Multiplexed Native Mass Spectrometry Determination of Ligand Selectivity for Fatty Acid-Binding Proteins.

Although multiple approaches for characterizing protein-ligand interactions are available in target-based drug discovery, their throughput for determining selectivity is quite limited. Herein, we describe the application of native mass spectrometry for rapid, multiplexed screening of the selectivity of eight small-molecule ligands for five fatty acid-binding protein isoforms. Using high-resolution mass spectrometry, we were able to identify and quantify up to 20 different protein species in a single spectrum. We show that selectivity profiles generated by native mass spectrometry are in good agreement with those of traditional solution-phase techniques such as isothermal titration calorimetry and fluorescence polarization. Furthermore, we propose strategies for effective investigation of selectivity by native mass spectrometry, thus highlighting the potential of this technique to be used as an orthogonal method to traditional biophysical approaches for rapid, multiplexed screening of protein-ligand complexes.

Patients' Preferences for Cytoreductive Treatments in Newly Diagnosed Metastatic Prostate Cancer: The IP5-MATTER Study.

BACKGROUND AND OBJECTIVE: Cytoreductive treatments for patients diagnosed with de novo synchronous metastatic hormone-sensitive prostate cancer (mHSPC) confer incremental survival benefits over systemic therapy, but these may lead to added toxicity and morbidity. Our objective was to determine patients' preferences for, and trade-offs between, additional cytoreductive prostate and metastasis-directed interventions. METHODS: A prospective multicentre discrete choice experiment trial was conducted at 30 hospitals in the UK between December 3, 2020 and January 25, 2023 (NCT04590976). The individuals were eligible for inclusion if they were diagnosed with de novo synchronous mHSPC within 4 mo of commencing androgen deprivation therapy and had performance status 0-2. A discrete choice experiment instrument was developed to elicit patients' preferences for cytoreductive prostate radiotherapy, prostatectomy, prostate ablation, and stereotactic ablative body radiotherapy to metastasis. Patients chose their preferred treatment based on seven attributes. An error-component conditional logit model was used to estimate the preferences for and trade-offs between treatment attributes. KEY FINDINGS AND LIMITATIONS: A total of 352 patients were enrolled, of whom 303 completed the study. The median age was 70 yr (interquartile range [IQR] 64-76) and prostate-specific antigen was 94 ng/ml (IQR 28-370). Metastatic stages were M1a 10.9% (33/303), M1b 79.9% (242/303), and M1c 7.6% (23/303). Patients preferred treatments with longer survival and progression-free periods. Patients were less likely to favour cytoreductive prostatectomy with systemic therapy (Coef. -0.448; [95% confidence interval {CI} -0.60 to -0.29]; p < 0.001), unless combined with metastasis-directed therapy. Cytoreductive prostate radiotherapy or ablation with systemic therapy, number of hospital visits, use of a "day-case" procedure, or addition of stereotactic ablative body radiotherapy did not impact treatment choice. Patients were willing to accept an additional cytoreductive treatment with 10 percentage point increases in the risk of urinary incontinence and fatigue to gain 3.4 mo (95% CI 2.8-4.3) and 2.7 mo (95% CI 2.3-3.1) of overall survival, respectively. CONCLUSIONS AND CLINICAL IMPLICATIONS: Patients are accepting of additional cytoreductive treatments for survival benefit in mHSPC, prioritising preservation of urinary function and avoidance of fatigue. PATIENT SUMMARY: We performed a large study to ascertain how patients diagnosed with advanced (metastatic) prostate cancer at their first diagnosis made decisions regarding additional available treatments for their prostate and cancer deposits (metastases). Treatments would not provide cure but may reduce cancer burden (cytoreduction), prolong life, and extend time without cancer progression. We reported that most patients were willing to accept additional treatments for survival benefits, in particular treatments that preserved urinary function and reduced fatigue.

A cluster randomised trial of a rational emotive behavior therapy (REBT) program and a mindfulness-acceptance-commitment (MAC) program, with South African adolescent rugby players.

Until recently, research examining the application of Rational Emotive Behavior Therapy (REBT) in sports settings was virtually absent in South Africa. Despite the growing evidence of REBT's potential as a psychological intervention in Western nations, its use within the multicultural and sports-fervent context of South Africa remains unexplored. Moreover, limited research has addressed the impact of REBT on rugby players, with only a few case studies being reported. The current experiment employs a cluster randomised trial (CRT) to compare the effects of a 7-week preferential REBT program with a 7-week Mindfulness-Acceptance-Commitment (MAC) program on irrational beliefs, competitive anxiety and subjective performance, among adolescent South African rugby players. We also include a wait-list control group who received neither REBT nor MAC. Results indicate that athletes receiving REBT reported greater improvements in irrational beliefs, anxiety, and subjective performance, while that athletes receiving MAC also reported some improvements in anxiety. This study highlights the potential of REBT as a valuable psychological intervention in the context of South African adolescent rugby players.

Type I interferon induced during chronic viral infection favors B-cell development in the thymus.

Chronic viral infections cause thymic involution yet the potential for broader, longer-term impact on thymic composition remains unexplored. Here we show that chronic, but not acute, lymphocytic choriomeningitis virus infection promotes a unique population of immature B cells in the thymus. We show that chronic viral infection promotes signals within the thymus, including the expression of B-cell activating factor (BAFF), that favor the maturation of this population as these cells acquire expression of CD19 and immunoglobulin M. Mechanistically, type I interferon (IFN-I), predominantly IFNß, signals to thymic hematopoietic cells, strongly delaying T-cell development at the earliest precursor stage. Furthermore, IFN-I signaling to the nonhematopoietic compartment provides a second signal essential to favor B-cell differentiation and maturation within the thymus. Importantly, chronic infection yields changes in the B-cell population for at least 50 days following infection, long after thymic atrophy has subsided. Thus, the inflammatory milieu induced by chronic viral infection has a profound, and long-lasting, effect on thymic composition leading to the generation of a novel population of thymic B cells.

Poststroke cognitive outcome is better accounted for by white matter abnormalities automated segmentation than visual analysis.

BACKGROUND AND AIMS: The association between white matter abnormalities (WMA) and cognitive decline previously reported in poststroke patients has been mainly documented using visual scales. However, automated segmentation of WMA provides a precise determination of the volume of WMA. Nonetheless, it is rarely used in the stroke population and its potential advantage over visual scales is still unsettled. The objective of this study was to examine whether automated segmentation of WMA provides a better account than the visual Fazekas and Wahlund scales of the decline in executive functions and processing speed in stroke patients. METHODS: The analyses were conducted on the 358 patients of the GRECogVASC cohort with an MRI performed at six months poststroke in the Amiens center. WMA were visually analyzed using the Fazekas (subcortical abnormalities) and Wahlund scales. Segmentation was performed using LST (3.0.3). Following preliminary studies to determine the optimal segmentation threshold, we examined the relationship between cognitive status and WMA volume computed at each threshold using receiver operating characteristic (ROC) curves. Finally, we assessed the ability of both Fazekas and Wahlund visual scores and WMA volume to account for cognitive scores by using a bivariate Pearson correlation analysis, comparing correlation coefficients with the Fisher transformation and repeating correlation analysis after adjustment for the lesion volume. RESULTS: Increasing the threshold led to an underestimation of WMA (P=0.0001) (significant for a threshold ≥0.2) and an improvement in correct rejection of signal changes in the stroke cavity (P=0.02) (significant for a threshold ≤0.5), susceptibility artifacts (P=0.002) (significant for a threshold ≤0.6), and corticospinal degeneration (P=0.03) (significant for a threshold ≤0.5). WMA volume decreased with increasing threshold (P=0.0001). Areas under the curve (AUC) did not differ according to the threshold (processing speed: P=0.85, executive cognitive functions: P=0.7). Correlation coefficients between cognitive scores and WMA were higher for WMA volume than the Fazekas (processing speed: Z=-3.442, P=0.001; executive functions: Z=-2.751, P=0.006) and Wahlund scores (processing speed: Z=-3.615, P=0.0001; executive functions: Z=-2.769, P=0.006). Adjustment for lesion volume did not alter the correlations with WMA volume (processing speed: r=-0.327 [95%CI: -0.416; -0.223], P=0.0001; executive functions: r=-0.262 [95%CI: -0.363; -0.150], P=0.0001). CONCLUSION: This study shows that WMA volume assessed by automated segmentation provides a better account of cognitive disorders than visual analysis. This should favor its wider use to refine imaging determinants of poststroke cognitive disorders.

The impact of hospital presentation time on stroke outcomes: A nationally representative Irish cohort study.

OBJECTIVES: There is conflicting evidence regarding the outcomes of acute stroke patients who present to hospital within normal working hours ('in-hours') compared with the 'out-of-hours' period. This study aimed to assess the effect of time of stroke presentation on outcomes within the Irish context, to inform national stroke service delivery. MATERIALS AND METHODS: A secondary analysis of data from the Irish National Audit of Stroke (INAS) from Jan 2016 to Dec 2019 was carried out. Patient and process outcomes were assessed for patients presenting 'in-hours' (8:00-17:00 Monday-Friday) compared with 'out-of-hours' (all other times). RESULTS: Data on arrival time were available for 13,996 patients (male 56.2%; mean age 72.5 years), of which 55.7% presented 'out-of-hours'. In hospital mortality was significantly lower among those admitted 'in-hours' (11.3%, n = 534) compared with 'out-of-hours' (12.8%, n = 749); (adjusted Odds Ratio (OR) 0.82; 95% Confidence Interval CI [95% CI] 0.72-0.89). Poor functional outcome at discharge (Modified Rankin Scale ≥ 3) was also significantly lower in those presenting 'in-hours' (adjusted OR 0.79; 95% CI 0.68-0.91). In patients receiving thrombolysis, mean door to needle time was shorter for 'in-hours' presentation at 55.8 mins (n = 562; SD 35.43 mins), compared with 'out-of-hours' presentation at 80.5 mins (n = 736; SD 38.55 mins, p < .001). CONCLUSION: More than half of stroke patients in Ireland present 'out-of-hours' and these presentations are associated with a higher mortality and a lower odds of functional independence at discharge. It is imperative that stroke pathways consider the 24 hour period to ensure the delivery of effective stroke care, and modification of 'out-of-hours' stroke care is required to improve overall outcomes.

Secondhand Nicotine Absorption From E-Cigarette Vapor vs Tobacco Smoke in Children.

Importance: With the prevalence of e-cigarette use (vaping) increasing worldwide, there are concerns about children's exposure to secondhand vapor. Objective: To compare nicotine absorption among children who are (1) exposed to secondhand tobacco smoke only or (2) exposed to secondhand vapor only with (3) those exposed to neither. Design, Setting, and Participants: The US Continuous National Health and Nutrition Examination Survey (NHANES) is a repeat cross-sectional survey. Participants are interviewed in their homes and, several days after, visit a mobile examination center to provide biological specimens. This study uses data from a nationally representative sample of US households from 2017 to 2020. Participants were children aged 3 to 11 years with serum cotinine levels incompatible with current firsthand nicotine use (ie, <15 µg/L). The final analysis was conducted on January 9, 2024. Exposures: Reported exposure to secondhand smoke or vapor indoors in the past 7 days (only secondhand smoke, only secondhand vapor, or neither). Covariates included age, sex, ethnicity, family income, body weight, and height. Main Outcomes and Measures: The primary outcome was serum cotinine concentration, an objective biomarker of nicotine absorption. Geometric mean cotinine levels and 95% CIs were calculated using log-normal tobit regression, accounting for the complex survey design and weights. Results: The mean (SD) age of the 1777 children surveyed was 7.4 (2.6) years, 882 (49.6%) were female, and 531 (29.9%) had family incomes below the poverty level. Nicotine absorption, as indexed by serum cotinine level, was highest among children only exposed to secondhand smoke (0.494 µg/L µg/L; 95% CI, 0.386-0.633 µg/L), followed by those exposed only to secondhand vapor (0.081 µg/L; 95% CI, 0.048-0.137 µg/L), equating to 83.6% (95% CI, 71.5%-90.5%; P < .001) lower nicotine absorption. Among children with no reported secondhand exposure, the geometric mean cotinine level was 0.016 µg/L (95% CI, 0.013-0.021 µg/L), or 96.7% (95% CI, 95.6%-97.6%; P < .001) lower than for those with exposure to secondhand smoke. Results were similar after covariate adjustment. Conclusions and Relevance: In this cross-sectional study of US children, nicotine absorption was much lower in children who were exposed to secondhand vapor vs secondhand smoke, but higher than in those exposed to neither. These findings suggest that switching from smoking to vaping indoors may substantially reduce, but not eliminate, children's secondhand exposure to nicotine and other noxious substances.

Breast Cancer in a Filipino Male: A Case Report and Brief Literature Review.

This is a case report of a 76-year-old Filipino male who presented with a six-year history of a steadily growing left breast mass. The mass was eventually diagnosed to be Invasive Ductal Carcinoma, Anatomic and Prognostic Stage IIIB (T4b cN0 M0), Grade 3, Luminal A. Subsequently, the patient underwent neoadjuvant chemotherapy of doxorubicin/cyclophosphamide and paclitaxel, followed by modified radical mastectomy with axillary lymph node dissection, concluded by post-mastectomy radiation therapy. The patient had complete clinical response to this trimodality therapy. The rarity of this case is juxtaposed and integrated with the present literature on male breast cancer.

Volumetric Analysis: Effect on Diagnosis and Management of Indeterminate Solid Pulmonary Nodules in Routine Clinical Practice.

OBJECTIVE: To evaluate the effect of volumetric analysis on the diagnosis and management of indeterminate solid pulmonary nodules in routine clinical practice. METHODS: This was a retrospective study with 107 computed tomography (CT) cases of solid pulmonary nodules (range, 6-15 mm), 57 pathology-proven malignancies (lung cancer, n = 34; metastasis, n = 23), and 50 benign nodules. Nodules were evaluated on a total of 309 CT scans (average number of CTs/nodule, 2.9 [range, 2-7]). CT scans were from multiple institutions with variable technique. Nine radiologists (attendings, n = 3; fellows, n = 3; residents, n = 3) were asked their level of suspicion for malignancy (low/moderate or high) and management recommendation (no follow-up, CT follow-up, or care escalation) for baseline and follow-up studies first without and then with volumetric analysis data. Effect of volumetry on diagnosis and management was assessed by generalized linear and logistic regression models. RESULTS: Volumetric analysis improved sensitivity (P = 0.009) and allowed earlier recognition (P < 0.05) of malignant nodules. Attending radiologists showed higher sensitivity in recognition of malignant nodules (P = 0.03) and recommendation of care escalation (P < 0.001) compared with trainees. Volumetric analysis altered management of high suspicion nodules only in the fellow group (P = 0.008). κ Statistics for suspicion for malignancy and recommended management were fair to substantial (0.38-0.66) and fair to moderate (0.33-0.50). Volumetric analysis improved interobserver variability for identification of nodule malignancy from 0.52 to 0.66 (P = 0.004) only on the second follow-up study. CONCLUSIONS: Volumetric analysis of indeterminate solid pulmonary nodules in routine clinical practice can result in improved sensitivity and earlier identification of malignant nodules. The effect of volumetric analysis on management recommendations is variable and influenced by reader experience.

Discovery of a Series of Orally Bioavailable Androgen Receptor Degraders for the Treatment of Prostate Cancer.

Androgen receptor (AR) signaling plays a key role in the progression of prostate cancer. This study describes the discovery and optimization of a novel series of AR PROTAC degraders that recruit the Cereblon (CRBN) E3 ligase. Having identified a series of AR ligands based on 4-(4-phenyl-1-piperidyl)-2-(trifluoromethyl)benzonitrile, our PROTAC optimization strategy focused on linker connectivity and CRBN ligand SAR to deliver potent degradation of AR in LNCaP cells. This work culminated in compounds 11 and 16 which demonstrated good rodent oral bioavailability. Subsequent SAR around the AR binding region brought in an additional desirable feature, degradation of the important treatment resistance mutation L702H. Compound 22 (AZ'3137) possessed an attractive profile showing degradation of AR and L702H mutant AR with good oral bioavailability across species. The compound also inhibited AR signaling in vitro and tumor growth in vivo in a mouse prostate cancer xenograft model.

Infiltrative Basal Cell Carcinoma (iBCC) Adjacent to a Desmoplastic Trichoepithelioma (DTE): A Case Report and Literature Review of iBCCs and DTEs.

The co-existence of an infiltrative basal cell carcinoma (iBCC) and a desmoplastic trichoepithelioma (DTE) within the same cutaneous lesion is a rare occurrence. iBCCs are relatively common malignant skin neoplasms that pose a risk for local tissue destruction and recurrence. DTEs are cutaneous neoplasms originating from hair follicles that may clinically and histologically appear similar to iBCCs but are ultimately benign. Distinguishing between these two entities is important given their differing destructive potential. Herein, we describe the case of a 36-year-old female with a single skin lesion on her left cheek that was comprised of both an iBCC distinct from a DTE, as verified by histopathologic analysis. A literature review highlights the rarity of such collision tumors and discusses the potential genetic links between these two histologically similar cutaneous neoplasms.

A quantitative modeling framework to understand the physiology of the hypothalamic-pituitary-adrenal axis and interaction with cortisol replacement therapy.

Congenital adrenal hyperplasia (CAH) is characterized by impaired adrenal cortisol production. Hydrocortisone (synthetic cortisol) is the drug-of-choice for cortisol replacement therapy, aiming to mimic physiological cortisol circadian rhythm. The hypothalamic-pituitary-adrenal (HPA) axis controls cortisol production through the pituitary adrenocorticotropic hormone (ACTH) and feedback mechanisms. The aim of this study was to quantify key mechanisms involved in the HPA axis activity regulation and their interaction with hydrocortisone therapy. Data from 30 healthy volunteers was leveraged: Endogenous ACTH and cortisol concentrations without any intervention as well as cortisol concentrations measured after dexamethasone suppression and single dose administration of (i) 0.5-10 mg hydrocortisone as granules, (ii) 20 mg hydrocortisone as granules and intravenous bolus. A stepwise model development workflow was used: A newly developed model for endogenous ACTH and cortisol was merged with a refined hydrocortisone pharmacokinetic model. The joint model was used to simulate ACTH and cortisol trajectories in CAH patients with varying degrees of enzyme deficiency, with or without hydrocortisone administration, and healthy individuals. Time-dependent ACTH-driven endogenous cortisol production and cortisol-mediated feedback inhibition of ACTH secretion processes were quantified and implemented in the model. Comparison of simulated ACTH and cortisol trajectories between CAH patients and healthy individuals showed the importance of administering hydrocortisone before morning ACTH secretion peak time to suppress ACTH overproduction observed in untreated CAH patients. The developed framework allowed to gain insights on the physiological mechanisms of the HPA axis regulation, its perturbations in CAH and interaction with hydrocortisone administration, paving the way towards cortisol replacement therapy optimization.

Compatibility of Generalized Noisy Qubit Measurements.

It is a crucial feature of quantum mechanics that not all measurements are compatible with each other. However, if measurements suffer from noise they may lose their incompatibility. Here, we consider the effect of white noise and determine the critical visibility such that all qubit measurements, i.e., all positive operator-valued measures (POVMs), become compatible, i.e., jointly measurable. In addition, we apply our methods to quantum steering and Bell nonlocality. We obtain a tight local hidden state model for two-qubit Werner states of visibility 1/2. This determines the exact steering bound for two-qubit Werner states and also provides a local hidden variable model that improves on previously known models. Interestingly, this proves that POVMs are not more powerful than projective measurements to demonstrate quantum steering for these states.

Differences in the prognostic role of age, extent of resection and tumor grade between astrocytoma IDHmt and oligodendroglioma: a single center cohort study.

PURPOSE: IDH-mutant glioma are classified as oligodendroglioma or astrocytoma on the basis of 1p19q-codeletion. Whether prognostic factors are similar between these tumor types is not well understood. EXPERIMENTAL DESIGN: Retrospective cohort study. Molecular characterization was performed with targeted next-generation sequencing. Tumor volumes were calculated using semi-automatic 3D segmentation on all pre- and postoperative MRI-scans. Overall survival was assessed with Cox proportional hazards model. RESULTS: 383 patients with newly diagnosed IDH-mutant glioma were followed-up for a median of 7.2 years. Grade 3 and grade 4 patients had significantly lower Karnofsky performance, with tumors having more contrast-enhancement. Patients also received more aggressive post-surgery treatment. Postoperative tumor volume is significantly and independently associated with survival (HR per cm3 1.19, 95% CI 1.03 - 1.39) in IDH-mutant glioma. Separate analysis of oligodendroglioma and astrocytoma showed a significant association of postoperative tumor volume in astrocytoma, but not in oligodendroglioma. Higher age and histological tumor grade were associated with worse survival in patients with oligodendroglioma, but not with astrocytoma. CONCLUSIONS: Our data support an initial strategy of extensive resection in both oligodendroglioma and astrocytoma patients. Other important prognostic factors differ between these tumor types, urging researchers and clinicians to keep treating these tumors as separate entities.

Clinical assessment of breastfeeding in preterm infants.

Breastmilk confers empirical benefits for preterm infants, however direct breastfeeding rates in this population remain low. For preterm infants, it may be useful to assess the volume of breastmilk transferred from mother to baby when breastfeeding, particularly during transition to oral feeding when breastfeeding attrition is high. Establishing breastfeeding in preterm infants is complex and without knowledge of milk intake during breastfeeds there is risk of inaccurate feed supplementation with subsequent effects on growth and nutrition. Here we review the evidence for clinical assessments of breastfeeding in preterm infants including test weighing, use of isotope labelled water and clinical observation tools designed to estimate adequacy of breastfeeds. Test weighing is a validated measurement, however requires rigorous protocols and further investigation in small infants. Use of isotope labelled water is a validated technique but, due to sampling requirements, reflects intake over days and weeks instead of individual feeds. Clinical observation tools assessed in preterm infants, have not been shown to reflect volumes of breastmilk intake. While current methods have limitations, the goal is to identify measurement tools to be used as temporary aids to facilitate transition to direct breastfeeding while minimising risk of inaccurate supplementation.

The Effect of Duration on Performance and Perceived Fatigability During Acute High-Intensity Interval Exercise in Young, Healthy Males and Females.

Few studies have explored the kinetics of performance and perceived fatigability during high-intensity interval training, despite its popularity. We aimed to characterize the kinetics of fatigability and recovery during an 8 × 4-min HIIT protocol, hypothesizing that most muscle function impairment would occur during the initial four intervals. Fifteen healthy males and females (mean ± standard deviation; age = 26 ± 5 years, V̇O2max = 46.8 ± 6.1 mL·kg-1·min-1) completed eight, 4-min intervals at 105% of critical power with 3 min of rest. Maximal voluntary knee extension contractions (MVCs) coupled with electrical nerve stimulation were performed at baseline and after the first, fourth, and eighth intervals. MVC, potentiated twitch force (Pt), and Db10:100 ratio all declined throughout HIIT (p < 0.05). MVC sharply declined after interval 1 (-15 ± 9% relative to baseline; p < 0.05) and had only further declined after interval 8 (-26 ± 11%; p < 0.05), but not interval 4 (-19 ± 13%; p > 0.05). Pt and Db10:100 also sharply declined after interval 1 (Pt: -18 ± 13%, Db10:100: -14 ± 20%; p < 0.05) and further declined after interval 4 (Pt: -35 ± 19%, Db10:100: -30 ± 20%; p < 0.05) but not interval 8 (Pt: -41 ± 19%; Db10:100: -32 ± 18%; p > 0.05). Voluntary activation did not significantly change across the HIIT protocol (p > 0.05). Evoked force recovery was significantly blunted as more intervals were completed: after interval 1, Pt recovered by 7 ± 11% compared to -6 ± 7% recovery after interval 8 (p < 0.05). Ratings of perceived effort, fatigue, and leg pain rose throughout the session (p < 0.05 for each) and were greater (effort and fatigue) for females (p < 0.05). Otherwise, males and females exhibited similar performance fatigability kinetics, with contractile function declines blunted in response to additional intervals.

Patient-reported outcomes in neuro-oncology.

PURPOSE OF REVIEW: To provide up-to-date evidence on patient-reported outcomes (PROs) in neuro-oncology, with a focus on the core constructs of health-related quality of life (HRQoL) and the use of PROs in clinical trials and clinical practice.[Supplemental Digital Content: Video Abstract PROs in Neuro-Oncology.mov]. RECENT FINDINGS: PROs are gaining importance in brain tumor research and medical care. For patients with a brain tumor, core PRO constructs are pain, difficulty communicating, perceived cognition, seizures, symptomatic adverse events, physical functioning and role and social functioning, which are assessed through patient-reported outcome measures (PROMs). Initiatives have been taken to improve the reliability and robustness of PRO data, including standardization of items included in clinical trial protocols (the SPIRIT-PRO extension) and formulation of PRO priority objectives for use in clinical trials (the SISAQOL-Innovative Medicines Initiative). In brain tumor patients with cognitive impairment, caregiver-reported outcomes may complement or replace PROs to increase accuracy. The next key challenge will be to widely implement PROs and apply PRO data in clinical practice to benefit patients with brain tumors. SUMMARY: PROs are clinically relevant endpoints providing information only known by the patient. Standardization of the use of PROs in clinical trials and wide implementation in clinical practice is needed to improve HRQoL of brain tumor patients.

Evidence of thermophilization in Afromontane forests.

Thermophilization is the directional change in species community composition towards greater relative abundances of species associated with warmer environments. This process is well-documented in temperate and Neotropical plant communities, but it is uncertain whether this phenomenon occurs elsewhere in the tropics. Here we extend the search for thermophilization to equatorial Africa, where lower tree diversity compared to other tropical forest regions and different biogeographic history could affect community responses to climate change. Using re-census data from 17 forest plots in three mountain regions of Africa, we find a consistent pattern of thermophilization in tree communities. Mean rates of thermophilization were +0.0086 °C·y-1 in the Kigezi Highlands (Uganda), +0.0032 °C·y-1 in the Virunga Mountains (Rwanda-Uganda-Democratic Republic of the Congo) and +0.0023 °C·y-1 in the Udzungwa Mountains (Tanzania). Distinct from other forests, both recruitment and mortality were important drivers of thermophilzation in the African plots. The forests studied currently act as a carbon sink, but the consequences of further thermophilization are unclear.