Comparison of Human and Soil Candida tropicalis Isolates with Reduced Susceptibility to Fluconazole

Infections caused by treatment-resistant non-albicans Candida species, such as C. tropicalis, has increased, which is an emerging challenge in the management of fungal infections. Genetically related diploid sequence type (DST) strains of C. tropicalis exhibiting reduced susceptibility to fluconazole circulated widely in Taiwan. To identify the potential source of these wildly distributed DST strains, we investigated the possibility of the presence in soil of such C. tropicalis strains by pulsed field gel electrophoresis (PFGE) and DST typing methods. A total of 56 C. tropicalis isolates were recovered from 26 out of 477 soil samples. Among the 18 isolates with reduced susceptibility to fluconazole, 9 belonged to DST149 and 3 belonged to DST140. Both DSTs have been recovered from our previous studies on clinical isolates from the Taiwan Surveillance of Antimicrobial Resistance of Yeasts (TSARY) program. Furthermore, these isolates were more resistant to agricultural azoles. We have found genetically related C. tropicalis exhibiting reduced susceptibility to fluconazole from the human hosts and environmental samples. Therefore, to prevent patients from acquiring C. tropicalis with reduced susceptibility to azoles, prudent use of azoles in both clinical and agricultural settings is advocated

Aharonov-Bohm interference in topological insulator nanoribbons

Topological insulators represent novel phases of quantum matter with an insulating bulk gap and gapless edges or surface states. The two-dimensional topological insulator phase was predicted in HgTe quantum wells and confirmed by transport measurements. Recently, Bi2Se3 and related materials have been proposed as three-dimensional topological insulators with a single Dirac cone on the surface and verified by angle-resolved photoemission spectroscopy experiments. Here, we show unambiguous transport evidence of topological surface states through periodic quantum interference effects in layered single-crystalline Bi2Se3 nanoribbons. Pronounced Aharonov-Bohm oscillations in the magnetoresistance clearly demonstrate the coverage of two-dimensional electrons on the entire surface, as expected from the topological nature of the surface states. The dominance of the primary h/e oscillation and its temperature dependence demonstrate the robustness of these electronic states. Our results suggest that topological insulator nanoribbons afford novel promising materials for future spintronic devices at room temperature.Comment: 5 pages, 4 figures, RevTex forma

Sex differences in the relative contribution of social and clinical factors to the Health Utilities Index Mark 2 measure of health-related quality of life in older home care clients

Abstract Background The heterogeneity evident among home care clients highlights the need for greater understanding of the clinical and social determinants of multi-dimensional health-related quality of life (HRQL) indices and of potential sex-differences in these determinants. We examined the relative contribution of social and clinical factors to HRQL among older home care clients and explored whether any of the observed associations varied by sex. Methods The Canadian-US sample included 514 clients. Self-reported HRQL was measured during in-home interviews (2002-04) using the Health Utilities Index Mark 2 (HUI2). Data on clients' sociodemographic, health and clinical characteristics were obtained with the Minimum Data Set for Home Care. The relative associations between clients' characteristics and HUI2 scores were examined using multivariable linear regression models. Results Women had a significantly lower mean HUI2 score than men (0.48, 95%CI 0.46-0.50 vs. 0.52, 0.49-0.55). Clients with distressed caregivers and poor self-rated health exhibited significantly lower HRQL scores after adjustment for a comprehensive list of clinical conditions. Several other factors remained statistically significant (arthritis, psychiatric illness, bladder incontinence, urinary tract infection) or clinically important (reported loneliness, congestive heart failure, pressure ulcers) correlates of lower HUI2 scores in adjusted analyses. These associations generally did not vary significantly by sex. Conclusion For females and males, HRQL scores were negatively associated with conditions predictive or indicative of disability and with markers of psychosocial stress. Despite sex differences in the prevalence of social and clinical factors likely to affect HRQL, few varied significantly by sex in their relative impact on HUI2 scores. Further exploration of differences in the relative importance of clinical and psychosocial well-being (e.g., loneliness) to HRQL among female and male clients may help guide the development of sex-specific strategies for risk screening and care management

A phase IIb, open-label, randomized controlled dose ranging multi-centre trial to evaluate the safety, tolerability, pharmacokinetics and exposure-response relationship of different doses of delpazolid in combination with bedaquiline delamanid moxifloxacin in adult subjects with newly diagnosed, uncomplicated, smear-positive, drug-sensitive pulmonary tuberculosis

BACKGROUND: Linezolid is an effective, but toxic anti-tuberculosis drug that is currently recommended for the treatment of drug-resistant tuberculosis. Improved oxazolidinones should have a better safety profile, while preserving efficacy. Delpazolid is a novel oxazolidinone developed by LegoChem Biosciences Inc. that has been evaluated up to phase 2a clinical trials. Since oxazolidinone toxicity can occur late in treatment, LegoChem Biosciences Inc. and the PanACEA Consortium designed DECODE to be an innovative dose-ranging study with long-term follow-up for determining the exposure-response and exposure-toxicity relationship of delpazolid to support dose selection for later studies. Delpazolid is administered in combination with bedaquiline, delamanid and moxifloxacin. METHODS: Seventy-five participants with drug-sensitive, pulmonary tuberculosis will receive bedaquiline, delamanid and moxifloxacin, and will be randomized to delpazolid dosages of 0 mg, 400 mg, 800 mg, 1200 mg once daily, or 800 mg twice daily, for 16 weeks. The primary efficacy endpoint will be the rate of decline of bacterial load on treatment, measured by MGIT liquid culture time to detection from weekly sputum cultures. The primary safety endpoint will be the proportion of oxazolidinone class toxicities; neuropathy, myelosuppression, or tyramine pressor response. Participants who convert to negative liquid media culture by week 8 will stop treatment after the end of their 16-week course and will be observed for relapse until week 52. Participants who do not convert to negative culture will receive continuation phase treatment with rifampicin and isoniazid to complete a six-month treatment course. DISCUSSION: DECODE is an innovative dose-finding trial, designed to support exposure-response modelling for safe and effective dose selection. The trial design allows assessment of occurrence of late toxicities as observed with linezolid, which is necessary in clinical evaluation of novel oxazolidinones. The primary efficacy endpoint is the change in bacterial load, an endpoint conventionally used in shorter dose-finding trials. Long-term follow-up after shortened treatment is possible through a safety rule excluding slow-and non-responders from potentially poorly performing dosages. TRIAL REGISTRATION: DECODE was registered in ClinicalTrials.gov before recruitment start on 22 October 2021 (NCT04550832)

Characteristics of outdoor falls among older people: A qualitative study

Background Falls are a major threat to older people’s health and wellbeing. Approximately half of falls occur in outdoor environments but little is known about the circumstances in which they occur. We conducted a qualitative study to explore older people’s experiences of outdoor falls to develop understanding of how they may be prevented. Methods We conducted nine focus groups across the UK (England, Wales, and Scotland). Our sample was from urban and rural settings and different environmental landscapes. Participants were aged 65+ and had at least one outdoor fall in the past year. We analysed the data using framework and content analyses. Results Forty-four adults aged 65 – 92 took part and reported their experience of 88 outdoor falls. Outdoor falls occurred in a variety of contexts, though reports suggested the following scenarios may have been more frequent: when crossing a road, in a familiar area, when bystanders were around, and with an unreported or unknown attribution. Most frequently, falls resulted in either minor or moderate injury, feeling embarrassed at the time of the fall, and anxiety about falling again. Ten falls resulted in fracture, but no strong pattern emerged in regard to the contexts of these falls. Anxiety about falling again appeared more prevalent among those that fell in urban settings and who made more visits into their neighbourhood in a typical week. Conclusions This exploratory study has highlighted several aspects of the outdoor environment that may represent risk factors for outdoor falls and associated fear of falling. Health professionals are recommended to consider outdoor environments as well as the home setting when working to prevent falls and increase mobility among older people

The North Staffordshire Osteoarthritis Project – NorStOP: Prospective, 3-year study of the epidemiology and management of clinical osteoarthritis in a general population of older adults

BACKGROUND: The clinical syndrome of joint pain and stiffness in older people is the commonest cause of disability and health care consultation in this age group. Yet there have been few prospective studies of its course over time and its impact on personal and social life. We plan a cohort study in the general population aged 50 years and over to determine the course and prognosis of hand, hip, knee and foot pain, and the impact of these syndromes on participation levels and health care use. METHODS: All patients aged 50 years and over registered with 3 local general practices are to be recruited to a population-based cohort study through the use of a two-stage mailing process. Participants will initially complete a "Health Survey" questionnaire. This will collect information on several areas of life including socio-demographics, general health, physical function, participation, and bodily pain. Those who state that they have experienced any hand problem or any pain in their hands, hips, knees, or feet in the previous 12 months, and also give permission to be re-contacted, will be mailed a "Regional Pains Survey" questionnaire which collects detailed information on the four selected body regions (hand, hips, knees, feet). Follow-up data for the three-year period subsequent to cohort recruitment will be collected through two sources: i) general practice medical records and ii) repeat mailed survey

Analysis of In-Vivo LacR-Mediated Gene Repression Based on the Mechanics of DNA Looping

Interactions of E. coli lac repressor (LacR) with a pair of operator sites on the same DNA molecule can lead to the formation of looped nucleoprotein complexes both in vitro and in vivo. As a major paradigm for loop-mediated gene regulation, parameters such as operator affinity and spacing, repressor concentration, and DNA bending induced by specific or non-specific DNA-binding proteins (e.g., HU), have been examined extensively. However, a complete and rigorous model that integrates all of these aspects in a systematic and quantitative treatment of experimental data has not been available. Applying our recent statistical-mechanical theory for DNA looping, we calculated repression as a function of operator spacing (58–156 bp) from first principles and obtained excellent agreement with independent sets of in-vivo data. The results suggest that a linear extended, as opposed to a closed v-shaped, LacR conformation is the dominant form of the tetramer in vivo. Moreover, loop-mediated repression in wild-type E. coli strains is facilitated by decreased DNA rigidity and high levels of flexibility in the LacR tetramer. In contrast, repression data for strains lacking HU gave a near-normal value of the DNA persistence length. These findings underscore the importance of both protein conformation and elasticity in the formation of small DNA loops widely observed in vivo, and demonstrate the utility of quantitatively analyzing gene regulation based on the mechanics of nucleoprotein complexes

Physics of Neutron Star Crusts

The physics of neutron star crusts is vast, involving many different research fields, from nuclear and condensed matter physics to general relativity. This review summarizes the progress, which has been achieved over the last few years, in modeling neutron star crusts, both at the microscopic and macroscopic levels. The confrontation of these theoretical models with observations is also briefly discussed.Comment: 182 pages, published version available at <http://www.livingreviews.org/lrr-2008-10