A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma.

Malignant mesothelioma is a rare tumour caused by asbestos exposure that originates mainly from the pleural lining or the peritoneum. Treatment options are limited, and the prognosis is dismal. Although immune checkpoint blockade (ICB) can improve survival outcomes, the determinants of responsiveness remain elusive. Here, we report the outcomes of a multi-centre phase II clinical trial (MiST4, NCT03654833) evaluating atezolizumab and bevacizumab (AtzBev) in patients with relapsed mesothelioma. We also use tumour tissue and gut microbiome sequencing, as well as tumour spatial immunophenotyping to identify factors associated with treatment response. MIST4 met its primary endpoint with 50% 12-week disease control, and the treatment was tolerable. Aneuploidy, notably uniparental disomy (UPD), homologous recombination deficiency (HRD), epithelial-mesenchymal transition and inflammation with CD68+ monocytes were identified as tumour-intrinsic resistance factors. The log-ratio of gut-resident microbial genera positively correlated with radiological response to AtzBev and CD8+ T cell infiltration, but was inversely correlated with UPD, HRD and tumour infiltration by CD68+ monocytes. In summary, a model is proposed in which both intrinsic and extrinsic determinants in mesothelioma cooperate to modify the tumour microenvironment and confer clinical sensitivity to AtzBev. Gut microbiota represent a potentially modifiable factor with potential to improve immunotherapy outcomes for individuals with this cancer of unmet need.

Fault rock heterogeneity can produce fault weakness and reduce fault stability.

Geological heterogeneity is abundant in crustal fault zones; however, its role in controlling the mechanical behaviour of faults is poorly constrained. Here, we present laboratory friction experiments on laterally heterogeneous faults, with patches of strong, rate-weakening quartz gouge and weak, rate-strengthening clay gouge. The experiments show that the heterogeneity leads to a significant reduction in strength and frictional stability in comparison to compositionally identical faults with homogeneously mixed gouges. We identify a combination of weakening effects, including smearing of the weak clay; differential compaction of the two gouges redistributing normal stress; and shear localization producing stress concentrations in the strong quartz patches. The results demonstrate that geological heterogeneity and its evolution can have pronounced effects on fault strength and stability and, by extension, on the occurrence of slow-slip transients versus earthquake ruptures and the characteristics of the resulting events, and should be further studied in lab experiments and earthquake source modelling.

Primary care performance of alternatively licenced physicians in Ontario, Canada: a cross-sectional study using administrative data.

OBJECTIVES: Medical Regulatory Authorities (MRAs) provide licences to physicians and monitor those physicians once in practice to support their continued competence. In response to physician shortages, many Canadian MRAs developed alternative licensure routes to allow physicians who do not meet traditional licensure criteria to obtain licences to practice. Many physicians have gained licensure through alternative routes, but the performance of these physicians in practice has not been previously examined. This study compared the performance of traditionally and alternatively licenced physicians in Ontario using quality indicators of primary care. The purpose of this study was to examine the practice performance of alternatively licenced physicians and provide evaluative evidence for alternative licensure policies. DESIGN: A cross-sectional retrospective examination of Ontario health administrative data was conducted using Poisson regression analyses to compare the performance of traditionally and alternatively licenced physicians. SETTING: Primary care in Ontario, Canada. PARTICIPANTS: All family physicians who were licenced in Ontario between 2000 and 2012 and who had complete medical billing data in 2014 were included (n=11 419). OUTCOME MEASURES: Primary care quality indicators were calculated for chronic disease management, preventive paediatric care, cancer screening and hospital readmission rates using Ontario health administrative data. RESULTS: Alternatively licenced physicians performed similarly to traditionally licenced physicians in many primary care performance measures. Minimal differences were seen across groups in indicators of diabetic care, congestive heart failure care, asthma care and cancer screening rates. Larger differences were found in preventive care for children less than 2 years of age, particularly for alternatively licenced physicians who entered Ontario from another Canadian province. CONCLUSIONS: Our findings demonstrate that alternatively licenced physicians perform similarly to traditionally licenced physicians across many indicators of primary care. Our study also demonstrates the utility of administrative data for examining physician performance and evaluating medical regulatory policies and programmes.

A 4D view on the evolution of metamorphic dehydration reactions.

Metamorphic reactions influence the evolution of the Earth's crust in a range of tectonic settings. For example hydrous mineral dehydration in a subducting slab can produce fluid overpressures which may trigger seismicity. During reaction the mechanisms of chemical transport, including water expulsion, will dictate the rate of transformation and hence the evolution of physical properties such as fluid pressure. Despite the importance of such processes, direct observation of mineral changes due to chemical transport during metamorphism has been previously impossible both in nature and in experiment. Using time-resolved (4D) synchrotron X-ray microtomography we have imaged a complete metamorphic reaction and show how chemical transport evolves during reaction. We analyse the dehydration of gypsum to form bassanite and H2O which, like most dehydration reactions, produces a solid volume reduction leading to the formation of pore space. This porosity surrounds new bassanite grains producing fluid-filled moats, across which transport of dissolved ions to the growing grains occurs via diffusion. As moats grow in width, diffusion and hence reaction rate slow down. Our results demonstrate how, with new insights into the chemical transport mechanisms, we can move towards a more fundamental understanding of the hydraulic and chemical evolution of natural dehydrating systems.

Bivariate genome-wide association analysis of the growth and intake components of feed efficiency.

Single nucleotide polymorphisms (SNPs) associated with average daily gain (ADG) and dry matter intake (DMI), two major components of feed efficiency in cattle, were identified in a genome-wide association study (GWAS). Uni- and multi-SNP models were used to describe feed efficiency in a training data set and the results were confirmed in a validation data set. Results from the univariate and bivariate analyses of ADG and DMI, adjusted by the feedlot beef steer maintenance requirements, were compared. The bivariate uni-SNP analysis identified (P-value <0.0001) 11 SNPs, meanwhile the univariate analyses of ADG and DMI identified 8 and 9 SNPs, respectively. Among the six SNPs confirmed in the validation data set, five SNPs were mapped to KDELC2, PHOX2A, and TMEM40. Findings from the uni-SNP models were used to develop highly accurate predictive multi-SNP models in the training data set. Despite the substantially smaller size of the validation data set, the training multi-SNP models had slightly lower predictive ability when applied to the validation data set. Six Gene Ontology molecular functions related to ion transport activity were enriched (P-value <0.001) among the genes associated with the detected SNPs. The findings from this study demonstrate the complementary value of the uni- and multi-SNP models, and univariate and bivariate GWAS analyses. The identified SNPs can be used for genome-enabled improvement of feed efficiency in feedlot beef cattle, and can aid in the design of empirical studies to further confirm the associations.

Enhanced hematite water electrolysis using a 3D antimony-doped tin oxide electrode.

We present herein an example of nanocrystalline antimony-doped tin oxide (nc-ATO) disordered macroporous "inverse opal" 3D electrodes as efficient charge-collecting support structures for the electrolysis of water using a hematite surface catalyst. The 3D macroporous structures were created via templating of polystyrene spheres, followed by infiltration of the desired precursor solution and annealing at high temperature. Using cyclic voltammetry and electrochemical impedance spectroscopy, it was determined that the use of this 3D transparent conducting oxide with a hematite surface catalyst allowed for a 7-fold increase in active surface area for water splitting with respect to its 2D planar counterpart. This ratio of surface areas was evaluated based on the presence of oxidized trap states on the hematite surface, as determined from the equivalent circuit analysis of the Nyquist plots. Furthermore, the presence of nc-ATO 2D and 3D "underlayer" structures with hematite deposited on top resulted in decreased charge transfer resistances and an increase in the number of available active surface sites at the semiconductor-liquid junction when compared to hematite films lacking any nc-ATO substructures. Finally, absorption, transmission, and reflectance spectra of all of the tested films were measured, suggesting the feasibility of using 3D disordered structures in photoelectrochemical reactions, due to the high absorption of photons by the surface catalyst material and trapping of light within the structure.

Size-dependent absolute quantum yields for size-separated colloidally-stable silicon nanocrystals.

Size-selective precipitation was used to successfully separate colloidally stable allylbenzene-capped silicon nanocrystals into several visible emitting monodisperse fractions traversing the quantum size effect range of 1-5 nm. This enabled the measurement of the absolute quantum yield and lifetime of photoluminescence of allylbenzene-capped silicon nanocrystals as a function of size. The absolute quantum yield and lifetime are found to monotonically decrease with decreasing nanocrystal size, which implies that nonradiative vibrational and surface defect effects overwhelm spatial confinement effects that favor radiative relaxation. Visible emission absolute quantum yields as high as 43% speak well for the development of "green" silicon nanocrystal color-tunable light emitting diodes that can potentially match the performance of their toxic heavy metal chalcogenide counterparts.

Colloidally stable silicon nanocrystals with near-infrared photoluminescence for biological fluorescence imaging.

Luminescent silicon nanocrystals (ncSi) are showing great promise as photoluminescent tags for biological fluorescence imaging, with size-dependent emission that can be tuned into the near-infrared biological window and reported lack of toxicity. Here, colloidally stable ncSi with NIR photoluminescence are synthesized from (HSiO1.5)n sol-gel glasses and are used in biological fluorescence imaging. Modifications to the thermal processing conditions of (HSiO1.5)n sol-gel glasses, the development of new ncSi oxide liberation chemistry, and an appropriate alkyl surface passivation scheme lead to the formation of colloidally stable ncSi with photoluminescence centered at 955 nm. Water solubility and biocompatibility are achieved through encapsulation of the hydrophobic alkyl-capped ncSi within PEG-terminated solid lipid nanoparticles. Their applicability to biological imaging is demonstrated with the in-vitro fluorescence labelling of human breast tumor cells.

Physician-patient encounters: the structure of performance in family and general office practice.

INTRODUCTION: The College of Physicians and Surgeons of Ontario, the regulatory authority for physicians in Ontario, Canada, conducts peer assessments of physicians' practices as part of a broad quality assurance program. Outcomes are summarized as a single score and there is no differentiation between performance in various aspects of care. In this study we test the hypothesis that physician performance is multidimensional and that dimensions can be defined in terms of physician-patient encounters. METHODS: Peer assessment data from 532 randomly selected family practitioners were analyzed using factor analysis to assess the dimensional structure of performance. Content validity was confirmed through consultation sessions with 130 physicians. Multiple-item measures were constructed for each dimension and reliability calculated. Analysis of variance determined the extent to which multiple-item measure scores would vary across peer assessment outcomes. RESULTS: Six performance dimensions were confirmed: acute care, chronic conditions, continuity of care and referrals, well care and health maintenance, psychosocial care, and patient records. DISCUSSION: Physician performance is multidimensional, including types of physician-patient encounters and variation across dimensions, as demonstrated by individual practice. A conceptual framework for multidimensional performance may inform the design of meaningful evaluation and educational recommendations to meet the individual performance of practicing physicians.

Effectiveness of an enhanced peer assessment program: introducing education into regulatory assessment.

INTRODUCTION: The College of Physicians and Surgeons of Ontario developed an enhanced peer assessment (EPA), the goal of which was to provide participating physicians educational value by helping them identify specific learning needs and aligning the assessment process with the principles of continuing education and professional development. In this article, we examine the educational value of the EPA and whether physicians will change their practice as a result of the recommendations received during the assessment. METHODS: A group of 41 randomly selected physicians (23 general or family practitioners, 7 obstetrician-gynecologists, and 11 general surgeons) agreed to participate in the EPA pilot. Nine experienced peer assessors were trained in the principles of knowledge translation and the use of practice resources (tool kits) and clinical practice guidelines. The EPA was evaluated through the use of a postassessment questionnaire and focus groups. RESULTS: The physicians felt that the EPA was fair and educationally valuable. Most focus group participants indicated that they implemented recommendations made by the assessor and made changes to some aspect of their practice. The physicians' suggestions for improvement included expanding the assessment beyond the current medical record review and interview format (eg, to include multisource feedback), having assessments occur at regular intervals (eg, every 5 to 10 years), and improving the administrative process by which physicians apply for educational credit for EPA activities. CONCLUSIONS: The EPA pilot study has demonstrated that providing detailed individualized feedback and optimizing the one-to-one interaction between assessors and physicians is a promising method for changing physician behavior. The college has started the process of aligning all its peer assessments with the principles of continuing professional development outlined in the EPA model.

Reversibility of the reproductive toxicity of gossypol in peripubertal bulls.

Gossypol has been shown to impair sperm production in male ruminants. The purpose of this study was to determine if the adverse effects of gossypol on spermatogenesis in peripubertal bulls were reversible. Twenty-eight crossbred Angus bulls were allocated into treated and control groups at 11 months of age. For 8 weeks, treated bulls were fed a ration containing 8 mg of free gossypol per kilogram of body weight per day while control bulls were fed a soybean meal ration free of gossypol. At 28-days intervals, scrotal circumference was measured and semen collected to assess sperm motility and morphology. Seven control and seven treated animals were castrated 56 days after the start of the experiment and the testes were examined histologically. The remaining bulls were fed a gossypol-free diet for 210 days prior to castration. There were significant increases in primary and secondary sperm abnormalities in treated bulls 28 and 56 days after gossypol feeding. The number of sperm with proximal droplets was significantly higher in gossypol-treated bulls, suggesting testicular degeneration. There was no significant effect on the sperm motility, scrotal circumference, or histopathological characteristics of the testes. Four weeks after the end of gossypol feeding, primary and secondary abnormalities were still increased in gossypol-treated bulls, however in subsequent collection periods the percentage of abnormalities were similar between groups. At 210 days, there was no treatment effect on scrotal circumference, and histological characteristics of the testes were not different between groups. The deleterious effects of gossypol on the morphological characteristics of spermatozoa were reversible. Gossypol (8 mg/kg per day for 56 days) increased sperm abnormalities but the effects were reversible.

Educational interventions to improve practice of nonspecialty physicians who are identified in need by peer review.

This article reports on the peer review process of the College of Physicians and Surgeons of Ontario, the licensing and regulatory authority, and the effect of educational interventions on physicians identified to be in need. Since 1980, the college has assessed more than 175 random and targeted nonspecialist physicians each year. A structured remediation process has been employed for those in need. Extensive data files have been maintained by the college. A majority of physicians identified as needing improvement improved and maintained their improved performance. The simple structured interventions employed by the college demonstrate an educational intervention that produces practice improvement.