Metabolic flexibility is an important component of adaptation to stressful environments, including thermal stress and latitudinal adaptation. A long history of population genetic studies suggest that selection on core metabolic enzymes may shape life histories by altering metabolic flux. However, the direct relationship between selection on thermal stress hardiness and metabolic flux has not previously been tested. We investigated flexibility of nutrient catabolism during cold stress in Drosophila melanogaster artificially selected for fast or slow recovery from chill coma (i.e. cold-hardy or -susceptible), specifically testing the hypothesis that stress adaptation increases metabolic turnover. Using (13)C-labelled glucose, we first showed that cold-hardy flies more rapidly incorporate ingested carbon into amino acids and newly synthesized glucose, permitting rapid synthesis of proline, a compound shown elsewhere to improve survival of cold stress. Second, using glucose and leucine tracers we showed that cold-hardy flies had higher oxidation rates than cold-susceptible flies before cold exposure, similar oxidation rates during cold exposure, and returned to higher oxidation rates during recovery. Additionally, cold-hardy flies transferred compounds among body pools more rapidly during cold exposure and recovery. Increased metabolic turnover may allow cold-adapted flies to better prepare for, resist and repair/tolerate cold damage. This work illustrates for the first time differences in nutrient fluxes associated with cold adaptation, suggesting that metabolic costs associated with cold hardiness could invoke resource-based trade-offs that shape life histories.

Introduction

Developing guidelines to inform the use of antiretroviral pre-exposure prophylaxis (PrEP) for HIV prevention in resource-limited settings must necessarily be informed by considering the resources and infrastructure needed for PrEP delivery. We describe an approach that identifies subpopulations of cisgender men who have sex with men (MSM) and transgender women (TGW) to prioritize for the rollout of PrEP in resource-limited settings.

Methods

We use data from the iPrEx study, a multi-national phase III study of PrEP for HIV prevention in MSM/TGW, to build statistical models that identify subpopulations at high risk of HIV acquisition without PrEP, and with high expected PrEP benefit. We then evaluate empirically the population impact of policies recommending PrEP to these subpopulations, and contrast these with existing policies.

Results

A policy recommending PrEP to a high risk subpopulation of MSM/TGW reporting condomless receptive anal intercourse over the last 3 months (estimated 3.3% 1-year HIV incidence) yields an estimated 1.95% absolute reduction in 1-year HIV incidence at the population level, and 3.83% reduction over 2 years. Importantly, such a policy requires rolling PrEP out to just 59.7% of MSM/TGW in the iPrEx population. We find that this policy is identical to that which prioritizes MSM/TGW with high expected PrEP benefit. It is estimated to achieve nearly the same reduction in HIV incidence as the PrEP guideline put forth by the US Centers for Disease Control, which relies on the measurement of more behavioral risk factors and which would recommend PrEP to a larger subset of the MSM/TGW population (86% vs. 60%).

Conclusions

These findings may be used to focus future mathematical modelling studies of PrEP in resource-limited settings on prioritizing PrEP for high-risk subpopulations of MSM/TGW. The statistical approach we took could be employed to develop PrEP policies for other at-risk populations and resource-limited settings.

Detecting polarized light from self-luminous exoplanets has the potential to provide key information about rotation, surface gravity, cloud grain size, and cloud coverage. While field brown dwarfs with detected polarized emission are common, no exoplanet or substellar companion has yet been detected in polarized light. With the advent of high contrast imaging spectro-polarimeters such as GPI and SPHERE, such a detection may now be possible with careful treatment of instrumental polarization. In this paper, we present 28 minutes of H-band GPI polarimetric observations of the benchmark T5.5 companion HD 19467 B. We detect no polarization signal from the target, and place an upper limit on the degree of linear polarization of pCL99.73% ≤ 2.4%. We discuss our results in the context of T dwarf cloud models and photometric variability.

Background

Diagnosis of Gleason 6 prostate cancer can leave uncertainty about the presence of undetected aggressive disease.

Objective

To evaluate the utility of a four kallikrein (4K) panel in predicting the presence of high-grade cancer in men on active surveillance.

Design, setting, and participants

Plasma collected before the first and subsequent surveillance biopsies was assessed for 718 men prospectively enrolled in the multi-institutional Canary PASS trial. Biopsy data were split 2:1 into training and test sets. We developed statistical models that included clinical information and either the 4Kpanel or serum prostate-specific antigen (PSA).

Outcome measurements and statistical analysis

The endpoint was reclassification to Gleason ≥7. We used receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) to assess discriminatory capacity, and decision curve analysis (DCA) to report clinical net benefit.

Results and limitations

Significant predictors for reclassification were 4Kpanel (odds ratio [OR] 1.54, 95% confidence interval [CI] 1.31-1.81) or PSA (OR 2.11, 95% CI 1.53-2.91), ≥20% cores positive (OR 2.10, 95% CI 1.33-3.32), two or more prior negative biopsies (OR 0.19, 95% CI 0.04-0.85), prostate volume (OR 0.47, 95% CI 0.31-0.70), and body mass index (OR 1.09, 95% CI 1.04-1.14). ROC curve analysis comparing 4K and base models indicated that the 4Kpanel improved accuracy for predicting reclassification (AUC 0.78 vs 0.74) at the first surveillance biopsy. Both models performed comparably for prediction of reclassification at subsequent biopsies (AUC 0.75 vs 0.76). In DCA, both models showed higher net benefit compared to biopsy-all and biopsy-none strategies. Limitations include the single cohort nature of the study and the small numbers; results should be validated in another cohort before clinical use.

Conclusions

The 4Kpanel provided incremental value over routine clinical information in predicting high-grade cancer in the first biopsy after diagnosis. The 4Kpanel did not add predictive value to the base model at subsequent surveillance biopsies.

Patient summary

Active surveillance is a management strategy for many low-grade prostate cancers. Repeat biopsies monitor for previously undetected high-grade cancer. We show that a model with clinical variables, including a panel of four kallikreins, indicates the presence of high-grade cancer before a biopsy is performed.

Background

For men on active surveillance for prostate cancer, biomarkers may improve prediction of reclassification to higher grade or volume cancer. This study examined the association of urinary PCA3 and TMPRSS2:ERG (T2:ERG) with biopsy-based reclassification.

Methods

Urine was collected at baseline, 6, 12, and 24 months in the multi-institutional Canary Prostate Active Surveillance Study (PASS), and PCA3 and T2:ERG levels were quantitated. Reclassification was an increase in Gleason score or ratio of biopsy cores with cancer to ≥34%. The association of biomarker scores, adjusted for common clinical variables, with short- and long-term reclassification was evaluated. Discriminatory capacity of models with clinical variables alone or with biomarkers was assessed using receiver operating characteristic (ROC) curves and decision curve analysis (DCA).

Results

Seven hundred and eighty-two men contributed 2069 urine specimens. After adjusting for PSA, prostate size, and ratio of biopsy cores with cancer, PCA3 but not T2:ERG was associated with short-term reclassification at the first surveillance biopsy (OR = 1.3; 95% CI 1.0-1.7, p = 0.02). The addition of PCA3 to a model with clinical variables improved area under the curve from 0.743 to 0.753 and increased net benefit minimally. After adjusting for clinical variables, neither marker nor marker kinetics was associated with time to reclassification in subsequent biopsies.

Conclusions

PCA3 but not T2:ERG was associated with cancer reclassification in the first surveillance biopsy but has negligible improvement over clinical variables alone in ROC or DCA analyses. Neither marker was associated with reclassification in subsequent biopsies.

During the first-light run of the Gemini Planet Imager we obtained K-band spectra of exoplanets HR 8799 c and d. Analysis of the spectra indicates that planet d may be warmer than planet c. Comparisons to recent patchy cloud models and previously obtained observations over multiple wavelengths confirm that thick clouds combined with horizontal variation in the cloud cover generally reproduce the planets' spectral energy distributions. When combined with the 3 to 4 μm photometric data points, the observations provide strong constraints on the atmospheric methane content for both planets. The data also provide further evidence that future modeling efforts must include cloud opacity, possibly including cloud holes, disequilibrium chemistry, and super-solar metallicity.

We present the first results from the polarimetry mode of the Gemini Planet Imager (GPI), which uses anew integral field polarimetry architecture to provide high contrast linear polarimetry with minimal systematic biases between the orthogonal polarizations. We describe the design, data reduction methods, and performance of polarimetry with GPI. Point-spread function (PSF) subtraction via differential polarimetry suppresses unpolarized starlight by a factor of over 100, and provides sensitivity to circumstellar dust reaching the photon noise limit for these observations. in the case of the circumstellar disk around HR 4796A,GPI's advanced adaptive optics system reveals the disk clearly even prior to PSF subtraction. In polarized light, the disk is seen all the way in to its semi-minor axis for the first time. The disk exhibits surprisingly strong asymmetry in polarized intensity, with the west side ≳9 times brighter than the east side despite the fact that the east side is slightly brighter in total intensity. Based on a synthesis of the total and polarized intensities, we now believe that the west side is closer to us, contrary to most prior interpretations. Forward scattering by relatively large silicate dust particles leads to the strong polarized intensity on thewest side, and the ring must be slightly optically thick in order to explain the lower brightness in total intensity there. These findings suggest that the ring is geometrically narrow and dynamically cold, perhaps shepherded by larger bodies in the same manner as Saturn's Fring.

We present the first scattered-light image of the debris disk around HD 131835 in the H band using the Gemini Planet Imager. HD 131835 is a ∼15 Myr old A2IV star at a distance of ∼120 pc in the Sco-Cen OB association. We detect the disk only in polarized light and place an upper limit on the peak total intensity. No point sources resembling exoplanets were identified. Compared to its mid-infrared thermal emission, in scattered light the disk shows similar orientation but different morphology. The scattered-light disk extends from ∼75 to ∼210 AU in the disk plane with roughly flat surface density. Our Monte Carlo radiative transfer model can describe the observations with a model disk composed of a mixture of silicates and amorphous carbon. In addition to the obvious brightness asymmetry due to stronger forward scattering, we discover a weak brightness asymmetry along the major axis, with the northeast side being 1.3 times brighter than the southwest side at a 3σ level.