Critical factors in the translation of improved antimicrobial strategies for medical implants and devices

Biomaterials-associated infection incidence represents an increasing clinical challenge as more people gain access to medical device technologies worldwide and microbial resistance to current approaches mounts. Few reported antimicrobial approaches to implanted biomaterials ever get commercialized for physician use and patient benefit. This is not for lack of ideas since many thousands of claims to new approaches to antimicrobial efficacy are reported. Lack of translation of reported ideas into medical products approved for use, results from conflicting goals and purposes between the various participants involved in conception, validation, development, commercialization, safety and regulatory oversight, insurance reimbursement, and legal aspects of medical device innovation. The scientific causes, problems and impressive costs of the limiting clinical options for combating biomaterials-associated infection are well recognized. Demands for improved antimicrobial technologies constantly appear. Yet, the actual human, ethical and social costs and consequences of their occurrence are less articulated. Here, we describe several clinical cases of biomaterials-associated infections to illustrate the often-missing human elements of these infections. We identify the current societal forces at play in translating antimicrobial research concepts into clinical implant use and their often-orthogonal constituencies, missions and policies. We assert that in the current complex environment between researchers, funding agencies, physicians, patients, providers, producers, payers, regulatory agencies and litigators, opportunities for translatable successes are minimized under the various risks assumed in the translation process. This argues for an alternative approach to more effectively introduce new biomaterials and device technologies that can address the clinical issues by providing patients and medical practitioners new options for desperate clinical conditions ineffectively addressed by biomedical innovation.     

Changes in Illness Perceptions and Quality of Life During Participation in Cardiac Rehabilitation

Background

The beliefs patients hold about their disease and corresponding treatment have been shown to predict recovery in cardiac patients.

Purpose

However, it is not known to what extent these beliefs change during participation in cardiac rehabilitation and whether this is related to psychological indicators of outcome.

Method

Illness perceptions and health-related quality of life (HRQOL) were measured upon entry to (T0) and completion of (T1) a 3-month outpatient cardiac rehabilitation program in 158 cardiac patients.

Results

Repeated-measures ANOVA revealed that all illness perceptions other than timeline and personal control changed significantly over the course of cardiac rehabilitation. Overall, cardiac rehabilitation patients came to view their illness as more benign. Further analysis revealed that perceiving fewer emotional consequences of the illness, gaining a better understanding, and attributing fewer symptoms to the illness at the end of cardiac rehabilitation, was related to better HRQOL.

Conclusion

Illness perceptions change during cardiac rehabilitation and these changes are associated with enhanced quality of life. Clinical trials have shown illness beliefs in cardiac patients to be modifiable during hospital admission; our results suggest that cardiac rehabilitation may provide a second window of opportunity during which illness perceptions can be actively monitored and modified if maladaptive.     

Morphology of the human internal vertebral venous plexus: A cadaver study after intravenous araldite CY 221 injection

Reviewing the literature on the vascular anatomy of the spinal epidural space, it appeared that the knowledge of the internal vertebral venous plexus is limited. Injection studies of the entire internal vertebral venous plexus after application of modern techniques, to the best of our knowledge, have never been performed. Based on the clinical importance of these structures, it was decided to study the human vertebral venous system after Araldite CY 221 injection, in order to update the morphological characteristics of the internal vertebral venous system. The vertebral venous systems of ten fresh human cadavers, between 64 and 93 years of age, were injected with Araldite CY 221 mixture. All cadavers were dissected and the posterior and anterior internal vertebral venous plexuses were studied in detail. The anterior part of the internal vertebral venous plexus is fairly constant. On the contrary, the posterior internal vertebral venous plexus showed a striking segmental and interindividual variability. In the thoracic area, two types of traversing veins are observed. Both types show a somewhat symmetrical “inversed V” configuration. No anatomical valves were observed. Nevertheless, anterograde flushing (via the femoral veins) of the vertebral venous system appeared to proceed much faster than retrograde flushing (via the superior vena cava). The classical picture of the internal vertebral venous plexus appears a simplification of the actual situation. Especially in the posterior part, segmental and interindividual differences are prominent. The preferential direction of the flow during flushing suggests the presence of functional valves, which are probably located in the thoracic part of the posterior internal vertebral venous plexus, resulting from the typical shape of the veins in this area. This might explain the difficulties with imaging of the posterior part of the internal vertebral venous plexus in vitro as well as in vivo. Further study is needed to determine whether the configuration of the posterior internal vertebral venous plexus in younger individuals is different, compared with the presently studied aged subjects. Anat. Rec. 249:285–294, 1997. © 1997 Wiley-Liss, Inc.     

Multiplex PCR assays for simultaneous detection of six major serotypes and two virulence-associated phenotypes of Streptococcus suis in tonsillar specimens from pigs

Multiplex PCR assays for the detection and identification of various Streptococcus suis strains in tonsillar specimens from pigs were developed and evaluated. In two separate reactions, five distinct DNA targets were amplified. Three targets, based on the S. suis capsular polysaccharide (cps) genes specific for serotypes 1 (and 14), 7, and 9, were amplified in multiplex PCR I. Two other targets, based on the serotype 2- (and 1/2-) specific cps gene and the epf gene, encoding the EF proteins of virulent serotype 2 and highly virulent serotype 1 strains, were amplified in multiplex PCR II. To identify false-negative results, firefly luciferase (luc) DNA and primers based on the luc gene were included in the assay. The multiplex PCR assays were evaluated with tonsillar specimens from pigs infected with S. suis strains. The results obtained with the PCR assays were compared with the results obtained with a bacteriological examination. Most (94%) of the results obtained with multiplex PCR assays were confirmed by the bacteriological examination. The PCR method seems to be more sensitive compared to the bacteriological method, since the remaining 6% of the samples were positive by PCR and negative by bacteriological examination. These results indicate that the PCR method is highly specific for the detection of S. suis strains most frequently involved in clinical disease in infected pig herds. The serotypes found by PCR in tonsillar specimens from diseased pigs were compared with the serotypes of the strains isolated from the affected tissues of the same pigs. The results showed that there is significant association between carriership and clinical illness for S. suis serotype 9 and EF-positive serotype 2 strains and not for serotype 7 and EF-negative serotype 2 (or 1/2) strains.     

Titin as a modular spring: emerging mechanisms for elasticity control by titin in cardiac physiology and pathophysiology

Titin is a giant elastic protein that functions as a molecular spring that develops passive muscle stiffness. Here we discuss the molecular basis of titin's extensibility, how titin's contribution to passive muscle stiffness may be adjusted and how adjustment of titin's stiffness may influence muscle contraction. We also focus on ligands that link titin to membrane channel activity, protein turnover and gene expression.     

Vascular endothelial growth factor-165 overexpression stimulates angiogenesis and induces cyst formation and macrophage infiltration in human ovarian cancer xenografts

Vascular endothelial growth factor (VEGF) is suggested to be an important regulator of angiogenesis in ovarian cancer. We have evaluated the effects of VEGF overexpression on the histology and growth rate of human ovarian cancer xenografts. OVCAR-3 human ovarian cancer cells were stably transfected with an expression vector encoding the 165-amino acid isoform of VEGF. As subcutaneous xenografts, moderately and highly VEGF(165)-overexpressing OVCAR-3 cells formed tumors with large cysts. Immunohistochemistry demonstrated an increase in the number of CD31-positive microvessels, some of which were larger in diameter than those in the parental tumors, as well as extensive vascular rimming around the cysts. Weakly VEGF(165)-overexpressing tumors also contained an increased number of CD31-positive microvessels and occasional vascular rimming, but cysts were not present. Immunohistochemistry further revealed the presence of monocytes and macrophages in both parental and VEGF(165)-overexpressing xenografts. Interestingly, the number of monocytes/macrophages was greatly increased in moderately and highly VEGF(165)-overexpressing xenografts and large areas populated with monocytes/macrophages were detected within the tumor stroma. Although the higher number of CD31-positive cells would suggest a better vascularization pattern in VEGF(165)-overexpressing xenografts, tumor growth rates were not increased when compared with that of parental xenografts. These data provide functional evidence for a role of VEGF(165) in cyst formation and monocyte/macrophage infiltration.     

T cells are necessary for ILC2 activation in house dust mite‐induced allergic airway inflammation in mice

Allergic asthma is a chronic inflammation of the airways mediated by an adaptive type 2 immune response. Upon allergen exposure, group 2 innate lymphoid cells (ILC2s) can be rapidly activated and represent an early innate source of IL‐5 and IL‐13. Here, we used a house dust mite (HDM)‐driven asthma mouse model to study the induction of ILC2s in allergic airway inflammation. In BALF, lungs, and lymph nodes, ILC2 activation is critically dependent on prior sensitization with HDM. Importantly, T cells are required for ILC2 induction, whereby T‐cell activation precedes ILC2 induction. During HDM‐driven allergic airway inflammation the accumulation of ILC2s in BALF is IL‐33 independent, although infiltrating ILC2s produce less cytokines in Il33^?/? mice. Transfer of in vitro polarized OVA‐specific OT‐II Th2 cells alone or in combination with Th17 cells followed by OVA and HDM challenge is not sufficient to induce ILC2, despite significant eosinophilic inflammation and T‐cell activation. In this asthma model, ILC2s are therefore not an early source of Th2 cytokines, but rather contribute to type 2 inflammation in which Th2 cells play a key role. Taken together, ILC2 induction in HDM‐mediated allergic airway inflammation in mice critically depends on activation of T cells.     

MECP2 variation in Rett syndrome—An overview of current coverage of genetic and phenotype data within existing databases

Rett syndrome (RTT) is a monogenic rare disorder that causes severe neurological problems. In most cases, it results from a loss‐of‐function mutation in the gene encoding methyl‐CPG‐binding protein 2 (MECP2). Currently, about 900 unique MECP2 variations (benign and pathogenic) have been identified and it is suspected that the different mutations contribute to different levels of disease severity. For researchers and clinicians, it is important that genotype–phenotype information is available to identify disease‐causing mutations for diagnosis, to aid in clinical management of the disorder, and to provide counseling for parents. In this study, 13 genotype–phenotype databases were surveyed for their general functionality and availability of RTT‐specific MECP2 variation data. For each database, we investigated findability and interoperability alongside practical user functionality, and type and amount of genetic and phenotype data. The main conclusions are that, as well as being challenging to find these databases and specific MECP2 variants held within, interoperability is as yet poorly developed and requires effort to search across databases. Nevertheless, we found several thousand online database entries for MECP2 variations and their associated phenotypes, diagnosis, or predicted variant effects, which is a good starting point for researchers and clinicians who want to provide, annotate, and use the data.     

Wall shear stress calculations based on 3D cine phase contrast MRI and computational fluid dynamics: a comparison study in healthy carotid arteries

Wall shear stress (WSS) is involved in many pathophysiological processes related to cardiovascular diseases, and knowledge of WSS may provide vital information on disease progression. WSS is generally quantified with computational fluid dynamics (CFD), but can also be calculated using phase contrast MRI (PC‐MRI) measurements. In this study, our objectives were to calculate WSS on the entire luminal surface of human carotid arteries using PC‐MRI velocities (WSS_MRI) and to compare it with WSS based on CFD (WSS_CFD). Six healthy volunteers were scanned with a 3 T MRI scanner. WSS_CFD was calculated using a generalized flow waveform with a mean flow equal to the mean measured flow. WSS_MRI was calculated by estimating the velocity gradient along the inward normal of each mesh node on the luminal surface. Furthermore, WSS was calculated for a down‐sampled CFD velocity field mimicking the MRI resolution (WSS_CFDlowres). To ensure minimum temporal variation, WSS was analyzed only at diastole. The patterns of WSS_CFD and WSS_MRI were compared by quantifying the overlap between low, medium and high WSS tertiles. Finally, WSS directions were compared by calculating the angles between the WSS_CFD and WSS_MRI vectors. WSS_MRI magnitude was found to be lower than WSS_CFD (0.62 ± 0.18 Pa versus 0.88 ± 0.30 Pa, p < 0.01) but closer to WSS_CFDlowres (0.56 ± 0.18 Pa, p < 0.01). WSS_MRI patterns matched well with those of WSS_CFD. The overlap area was 68.7 ± 4.4% in low and 69.0 ± 8.9% in high WSS tertiles. The angles between WSS_MRI and WSS_CFD vectors were small in the high WSS tertiles (20.3 ± 8.2°), but larger in the low WSS tertiles (65.6 ± 17.4°). In conclusion, although WSS_MRI magnitude was lower than WSS_CFD, the spatial WSS patterns at diastole, which are more relevant to the vascular biology, were similar. PC‐MRI‐based WSS has potential to be used in the clinic to indicate regions of low and high WSS and the direction of WSS, especially in regions of high WSS. Copyright © 2014 John Wiley & Sons, Ltd.     

Sex Differences in Subjective and Actigraphic Sleep Measures: A Population-Based Study of Elderly Persons

Study Objectives:

To investigate and explain sex differences in subjective and actigraphic sleep parameters in community-dwelling elderly persons.

Design:

Cross-sectional study.

Setting:

The study was embedded in the Rotterdam Study, a population-based study.

Participants:

Nine hundred fifty-six participants aged 59 to 97 years.

Interventions:

N/A.

Measurements and Results:

Participants wore an actigraph and kept a sleep diary for an average of 6 consecutive nights. Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index. Unadjusted sex differences in sleep parameters were assessed with t tests. Women reported shorter total sleep time, a less favorable sleep-onset latency, lower sleep efficiency, and worse global sleep quality, as compared with men. When assessed with actigraphy, however, women were found to have longer and less-fragmented sleep than men. Sex differences in diary-reported sleep duration and other subjective sleep parameters were attenuated by adjustment for marital status, the use of sleep medication, and other covariates, but all sex differences remained significant in a multivariate-adjusted model. Sex differences in actigraphic sleep parameters were barely attenuated by multivariate adjustment, although the shorter actigraphically measured sleep duration in men was partly explained by their higher alcohol consumption. Some covariates (eg, sleep medication) had a different relationship with diary-reported or actigraphic total sleep time in men and women.

Conclusions:

If assessed by diary or interview, elderly women consistently reported shorter and poorer sleep than elderly men. In contrast, actigraphic sleep measures showed poorer sleep in men. These discrepancies are partly explained by determinants of sleep duration, such as sleep medication use and alcohol consumption.

Citation:

van den Berg JF; Miedema HME; Tulen JHM; Hofman A; Knuistingh Neven A; Tiemeier H. Sex differences in subjective and actigraphic sleep measures: a population-based study of elderly persons. SLEEP 2009;32(10):1367-1375.