Dynamic ploidy changes drive fluconazole resistance in human cryptococcal meningitis.

BACKGROUND: Cryptococcal meningitis (CM) causes an estimated 180,000 deaths annually, predominantly in sub-Saharan Africa, where most patients receive fluconazole (FLC) monotherapy. While relapse after FLC monotherapy with resistant strains is frequently observed, the mechanisms and impact of emergence of FLC resistance in human CM are poorly understood. Heteroresistance (HetR) - a resistant subpopulation within a susceptible strain - is a recently described phenomenon in Cryptococcus neoformans (Cn) and Cryptococcus gattii (Cg), the significance of which has not previously been studied in humans. METHODS: A cohort of 20 patients with HIV-associated CM in Tanzania was prospectively observed during therapy with either FLC monotherapy or in combination with flucytosine (5FC). Total and resistant subpopulations of Cryptococcus spp. were quantified directly from patient cerebrospinal fluid (CSF). Stored isolates underwent whole genome sequencing and phenotypic characterization. RESULTS: Heteroresistance was detectable in Cryptococcus spp. in the CSF of all patients at baseline (i.e., prior to initiation of therapy). During FLC monotherapy, the proportion of resistant colonies in the CSF increased during the first 2 weeks of treatment. In contrast, no resistant subpopulation was detectable in CSF by day 14 in those receiving a combination of FLC and 5FC. Genomic analysis revealed high rates of aneuploidy in heteroresistant colonies as well as in relapse isolates, with chromosome 1 (Chr1) disomy predominating. This is apparently due to the presence on Chr1 of ERG11, which is the FLC drug target, and AFR1, which encodes a drug efflux pump. In vitro efflux levels positively correlated with the level of heteroresistance. CONCLUSION: Our findings demonstrate for what we believe is the first time the presence and emergence of aneuploidy-driven FLC heteroresistance in human CM, association of efflux levels with heteroresistance, and the successful suppression of heteroresistance with 5FC/FLC combination therapy. FUNDING: This work was supported by the Wellcome Trust Strategic Award for Medical Mycology and Fungal Immunology 097377/Z/11/Z and the Daniel Turnberg Travel Fellowship

Profitability determination in the United Kingdom brewing industry

This project analyses the determination of profitability in the United Kingdom brewing industry during the period 1972-1982. It is based on a. sample of fifteen brewing companies including the major national and regional companies. The study examines previous literature on the determination of profitability in industry in general, and the brewing industry in particular. (PIMS: Schoeffler 1977, Price Commission, 1977) It examines in some depth the debate as to whether higher market-share leads to greater profitability, and analyses the belief that an industry study should look at groups of firms within industries rather than aggregated data across industries. (Hatten and Schendel 1977. Porter 1980 and Woo 198*1) The study looks at the effect on profitability of nine independent variables paying special attention to the effects of market-share. The analysis categorises firms into strategic groups using a combination of qualitative and quantitative data. It also compares and contrasts the results with the experiences of the Dutch and United States brewing industries. The results suggest that the size (in terms of turnover) of the brewery company determines the strategies they pursue and how these strategies affect profitability. A U-shaped curve relationship between market-share and profitability is identified and strategic groups are determined on the basis of how similar the brewers adopted strategies were during the study period. The results show the problems of transferring a methodology from one industry to another. In comparison to the Dutch and United States experiences, the United Kingdom brewers have been subject to a more volatile industry environment due mainly to changing consumer tastes. The expensive manufacturing and marketing strategies adopted by the national brewers in an attempt to capitalize on these changes led to their generally lower profitability when compared to the regional and small brewers during the study period

Constraints on the mother foundresses : contrasts in Anglican and Roman Catholic religious headship in Victorian England

This thesis investigates some of the most important 6 constraints placed upon the mother foundresses of Anglican and Roman Catholic religious communities in Victorian England. It begins by considering how, reestablishing and establishing active, female, religious foundations, these societies offered single women of the time an unusually useful and dedicated life. It demonstrates that the foundresses initiated, administered, and coordinated works of charity, education, nursing, and other missions. They also sought professional status for their members. Finally, they were often supported in their work by lay men and women, especially women. In general, however, they were constrained in this work by society, the family, and the clergy of their respective churches. Of these constraints, anti-Catholicism was the most important. It affected not only Roman Catholics, but also Anglo- Catholics and caused both groups of religious to lead what was, in many respects, a "hidden life". The religious vows of poverty, chastity and obedience were unduly condemned as undermining family values. And their relationship with the clergy was problematic: bishops were most concerned with their own jurisdiction and authority and parish priests with their own influence. Finally, secessions of sisters caused serious internal problems, but none so severe as to bring about the abdication of the foundresses. And, paradoxically, if obstacles beset the foundresses in establishing their works at home, abroad they were welcomed by diocesans. Hence, their work expanded around the world: throughout the British Empire amongst the Anglicans; into historically Catholic nations for the Romans; and to the United States of America for both Anglicans and Roman Catholics. In these places, foundresses furnish examples of female leadership rare in the nineteenth century. The thesis concludes by showing how tenaciously both Anglican and Roman foundresses sought the recognition of their respective churches, and yet in achieving it, whether informally or formally, placed the most significant constraint of all upon their work

Competitive Boosterism: How Milwaukee Lost the Braves

By any measure, major-league baseball in North America surely qualifies as big business. The national pastime is a vital component of today\u27s urban political economy, and baseball teams resemble other high-prestige businesses in that cities must compete for the privilege of hosting them - whatever their true worth. A study analyzes the transfer of the Milwaukee Braves baseball franchise to Atlanta in 1965 as the outcome of competitive boosterism or the active participation of local elites in luring trade, industry, and investment from other cities for the purpose of economic development

The decline and rise of neighbourhoods: the importance of neighbourhood governance

There is a substantial literature on the explanation of neighbourhood change. Most of this literature concentrates on identifying factors and developments behind processes of decline. This paper reviews the literature, focusing on the identification of patterns of neighbourhood change, and argues that the concept of neighbourhood governance is a missing link in attempts to explain these patterns. Including neighbourhood governance in the explanations of neighbourhood change and decline will produce better explanatory models and, finally, a better view about what is actually steering neighbourhood change

Effects of noise exposure on young adults with normal audiograms II: Behavioral measures

An estimate of lifetime noise exposure was used as the primary predictor of performance on a range of behavioral tasks: frequency and intensity difference limens, amplitude modulation detection, interaural phase discrimination, the digit triplet speech test, the co-ordinate response speech measure, an auditory localization task, a musical consonance task and a subjective report of hearing ability. One hundred and thirty-eight participants (81 females) aged 18–36 years were tested, with a wide range of self-reported noise exposure. All had normal pure-tone audiograms up to 8 kHz. It was predicted that increased lifetime noise exposure, which we assume to be concordant with noise-induced cochlear synaptopathy, would elevate behavioral thresholds, in particular for stimuli with high levels in a high spectral region. However, the results showed little effect of noise exposure on performance. There were a number of weak relations with noise exposure across the test battery, although many of these were in the opposite direction to the predictions, and none were statistically significant after correction for multiple comparisons. There were also no strong correlations between electrophysiological measures of synaptopathy published previously and the behavioral measures reported here. Consistent with our previous electrophysiological results, the present results provide no evidence that noise exposure is related to significant perceptual deficits in young listeners with normal audiometric hearing. It is possible that the effects of noise-induced cochlear synaptopathy are only measurable in humans with extreme noise exposures, and that these effects always co-occur with a loss of audiometric sensitivity

Antiferromagnetism in a family of S=1 square lattice coordination polymers NiX2(pyz)2 (X=Cl, Br, I, NCS; pyz=Pyrazine)

The crystal structures of NiX2(pyz)2 (X = Cl (1), Br (2), I (3), and NCS (4)) were determined by synchrotron X-ray powder diffraction. All four compounds consist of two-dimensional (2D) square arrays self-assembled from octahedral NiN4X2 units that are bridged by pyz ligands. The 2D layered motifs displayed by 1–4 are relevant to bifluoride-bridged [Ni(HF2)(pyz)2]EF6 (E = P, Sb), which also possess the same 2D layers. In contrast, terminal X ligands occupy axial positions in 1–4 and cause a staggered packing of adjacent layers. Long-range antiferromagnetic (AFM) order occurs below 1.5 (Cl), 1.9 (Br and NCS), and 2.5 K (I) as determined by heat capacity and muon-spin relaxation. The single-ion anisotropy and g factor of 2, 3, and 4 were measured by electron-spin resonance with no evidence for zero–field splitting (ZFS) being observed. The magnetism of 1–4 spans the spectrum from quasi-two-dimensional (2D) to three-dimensional (3D) antiferromagnetism. Nearly identical results and thermodynamic features were obtained for 2 and 4 as shown by pulsed-field magnetization, magnetic susceptibility, as well as their Néel temperatures. Magnetization curves for 2 and 4 calculated by quantum Monte Carlo simulation also show excellent agreement with the pulsed-field data. Compound 3 is characterized as a 3D AFM with the interlayer interaction (J⊥) being slightly stronger than the intralayer interaction along Ni–pyz–Ni segments (Jpyz) within the two-dimensional [Ni(pyz)2]2+ square planes. Regardless of X, Jpyz is similar for the four compounds and is roughly 1 K

Seven-Year Distress Trajectories in Uveal Melanoma Survivors

ObjectiveSevere or persistent distress is associated with poorer quality of life in cancer survivors. Distress follows distinct trajectories within different population subgroups. Identifying characteristics and causes of trajectories can assist intervention development and targeting. In a 7-year study of uveal melanoma survivors, we aimed to characterize anxiety, depression, and fear of cancer recurrence (FCR) trajectories, and identify whether concerns about symptoms and functional problems over the first 3 years of survivorship predict memberships of high distress trajectories.MethodIn a closed cohort study, we used growth mixture modeling (GMM) to identify statistically optimal trajectories over 6-, 12-, 24-, 36-, 48-, 60-, 72-, and 84-month time point posttreatment in 475 patients. We then regressed trajectory memberships onto a 3-year series of measures of concerns about symptoms and functional problems, controlling demographic, clinical, and 6-month anxiety, depression, or FCR indicators.ResultsAnxiety, depression, and FCR were represented by two-class linear GMMs. The majority scored consistently low, but 17.5% showed consistently elevated anxiety, 10.9% consistently elevated depression, and 19.4% consistently elevated FCR. Higher anxiety trajectory membership was predicted by greater concerns about symptoms at 6 and 24 months, higher depression trajectory membership by symptoms at 24 months, and higher FCR trajectory membership by symptoms at 6 and 24 months and functional problems at 12 months.ConclusionsMuch of the burden of persistent distress in cancer patients falls on a small proportion of survivors. Concerns about symptoms and functional problems are potential risk factors for distress. (PsycInfo Database Record (c) 2023 APA, all rights reserved)

In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015