We report a cross-sectional study comparing the health-related quality of life (HRQOL) of individuals residing in the proximity of a wind farm to those residing in a demographically matched area ...sufficiently displaced from wind turbines. The study employed a nonequivalent comparison group posttest-only design. Self-administered questionnaires, which included the brief version of the World Health Organization quality of life scale, were delivered to residents in two adjacent areas in semirural New Zealand. Participants were also asked to identify annoying noises, indicate their degree of noise sensitivity, and rate amenity. Statistically significant differences were noted in some HRQOL domain scores, with residents living within 2 km of a turbine installation reporting lower overall quality of life, physical quality of life, and environmental quality of life. Those exposed to turbine noise also reported significantly lower sleep quality, and rated their environment as less restful. Our data suggest that wind farm noise can negatively impact facets of HRQOL.
Research in toxicology relies on in vitro models such as cell lines. These living models are prone to change and may be described in publications with insufficient information or quality control ...testing. This article sets out recommendations to improve the reliability of cell-based research.
This article examines the association between perceptions of neighborhood problems and health‐related quality of life (HRQOL) in a sample of New Zealand residents (n = 692). A modified version of the ...Neighborhood Problems Scale (originally developed by Steptoe and Feldman, 2001) and the World Health Organization Quality of Life (WHOQOL‐BREF) were used to assess perceptions of neighborhood problems and HRQOL, respectively. Multiple linear regression analyses were conducted to assess the association between perceptions of neighborhood problems and each of the WHOQOL‐BREF domains: physical, psychological, social, and environmental HRQOL. Perceptions of neighborhood problems and gender interacted in the physical HRQOL regression; the negative association between perceived neighborhood problems and physical HRQOL was stronger for males compared with females. Neighborhood problems were also negatively predictive of psychological, social, and environmental HRQOL. Overall, our results suggest that the various aspects of well‐being may be influenced by perceptions of neighborhood problems.
To determine whether adding selfreported health and functional status data to a diagnostic risk-score model explains additional variance in predicting inpatient admissions and costs.
Retrospective ...observational analysis.
We used data from a Health Status Questionnaire (HSQ), completed by 6407 Kaiser Permanente Northwest Medicare patients between December 2006 and October 2008. We used answers from 3 items on the HSQ: (1) General Self-rated Health score, (2) needing help with 1 or more activities of daily living, and (3) having a bothersome health condition. We calculated a DxCG relative risk score from utilization information in the year prior to the survey, using electronic medical records. We compared: (1) DxCG as the sole independent variable and (2) DxCG plus the 3 items as independent variables. We estimated area under the curve (AUC) for each model. Any inpatient admission (yes/no) and being in the top 10% of costs (in the year after survey) were the dependent variables for the first and second logistic regression models, respectively.
The 3 items explained an additional 2.8% and 4.0% of variance for inpatient admissions and top 10% of costs,respectively, in addition to the variance explained by the DxCG score alone. For DxCG alone, the AUC was 0.686 (95% confidence interval CI 0.663-0.710) and 0.741 (95% CI 0.719- 0.764), respectively, for inpatient admissions and top 10% of costs and improved to 0.709 (95% CI 0.687-0.730) and 0.770 (95% CI 0.749-0.790) when the 3 self-reported items were added.
Using self-reported health information improved the predictive power of a DxCG model to forecast inpatient admissions and patient cost-tier.
Summary Background Identification of robust biomarkers of malignancy and methods to establish disease progression is a major goal in paediatric neuro-oncology. We investigated whether methylation of ...the TERT promoter can be a biomarker for malignancy and patient outcome in paediatric brain tumours. Methods For the discovery cohort, we used samples obtained from patients with paediatric brain tumours and individuals with normal brain tissues stored at the German Cancer Research Center (Heidelberg, Germany). We used methylation arrays for genome-wide assessment of DNA. For the validation cohort, we used samples obtained from several tissues for which full clinical and follow-up data were available from two hospitals in Toronto (ON, Canada). We did methylation analysis using quantitative Sequenom and pyrosequencing of an identified region of the TERT promoter. We assessed TERT expression by real-time PCR. To establish whether the biomarker could be used to assess and predict progression, we analysed methylation in paired samples of tumours that transformed from low to high grade and from localised to metastatic, and in choroid plexus tumours of different grades. Finally, we investigated overall survival in patients with posterior fossa ependymomas in which the identified region was hypermethylated or not. All individuals responsible for assays were masked to the outcome of the patients. Findings Analysis of 280 samples in the discovery cohort identified one CpG site (cg11625005) in which 78 (99%) of 79 samples from normal brain tissues and low-grade tumours were not hypermethylated, but 145 (72%) of 201 samples from malignant tumours were hypermethylated (>15% methylated; p<0·0001). Analysis of 68 samples in the validation cohort identified a subset of five CpG sites (henceforth, upstream of the transcription start site UTSS) that was hypermethylated in all malignant paediatric brain tumours that expressed TERT but not in normal tissues that did not express TERT (p<0·0001). UTSS had a positive predictive value of 1·00 (95% CI 0·95–1·00) and a negative predictive value of 0·95 (0·87–0·99). In two paired samples of paediatric gliomas, UTSS methylation increased during transformation from low to high grade; it also increased in two paired samples that progressed from localised to metastatic disease. Two of eight atypical papillomas that had high UTSS methylation progressed to carcinomas, while the other six assessed did not progress or require additional treatment. 5-year overall survival was 51% (95% CI 31–71) for 25 patients with hypermethylated UTSS posterior fossa ependymomas and 95% (86–100) for 20 with non-hypermethylated tumours (p=0·0008). 5-year progression-free survival was 86% (68–100) for the 25 patients with non-hypermethylated UTSS tumours and 30% (10–50) for those with hypermethylated tumours (p=0·0008). Interpretation Hypermethylation of the UTSS region in the TERT promoter is associated with TERT expression in cancers. In paediatric brain tumours, UTSS hypermethylation is associated with tumour progression and poor prognosis. This region is easy to amplify, and the assay to establish hypermethylation can be done on most tissues in most clinical laboratories. Therefore the UTSS region is a potentially accessible biomarker for various cancers. Funding The Canadian Institute of Health Research and the Terry Fox Foundation.
DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not ...well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.
Amplification of the
C19MC
oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In ...this study, we sought to evaluate the diagnostic specificity of
C19MC
and LIN28, and the clinical and biological spectra of
C19MC
amplified and/or LIN28+ CNS-PNETs. We interrogated 450 pediatric brain tumors using FISH and IHC analyses and demonstrate that
C19MC
alteration is restricted to a sub-group of CNS-PNETs with high LIN28 expression; however, LIN28 immunopositivity was not exclusive to CNS-PNETs but was also detected in a proportion of other malignant pediatric brain tumors including rhabdoid brain tumors and malignant gliomas.
C19MC
amplified/LIN28+ group 1 CNS-PNETs arose predominantly in children <4 years old; a majority arose in the cerebrum but 24 % (13/54) of tumors had extra-cerebral origins. Notably, group 1 CNS-PNETs encompassed several histologic classes including embryonal tumor with abundant neuropil and true rosettes (ETANTR), medulloepithelioma, ependymoblastoma and CNS-PNETs with variable differentiation. Strikingly, gene expression and methylation profiling analyses revealed a common molecular signature enriched for primitive neural features, high LIN28/LIN28B and DNMT3B expression for all group 1 CNS-PNETs regardless of location or tumor histology. Our collective findings suggest that current known histologic categories of CNS-PNETs which include ETANTRs, medulloepitheliomas, ependymoblastomas in various CNS locations, comprise a common molecular and diagnostic entity and identify inhibitors of the LIN28/let7/PI3K/mTOR axis and DNMT3B as promising therapeutics for this distinct histogenetic entity.
Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI ...monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.
Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201.
To determine whether brimonidine 0.2% can control intraocular pressure (IOP) spikes as well as apraclonidine 1.0% can in those patients undergoing argon laser trabeculoplasty (ALT).
Prospective, ...randomized, double-masked, clinical trial.
A total of 56 eyes of 41 patients with open-angle glaucoma or ocular hypertension were entered in the study; 46 eyes of 41 patients were eventually used for the final analysis.
Patients were randomized to receive either brimonidine 0.2% or apraclonidine 1.0% before and after 360° ALT. Both patient and physician were masked as to which agent each patient received.
Intraocular pressure measurements were recorded before surgery and at 1, 2, and 4 hours after surgery. The difference between the preoperative IOP (baseline) and the highest recorded postoperative IOP was recorded as the maximum IOP change. The mean of the maximum IOP change for each group was analyzed using a two-sample, one-tailed
t test.
The mean of the maximum IOP change in the brimonidine 0.2% group was −2.6 ± 3.6 mmHg, and the mean for the apraclonidine 1.0% group was −2.3 ± 3.7 mmHg (
P = 0.8). No patient had a pressure spike greater than 10 mmHg.
Brimonidine 0.2% appears to be as effective as apraclonidine 1.0% in preventing IOP spikes after argon laser trabeculoplasty.
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