A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC.

Radiographic Progression-Free Survival and Clinical Progression-Free Survival as Potential Surrogates for Overall Survival in Men With Metastatic Hormone-Sensitive Prostate Cancer.

PURPOSE: Despite major increases in the longevity of men with metastatic hormone-sensitive prostate cancer (mHSPC), most men still die of prostate cancer. Phase III trials assessing new therapies in mHSPC with overall survival (OS) as the primary end point will take approximately a decade to complete. We investigated whether radiographic progression-free survival (rPFS) and clinical PFS (cPFS) are valid surrogates for OS in men with mHSPC and could potentially be used to expedite future phase III clinical trials. METHODS: We obtained individual patient data (IPD) from 9 eligible randomized trials comparing treatment regimens (different androgen deprivation therapy [ADT] strategies or ADT plus docetaxel in the control or research arms) in mHSPC. rPFS was defined as the time from random assignment to radiographic progression or death from any cause whichever occurred first; cPFS was defined as the time from random assignment to the date of radiographic progression, symptoms, initiation of new treatment, or death, whichever occurred first. We implemented a two-stage meta-analytic validation model where conditions of patient-level and trial-level surrogacy had to be met. We then computed the surrogate threshold effect (STE). RESULTS: IPD from 6,390 patients randomly assigned from 1994 to 2012 from 13 units were pooled for a stratified analysis. The median OS, rPFS, and cPFS were 4.3 (95% CI, 4.2 to 4.5), 2.4 (95% CI, 2.3 to 2.5), and 2.3 years (95% CI, 2.2 to 2.4), respectively. The STEs were 0.80 and 0.81 for rPFS and cPFS end points, respectively. CONCLUSION: Both rPFS and cPFS appear to be promising surrogate end points for OS. The STE of 0.80 or higher makes it viable for either rPFS or cPFS to be used as the primary end point that is surrogate for OS in phase III mHSPC trials with testosterone suppression alone as the backbone therapy and would expedite trial conduct.

Collective Dynamics, Diversification and Optimal Portfolio Construction for Cryptocurrencies.

Since its conception, the cryptocurrency market has been frequently described as an immature market, characterized by significant swings in volatility and occasionally described as lacking rhyme or reason. There has been great speculation as to what role it plays in a diversified portfolio. For instance, is cryptocurrency exposure an inflationary hedge or a speculative investment that follows broad market sentiment with amplified beta? We have recently explored similar questions with a clear focus on the equity market. There, our research revealed several noteworthy dynamics such as an increase in the market's collective strength and uniformity during crises, greater diversification benefits across equity sectors (rather than within them), and the existence of a "best value" portfolio of equities. In essence, we can now contrast any potential signatures of maturity we identify in the cryptocurrency market and contrast these with the substantially larger, older and better-established equity market. This paper aims to investigate whether the cryptocurrency market has recently exhibited similar mathematical properties as the equity market. Instead of relying on traditional portfolio theory, which is grounded in the financial dynamics of equity securities, we adjust our experimental focus to capture the presumed behavioral purchasing patterns of retail cryptocurrency investors. Our focus is on collective dynamics and portfolio diversification in the cryptocurrency market, and examining whether previously established results in the equity market hold in the cryptocurrency market and to what extent. The results reveal nuanced signatures of maturity related to the equity market, including the fact that correlations collectively spike around exchange collapses, and identify an ideal portfolio size and spread across different groups of cryptocurrencies.

MRI texture analysis of acetabular cancellous bone can discriminate between normal, cam positive, and cam-FAI hips.

OBJECTIVES: To compare the MRI texture profile of acetabular subchondral bone in normal, asymptomatic cam positive, and symptomatic cam-FAI hips and determine the accuracy of a machine learning model for discriminating between the three hip classes. METHODS: A case-control, retrospective study was performed including 68 subjects (19 normal, 26 asymptomatic cam, 23 symptomatic cam-FAI). Acetabular subchondral bone of unilateral hip was contoured on 1.5 T MR images. Nine first-order 3D histogram and 16 s-order texture features were evaluated using specialized texture analysis software. Between-group differences were assessed using Kruskal-Wallis and Mann-Whitney U tests, and differences in proportions compared using chi-square and Fisher's exact tests. Gradient-boosted ensemble methods of decision trees were created and trained to discriminate between the three groups of hips, with percent accuracy calculated. RESULTS: Sixty-eight subjects (median age 32 (28-40), 60 male) were evaluated. Significant differences among all three groups were identified with first-order (4 features, all p ≤ 0.002) and second-order (11 features, all p ≤ 0.002) texture analyses. First-order texture analysis could differentiate between control and cam positive hip groups (4 features, all p ≤ 0.002). Second-order texture analysis could additionally differentiate between asymptomatic cam and symptomatic cam-FAI groups (10 features, all p ≤ 0.02). Machine learning models demonstrated high classification accuracy of 79% (SD 16) for discriminating among all three groups. CONCLUSION: Normal, asymptomatic cam positive, and cam-FAI hips can be discriminated based on their MRI texture profile of subchondral bone using descriptive statistics and machine learning algorithms. CLINICAL RELEVANCE STATEMENT: Texture analysis can be performed on routine MR images of the hip and used to identify early changes in bone architecture, differentiating morphologically abnormal from normal hips, prior to onset of symptoms. KEY POINTS: • MRI texture analysis is a technique for extracting quantitative data from routine MRI images. • MRI texture analysis demonstrates that there are different bone profiles between normal hips and those with femoroacetabular impingement. • Machine learning models can be used in conjunction with MRI texture analysis to accurately differentiate between normal hips and those with femoroacetabular impingement.

Dual-domain analysis of gun violence incidents in the United States.

This paper applies new and recently introduced approaches to study trends in gun violence in the United States. We use techniques in both the time and frequency domain to provide a more complete understanding of gun violence dynamics. We analyze gun violence incidents on a state-by-state basis as recorded by the Gun Violence Archive. We have numerous specific phenomena of focus, including periodicity of incidents, locations in time where behavioral changes occur, and shifts in gun violence patterns since April 2020. First, we implement a recently introduced method of spectral density estimation for nonstationary time series to investigate periodicity on a state-by-state basis, including revealing where periodic behaviors change with time. We can also classify different patterns of behavioral changes among the states. We then aim to understand the most significant shifts in gun violence since numerous key events in 2020, including the COVID-19 pandemic, lockdowns, and periods of civil unrest. Our dual-domain analysis provides a more thorough understanding and challenges numerous widely held conceptions regarding the prevalence of gun violence incidents.

Management of Patients with Advanced Prostate Cancer: Report from the Advanced Prostate Cancer Consensus Conference 2021.

BACKGROUND: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but various areas of management still lack high-level evidence to inform clinical practice. The 2021 Advanced Prostate Cancer Consensus Conference (APCCC) addressed some of these questions to supplement guidelines that are based on level 1 evidence. OBJECTIVE: To present the voting results from APCCC 2021. DESIGN, SETTING, AND PARTICIPANTS: The experts identified three major areas of controversy related to management of advanced prostate cancer: newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), the use of prostate-specific membrane antigen ligands in diagnostics and therapy, and molecular characterisation of tissue and blood. A panel of 86 international prostate cancer experts developed the programme and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 107 pre-defined questions, which were developed by both voting and non-voting panel members prior to the conference following a modified Delphi process. RESULTS AND LIMITATIONS: The voting reflected the opinions of panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results reported in the Supplementary material. CONCLUSIONS: These voting results from a panel of experts in advanced prostate cancer can help clinicians and patients to navigate controversial areas of management for which high-level evidence is scant. However, diagnostic and treatment decisions should always be individualised according to patient characteristics, such as the extent and location of disease, prior treatment(s), comorbidities, patient preferences, and treatment recommendations, and should also incorporate current and emerging clinical evidence and logistic and economic constraints. Enrolment in clinical trials should be strongly encouraged. Importantly, APCCC 2021 once again identified salient questions that merit evaluation in specifically designed trials. PATIENT SUMMARY: The Advanced Prostate Cancer Consensus Conference is a forum for discussing current diagnosis and treatment options for patients with advanced prostate cancer. An expert panel votes on predefined questions focused on the most clinically relevant areas for treatment of advanced prostate cancer for which there are gaps in knowledge. The voting results provide a practical guide to help clinicians in discussing treatment options with patients as part of shared decision-making.

In search of peak human athletic potential: A mathematical investigation.

This paper applies existing and new approaches to study trends in the performance of elite athletes over time. We study both track and field scores of men and women athletes on a yearly basis from 2001 to 2019, revealing several trends and findings. First, we perform a detailed regression study to reveal the existence of an "Olympic effect," where average performance improves during Olympic years. Next, we study the rate of change in athlete performance and fail to reject the notion that athlete scores are leveling off, at least among the top 100 annual scores. Third, we examine the relationship in performance trends among men and women's categories of the same event, revealing striking similarity, together with some anomalous events. Finally, we analyze the geographic composition of the world's top athletes, attempting to understand how the diversity by country and continent varies over time across events. We challenge a widely held conception of athletics that certain events are more geographically dominated than others. Our methods and findings could be applied more generally to identify evolutionary dynamics in group performance and highlight spatiotemporal trends in group composition.

Comparing the dynamics of COVID-19 infection and mortality in the United States, India, and Brazil.

This paper compares and contrasts the spread and impact of COVID-19 in the three countries most heavily impacted by the pandemic: the United States (US), India and Brazil. All three of these countries have a federal structure, in which the individual states have largely determined the response to the pandemic. Thus, we perform an extensive analysis of the individual states of these three countries to determine patterns of similarity within each. First, we analyse structural similarity and anomalies in the trajectories of cases and deaths as multivariate time series. Next, we study the lengths of the different waves of the virus outbreaks across the three countries and their states. Finally, we investigate suitable time offsets between cases and deaths as a function of the distinct outbreak waves. In all these analyses, we consistently reveal more characteristically distinct behaviour between US and Indian states, while Brazilian states exhibit less structure in their wave behaviour and changing progression between cases and deaths.

Collective correlations, dynamics, and behavioural inconsistencies of the cryptocurrency market over time.

This paper introduces new methods to study behaviours among the 52 largest cryptocurrencies between 01-01-2019 and 30-06-2021. First, we explore evolutionary correlation behaviours and apply a recently proposed turning point algorithm to identify regimes in market correlation. Next, we inspect the relationship between collective dynamics and the cryptocurrency market size-revealing an inverse relationship between the size of the market and the strength of collective dynamics. We then explore the time-varying consistency of the relationships between cryptocurrencies' size and their returns and volatility. There, we demonstrate that there is greater consistency between size and volatility than size and returns. Finally, we study the spread of volatility behaviours across the market changing with time by examining the structure of Wasserstein distances between probability density functions of rolling volatility. We demonstrate a new phenomenon of increased uniformity in volatility during market crashes, which we term volatility dispersion.

Estimating a continuously varying offset between multivariate time series with application to COVID-19 in the United States.

This paper introduces new methods to track the offset between two multivariate time series on a continuous basis. We then apply this framework to COVID-19 counts on a state-by-state basis in the United States to determine the progression from cases to deaths as a function of time. Across multiple approaches, we reveal an "up-down-up" pattern in the estimated offset between reported cases and deaths as the pandemic progresses. This analysis could be used to predict imminent increased load on a healthcare system and aid the allocation of additional resources in advance.

Performance of Multiple Metagenomics Pipelines in Understanding Microbial Diversity of a Low-Biomass Spacecraft Assembly Facility.

NASA planetary protection (PP) requires an assessment of the biological contamination of the potential microbial burden on spacecraft destined to explore planetary bodies that may harbor signs of life, like Mars and Europa. To help meet these goals, the performance of multiple metagenomic pipelines were compared and assessed for their ability to detect microbial diversity of a low-biomass clean room environment used to build spacecraft destined to these planetary bodies. Four vendors were chosen to implement their own metagenomic analysis pipeline on the shotgun sequences retrieved from environmental surfaces in the relevant environments at NASA's Jet Propulsion Laboratory. None of the vendors showed the same microbial profile patterns when analyzing same raw dataset since each vendor used different pipelines, which begs the question of the validity of a single pipeline to be recommended for future NASA missions. All four vendors detected species of interest, including spore-forming and extremotolerant bacteria, that have the potential to hitch-hike on spacecraft and contaminate the planetary bodies explored. Some vendors demonstrated through functional analysis of the metagenomes that the molecular mechanisms for spore-formation and extremotolerance were represented in the data. However, relative abundances of these microorganisms varied drastically between vendor analyses, questioning the ability of these pipelines to quantify the number of PP-relevant microorganisms on a spacecraft surface. Metagenomics offers tantalizing access to the genetic and functional potential of a microbial community that may offer NASA a viable method for microbial burden assays for planetary protection purposes. However, future development of technologies such as streamlining the processing of shotgun metagenome sequence data, long read sequencing, and all-inclusive larger curated and annotated microbial genome databases will be required to validate and translate relative abundances into an actionable assessment of PP-related microbes of interest. Additionally, the future development of machine learning and artificial intelligence techniques could help enhance the quality of these metagenomic analyses by providing more accurate identification of the genetic and functional potential of a microbial community.

Utility of machine learning of apparent diffusion coefficient (ADC) and T2-weighted (T2W) radiomic features in PI-RADS version 2.1 category 3 lesions to predict prostate cancer diagnosis.

PURPOSE: To evaluate if machine learning (ML) of radiomic features extracted from apparent diffusion coefficient (ADC) and T2-weighted (T2W) MRI can predict prostate cancer (PCa) diagnosis in Prostate Imaging-Reporting and Data System (PI-RADS) version 2.1 category 3 lesions. METHODS: This multi-institutional review board-approved retrospective case-control study evaluated 158 men with 160 PI-RADS category 3 lesions (79 peripheral zone, 81 transition zone) diagnosed at 3-Tesla MRI with histopathology diagnosis by MRI-TRUS-guided targeted biopsy. A blinded radiologist confirmed PI-RADS v2.1 score and segmented lesions on axial T2W and ADC images using 3D Slicer, extracting radiomic features with an open-source software (Pyradiomics). Diagnostic accuracy for (1) any PCa and (2) clinically significant (CS; International Society of Urogenital Pathology Grade Group ≥ 2) PCa was assessed using XGBoost with tenfold cross -validation. RESULTS: From 160 PI-RADS 3 lesions, there were 50.0% (80/160) PCa, including 36.3% (29/80) CS-PCa (63.8% [51/80] ISUP 1, 23.8% [19/80] ISUP 2, 8.8% [7/80] ISUP 3, 3.8% [3/80] ISUP 4). The remaining 50.0% (80/160) lesions were benign. ML of all radiomic features from T2W and ADC achieved area under receiver operating characteristic curve (AUC) for diagnosis of (1) CS-PCa 0.547 (95% Confidence Intervals 0.510-0.584) for T2W and 0.684 (CI 0.652-0.715) for ADC and (2) any PCa 0.608 (CI 0.579-0.636) for T2W and 0.642 (CI 0.614-0.0.670) for ADC. CONCLUSION: Our results indicate ML of radiomic features extracted from T2W and ADC achieved at best moderate accuracy for determining which PI-RADS category 3 lesions represent PCa.

Efficiency of communities and financial markets during the 2020 pandemic.

This paper investigates the relationship between the spread of the COVID-19 pandemic, the state of community activity, and the financial index performance across 20 countries. First, we analyze which countries behaved similarly in 2020 with respect to one of three multivariate time series: daily COVID-19 cases, Apple mobility data, and national equity index price. Next, we study the trajectories of all three of these attributes in conjunction to determine which exhibited greater similarity. Finally, we investigate whether country financial indices or mobility data responded more quickly to surges in COVID-19 cases. Our results indicate that mobility data and national financial indices exhibited the most similarity in their trajectories, with financial indices responding quicker. This suggests that financial market participants may have interpreted and responded to COVID-19 data more efficiently than governments. Furthermore, results imply that efforts to study community mobility data as a leading indicator for financial market performance during the pandemic were misguided.

Trends in COVID-19 prevalence and mortality: A year in review.

This paper introduces new methods to study the changing dynamics of COVID-19 cases and deaths among the 50 worst-affected countries throughout 2020. First, we analyse the trajectories and turning points of rolling mortality rates to understand at which times the disease was most lethal. We demonstrate five characteristic classes of mortality rate trajectories and determine structural similarity in mortality trends over time. Next, we introduce a class of virulence matrices to study the evolution of COVID-19 cases and deaths on a global scale. Finally, we introduce three-way inconsistency analysis to determine anomalous countries with respect to three attributes: countries' COVID-19 cases, deaths and human development indices. We demonstrate the most anomalous countries across these three measures are Pakistan, the United States and the United Arab Emirates.

COVID-19 second wave mortality in Europe and the United States.

This paper introduces new methods to analyze the changing progression of COVID-19 cases to deaths in different waves of the pandemic. First, an algorithmic approach partitions each country or state's COVID-19 time series into a first wave and subsequent period. Next, offsets between case and death time series are learned for each country via a normalized inner product. Combining these with additional calculations, we can determine which countries have most substantially reduced the mortality rate of COVID-19. Finally, our paper identifies similarities in the trajectories of cases and deaths for European countries and U.S. states. Our analysis refines the popular conception that the mortality rate has greatly decreased throughout Europe during its second wave of COVID-19; instead, we demonstrate substantial heterogeneity throughout Europe and the U.S. The Netherlands exhibited the largest reduction of mortality, a factor of 16, followed by Denmark, France, Belgium, and other Western European countries, greater than both Eastern European countries and U.S. states. Some structural similarity is observed between Europe and the United States, in which Northeastern states have been the most successful in the country. Such analysis may help European countries learn from each other's experiences and differing successes to develop the best policies to combat COVID-19 as a collective unit.

Dynamics, behaviours, and anomaly persistence in cryptocurrencies and equities surrounding COVID-19.

This paper uses new and recently introduced methodologies to study the similarity in the dynamics and behaviours of cryptocurrencies and equities surrounding the COVID-19 pandemic. We study two collections; 45 cryptocurrencies and 72 equities, both independently and in conjunction. First, we examine the evolution of cryptocurrency and equity market dynamics, with a particular focus on their change during the COVID-19 pandemic. We demonstrate markedly more similar dynamics during times of crisis. Next, we apply recently introduced methods to contrast trajectories, erratic behaviours, and extreme values among the two multivariate time series. Finally, we introduce a new framework for determining the persistence of market anomalies over time. Surprisingly, we find that although cryptocurrencies exhibit stronger collective dynamics and correlation in all market conditions, equities behave more similarly in their trajectories and extremes, and show greater persistence in anomalies over time.

Effect of phase of enhancement on texture analysis in renal masses evaluated with non-contrast-enhanced, corticomedullary, and nephrographic phase-enhanced CT images.

OBJECTIVE: To compare texture analysis (TA) features of solid renal masses on renal protocol (non-contrast enhanced [NECT], corticomedullary [CM], nephrographic [NG]) CT. MATERIALS AND METHODS: A total of 177 consecutive solid renal masses (116 renal cell carcinoma [RCC]; 51 clear cell [cc], 40 papillary, 25 chromophobe, and 61 benign masses; 49 oncocytomas, 12 fat-poor angiomyolipomas) with three-phase CT between 2012 and 2017 were studied. Two blinded radiologists independently assessed tumor heterogeneity (5-point Likert scale) and segmented tumors. TA features (N = 25) were compared between groups and between phases. Accuracy (area under the curve [AUC]) for RCC versus benign and cc-RCC versus other masses was compared. RESULTS: Subjectively, tumor heterogeneity differed between phases (p < 0.01) and between tumors within the same phase (p = 0.03 [NECT] and p < 0.01 [CM, NG]). Inter-observer agreement was moderate to substantial (intraclass correlation coefficient = 0.55-0.73). TA differed in 92.0% (23/25) features between phases (p < 0.05) except for GLNU and f6. More TA features differed significantly on CM (80.0% [20/25]) compared with NG (40.0% [10/25]) and NECT (16.0% [4/25]) (p < 0.01). For RCC versus benign, AUCs of texture features did not differ comparing CM and NG (p > 0.05), but were higher for 20% (5/25) and 28% (7/25) of features comparing CM and NG with NECT (p < 0.05). For cc-RCC versus other, 36% (9/25) and 40% (10/25) features on CM had higher AUCs compared with NECT and NG images (p < 0.05). CONCLUSION: Texture analysis of renal masses differs, when evaluated subjectively and quantitatively, by phase of CT enhancement. The corticomedullary phase had the highest discriminatory value when comparing masses and for differentiating cc-RCC from other masses. KEY POINTS: • Subjectively evaluated renal tumor heterogeneity on CT differs by phase of enhancement. • Quantitative CT texture analysis features in renal tumors differ by phases of enhancement with the corticomedullary phase showing the highest number and most significant differences compared with non-contrast-enhanced and nephrographic phase images. • For diagnosis of clear cell RCC, corticomedullary phase texture analysis features had improved accuracy of classification in approximately 40% of features studied compared with non-contrast-enhanced and nephrographic phase images.

Changes to the extreme and erratic behaviour of cryptocurrencies during COVID-19.

This paper introduces new methods for analysing the extreme and erratic behaviour of time series to evaluate the impact of COVID-19 on cryptocurrency market dynamics. Across 51 cryptocurrencies, we examine extreme behaviour through a study of distribution extremities, and erratic behaviour through structural breaks. First, we analyse the structure of the market as a whole and observe a reduction in self-similarity as a result of COVID-19, particularly with respect to structural breaks in variance. Second, we compare and contrast these two behaviours, and identify individual anomalous cryptocurrencies. Tether (USDT) and TrueUSD (TUSD) are consistent outliers with respect to their returns, while Holo (HOT), NEXO (NEXO), Maker (MKR) and NEM (XEM) are frequently observed as anomalous with respect to both behaviours and time. Even among a market known as consistently volatile, this identifies individual cryptocurrencies that behave most irregularly in their extreme and erratic behaviour and shows these were more affected during the COVID-19 market crisis.