK, L., et al. : Impact of Adaptive Rate Pacing Controlled by a Right Ventricular Impedance Sensor on Cardiac Output in Response to Exercise. This study examined the effects of adaptive rate pacing controlled by closed-loop right ventricular impedance sensing on exercise hemodynamics. Twelve patients in whom Biotronik INOS²⁺ pacemakers had been implanted 4–6 weeks earlier participated in the study. All patients completed two graded, symptom-limited exercise tests. The pacemaker was programmed to DDDR with an upper rate limit of 75–85% of the age-predicted maximum heart rate and a lower rate limit of 45–60 ppm. Heart rate was recorded continuously. An average of 5 beats during the last 10 seconds of each exercise stage was used in the analysis. Oxygen uptake (VO₂) was measured using open circuit spirometry. The VO₂ values from the final 15 seconds of each exercise stage were used for analysis. Stroke volume and cardiac output were measured during the last minute of each stage using impedance cardiography. The test-retest reliability of heart rate and cardiac output responses to graded exercise was assessed using repeated measures analysis of variance, for which the reliability coefficients were r = 0.993 and r = 0.954, respectively (P < 0.01). There were significant correlations (P < 0.01) between VO₂ and heart rate and between VO₂ and cardiac output, with correlation coefficients of r = 0.907 and r = 0.824, respectively. This method of adaptive rate pacing produced reliable, positive hemodynamic responses to graded exercise on a test-retest basis. (PACE 2003; 26:[Pt. II]:244–247)     

低功能孤独症谱系障碍患儿适应性行为的研究

目的 分析不同年龄段低功能孤独症谱系障碍(ASD)患儿的适应性行为特点,为其教育辅导提供指导意见。方法 将2015-2018年于上海市闵行区启智学校就读的71名4~12岁ASD患儿按年龄分为两组,即4~≤8岁组和>8~12岁组,用文兰适应行为量表中文版评估患儿的适应性行为,取得两组患儿沟通、日常生活技能、社会化和运动技能领域的标准分,使用t检验比较两组患儿各领域标准分的差异。结果 4~≤8岁组患儿运动技能领域的标准分最高,为75.40±11.43,其次是沟通领域,标准分为60.20±11.58,日常生活技能和社会化这两个领域的标准分最低,分别为57.60±4.96和56.70±6.25。>8~12岁组运动技能、沟通、日常生活技能和社会化领域的标准分分别为70.70±13.21、55.10±8.62、53.40±7.27和53.10±4.40。两组之间t检验的结果显示,除了运动技能领域外,沟通、日常生活技能和社会化领域标准分差异均有统计学意义(t=2.13、2.91、2.66,P<0.05)。结论 社会化和日常生活技能是低功能 ASD患儿最为落后的两个领域,其次是沟通领域,并且随着年龄的增长,落后的程度会越来越严重。而运动技能领域落后程度相对较小,且与年龄增长相关性不显著。     

Neuroinflammation in the peripheral nerve: Cause,modulator, or bystander in peripheral neuropathies?

The role of innate and adaptive inflammation as a primary driver or modifier of neuropathy in premorbidly normal nerves, and as a critical player in amplifying neuropathies of other known causes (e.g., genetic, metabolic) is incompletely understood and under‐researched, despite unmet clinical need. Also, cellular and humoral components of the adaptive and innate immune system are substantial disease modifying agents in the context of neuropathies and, at least in some neuropathies, there is an identified tight interrelationship between both compartments of the immune system. Additionally, the quadruple relationship between Schwann cell, axon, macrophage, and endoneurial fibroblast, with their diverse membrane bound and soluble signalling systems, forms a distinct focus for investigation in nerve diseases with inflammation secondary to Schwann cell mutations and possibly others. Identification of key immunological effector pathways that amplify neuropathic features and associated clinical symptomatology including pain should lead to realistic and timely possibilities for translatable therapeutic interventions using existing immunomodulators, alongside the development of novel therapeutic targets. GLIA 2016;64:475–486     

Genomic donor cassette sharing during VLRA and VLRC assembly in jawless vertebrates

Lampreys possess two T-like lymphocyte lineages that express either variable lymphocyte receptor (VLR) A or VLRC antigen receptors. VLRA⁺ and VLRC⁺ lymphocytes share many similarities with the two principal T-cell lineages of jawed vertebrates expressing the αβ and γδ T-cell receptors (TCRs). During the assembly of VLR genes, several types of genomic cassettes are inserted, in step-wise fashion, into incomplete germ-line genes to generate the mature forms of antigen receptor genes. Unexpectedly, the structurally variable components of VLRA and VLRC receptors often possess partially identical sequences; this phenomenon of module sharing between these two VLR isotypes occurs in both lampreys and hagfishes. By contrast, VLRA and VLRC molecules typically do not share their building blocks with the structurally analogous VLRB receptors that are expressed by B-like lymphocytes. Our studies reveal that VLRA and VLRC germ-line genes are situated in close proximity to each other in the lamprey genome and indicate the interspersed arrangement of isotype-specific and shared genomic donor cassettes; these features may facilitate the shared cassette use. The genomic structure of the VLRA/VLRC locus in lampreys is reminiscent of the interspersed nature of the TCRA/TCRD locus in jawed vertebrates that also allows the sharing of some variable gene segments during the recombinatorial assembly of TCR genes.The only two extant taxa of jawless vertebrates (agnatha), lampreys and hagfishes, occupy a unique position in chordate phylogeny and thus are a focal point for studies in comparative immunology. Although jawless vertebrates were shown to reject skin allografts and to produce serum agglutinins to mammalian red blood cells and bacteria (1, 2), the cellular and molecular bases for these adaptive responses remained elusive until the recent identification of their alternative adaptive immune system (3). In contrast to the antigen receptors of jawed vertebrates, whose structural framework is the Ig-domain, the basic building block of agnathan antigen receptors is the leucine-rich repeat (LRR) (4–6). In analogy to the situation in jawed vertebrates, mature genes of so-called variable lymphocyte receptors (VLRs) are combinatorially assembled from different types of genomic donor LRR cassettes; their sequences are inserted into incomplete germ-line VLR genes (4–6). A gene conversion-like process is postulated to underlie the VLR gene assembly (7, 8), through the activity of orthologs of mammalian activation-induced cytidine deaminase (AID), termed cytidine deaminases 1 and 2 (CDA1 and CDA2) (7, 9). As is the case for T-cell receptors (TCRs) and B-cell receptors (BCRs) of jawed vertebrates, combinatorial VLR assembly generates vast repertoires of diverse anticipatory receptors (4–6).Three VLR genes, VLRA, VLRB and VLRC, have been identified in lampreys and hagfishes (3, 9–12). The three VLR isotypes are differentially expressed by three distinct populations of lymphocytes in lampreys (9, 13). The two types of T-like cells of lamprey, VLRA⁺ and VLRC⁺ lymphocytes, are generated in the thymoid, a lymphoepithelial tissue equivalent to the thymus (13–15); this situation is analogous to the development in the thymus of the two distinct αβ and γδ T-cell lineages in jawed vertebrates. The VLRB⁺ cells appear to be generated in hematopoietic tissues outside of the thymoid (14), much like B cells in jawed vertebrates. These findings suggest that these basic pathways of lymphocyte differentiation already existed in a common ancestor of jawed and jawless vertebrates (4–6, 16).The close developmental relationship of the two principal lineages of T lymphocytes in jawed vertebrates is reflected in the unique genomic organization of the TCR genes that encode the four chains of the two different heterodimeric αβ and γδ TCRs (17). Here, we examine the sequence diversity and genomic organization of VLRA and VLRC receptor genes to gain insight into their functional and evolutionary relationship.     

Adaptive evolution toward larger size in mammals

The notion that large body size confers some intrinsic advantage to biological species has been debated for centuries. Using a phylogenetic statistical approach that allows the rate of body size evolution to vary across a phylogeny, we find a long-term directional bias toward increasing size in the mammals. This pattern holds separately in 10 of 11 orders for which sufficient data are available and arises from a tendency for accelerated rates of evolution to produce increases, but not decreases, in size. On a branch-by-branch basis, increases in body size have been more than twice as likely as decreases, yielding what amounts to millions and millions of years of rapid and repeated increases in size away from the small ancestral mammal. These results are the first evidence, to our knowledge, from extant species that are compatible with Cope’s rule: the pattern of body size increase through time observed in the mammalian fossil record. We show that this pattern is unlikely to be explained by several nonadaptive mechanisms for increasing size and most likely represents repeated responses to new selective circumstances. By demonstrating that it is possible to uncover ancient evolutionary trends from a combination of a phylogeny and appropriate statistical models, we illustrate how data from extant species can complement paleontological accounts of evolutionary history, opening up new avenues of investigation for both.The idea that large size confers some intrinsic advantage has lingered in the psyche of biologists for centuries. Researchers have proposed that bigger body sizes can increase tolerance to environmental extremes (1), reduce mortality (2), and enhance predation success (3), among other advantages. In support of these conjectures, analyses from a range of different taxonomic groups demonstrate that larger individuals within populations have significantly enhanced survival, fecundity, and mating success (4, 5). If these advantages are general and have played out over long time scales, they could explain the existence of Cope’s rule (6): a broad trend toward increasing size through time (4, 5, 7).Mammals evolved from a relatively small common ancestor over 165 Ma (8–10) and went on to form one of the largest and most successful vertebrate radiations in Earth’s history. Mammals vary greatly in size, spanning almost eight orders of magnitude. This variation implies that some groups have experienced much greater evolutionary change in size from the ancestral form than others. Indeed, the mammalian fossil record provides the clearest evidence in support of Cope’s rule over long evolutionary time scales (6, 11, 12).Despite the paleontological support, evidence for Cope’s rule remains elusive from studies of extant data alone (13–15), including studies of the mammals (16). A possible reason for the discrepancy between paleontological and extant data might be that conventional comparative methods for studying trends within extant data implicitly assume homogeneous evolutionary patterns and processes. When these assumptions are violated, it renders the homogeneous modeling approach incomplete at best and at worst, a source of potential bias in the study of historical evolutionary change; for example, reconstructions of probable ancestral values can be biased toward average or intermediate values (17, 18), which would thereby mask long-term evolutionary trends that are apparent from the fossil record.Previously, we have shown that rates of body size evolution in mammals routinely violate the assumption of homogeneity (19), but how these rate changes might be related to size itself has not been studied. If changes toward larger size in the mammals have consistently occurred at rates that differ from changes toward smaller size, then reconstructed ancestral states accounting for these rate differences may track more closely the observed fossil record. Such a pattern would allow the detection of size-related evolutionary trends from extant data (Fig. S1).Here, we apply a statistical phylogenetic approach for reconstructing mammalian evolutionary history that allows the rate of evolution to vary throughout a phylogenetic tree without prior knowledge or specification of where and when rate shifts occurred. We use this method to test for size-related biases in rates of morphological change and ask whether accounting for any such bias allows us to predict a generalized pattern of size increase in the mammals in line with the generalized pattern of size increase observed in the fossil record. Finally, we consider whether a size-related bias in the rate of morphological evolution can help to choose among the several macroevolutionary processes that have been suggested to give rise to Cope’s rule.