Unique safety issues associated with virus-vectored vaccines: Potential for and theoretical consequences of recombination with wild type virus strains

In 2003 and 2013, the World Health Organization convened informal consultations on characterization and quality aspects of vaccines based on live virus vectors. In the resulting reports, one of several issues raised for future study was the potential for recombination of virus-vectored vaccines with wild type pathogenic virus strains. This paper presents an assessment of this issue formulated by the Brighton Collaboration.To provide an appropriate context for understanding the potential for recombination of virus-vectored vaccines, we review briefly the current status of virus-vectored vaccines, mechanisms of recombination between viruses, experience with recombination involving live attenuated vaccines in the field, and concerns raised previously in the literature regarding recombination of virus-vectored vaccines with wild type virus strains. We then present a discussion of the major variables that could influence recombination between a virus-vectored vaccine and circulating wild type virus and the consequences of such recombination, including intrinsic recombination properties of the parent virus used as a vector; sequence relatedness of vector and wild virus; virus host range, pathogenesis and transmission; replication competency of vector in target host; mechanism of vector attenuation; additional factors potentially affecting virulence; and circulation of multiple recombinant vectors in the same target population. Finally, we present some guiding principles for vector design and testing intended to anticipate and mitigate the potential for and consequences of recombination of virus-vectored vaccines with wild type pathogenic virus strains.     

Deriving reference values for nerve conduction studies from existing data using mixture model clustering

Objective: to obtain locally valid reference values (RVs) from existing nerve conduction study (NCS) data.Methods: we used age, sex, height and limb temperature-based mixture model clustering (MMC) to identify normal and abnormal measurements on NCS data from two university hospitals. We compared MMC-derived RVs to published data; examined the effect of using different variables; validated MMC-derived RVs using independent data from 26 healthy control subjects and investigated their clinical applicability for the diagnosis of polyneuropathy.Results: MMC-derived RVs were similar to published RVs. Clustering can be achieved using only sex and age as variables. MMC is likely to yield reliable results with fewer abnormal than normal measurements and when the total number of measurements is at least 300. Measurements from healthy controls fell within the 95% MMC-derived prediction interval in 97.4% of cases.Conclusions: MMC can be used to obtain RVs from existing data, providing a locally valid, accurate reflection of the (ab)normality of an NCS result.Significance: MMC can be used to generate locally valid RVs for any test for which sufficient data are available.¹     

Diagnostic sensitivity of electrophysiology and ultrasonography in ulnar neuropathies of different severity

ObjectiveTo assess the diagnostic performance of electrophysiology and nerve ultrasound in ulnar neuropathies of varying clinical severity in 135 consecutive patients.MethodsClinical severity of ulnar neuropathy was graded on a 4 point scale from very mild (symptoms only) to severe (marked atrophy of intrinsic hand muscles). Sensitivity and localization ability of electrophysiology and nerve ultrasound were assessed for each point of the scale.ResultsUltrasound had higher sensitivity than electrophysiology in clinically very mild (20% and 3% for ultrasound and electrophysiology, respectively) and mild (62% and 47% for ultrasound and electrophysiology, respectively) neuropathies, had greater localizing ability in axonal ulnar neuropathies, and identified nerve hypermobility.Ultrasound nerve cross-sectional area had strong positive correlation with both clinical and electrophysiological severity scores, but with significant overlap across the severity groups.ConclusionThe diagnostic work-up of ulnar neuropathies was improved by using both electrophysiology and ultrasound at all levels of clinical severity. Ultrasound increased the diagnostic yield in very mild and mild neuropathies, localized all the ulnar neuropathies with abnormal non-localizing electrophysiology and identified nerve hypermobility.SignificanceThis is the first detailed analysis of the diagnostic performance of electrophysiology and ultrasound in ulnar neuropathies of varying severity.     

Association of dietary acid-base load and psychological disorders among Iranian women: A cross-sectional study

Metabolic acidosis, which can be affected by dietary acid-base load, seems to be associated with psychological disorders through different pathways. Given limited evidence on dietary acid-base load, we aimed to examine the association of dietary acid-base load with psychological disorders in Iranian women. This cross-sectional study was performed on 447 female subjects (20–50 years old). Dietary intake was assessed using a valid food frequency questionnaire for Iran. Dietary acid-base load was calculated through different indices including potential renal acid load (PRAL), net endogenous acid production (NEAP), and dietary acid load (DAL). To assess psychological disorders, an Iranian validated version of depression, anxiety, and stress scale (DASS-21) was used. The mean value of PRAL, NEAP, and DAL were -8.87mEq/da, 37.94mEq/day, and 30.77mEq/day, respectively. Considering a wide range of confounding variables, compared with the first tertile, a significant positive association was observed between dietary acid-base load and depression (OR_PRAL: 3.63; 95 %CI:1.97, 6.71; P_trend = 0.0001) (OR_NEAP:3.42; 95 %CI: 1.87, 6.23; P_trend = 0.0001) (OR_DAL: 3.02; 95 %CI: 1.64, 5.58; P_trend = 0.0001). Women in the high dietary acid-base load category had higher anxiety (OR_PRAL: 3.31; 95 %CI: 1.81, 6.06; P_trend = 0.0001) (OR_NEAP:3.47; 95 %CI: 1.90, 6.33; P_trend = 0.0001) (OR_DAL: 3.25; 95 %CI: 1.76, 5.98; P_trend = 0.0001). Moreover, there was a strong positive relationship between dietary acid-base load and psychologicaldistress (OR_PRAL: 3.79; 95 %CI: 2.09, 6.90; P_trend = 0.0001) (OR_NEAP: 3.67; 95 %CI: 2.04, 6.58; P_trend = 0.0001) (OR_DAL: 3.00; 95 %CI: 1.66, 5.43; P_trend = 0.0001). Women with higher dietary acid-base load score had greater odds for depression, anxiety, and psychological distress compared to lower ones.     

MiR-125b在甲状腺癌患者中的表达及其意义

目的探讨miR-125b在甲状腺癌患者中的表达及其意义。方法选取甲状腺乳头状癌组织及其配对的癌旁组织各20例,所有患者均经超声及病理确诊。实时荧光定量PCR检测miR-125b mRNA的表达,Western Blot检测Foxp3、LC 3Ⅰ和LC 3Ⅱ蛋白的表达。将人甲状腺乳头状癌细胞系MDA-T32随机分为3组:对照组(不处理)、阴性对照组(转染无义序列)和miR-125b组(转染miR-125b mimics),实时荧光定量PCR检测miR-125b mRNA的表达,MTT法检测癌细胞对顺铂的敏感性,Western Blot检测Foxp3、LC 3Ⅰ和LC 3Ⅱ蛋白的表达。结果与癌旁组织对比,甲状腺癌组织中MiR-125b mRNA的表达显著降低(P <0.05),Foxp3蛋白表达显著增加(P <0.05)。与对照组相比,miR-125b组细胞中MiR-125b mRNA的表达显著增加(P <0.05),Foxp3蛋白的表达显著降低(P <0.05)。与对照组相比,在顺铂浓度为30μg/ml时,miR-125b组细胞活性显著降低(P <0.05)。在顺铂浓度为0、15、60、120μg/ml时,各组间细胞活性的对比无显著差异(P> 0.05)。与癌旁组织对比,甲状腺癌组织中LC 3Ⅱ蛋白的表达显著增加(P <0.05)。与对照组相比,miR-125b组细胞中LC 3Ⅱ蛋白的表达显著降低(P <0.05)。LC 3Ⅰ蛋白的表达在各组间对比无显著变化(P> 0.05)。结论miR-125b在甲状腺癌中下调,miR-125b介导的Foxp3下调可抑制自噬,并增强甲状腺癌细胞对顺铂的敏感性。     

Causal Inference and Estimands in Clinical Trials

Abstract

The National Research Council’s report on the prevention and treatment of missing data highlighted the need to clearly specify causal estimands. This focus fundamentally changed how the missing data problem was perceived and addressed in clinical trials. The recent ICH E9(R1) addendum is another major step in promoting the use of the causal estimands framework that should further influence how clinical trial protocols and statistical analysis plans are written and implemented. The language of potential outcomes that is widely accepted in the causal inference literature is not widely recognized in the clinical trialists community and was not used in defining causal estimands in the NRC report or the ICH E9(R1). In this article, we attempt to bridge the gap between the causal inference community and clinical trialists to further advance the use of causal estimands in clinical trial settings. We illustrate how concepts from causal literature, such as potential outcomes and dynamic treatment regimens, can facilitate defining and implementing causal estimands and may provide a unifying language to describing the targets for both observational and randomized clinical trials.     

ECFS standards of care on CFTR-related disorders: Updated diagnostic criteria

This paper is the first in a series providing updated guidance on the definition, evaluation and management of people with a Cystic Fibrosis Transmembrane conductance Regulator (CFTR)-Related Disorder (CFTR-RD). The need for this update relates to more precise characterisation of CFTR gene variants and improved assessment of CFTR protein dysfunction. The exercise is co-ordinated by the European CF Society Standards of Care Committee and Diagnostic Network Working Group and involves stakeholder engagement. This first paper was produced by a core group using an extensive literature review and papers graded for their quality. Subsequent wider stakeholder agreement was achieved.The definition of a CFTR-RD remains “a clinical condition with evidence of CFTR protein dysfunction that does not fulfil the diagnostic criteria for CF”. Clearer guidance on CFTR dysfunction and relevant CFTR variants will be provided. Thresholds for clinical presentations are presented and the paradigm that pathobiological processes may be evident in more than one organ is agreed. In this paper we reflect on the early patient journey, highlighting that CF specialists as well as other relevant specialists should be involved in the care of people with a CFTR-RD.     

Current oscillatory phenomena based on electrogenerated superoxide ion at the HMDE in dimethylsulfoxide

A study on the current oscillation based on the electrogenerated superoxide ion $({\mathrm{O}}_2^{\text{<mglyph src="https://sdfestaticassets-us-east-1.sciencedirectassets.com/shared-assets/16/entities/rad"></mglyph>}-})$ at a hanging mercury drop electrode (HMDE) in dimethylsulfoxide solution containing tetra-n-alkylammonium perchlorate as the electrolyte was carried out. Cyclic voltammetric, potential step chronoamperometric, normal and reverse pulse voltammetric techniques were employed in this study. A bare glassy carbon electrode, a liquid hemispherical mercury (Hg) drop-coated gold (Au) electrode and a Hg film-coated Au electrode were also used as working electrodes to understand the mechanism of the current oscillation. The experimental conditions were optimized for a simple, regular and reproducible current oscillation. The specific adsorption phenomenon of iodide ion and the adsorption of the alkyl chain of the supporting electrolyte on the HMDE surface were also considered to clarify the experimental factors governing the current oscillation phenomenon. It has been concluded that the oscillation is mainly due to the promoted oxidation (dissolution) of the HMDE itself by the adsorption of ${\mathrm{O}}_2^{\text{<mglyph src="https://sdfestaticassets-us-east-1.sciencedirectassets.com/shared-assets/16/entities/rad"></mglyph>}-}$, resulting in the formation–destruction of a passive film such as ${\mathrm{Hg}}_2({\mathrm{O}}_2^{\text{<mglyph src="https://sdfestaticassets-us-east-1.sciencedirectassets.com/shared-assets/16/entities/rad"></mglyph>}-}{)}_2$ on the electrode surface. A probable mechanism for the observed current oscillation is discussed.     

基于GMPGIS全球变暖情景下人参未来生态适宜产区变化

目的:通过开展未来时期人参全球潜在生态适宜产区分析,为其合理规划生产布局提供科学依据。方法:采用"药用植物全球产地生态适宜性区划信息系统"(Global Geographic Information System for Medicinal Plant,GMPGIS),以人参本草文献记载的道地产区、野生分布区以及当前主产区人参生态因子数值为依据,对其在全球范围内的潜在生态分布区进行分析。结果:亚洲东部、北美洲中部及东部、欧洲中南部及大洋洲东部地区是当前人参全球范围内的主要适生区域。随着全球气候变暖,在温室气体排放相对较少的A1b模型和排放较多的A2a模型下,2050年人参潜在生态适宜产区面积约为9 500×10~3km~2,比当前产区适宜面积增加了7.05%~7.12%,增长区域主要分布在亚洲东北部和欧洲北部地区;2100年人参适宜产区面积约为10 800×10~3km~2,比当前产区适宜面积增加了22.89%~27.41%,增长区域主要分布在欧洲北部及亚洲中部及东部地区。结论:气温升高有助于人参适宜产区增加,本研究结果可为人参生产布局规划、引种栽培、规模化种植提供科学依据。     

Transmastoid Approach for Resurfacing the Superior Semicircular Canal Dehiscence with a Dumpling Structure

Background:

Superior semicircular canal dehiscence (SSCD) is gradually recognized by otologists in recent years. The patients with SSCD have a syndrome comprising a series of vestibular symptoms and hearing function disorders which can be cured by the operation. In this study, we evaluated the characteristics of patients with SSCD and determined the effectiveness of treating this syndrome by resurfacing the canal via the transmastoid approach using a dumpling structure.

Methods:

Patients with SSCD, confirmed by high-resolution computed tomography and hospitalized at Beijing Tongren Hospital between November 2009 and October 2012, were included in the study. All of the patients underwent the unilateral transmastoid approach for resurfacing the canal, and received regular follow-up after surgery. Data from preoperative medical records and postoperative follow-up were comparatively analyzed to evaluate the effect of surgery.

Results:

In total, 10 patients and 13 ears (three left ears, four right ears, three bilateral ears) were evaluated in the study, which included 7 men and 3 women. Different symptoms and distinctive manifestations of vestibular evoked myogenic potential were found in these patients. After surgery, 4 patients had complete resolution, 5 had partial resolution, and 1 patient, with bilateral SSCD, had aggravation. None of the patients suffered from serious complications such as sensorineural hearing loss, facial paralysis, cerebrospinal fluid leakage, or intracranial hypertension.

Conclusions:

In patients with unilateral SSCD, resurfacing the canal via the transmastoid approach using a dumpling structure is an effective and safe technique. However, more consideration is needed for patients with bilateral SSCD.