Daptomycin versus vancomycin for osteoarticular infections due to methicillin-resistant Staphylococcus aureus (MRSA): a nested case-control study

Vancomycin is the standard antibiotic for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. While daptomycin is approved for MRSA bacteremia, its effectiveness in osteoarticular infections (OAIs) has not been established. A 1:2 nested case-control study of adult patients with MRSA OAIs admitted to an academic center from 2005 to 2010 was carried out. Clinical outcomes and drug toxicity in patients treated with daptomycin versus vancomycin were compared. Twenty patients with MRSA OAIs treated with daptomycin were matched to 40 patients treated with vancomycin. The median age of the patients was 52 years (range, 25-90), and 40 (67 %) were male. Most patients had osteomyelitis (82 %), predominantly from a contiguous source (87 %). Forty percent were diabetics. Diabetic patients were more likely to receive vancomycin than daptomycin [20 (50 %) vs. 4 (20 %); p = 0.03]. Vancomycin was more often combined with antibiotics other than daptomycin [22 (55 %) vs. 5 (25 %); p = 0.03]. The median total antibiotic treatment duration was 48 (daptomycin) vs. 46 days (vancomycin) (p = 0.5). Ninety percent of daptomycin-treated patients had previously received vancomycin for a median of 14.5 days (range, 2-36). Clinical success rates were similar between daptomycin and vancomycin at 3 months [15 (75 %) vs. 27 (68 %); p = 0.8] and 6 months [14 (70 %) vs. 23 (58 %); p = 0.5], even after propensity score-based adjustment for antibiotic assignment. The frequency of adverse events was similar between treatment groups [1 (5 %) vs. 7 (18 %); p = 0.2]. Daptomycin and vancomycin achieved similar rates of clinical success and drug tolerability. Daptomycin is a reasonable alternative for treating MRSA OAIs, particularly in patients where therapy with vancomycin has not been well tolerated.

Do Integration Policies Affect Immigrants' Voluntary Engagement? An Exploration at Switzerland's Subnational Level

This paper investigates whether integration policies influence immigrants' propensity to volunteer, the latter being an important element of immigrants' integration into the host society. By distinguishing different categories of integration policies at Switzerland's subnational level and applying a Bayesian multilevel approach, our results suggest varying policy effects: while policies fostering socio-structural rights enhance immigrants' propensity to volunteer, we observe a negative curvilinear relationship between cultural rights and obligations and immigrants' volunteerism implying that a combination of cultural entitlements and obligations is most conducive to immigrants' civic engagement.

Clinical response to chemotherapy in oesophageal adenocarcinoma patients is linked to defects in mitochondria

Chemotherapeutic drugs kill cancer cells, but it is unclear why this happens in responding patients but not in non-responders. Proteomic profiles of patients with oesophageal adenocarcinoma may be helpful in predicting response and selecting more effective treatment strategies. In this study, pretherapeutic oesophageal adenocarcinoma biopsies were analysed for proteomic changes associated with response to chemotherapy by MALDI imaging mass spectrometry. Resulting candidate proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and investigated for functional relevance in vitro. Clinical impact was validated in pretherapeutic biopsies from an independent patient cohort. Studies on the incidence of these defects in other solid tumours were included. We discovered that clinical response to cisplatin correlated with pre-existing defects in the mitochondrial respiratory chain complexes of cancer cells, caused by loss of specific cytochrome c oxidase (COX) subunits. Knockdown of a COX protein altered chemosensitivity in vitro, increasing the propensity of cancer cells to undergo cell death following cisplatin treatment. In an independent validation, patients with reduced COX protein expression prior to treatment exhibited favourable clinical outcomes to chemotherapy, whereas tumours with unchanged COX expression were chemoresistant. In conclusion, previously undiscovered pre-existing defects in mitochondrial respiratory complexes cause cancer cells to become chemosensitive: mitochondrial defects lower the cells' threshold for undergoing cell death in response to cisplatin. By contrast, cancer cells with intact mitochondrial respiratory complexes are chemoresistant and have a high threshold for cisplatin-induced cell death. This connection between mitochondrial respiration and chemosensitivity is relevant to anticancer therapeutics that target the mitochondrial electron transport chain.

Individual socialization or politocultural context? The cultural roots of volunteering in Switzerland

Volunteering rates in Switzerland vary substantially across language regions. In this article, we investigate the cultural roots of this variation by presenting and empirically testing two different conceptualizations of how linguistic culture is related to individual volunteering. Whereas the first perspective perceives the individual as belonging to a particular language community and its norms and values as crucial for individual volunteering, the other sees the linguistic culture mainly as an important context in which an individual lives and which therefore influences individual volunteering. Empirically, we base our analysis on new survey data from 60 Swiss communes and apply a Bayesian multi-level analysis in order to disentangle the linguistic group from contextual effects. Our analysis supports the view that cultural patterns of civic self-organization can indeed explain regional volunteering behaviour in Switzerland. Whereas the propensity to volunteer is generally highest in German-speaking Switzerland, our findings reveal that it is the group of French speakers that exhibits the highest propensity to volunteer when controlling for language region.

An Extended Hierarchical Task Analysis for Error Prediction in Medical Devices

This paper introduces an extended hierarchical task analysis (HTA) methodology devised to evaluate and compare user interfaces on volumetric infusion pumps. The pumps were studied along the dimensions of overall usability and propensity for generating human error. With HTA as our framework, we analyzed six pumps on a variety of common tasks using Norman’s Action theory. The introduced method of evaluation divides the problem space between the external world of the device interface and the user’s internal cognitive world, allowing for predictions of potential user errors at the human-device level. In this paper, one detailed analysis is provided as an example, comparing two different pumps on two separate tasks. The results demonstrate the inherent variation, often the cause of usage errors, found with infusion pumps being used in hospitals today. The reported methodology is a useful tool for evaluating human performance and predicting potential user errors with infusion pumps and other simple medical devices.

Comparison of pain-resilient working individuals to population-based case controls with/without momentary low back pain

Background: Few studies have examined the 20% of individuals who never experience an episode of low back pain (LBP). To date, no investigation has been undertaken that examines a group who claim to have never experienced LBP in their lifetime in comparison to two population-based case–control groups with and without momentary LBP. This study investigates whether LBP-resilient workers between 50 and 65 years had better general health, demonstrated more positive health behaviour and were better able to achieve routine activities compared with both case–control groups. Methods: Forty-two LBP-resilient participants completed the same pain assessment questionnaire as a population-based LBP sample from a nationwide, large-scale cross-sectional survey in Switzerland. The LBP-resilient participants were pairwise compared to the propensity score-matched case controls by exploring differences in demographic and work characteristics, and by calculating odds ratios (ORs) and effect sizes. A discriminant analysis explored group differences, while the multiple logistic regression analysis specified single indicators which accounted for group differences. Results: LBP-resilient participants were healthier than the case controls with momentary LBP and achieved routine activities more easily. Compared to controls without momentary LBP, LBP-resilient participants had a higher vitality, a lower workload, a healthier attitude towards health and behaved more healthily by drinking less alcohol. Conclusions: By demonstrating a difference between LBP-resilient participants and controls without momentary LBP, the question that arises is what additional knowledge can be attained. Three underlying traits seem to be relevant about LBP-resilient participants: personality, favourable work conditions and subjective attitudes/attributions towards health. These rationales have to be considered with respect to LBP prevention.

Fixed and Flexible: Coexistence of Obligate and Facultative Migratory Strategies in a Freshwater Fish

Migration is an important event in many animal life histories, but the degree to which individual animals participate in seasonal migrations often varies within populations. The powerful ecological and evolutionary consequences of such partial migration are now well documented, but the underlying mechanisms are still heavily debated. One potential mechanism of partial migration is between-individual variation in body condition, where animals in poor condition cannot pay the costs of migration and hence adopt a resident strategy. However, underlying intrinsic traits may overrule such environmental influence, dictating individual consistency in migratory patterns. Unfortunately, field tests of individual consistency compared to the importance of individual condition on migratory propensity are rare. Here we analyse 6 years of field data on roach migration, gathered by tagging almost 3000 individual fish and monitoring their seasonal migrations over extended periods of time. Our aims were to provide a field test of the role of condition in wild fish for migratory decisions, and also to assess individual consistency in migratory tendency. Our analyses reveal that (1) migratory strategy, in terms of migration/residency, is highly consistent within individuals over time and (2) there is a positive relationship between condition and the probability of migration, but only in individuals that adopt a migratory strategy at some point during their lives. However, life-long residents do not differ in condition to migrants, hence body condition is only a good predictor of migratory tendency in fish with migratory phenotypes and not a more general determinant of migratory tendency for the population. As resident individuals can achieve very high body condition and still remain resident, we suggest that our data provides some of the first field evidence to show that both facultative and obligate strategies can co-exist within populations of migratory animals.

To boldly go: individual differences in boldness influence migratory tendency

Partial migration, whereby only a fraction of the population migrates, is thought to be the most common type of migration in the animal kingdom, and can have important ecological and evolutionary consequences. Despite this, the factors that influence which individuals migrate and which remain resident are poorly understood. Recent work has shown that consistent individual differences in personality traits in animals can be ecologically important, but field studies integrating personality traits with migratory behaviour are extremely rare. In this study, we investigate the influence of individual boldness, an important personality trait, upon the migratory propensity of roach, a freshwater fish, over two consecutive migration seasons. We assay and individually tag 460 roach and show that boldness influences migratory propensity, with bold individuals being more likely to migrate than shy fish. Our data suggest that an extremely widespread personality trait in animals can have significant ecological consequences via influencing individual-level migratory behaviour.

Inherited and noninherited sources of variation in metastasis and the growth rate of tumors: Implications for tumor evolution and therapy

I have undertaken measurements of the genetic (or inherited) and nongenetic (or noninherited) components of the variability of metastasis formation and tumor diameter doubling time in more than 100 metastatic lines from each of three murine tumors (sarcoma SANH, sarcoma SA4020, and hepatocarcinoma HCA-I) syngeneic to C3Hf/Kam mice. These lines were isolated twice from lung metastases and analysed immediately thereafter to obtain the variance to spontaneous lung metastasis and tumor diameter doubling time. Additional studies utilized cells obtained from within 4 passages of isolation. Under the assumption that no genetic differences in metastasis formation or diameter doubling time existed among the cells of a given line, the variance within a line would estimate nongenetic variation. The variability derived from differences between lines would represent genetic origin. The estimates of the genetic contribution to the variation of metastasis and tumor diameter doubling time were significantly greater than zero, but only in the metastatic lines of tumor SANH was genetic variation the major source of metastatic variability (contributing 53% of the variability). In the tumor cell lines of SA4020 and HCA-I, however, the contribution of nongenetic factors predominated over genetic factors in the variability of the number of metastasis and tumor diameter doubling time. A number of other parameters examined, such as DNA content, karyotype, and selection and variance analysis with passage in vivo, indicated that genetic differences existed within the cell lines and that these differences were probably created by genetic instability. The mean metastatic propensity of the lines may have increased somewhat during their isolation and isotransplantation, but the variance was only slightly affected, if at all. Analysis of the DNA profiles of the metastatic lines of SA4020 and HCA-I revealed differences between these lines and their primary parent tumors, but not among the SANH lines and their parent tumor. Furthermore, there was a direct correlation between the extent of genetic influence on metastasis formation and the ability of the tumor cells to develop resistance to cisplatinum. Thus although nongenetic factors might predominate in contributing to metastasis formation, it is probably genetic variation and genetic instability that cause the progression of tumor cells to a more metastatic phenotype and leads to the emergence of drug resistance. ^

Life-threatening adverse events following therapeutic opioid administration in adults: Is pharmacogenetic analysis useful?

BACKGROUND Systemic approaches are needed to understand how variations in the genes associated with opioid pharmacokinetics and response can be used to predict patient outcome. The application of pharmacogenetic analysis to two cases of life-threatening opioid-induced respiratory depression is presented. The usefulness of genotyping in the context of these cases is discussed. METHODS A panel of 20 functional candidate polymorphisms in genes involved in the opioid biotransformation pathway (CYP2D6, UGT2B7, ABCB1, OPRM1, COMT) were genotyped in these two patients using commercially available genotyping assays. RESULTS In case 1, the patient experienced adverse outcomes when administered codeine and morphine, but not hydromorphone. Genetic test results suggested that this differential response may be due to an inherent propensity to generate active metabolites from both codeine and morphine. These active metabolites are not generated with hydromorphone. In case 2, the patient experienced severe respiratory depression during postoperative recovery following standard doses of morphine. The patient was found to carry genetic variations that result in decreased morphine efflux transporter activity at the blood-brain barrier and increased sensitivity to opioids. CONCLUSIONS Knowledge of the relative contribution of pharmacogenetic biomarkers and their influence on opioid response are continually evolving. Pharmacogenetic analysis, together with clinical history, has the potential to provide mechanistic insight into severe respiratory depressive events in patients who receive opioids at therapeutic doses.

A study of nurses' judgement of and participation in decision-making for nursing home placement for the elderly

This study investigated the effects of patient variables (physical and cognitive disability, significant others' preference and social support) on nurses' nursing home placement decision-making and explored nurses' participation in the decision-making process.^ The study was conducted in a hospital in Texas. A sample of registered nurses on units that refer patients for nursing home placement were asked to review a series of vignettes describing elderly patients that differed in terms of the study variables and indicate the extent to which they agreed with nursing home placement on a five-point Likert scale. The vignettes were judged to have good content validity by a group of five colleagues (expert consultants) and test-retest reliability based on the Pearson correlation coefficient was satisfactory (average of.75) across all vignettes.^ The study tested the following hypotheses: Nurses have more of a propensity to recommend placement when (1) patients have severe physical disabilities; (2) patients have severe cognitive disabilities; (3) it is the significant others' preference; and (4) patients have no social support nor alternative services. Other hypotheses were that (5) a nurse's characteristics and extent of participation will not have a significant effect on their placement decision; and (6) a patient's social support is the most important, single factor, and the combination of factors of severe physical and cognitive disability, significant others' preference, and no social support nor alternative services will be the most important set of predictors of a nurse's placement decision.^ Analysis of Variance (ANOVA) was used to analyze the relationships implied in the hypothesis. A series of one-way ANOVA (bivariate analyses) of the main effects supported hypotheses one-five.^ Overall, the n-way ANOVA (multivariate analyses) of the main effects confirmed that social support was the most important single factor controlling for other variables. The 4-way interaction model confirmed that the most predictive combination of patient characteristics were severe physical and cognitive disability, no social support and the significant others did not desire placement. These analyses provided an understanding of the importance of the influence of specific patient variables on nurses' recommendations regarding placement. ^

Molecular mechanisms of prostatic carcinoma growth and progression

Prostate cancer represents the most commonly diagnosed malignancies in American men and is the second leading cause of male cancer deaths. The overall objectives of this research were designed to understand the cellular and molecular mechanisms of prostatic carcinoma growth and progression. This dissertation was divided into two major parts: (1) to clone and characterize soluble factor(s) associated with bone that may mediate prostatic carcinoma growth and progression; (2) to investigate the roles of extracellular matrix in prostatic carcinogenesis.^ The propensity of prostate cancer cells to metastasize to the axial skeleton and the subsequent osteoblastic reactions observed in the bone indicate the possible reciprocal cellular interaction between prostate cancer cells and the bone microenvironment. To understand the molecular and cellular basis of this interaction, I focused on the identification and cloning of soluble factor(s) from bone stromal cells that may exert direct mitogenic action on cultured prostate cells. A novel BPGF-1 gene expressed specifically by bone and male accessory sex organs (prostate, seminal vesicles, and coagulating gland) was identified and cloned.^ The BPGF-1 was identified and cloned from a cDNA expression library prepared from a human bone stromal cell line, MS. The conditioned medium (CM) of this cell line contains mitogenic materials that induce human prostate cancer cell growth both in vivo and in vitro. The cDNA expression library was screened by an antibody prepared against the mitogenic fraction of the CM.^ The cloned BPGF-1 cDNA comprises 3171 nucleotides with a single open reading frame of 1620 nucleotides encoding 540 amino acids. The BPGF-1 gene encodes two transcripts (3.3 and 2.5 kb) with approximately equal intensity in human cells and tissues, but only one transcript (2.5 kb) in rat and mouse tissues. Southern blot analysis of human genomic DNA revealed a single BPGF-1 gene. The BPGF-1 gene is expressed predominantly in bone and seminal vesicles, but at a substantially lower level in prostate. Polyclonal antibodies generated from synthetic peptides that correspond to the nucleotide sequences of the cloned BPGF-1 cDNA reacted with a putative BPGF-1 protein with an apparent molecular weight of 70 kDa. The conditioned media isolated from COS cells transfected with BPGF-1 cDNA stimulated the proliferation and increased the anchorage-independent growth of prostate epithelial cells. These findings led us to hypothesize that BPGF-1 expression in relevant organs, such as prostate, seminal vesicles, and bone, may lead to local prostate cancer growth, metastasis to the seminal vesicles, and subsequently dissemination to the skeleton.^ To assess the importance of extracellular matrix in prostatic carcinogenesis, the role of extracellular matrix in induction of rat prostatic carcinoma growth in vivo was evaluated. NbE-1, a nontumorigenic rat prostatic epithelial cell line, was induced to form carcinoma in athymic nude hosts by coinjecting them with Matrigel and selected extracellular matrix components. Induction of prostatic tumor formation by laminin and collagen IV was inhibited by their respective antibodies. Prostatic epithelial cells cloned from the tumor tissues were found to form tumors in athymic nude hosts in the absence of exogenously added extracellular matrix. These results suggest that extracellular matrix induce irreversibly prostatic epithelial cells that behave distinctively different from the parental prostatic epithelial cell line. ^

Cultural beliefs and hypertension in rural Philippines

Hypertension (HTN), the major risk factor for cardiovascular disease (CVD), is emerging as a major public health problem in the Philippines. CVD has been the leading cause of mortality in the Philippines since 1990. ^ Although research has shown that certain populations have a greater propensity for HTN, and that culture may be a factor, empirical investigations of the influence of cultural beliefs on HTN are lacking. ^ The operational aims of this study were to: (a) develop and examine the reliability (test-retest, internal consistency) and validity (content) of a questionnaire which measures factors related to HTN; (b) administer the questionnaire; and (c) measure blood pressure, height, and weight of the ≥ 30 year old residents of San Antonio, Nueva Ecija, Philippines. ^ The analytic aims were to determine the: (a) cultural beliefs relating to HTN; (b) associations between cultural beliefs and HTN; and (c) extent to which cultural beliefs versus biological, behavioral, socioeconomic, and access factors are associated with HTN. ^ A cluster survey was conducted among 336 residents ≥ 30 years old in May, 1998. Sixty clusters of households were derived using probability proportionate to size sampling technique. Seven households per cluster were visited and one respondent per household was randomly chosen for interview and measurement of blood pressure, height and weight. A response rate of 84% (336/400) was achieved. ^ Results showed that the test-retest reliability of cultural belief items was 0.69–0.96. Internal consistency reliability was 0.74. ^ HTN (SBP ≥ 140; or DBP ≥ 90 mmHg; or currently taking anti-hypertensive medication) prevalence was 23/100. Univariate logistic regression showed cultural beliefs to be significantly associated (p < 0.037) with HTN. However, multivariate analysis showed that only age ≥ 50 (p = 0.000), family history of HTN (p = 0.004) and body mass index ≥ 25 (p = 0.003) were significant predictors. ^ In the absence of fully implemented programs to prevent and control HTN, the current prevalence is only expected to increase, leading to substantial increases in morbidity and mortality and health care cost. It is recommended that research which focuses on designing, implementing, and evaluating culturally appropriate community-wide programs on HTN prevention and control be undertaken in this community. ^

Bacterial meningitis causes two distinct forms of cellular damage in the hippocampal dentate gyrus in infant rats.

Bacterial meningitis causes neurological sequelae in up to 50% of survivors. Two pathogens known for their propensity to cause severe neurological damage are Streptococcus pneumoniae and group B streptococci. Some forms of neuronal sequelae, such as learning and memory deficits, have been associated with neuronal injury in the hippocampus. To learn more about hippocampal injury in meningitis, we performed a comparative study in bacterial meningitis due to S. pneumoniae and group B streptococcus, in which 11-day-old infant rats were infected intracisternally with either of the two pathogens. Histopathological examination of the neuronal injury in the dentate gyrus of the hippocampus showed that S. pneumoniae caused predominantly classical apoptotic cell death. Cells undergoing apoptosis were located only in the subgranular zone and stained positive for activated caspase-3 and TUNEL. Furthermore, dividing progenitor cells seemed particularly sensitive to this form of cell death. Group B streptococcus was mainly responsible for a caspase-3-independent (and TUNEL-negative) form of cell death. Compared with the morphological features found in apoptosis (e.g., apoptotic bodies), this form of neuronal death was characterized by clusters of uniformly shrunken cells. It affected the dentate gyrus throughout the blade, showing no preferences for immature or mature neurons. Thus, depending on the infecting agent, bacterial meningitis causes two distinct forms of cell injury in the dentate gyrus.

Running the Gauntlet: Inhibitory Effects of Algal Turfs on the Processes of Coral Recruitment

Mortality of corals is increasing due to bleaching, disease and algal overgrowth. In the Caribbean, low rates of coral recruitment contribute to the slow or undetectable rates of recovery in reef ecosystems. Although algae have long been suspected to interfere with coral recruitment, the mechanisms of that interaction remain unclear. We experimentally tested the effects of turf algal abundance on 3 sequential factors important to recruitment of corals: the biophysical delivery of planktonic coral larvae, their propensity to settle, and the availability of microhabitats where they survive. We deployed coral settlement plates inside and outside damselfish Stegastes spp. gardens and cages. Damselfish aggression reduced herbivory from fishes, and cages became fouled with turf algae, both locally increasing algal biomass surrounding the plates. This reduced flushing rates in nursery microhabitats on the plate underside, limiting larvae available for settlement. Coral spat settled preferentially on an early successional crustose coralline alga Titanoderma prototypum but also on or near other coralline algae, biofilms, and calcareous polychaete worm tubes. Post-settlement survival was highest in the fully grazed, lowest algal biomass treatment, and after 27 mo 'spat' densities were 73 % higher in this treatment. The 'gauntlet' refers to the sequence of ecological processes through which corals must survive to recruit. The highest proportion of coral spat successfully running the gauntlet did so under conditions of low algal biomass resulting from increased herbivory. If coral recruitment is heavily controlled at very local scales by this gauntlet, then coral reef managers could improve a reef's recruitment potential by managing for reduced algal biomass.