Preclinical treatment outcome evaluation of tuberculosis (TB) occurs primarily in mice. Current designs compare relapse rates of different regimens at selected time points, but lack information about the correlation between treatment length and treatment outcome, which is required to efficiently estimate a regimens' treatment-shortening potential. Therefore we developed a new approach. BALB/c mice were infected with a Mycobacterium tuberculosis Beijing genotype strain and were treated with rifapentine-pyrazinamide-isoniazid-ethambutol (RpZHE), rifampicin-pyrazinamide-moxifloxacin-ethambutol (RZME) or rifampicin-pyrazinamide-moxifloxacin-isoniazid (RZMH). Treatment outcome was assessed in n = 3 mice after 9 different treatment lengths between 2-6 months. Next, we created a mathematical model that best fitted the observational data and used this for inter-regimen comparison. The observed data were best described by a sigmoidal Emax model in favor over linear or conventional Emax models. Estimating regimen-specific parameters showed significantly higher curative potentials for RZME and RpZHE compared to RZMH. In conclusion, we provide a new design for treatment outcome evaluation in a mouse TB model, which (i) provides accurate tools for assessment of the relationship between treatment length and predicted cure, (ii) allows for efficient comparison between regimens and (iii) adheres to the reduction and refinement principles of laboratory animal use.

Rheumatoid arthritis (RA) is a fluctuating progressive disease requiring frequent symptom assessment for appropriate management. Continuous tracking using digital technologies may provide greater insights of a patient's experience. This prospective study assessed the feasibility, reliability, and clinical utility of using novel digital technologies to remotely monitor participants with RA. Participants with moderate to severe RA and non-RA controls were monitored continuously for 14 days using an iPhone with an integrated bespoke application and an Apple Watch. Participants completed patient-reported outcome measures and objective guided tests designed to assess disease-related impact on physical function. The study was completed by 28 participants with RA, 28 matched controls, and 2 unmatched controls. Completion rates for all assessments were > 97% and were reproducible over time. Several guided tests distinguished between RA and control cohorts (e.g., mean lie-to-stand time [seconds]: RA: 4.77, control: 3.25; P < 0.001). Participants with RA reporting greater stiffness, pain, and fatigue had worse guided test performances (e.g., wrist movement [P < 0.001] and sit-to-stand transition time [P = 0.009]) compared with those reporting lower stiffness, pain, and fatigue. This study demonstrates that digital technologies can be used in a well-controlled, remote clinical setting to assess the daily impact of RA.

Although endometrioid endometrial cancer (EEC; comprising ~80% of all endometrial cancers diagnosed) is typically associated with favourable patient outcome, a significant portion (~20%) of women with this subtype will relapse. We hypothesised that gene expression predictors of the more aggressive non-endometrioid endometrial cancers (NEEC) could be used to predict EEC patients with poor prognosis. To explore this hypothesis, we performed meta-analysis of 12 gene expression microarray studies followed by validation using RNA-Seq data from The Cancer Genome Atlas (TCGA) and identified 1,253 genes differentially expressed between EEC and NEEC. Analysis found 121 genes were associated with poor outcome among EEC patients. Forward selection likelihood-based modelling identified a 9-gene signature associated with EEC outcome in our discovery RNA-Seq dataset which remained significant after adjustment for clinical covariates, but was not significant in a smaller RNA-Seq dataset. Our study demonstrates the value of employing meta-analysis to improve the power of gene expression microarray data, and highlight genes and molecular pathways of importance for endometrial cancer therapy.

Microvascular networks of human basal cell carcinomas (BCC) and surrounding skin were assessed with optical coherence angiography (OCA) in conjunction with photodynamic therapy (PDT). OCA images were collected and analyzed in 31 lesions pre-treatment, and immediately/24 hours/3-12 months post-treatment. Pre-treatment OCA enabled differentiation between prevalent subtypes of BCC (nodular and superficial) and nodular-with-necrotic-core BCC subtypes with a diagnostic accuracy of 78%; this can facilitate more accurate biopsy reducing sampling error and better therapy regimen selection. Post-treatment OCA images at 24 hours were 98% predictive of eventual outcome. Additional findings highlight the importance of pre-treatment necrotic core, vascular metrics associated with hypertrophic scar formation, and early microvascular changes necessary in both tumorous and peri-tumorous regions to ensure treatment success.

In orthognathic surgery, the use of patient-specific osteosynthesis devices is a novel approach used to transfer the virtual surgical plan to the patient. The aim of this study is to analyse the quality of mandibular anatomy reproduction using a mandible-first mandibular-PSI guided procedure on 22 patients. Three different positioning guide designs were compared in terms of osteosynthesis plate positioning and mandibular anatomical outcome. PSIs and positioning guides were designed according to virtual surgical plan and 3D printed using biocompatible materials. A CBCT scan was performed 1 month after surgery and postoperative mandibular models were segmented for comparison against the surgical plan. A precision comparison was carried out among the three groups. Correlations between obtained rami and plates discrepancies and between planned rami displacements and obtained rami discrepancies were calculated. Intraoperatively, all PSIs were successfully applied. The procedure was found to be accurate in planned mandibular anatomy reproduction. Different guide designs did not differ in mandibular outcome precision. Plate positional discrepancies influenced the corresponding ramus position, mainly in roll angle and vertical translation. Ramus planned displacement was found to be a further potential source of inaccuracy, possibly due to osteosynthesis surface interference.

The general relevance of the immune system for cancer development and therapy is increasingly recognized. However and although the immune contexture of most human cancer types has been determined, a global characterisation of the immune tumour microenvironment in hepatocellular carcinoma (HCC) is lacking. Equally, differences in the immune contexture of HCC between different patient subgroups and its effect on survival remain to be established. Here we report an in silico analysis of the immune contexture of human HCC. Using large deep sequencing HCC tumour, adjacent non-tumour and healthy liver high-dimensional data sets, we were able to reveal previously unrecognized differences in the immune contexture of HCC. Strikingly, we found that different etiologies and HCC stages were not associated with major changes in the immune contexture. In contrast, the presence of T cells and cytotoxic cells as well as the absence of macrophages and Th2 cells positively correlated with patient survival. Based on these novel findings, we developed a prognostic score that accurately distinguishes between patients with good and poor survival. Our study provides the first global characterisation of the immune contexture of HCC and will have direct implications for future HCC therapies.

An early and reliable prediction of outcomes after stroke is important for early effective stroke management and the adequate optimal planning of post-stroke rehabilitation and long-term care. Bioactive adrenomedullin (bio-ADM) is a 52-amino acid peptide that is an important peptide hormone in nervous system diseases. The aim of this study was to investigate the prognostic value of bio-ADM on outcomes after rehabilitation in patients with stroke. A total of 557 consecutive patients with a primary diagnosis of ischemic or hemorrhagic stroke (age 69.6-12.9 years, male 51.3%, ischemic stroke 72.5%), who were admitted to an in-patient early rehabilitation center directly after discharge from acute stroke hospital care, were enrolled in this prospective observational study. Plasma concentrations of bio-ADM were determined by using a chemiluminescence immunoassay (functional assay sensitivity 8 pg/ml). The early rehabilitation barthel index (ERBI) was used for the neurological assessment of the patients. The plasma bio-ADM level was analyzed in association with 6-month all-cause mortality as well as a composite outcome of all-cause mortality, unscheduled re-hospitalization, or transfer to a long-term care facility in a vegetative or minimally conscious state. Bio-ADM levels significantly increased in patients with ischemic stroke who died compared to surviving patients (40.4 pg/ml vs. 23.8 pg/ml, p < 0.001) or in those with composite outcomes compared to those with no events (36.9 pg/ml vs. 23.5 pg/ml, p < 0.001). Six-month all-cause mortality was higher in all patients with bio-ADM levels > 70 pg/ml (HR 4.83 [CI 2.28-10.2]). Patients with bio-ADM levels > 70 pg/ml also had higher rates of 6-month composite outcomes (HR 3.82 [CI 2.08-7.01]). Bio-ADM was an independent predictor of all-cause mortality and 6-month composite outcomes after adjusting for age, gender, and ERBI (adjusted OR 1.5; 95% CI 1.0-2.1; p = 0.047 and adjusted OR 1.48; 95% CI 1.1-2.0; p = 0.01, respectively). Bio-ADM may be a suitable novel biomarker to assess the outcomes of patients in rehabilitation after acute stroke. Elevated bio-ADM concentrations may have prognostic value for fatal and nonfatal events in patients with ischemic stroke during early rehabilitation.

Optimizing treatment planning is essential for advances in patient care and outcomes. Precisely tailored therapy for each patient remains a yearned-for goal. Cardiovascular modelling has the potential to simulate and predict the functional response before the actual intervention is performed. The objective of this study was to proof the validity of model-based prediction of haemodynamic outcome after aortic valve replacement. In a prospective study design virtual (model-based) treatment of the valve and the surrounding vasculature were performed alongside the actual surgical procedure (control group). The resulting predictions of anatomic and haemodynamic outcome based on information from magnetic resonance imaging before the procedure were compared to post-operative imaging assessment of the surgical control group in ten patients. Predicted vs. post-operative peak velocities across the valve were comparable (2.97 ± 1.12 vs. 2.68 ± 0.67 m/s; p = 0.362). In wall shear stress (17.3 ± 12.3 Pa vs. 16.7 ± 16.84 Pa; p = 0.803) and secondary flow degree (0.44 ± 0.32 vs. 0.49 ± 0.23; p = 0.277) significant linear correlations (p < 0.001) were found between predicted and post-operative outcomes. Between groups blood flow patterns showed good agreement (helicity p = 0.852, vorticity p = 0.185, eccentricity p = 0.333). Model-based therapy planning is able to accurately predict post-operative haemodynamics after aortic valve replacement. These validated virtual treatment procedures open up promising opportunities for individually targeted interventions.

CIC-DUX4 sarcoma (CDS) is a group of rare, mesenchymal, small round cell tumours that harbour the unique CIC-DUX4 translocation, which causes aberrant gene expression. CDS exhibits an aggressive course and poor clinical outcome, thus novel therapeutic approaches are needed for CDS treatment. Although patient-derived cancer models are an essential modality to develop novel therapies, none currently exist for CDS. Thus, the present study successfully established CDS patient-derived xenografts and subsequently generated two CDS cell lines from the grafted tumours. Notably, xenografts were histologically similar to the original patient tumour, and the expression of typical biomarkers was confirmed in the xenografts and cell lines. Moreover, the xenograft tumours and cell lines displayed high Src kinase activities, as assessed by peptide-based tyrosine kinase array. Upon screening 119 FDA-approved anti-cancer drugs, we found that only actinomycine D and doxorubicin were effectively suppress the proliferation among the drugs for standard therapy for Ewing sarcoma. However, we identified molecular targeting reagents, such as bortezomib and crizotinib that markedly suppressed the growth of CDS cells. Our models will be useful modalities to develop novel therapeutic strategies against CDS.

Lung adenocarcinoma (LUAD) is the main pathological subtype of Non-small cell lung cancer. We downloaded the gene expression profile and immune-related gene set from the TCGA and ImmPort database, respectively, to establish immune-related gene pairs (IRGPs). Then, IRGPs were subjected to univariate Cox regression analysis, LASSO regression analysis, and multivariable Cox regression analysis to screen and develop an IRGPs signature. The receiver operating characteristic curve (ROC) was applied for evaluating the predicting accuracy of this signature by calculating the area under ROC (AUC) and data from the GEO set was used to validate this signature. The relationship of 22 tumor-infiltrating immune cells (TIICs) to the immune risk score was also investigated. An IRGPs signature with 8 IRGPs was constructed. The AUC for 1- and 3-year overall survival in the TCGA set was 0.867 and 0.870, respectively. Similar results were observed in the AUCs of GEO set 1, 2 and 3 (GEO set 1 [1-year: 0.819; 3-year: 0.803]; GEO set 2 [1-year: 0.834; 3-year: 0.870]; GEO set 3 [1-year: 0.955; 3-year: 0.827]). Survival analysis demonstrated high-risk LUAD patients exhibited poorer prognosis. The multivariable Cox regression indicated that the risk score was an independent prognostic factor. The immune risk score was highly associated with several TIICs (Plasma cells, memory B cells, resting memory CD4 T cells, and activated NK cells). We developed a novel IRGPs signature for predicting 1- and 3- year overall survival in LUAD, which would be helpful for prognosis assessment of LUAD.

We have previously reported surrogate biomarkers of VEGF pathway activities with the potential to provide predictive information for anti-VEGF therapies. The aim of this study was to systematically evaluate a new VEGF-dependent gene signature (VDGs) in relation to molecular subtypes of ovarian cancer and patient prognosis. Using microarray profiling and cross-species analysis, we identified 140-gene mouse VDGs and corresponding 139-gene human VDGs, which displayed enrichment of vasculature and basement membrane genes. In patients who received bevacizumab therapy and showed partial response, the expressions of VDGs (summarized to yield VDGs scores) were markedly decreased in post-treatment biopsies compared with pre-treatment baselines. In contrast, VDGs scores were not significantly altered following bevacizumab treatment in patients with stable or progressive disease. Analysis of VDGs in ovarian cancer showed that VDGs as a prognostic signature was able to predict patient outcome. Correlation estimation of VDGs scores and molecular features revealed that VDGs was overrepresented in mesenchymal subtype and BRCA mutation carriers. These findings highlighted the prognostic role of VEGF-mediated angiogenesis in ovarian cancer, and proposed a VEGF-dependent gene signature as a molecular basis for developing novel diagnostic strategies to aid patient selection for VEGF-targeted agents.

An objective biomarker to predict the outcome of isolated rapid eye movement sleep behavior disorder (iRBD) is crucial for the management. This study aimed to investigate cognitive signature of brain [18F]FDG PET based on deep learning (DL) for evaluating patients with iRBD. Fifty iRBD patients, 19 with mild cognitive impairment (MCI) (RBD-MCI) and 31 without MCI (RBD-nonMCI), were prospectively enrolled. A DL model for the cognitive signature was trained by using Alzheimer's Disease Neuroimaging Initiative database and transferred to baseline [18F]FDG PET from the iRBD cohort. The results showed that the DL-based cognitive dysfunction score was significantly higher in RBD-MCI than in RBD-nonMCI. The AUC of ROC curve for differentiating RBD-MCI from RBD-nonMCI was 0.70 (95% CI 0.56-0.82). The baseline DL-based cognitive dysfunction score was significantly higher in iRBD patients who showed a decrease in CERAD scores during 2 years than in those who did not. Brain metabolic features related to cognitive dysfunction-related regions of individual iRBD patients mainly included posterior cortical regions. This work demonstrates that the cognitive signature based on DL could be used to objectively evaluate cognitive function in iRBD. We suggest that this approach could be extended to an objective biomarker predicting cognitive decline and neurodegeneration in iRBD.

Multigene expression signatures provide a molecular subdivision of early breast cancer associated with patient outcome. A gap remains in the validation of such signatures in clinical treatment groups of patients within population-based cohorts of unselected primary breast cancer representing contemporary disease stages and current treatments. A cohort of 3520 resectable breast cancers with RNA sequencing data included in the population-based SCAN-B initiative (ClinicalTrials.gov ID NCT02306096) were selected from a healthcare background population of 8587 patients diagnosed within the years 2010-2015. RNA profiles were classified according to 19 reported gene signatures including both gene expression subtypes (e.g. PAM50, IC10, CIT) and risk predictors (e.g. Oncotype DX, 70-gene, ROR). Classifications were analyzed in nine adjuvant clinical assessment groups: TNBC-ACT (adjuvant chemotherapy, n = 239), TNBC-untreated (n = 82), HER2+/ER- with anti-HER2+ ACT treatment (n = 110), HER2+/ER+ with anti-HER2 + ACT + endocrine treatment (n = 239), ER+/HER2-/LN- with endocrine treatment (n = 1113), ER+/HER2-/LN- with endocrine + ACT treatment (n = 243), ER+/HER2-/LN+ with endocrine treatment (n = 423), ER+/HER2-/LN+ with endocrine + ACT treatment (n = 433), and ER+/HER2-/LN- untreated (n = 200). Gene signature classification (e.g., proportion low-, high-risk) was generally well aligned with stratification based on current immunohistochemistry-based clinical practice. Most signatures did not provide any further risk stratification in TNBC and HER2+/ER- disease. Risk classifier agreement (low-, medium/intermediate-, high-risk groups) in ER+ assessment groups was on average 50-60% with occasional pair-wise comparisons having <30% agreement. Disregarding the intermediate-risk groups, the exact agreement between low- and high-risk groups was on average ~80-95%, for risk prediction signatures across all assessment groups. Outcome analyses were restricted to assessment groups of TNBC-ACT and endocrine treated ER+/HER2-/LN- and ER+/HER2-/LN+ cases. For ER+/HER2- disease, gene signatures appear to contribute additional prognostic value even at a relatively short follow-up time. Less apparent prognostic value was observed in the other groups for the tested signatures. The current study supports the usage of gene expression signatures in specific clinical treatment groups within population-based breast cancer. It also stresses the need of further development to reach higher consensus in individual patient classifications, especially for intermediate-risk patients, and the targeting of patients where current gene signatures and prognostic variables provide little support in clinical decision-making.

Diabetes mellitus (DM) serves as an important prognostic indicator in patients with cardiac-related illness. Our objective is to compare survival and neurological outcomes among diabetic and non-diabetic patients who were admitted to the hospital after an out-of-hospital cardiac arrest (OHCA). We searched MEDLINE and EMBASE for relevant articles from database inception to July 2018 without any language restriction. Studies were included if they evaluated patients who presented with OHCA, included mortality and neurological outcome data separately for DM patients and Non-DM patients and reported crude data, odds ratio (OR), relative risk (RR) or hazard ratio (HR). Two investigators independently reviewed the retrieved citations and assessed eligibility. The quality of included studies was evaluated using Newcastle-Ottawa quality assessment scale for cohort studies. Random-effect models using the generic variance method were used to create pooled odds ratios (OR) and 95% confidence intervals (CI). Heterogeneity was assessed using the I2 value. Survival and neurological outcomes (using modified rankin scale and cerebral performance category scale) after OHCA in hospitalized patients with DM compared with patients without DM. Out of 57 studies identified, six cohort studies met the inclusion criteria. In an analysis of unadjusted data, patients with DM had lower odds of survival, pooled OR 0.64; 95% CI, 0.52-0.78, [I2 = 90%]. When adjusted ORs were pooled, the association between DM and survival after OHCA was still significantly reduced, pooled OR 0.78, 95% CI, 0.68-0.89 [I2 = 55%]. Unadjusted pooled OR revealed poor neurological outcomes in patients with DM, pooled OR 0.55, 95% CI, 0.38-0.80 [I2 = 90%]. The result demonstrates significant poor outcomes of in-hospital survival and neurological outcomes among DM patients after OHCA.

Our study aimed to evaluate the usefulness of indocyanine green (ICG) angiography during conversional or revisional bariatric surgery. We prospectively enrolled all patients scheduled for reoperative bariatric surgery with gastric pouch resizing and ICG assessment and we compared them with a retrospective series of similar patients who did not receive ICG. The primary outcome was the rate of intraoperative change in the surgical strategy due to the ICG test. We included 32 prospective patients receiving intraoperatively an ICG perfusion test and 48 propensity score-matched controls. The mean age was 50.7 ± 9.7 years, 67 (83.7%) patients were female, and the mean BMI was 36.8 ± 5.3 kg/m2. The patient characteristics were similar in both groups. The ICG angiography was successfully conducted in all patients, and no change of the surgical strategy was necessary. Postoperative complications were similar in both groups (6.2% vs. 8.3%, p = 0.846), as well as operative time (125 ± 43 vs. 133 ± 47 min, p = 0.454) and length of hospital stay (2.8 ± 1.0 vs. 3.3 ± 2.2 days, p = 0.213). Our study suggested that ICG fluorescence angiography might not have been useful for assessing the blood supply of the gastric pouch in patients who underwent reoperative bariatric surgery. Therefore, it remains uncertain whether the application of this technique is indicated.

The development of head shape and volume may reflect neurodevelopmental outcome and therefore is of paramount importance in neonatal care. Here, we compare head morphology in 25 very preterm infants with a birth weight of below 1500 g and / or a gestational age (GA) before 32 completed weeks to 25 term infants with a GA of 37-42 weeks at term equivalent age (TEA) and identify possible risk factors for non-synostotic head shape deformities. For three-dimensional head assessments, a portable stereophotogrammetric device was used. The most common and distinct head shape deformity in preterm infants was dolichocephaly. Severity of dolichocephaly correlated with GA and body weight at TEA but not with other factors such as neonatal morbidity, sex or total duration of respiratory support. Head circumference (HC) and cranial volume (CV) were not significantly different between the preterm and term infant group. Digitally measured HC and the CV significantly correlated even in infants with head shape deformities. Our study shows that stereophotogrammetric head assessment is feasible in all preterm and term infants and provides valuable information on volumetry and comprehensive head shape characteristics. In a small sample of preterm infants, body weight at TEA was identified as a specific risk factor for the development of dolichocephaly.

Pathological links between neurodegenerative disease and cancer are emerging. LRRK2 overactivity contributes to Parkinson's disease, whereas our previous analyses of public cancer patient data revealed that decreased LRRK2 expression is associated with lung adenocarcinoma (LUAD). The clinical and functional relevance of LRRK2 repression in LUAD is unknown. Here, we investigated associations between LRRK2 expression and clinicopathological variables in LUAD patient data and asked whether LRRK2 knockout promotes murine lung tumorigenesis. In patients, reduced LRRK2 was significantly associated with ongoing smoking and worse survival, as well as signatures of less differentiated LUAD, altered surfactant metabolism and immunosuppression. We identified shared transcriptional signals between LRRK2-low LUAD and postnatal alveolarization in mice, suggesting aberrant activation of a developmental program of alveolar growth and differentiation in these tumors. In a carcinogen-induced murine lung cancer model, multiplex IHC confirmed that LRRK2 was expressed in alveolar type II (AT2) cells, a main LUAD cell-of-origin, while its loss perturbed AT2 cell morphology. LRRK2 knockout in this model significantly increased tumor initiation and size, demonstrating that loss of LRRK2, a key Parkinson's gene, promotes lung tumorigenesis.

Breathwork may offer simple tools for stress resilience. We conducted the largest parallel randomised-controlled trial on breathwork to date (NCT05676658) wherein 400 participants on the research platform Prolific were randomised, in blocks of 2 via remote software, to coherent breathing at ~ 5.5 breaths/min or a matched attention-placebo at 12 breaths/min, for ~ 10 min/day over 4 weeks. Participants were blinded to their allocated interventions, both of which were paced with equal inhalation:exhalation ratios. There were no differences on credibility and expectancy of benefit between conditions. At the primary timepoint post-intervention for the primary outcome subjective stress, there was no significant group by time interaction (F(1,377) = 0.089, p = 0.765, ηp2 < 0.001) nor main effect of group (F = 0.002, p = 0.961, ηp2 < 0.001), however there was a significant main effect of time (F = 72.1, p < 0.001, ηp2 = 0.161). Similar results were found at 1-month follow-up for stress and for secondary outcomes of anxiety, depression and wellbeing. There were overall improvements on these mental health and wellbeing outcomes from baseline to post-intervention and follow-up across both groups, yet the magnitude of this improvement was not different between arms. Accordingly, we found no measurable effect of coherent breathing over and above a well-designed breathwork placebo at improving mental health and wellbeing. Methodological considerations and recommendations for robust future research are discussed. Funder: Sasakawa Young Leaders Fellowship Fund, Tokyo, Japan.

Physical impairments following cancer treatment have been linked with the toxic effects of these treatments on muscle mass and strength, through their deleterious effects on skeletal muscle mitochondrial oxidative capacity. Accordingly, we designed the present study to explore relationships of skeletal muscle mitochondrial oxidative capacity with physical performance and perceived cancer-related psychosocial experiences of cancer survivors. We assessed skeletal muscle mitochondrial oxidative capacity using in vivo phosphorus-31 magnetic resonance spectroscopy (31P MRS), measuring the postexercise phosphocreatine resynthesis time constant, τPCr, in 11 post-chemotherapy participants aged 34-70 years. During the MRS procedure, participants performed rapid ballistic knee extension exercise to deplete phosphocreatine (PCr); hence, measuring the primary study outcome, which was the recovery rate of PCr (τPCr). Patient-reported outcomes of psychosocial symptoms and well-being were assessed using the Patient-Reported Outcomes Measurement Information System and the 36-Item Short Form health survey (SF-36). Rapid bioenergetic recovery, reflected through a smaller value of τPCr was associated with worse depression (rho ρ = - 0.69, p = 0.018, and Cohen's d = - 1.104), anxiety (ρ = - 0.61, p = .046, d = - 0.677), and overall mental health (ρ = 0.74, p = 0.010, d = 2.198) scores, but better resilience (ρ = 0.65, p = 0.029), and coping-self efficacy (ρ = 0.63, p = 0.04) scores. This is the first study to link skeletal muscle mitochondrial oxidative capacity with subjective reports of cancer-related behavioral toxicities. Further investigations are warranted to confirm these findings probing into the role of disease status and personal attributes in these preliminary results.

Gleason score 7 prostate cancer with a higher proportion of pattern 4 (G4) has been linked to genomic heterogeneity and poorer patient outcome. The current assessment of G4 proportion uses estimation by a pathologist, with a higher proportion of G4 more likely to trigger additional imaging and treatment over active surveillance. This estimation method has been shown to have inter-observer variability. Fifteen patients with Prostate Grade Group (GG) 2 (Gleason 3 + 4) and fifteen patients with GG3 (Gleason 4 + 3) disease were selected from the PROMIS study with 192 haematoxylin and eosin-stained slides scanned. Two experienced uropathologists assessed the maximum cancer core length (MCCL) and G4 proportion using the current standard method (visual estimation) followed by detailed digital manual annotation of each G4 area and measurement of MCCL (planimetric estimation) using freely available software by the same two experts. We aimed to compare visual estimation of G4 and MCCL to a pathologist-driven digital measurement. We show that the visual and digital MCCL measurement differs up to 2 mm in 76.6% (23/30) with a high degree of agreement between the two measurements; Visual gave a median MCCL of 10 ± 2.70 mm (IQR 4, range 5-15 mm) compared to digital of 9.88 ± 3.09 mm (IQR 3.82, range 5.01-15.7 mm) (p = 0.64) The visual method for assessing G4 proportion over-estimates in all patients, compared to digital measurements [median 11.2% (IQR 38.75, range 4.7-17.9%) vs 30.4% (IQR 18.37, range 12.9-50.76%)]. The discordance was higher as the amount of G4 increased (Bias 18.71, CI 33.87-48.75, r 0.7, p < 0.0001). Further work on assessing actual G4 burden calibrated to clinical outcomes might lead to the use of differing G4 thresholds of significance if the visual estimation is used or by incorporating semi-automated methods for G4 burden measurement.