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

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)

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

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

Fear of cancer recurrence and adverse cancer treatment outcomes: predicting 2- to 5-year fear of recurrence from post-treatment symptoms and functional problems in uveal melanoma survivors

Objective The fear of cancer recurrence (FCR) in later survivorship can lead to poorer mental health, quality of life and physical and functional recovery. Later-occurring FCR may be a consequence of late-emerging physical symptoms and functional problems from cancer or its treatment. Based on the self-regulation model, we predicted that persistent or escalating symptoms and functional problems would prospectively predict FCR observed 2–5 years after diagnosis and treatment. Methods This is a five-year study of 708 uveal melanoma (UM) patients, measuring self-reported visual and ocular symptoms, functional problems and FCR at 6, 12, 24, 36, 48 and 60 months post-diagnosis. A mixed measures design over four levels with observations staggered to represent prospective prediction. Criterion variables were FCR at 24, 36, 48 and 60 months. Predictors were symptom and function scores measured at the previous two observations to FCR. Controls were FCR measured at the previous observation to the criterion FCR measure and demographic, clinical and treatment variables. Results Linear mixed modelling showed that FCR was uniquely predicted by enduring symptoms, those that emerged two observations previously, but not symptoms arising at the previous observation. FCR was predicted by functional problems, which emerged in the observation prior to FCR, but not the observation previous to that. Conclusions Persistent or emerging post-treatment symptoms and functional limitations are probable risk factors for late-occurring FCR in UM survivors. Implications for Cancer Survivors Monitoring symptoms and functional limitations assists in identifying at-risk survivors and targeting preventive interventions. Self-regulation theory suggests that helping survivors to more realistically appraise symptoms and functional problems may prevent FCR

Predictors of emotional distress in uveal melanoma survivors: a systematic review

Uveal melanoma (UM) survivors can experience significant emotional distress, although the factors underpinning this are poorly understood. Systematic reviews of distress in UM only include cross-sectional studies, thereby limiting our understanding of causal factors. This review identified prospective clinical, demographic, social and psychological predictors of distress in UM survivors. A systematic search of the literature for English language prospective studies was conducted. Thirteen papers, reporting data from seven unique datasets were included in a narrative synthesis of the results. Younger age (3 studies from 3 datasets), physical health (including visual impairment, ocular symptoms, and other UM-related factors; 3 studies from 3 datasets), and psychological factors (mainly baseline distress; 3 studies from 3 datasets and worry about recurrence; 2 studies from 2 datasets), significantly predicted distress. There was no consistent evidence for other demographic, clinical or social variables (significant in \u3c50% of datasets). Generally, the quality of the papers was adequate. However, attrition rates were high or not reported in over half of the included studies. The findings of this review emphasise the importance of attempts to prevent and recognise distress immediately post-diagnosis of UM. Particular focus should be given to younger patients, those with physical and psychological health difficulties at the time of diagnosis, and those who develop adverse treatment symptoms during survivorship. More research into potential social and psychological variables and their role in predicting distress in survivors is recommended

Is accurate routine cancer prognostication psychologically harmful? 5-year outcomes of life expectancy prognostication in uveal melanoma survivors

Purpose Prognostication in cancer is growing in importance as increasingly accurate tools are developed. Prognostic accuracy intensifies ethical concerns that a poor prognosis could be psychologically harmful to survivors. Uveal melanoma (UM) prognostication allows survivors to be reliably told that life expectancy is either normal (good prognosis) or severely curtailed because of metastatic disease (poor prognosis). Treatment cannot change life expectancy. To identify whether prognosis is associated with psychological harm, we compared harm in UM survivors with good and poor prognoses and those who declined testing and compared these outcomes to general population norms. Methods Non-randomized 5-year study of a consecutive series of 708 UM survivors (51.6% male, mean age 69.03, SD=12.12) with observations at 6, 12, 24, 36, 48 and 60 months. We operationalized psychological harm as anxiety and depression symptoms, worry about cancer recurrence (WREC) and poor quality of life (QoL). Results Compared to other groups, survivors with poor prognoses showed initially elevated anxiety and depression and consistently elevated worry about local or distant recurrence over 5 years. Good prognoses were not associated with outcomes. Generally, no prognostic groups reported anxiety, depression and WREC or QoL scores that exceeded general population norms. Conclusions Using a large sample, we found that harm accruing from a poor prognosis was statistically significant over 5 years, but did not exceed general non-cancer population norms

Prediction of all-cause mortality from 24 month trajectories in patient-reported psychological, clinical and quality of life outcomes in uveal melanoma patients

AbstractA number of patient-reported outcomes (PROs) predict increased mortality after primary cancer treatment. Studies, though, are sometimes affected by methodological limitations. They often use control variables that poorly predict life expectancy, examine only one or two PROs thus not controlling potential confounding by unmeasured PROs, and observe PROs at only a single point in time. To predict all-cause mortality, this study used control variables affording good estimates of life expectancy, conducted multivariate analyses of multiple PROs to identify independent predictors, and monitored PROs two years after diagnosis. We recruited a consecutive sample of 824 patients with uveal melanoma between April 2008 and December 2014. PROs were variables shown to predict mortality in previous studies; anxiety, depression, visual and ocular symptoms, visual function impairment, worry about cancer recurrence, and physical, emotional, social and functional quality of life (QoL), measured 6, 12 and 24 months after diagnosis. We conducted Cox regression analyses with a census date of December 2018. Covariates were age, gender, marital and employment status, self-reported co-morbidities, tumor diameter and thickness, treatment modality and chromosome 3 mutation status, the latter a genetic mutation strongly associated with mortality. Single predictor analyses (with covariates), showed 6-month depression and poorer functional QoL predicting mortality, as did 6–12 month increases in anxiety and 6–12 month decreases in physical and functional QoL. Multivariate analyses using all PROs showed independent prediction by 6-month depression and decreasing QoL over 6–12 months and 12–24 months. Elevated depression scores six months post-diagnosis constituted an increased mortality risk. Early intervention for depressive symptoms may reduce mortality.</jats:p

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