Modelling the rheology of living cell cytoplasm: poroviscoelasticity and fluid-to-solid transition.

Eukaryotic cell rheology has important consequences for vital processes such as adhesion, migration, and differentiation. Experiments indicate that cell cytoplasm can exhibit both elastic and viscous characteristics in different regimes, while the transport of fluid (cytosol) through the cross-linked filamentous scaffold (cytoskeleton) is reminiscent of mass transfer by diffusion through a porous medium. To gain insights into this complex rheological behaviour, we construct a computational model for the cell cytoplasm as a poroviscoelastic material formulated on the principles of nonlinear continuum mechanics, where we model the cytoplasm as a porous viscoelastic scaffold with an embedded viscous fluid flowing between the pores to model the cytosol. Baseline simulations (neglecting the viscosity of the cytosol) indicate that the system exhibits seven different regimes across the parameter space spanned by the viscoelastic relaxation timescale of the cytoskeleton and the poroelastic diffusion timescale; these regimes agree qualitatively with experimental measurements. Furthermore, the theoretical model also allows us to elucidate the additional role of pore fluid viscosity, which enters the system as a distinct viscous timescale. We show that increasing this viscous timescale hinders the passage of the pore fluid (reducing the poroelastic diffusion) and makes the cytoplasm rheology increasingly incompressible, shifting the phase boundaries between the regimes.

Elastic jump propagation across a blood vessel junction.

The theory of small-amplitude waves propagating across a blood vessel junction has been well established with linear analysis. In this study, we consider the propagation of large-amplitude, nonlinear waves (i.e. shocks and rarefactions) through a junction from a parent vessel into two (identical) daughter vessels using a combination of three approaches: numerical computations using a Godunov method with patching across the junction, analysis of a nonlinear Riemann problem in the neighbourhood of the junction and an analytical theory which extends the linear analysis to the following order in amplitude. A unified picture emerges: an abrupt (prescribed) increase in pressure at the inlet to the parent vessel generates a propagating shock wave along the parent vessel which interacts with the junction. For modest driving, this shock wave divides into propagating shock waves along the two daughter vessels and reflects a rarefaction wave back towards the inlet. However, for larger driving the reflected rarefaction wave becomes transcritical, generating an additional shock wave. Just beyond criticality this new shock wave has zero speed, pinned to the junction, but for further increases in driving this additional shock divides into two new propagating shock waves in the daughter vessels.

The use of adjuvant chemotherapy is not associated with recurrence or cancer-specific death following curative resection for stage III rectal cancer: a competing risks analysis.

BACKGROUND: The role of adjuvant chemotherapy (AC) in stage III rectal cancer (RC) has been argued based on evidence from its use in colon cancer. Previous trials have analysed disease-free and overall survivals as endpoints, rather than disease recurrence. This study compares the competing risks incidences of recurrence and cancer-specific death between patients who did and did not receive AC for stage III RC. METHODS: Consecutive patients who underwent a potentially curative resection for stage III RC (1995-2019) at Concord Hospital, Sydney, Australia, were studied. AC was considered following multidisciplinary discussion. Primary outcome measures were the competing risks incidences of disease recurrence and cancer-specific death. Associations between these outcomes and use of AC (and other variables) were tested by regression modelling. RESULTS: Some 338 patients (213 male, mean age 64.4 years [SD12.7]) were included. Of these, 208 received AC. The use of AC was associated with resection year (adjusted OR [aOR] 1.74, 95%CI 1.27-2.38); age ≥75 years (aOR0.04, 95%CI 0.02-0.12); peripheral vascular disease (aOR0.08, 95%CI 0.01-0.74); and postoperative abdomino-pelvic abscess (aOR0.23, 95%CI 0.07-0.81). One hundred fifty-seven patients (46.5%) were diagnosed with recurrence; death due to RC occurred in 119 (35.2%). After adjustment for the competing risk of non-cancer death, neither recurrence nor RC-specific death was associated with AC (HR0.97, 95%CI 0.70-1.33 and HR0.72, 95%CI 0.50-1.03, respectively). CONCLUSION: This study found no significant difference in either recurrence or cancer-specific death between patients who did and did not receive AC following curative resection for stage III RC.

Facilitators and barriers to employment for persons with chronic spinal cord injury or disorder: A qualitative study framed by the person-environment-occupation model.

CONTEXT/OBJECTIVE: Prolonged unemployment is common for people living with a spinal cord injury or disorder (SCI/D) and can impact negatively on quality of life. The present study examines stakeholder perspectives and experiences with the job search process in order to identify service gaps and return-to-work solutions. DESIGN: In-depth semi-structured interviews were thematically analysed, with questions focused on factors that can help or hinder efforts to gain employment. Generated themes were then applied to the Person-Environment-Occupation (PEO) systems model of participation. SETTING: Community-based disability service provider in South Australia. PARTICIPANTS: Purposive sample of persons with SCI/D (n = 8) and rehabilitation professionals (n = 4). RESULTS: Person-centred themes were strongly endorsed by both groups and focused on incentives of, and motivation for, employment. Equally important to the job search process were individual expectations and attitudes, particularly job readiness. Environmental facilitators included employers' positive attitude, although workplace discrimination remained a concern. Occupation-based barriers, rather than opportunities, were identified - namely, difficulties in SCI/D self-management, the need for timely functional assessments, and more opportunities for education, upskilling and retraining. CONCLUSIONS: The PEO model provides a broad framework to better understand the complex return-to-work process for people with a SCI/D and, potentially, uncover tangible solutions. The suggestion is that vocational rehabilitation should go beyond skills training and include motivational support to enhance job readiness. This must be done on a case-by-case basis. There is also a need for active and covert discrimination to be addressed through employment policies. The findings will be used to develop intervention targets for a newly established vocational rehabilitation service.

Model selection in occupancy models: Inference versus prediction.

Occupancy models are a vital tool for ecologists studying the patterns and drivers of species occurrence, but their use often involves selecting among models with different sets of occupancy and detection covariates. The information-theoretic approach, which employs information criteria such as Akaike's information criterion (AIC) is arguably the most popular approach for model selection in ecology and is often used for selecting occupancy models. However, the information-theoretic approach risks selecting models that produce inaccurate parameter estimates due to a phenomenon called collider bias, a type of confounding that can arise when adding explanatory variables to a model. Using simulations, we investigated the consequences of collider bias (using an illustrative example called M-bias) in the occupancy and detection processes of an occupancy model, and explored the implications for model selection using AIC and a common alternative, the Schwarz criterion (or Bayesian information criterion, BIC). We found that when M-bias was present in the occupancy process, AIC and BIC selected models that inaccurately estimated the effect of the focal occupancy covariate, while simultaneously producing more accurate predictions of the site-level occupancy probability than other models in the candidate set. In contrast, M-bias in the detection process did not impact the focal estimate; all models made accurate inferences, while the site-level predictions of the AIC/BIC-best model were slightly more accurate. Our results show that information criteria can be used to select occupancy covariates if the sole purpose of the model is prediction, but must be treated with more caution if the purpose is to understand how environmental variables affect occupancy. By contrast, detection covariates can usually be selected using information criteria regardless of the model's purpose. These findings illustrate the importance of distinguishing between the tasks of parameter inference and prediction in ecological modeling. Furthermore, our results underline concerns about the use of information criteria to compare different biological hypotheses in observational studies.

The Test of Visuospatial Construction: A Novel Test of Non-motoric Visuoconstruction.

OBJECTIVE: The Test of Visuospatial Construction (TVSC) was designed as an easily administered measure of non-motor visuoconstruction, though only preliminary data exists regarding the clinical utility of this task. The current study examined the diagnostic accuracy of the TVSC by comparing performance between healthy subjects and various clinical groups. The authors also wanted to determine whether previous findings could be replicated regarding its effectiveness at tracking cognitive decline. METHOD: Archival data collected over a period of more than 10 years were utilized and the overall sample consisted of 955 individuals, 372 healthy subjects, and 583 subjects who were categorized into various clinical groups. Only TVSC test data and demographic variables were utilized for statistical analyses in this study. RESULTS: The control group obtained significantly higher scores on the TVSC than the clinical groups. AUC values were indicative of excellent discrimination between cases and controls. Exploratory ROC curve analyses suggested adequate to excellent discrimination between the control group and the individual clinical groups as well as between the mild cognitive impairment (MCI) subgroups and the two dementia groups. CONCLUSIONS: This study demonstrates that the TVSC can effectively differentiate between healthy subjects and neurologically compromised individuals. Additionally, the TVSC may be able to measure the progressive decline in visuoconstructive abilities that occurs as patients traverse the spectrum of MCI and dementia.

Exploring Social Cognition Tests to Differentiate Frontotemporal Dementia from Depression: A Two-Step Pilot Study.

Behavioral-variant frontotemporal dementia (bvFTD) is challenging to recognize, and often misdiagnosed as depression (DEP). Evidence suggests changes in social cognition (SoCog) precede general cognitive decline in bvFTD. Currently, there are no screening measures of social cognition. 17 bvFTD, 16 DEP, and 18 control participants underwent 6 SoCog tests measuring: emotion recognition; theory of mind; empathy; insight. We used χ 2 , Wilcoxon rank sum, Kruskal-Wallis tests to compare groups, with decision tree analysis to identify items that best differentiated bvFTD from DEP. bvFTD performed significantly worse on all SoCog tasks compared with other groups. Decision tree analysis yielded a 5-item test with ROC area under the curve of 0.973 (95% CI: 0.928, 1.0) for differentiating bvFTD versus depression. These results suggest that it may be feasible to develop a screening measure of social cognition.

Validation and extension of the quick dementia rating system (QDRS).

Informant report dementia severity staging measures, such as the Quick Dementia Rating System (QDRS) offer clinicians useful diagnostic and staging information. These measures also potentially avoid many of the pitfalls inherent in mental status examinations (e.g., cultural bias, educational bias, floor and ceiling effects). We derive cut points for the QDRS and comprehensively examine their classification accuracy in a large, diagnostically heterogeneous, rural, memory disorder clinic sample. Our findings suggest the QDRS may be helpful when used in the context of a comprehensive diagnostic and staging evaluation. When used in isolation, the QDRS is insufficiently accurate for diagnosis and staging of dementia.

TP53 Mutations Identified Using NGS Comprise the Overwhelming Majority of TP53 Disruptions in CLL: Results From a Multicentre Study.

Limited data exists to show the correlation of (tumour protein 53) TP53 mutation detected by Next generation sequencing (NGS) and the presence/absence of deletions of 17p13 detected by FISH. The study which is the largest series to date includes 2332 CLL patients referred for analysis of del(17p) by FISH and TP53 mutations by NGS before treatment. Using a 10% variant allele frequency (VAF) threshold, cases were segregated into high burden mutations (≥10%) and low burden mutations (<10%). TP53 aberrations (17p [del(17p)] and/or TP53 mutation) were detected in 320/2332 patients (13.7%). Using NGS analysis, 429 TP53 mutations were identified in 303 patients (13%). Of these 238 (79%) and 65 (21%) were cases with high burden and low burden mutations respectively. In our cohort, 2012 cases did not demonstrate a TP53 aberration (86.3%). A total of 159 cases showed TP53 mutations in the absence of del(17p) (49/159 with low burden TP53 mutations) and 144 cases had both TP53 mutation and del(17p) (16/144 with low burden mutations). Only 17/2332 (0.7%) cases demonstrated del(17p) with no TP53 mutation. Validated NGS protocols should be used in clinical decision making to avoid missing low-burden TP53 mutations and can detect the vast majority of TP53 aberrations.

Redefining the high-grade B cell lymphoma with double/triple rearrangements of MYC and BCL2/BCL6 genes. Learning from a case report.

We report a patient initially diagnosed with a triple hit high-grade B cell lymphoma (HGBL-TH), in which further morphologic, immunohistochemical, and next-generation sequencing studies of subsequent specimens disclosed it to be a germinal center diffuse large B cell lymphoma (GC-DLBCL) with BCL2/BCL6 gene translocations, PVT1-deletion, and gain of MYC genes evolving from a previous follicular lymphoma. However, fluorescence in situ hybridization (FISH) studies with the break-apart probe for MYC gene showed a fusion and two separated signals (red and green, respectively) leading to the interpretation of MYC gene translocation and a false diagnosis of a TH-lymphoma, according to the recent WHO classification. Nevertheless, PVT1 deletion plus MYC gain/amplification has been described as a cause of the double-hi transcription profile. These data highlight the need for new criteria to identify these highly aggressive lymphomas.

Global impacts of climate change on avian functional diversity.

Climate change is predicted to drive geographical range shifts, leading to fluctuations in species richness (SR) worldwide. However, the effect of these changes on functional diversity (FD) remains unclear, in part because comprehensive species-level trait data are generally lacking at global scales. Here, we use morphometric and ecological traits for 8268 bird species to estimate the impact of climate change on avian FD. We show that future bird assemblages are likely to undergo substantial shifts in trait structure, with a magnitude of change greater than predicted from SR alone, and a direction of change varying according to geographical location and trophic guild. For example, our models predict that FD of insect predators will increase at higher latitudes with concurrent losses at mid-latitudes, whereas FD of seed dispersing birds will fluctuate across the tropics. Our findings highlight the potential for climate change to drive continental-scale shifts in avian FD with implications for ecosystem function and resilience.

Apical Node Involvement Does Not Influence Prognosis After Potentially Curative Resection for Stage III Colorectal Cancer: A Competing Risks Analysis.

OBJECTIVE: To examine the independent prognostic value of ALN status in patients with stage III CRC. SUMMARY OF BACKGROUND DATA: Early CRC staging classified nodal involvement by level of involved nodes in the operative specimen, including both locoregional and apical node status, in contrast to the American Joint Committee on Cancer/tumor nodes metastasis (TNM) system where tumors are classified by the number of nodes involved. Whether ALN status has independent prognostic value remains controversial. METHODS: Consecutive patients who underwent curative resection for Stage III CRC from 1995 to 2012 at Concord Hospital, Sydney, Australia were studied. ALN status was classified as: (i) ALN absent, (ii) ALN present but not histologically involved, (iii) ALN present and involved. Outcomes were the competing risks incidence of CRC recurrence and CRC-specific death. Associations between these outcomes and ALN status were compared with TNM N status results. RESULTS: In 706 patients, 69 (9.8%) had an involved ALN, 398 (56.4%) had an uninvolved ALN and 239 (33.9%) had no ALN identified. ALN status was not associated with tumor recurrence [adjusted hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.84-1.26] or CRC-specific death (HR 1.14, CI 0.91-1.43). However, associations persisted between TNM N-status and both recurrence (HR 1.58, CI 1.21-2.06) and CRC-specific death (HR 1.59, CI 1.19-2.12). CONCLUSIONS: No further prognostic information was conferred by ALN status in patients with stage III CRC beyond that provided by TNM N status. ALN status is not considered to be a useful additional component in routine TNM staging of CRC.

Recurrence and colon cancer-specific death in patients with large bowel obstruction requiring urgent operation: a competing risks analysis.

AIM: Clinical presentation with large bowel obstruction has been proposed as a predictor of poor long-term oncological outcomes after resection for colorectal cancer. This study examines the association between obstruction and recurrence and cancer-specific death after resection for colon cancer. METHOD: Consecutive patients who underwent resection for colon cancer between 1995 and 2014 were drawn from a prospectively recorded hospital database with all surviving patients followed for at least 5 years. The outcomes of tumour recurrence and colon cancer-specific death were assessed by competing risks multivariable techniques with adjustment for potential clinical and pathological confounding variables. RESULTS: Recurrence occurred in 271 of 1485 patients who had a potentially curative resection. In bivariate analysis, obstruction was significantly associated with recurrence [hazard ratio (HR) 2.23, CI 1.52-3.26, p < 0.001] but this association became nonsignificant after adjustment for confounders (HR 1.53, CI 0.95-2.46, p = 0.080). Colon cancer-specific death occurred in 238 of 295 patients who had a noncurative resection. Obstruction was not significantly associated with cancer-specific death (HR 1.02, CI 0.72-1.45, p = 0.903). In patients who had a noncurative resection, the competing risks incidence of colon cancer-specific death was not significantly greater in obstructed than in unobstructed patients (HR 1.02, CI 0.72-1.45, p = 0.903). CONCLUSION: Whilst the immediate clinical challenge of an individual patient presenting with large bowel obstruction must be addressed by the surgeon, the patient's long-term oncological outcomes are unrelated to obstruction per se.

Impacts of invasive plants on animal behaviour.

The spread of invasive species is a threat to ecosystems worldwide. However, we know relatively little about how invasive species affect the behaviour of native animals, even though behaviour plays a vital role in the biotic interactions which are key to understanding the causes and impacts of biological invasions. Here, we explore how invasive plants - one of the most pervasive invasive taxa - impact the behaviour of native animals. To promote a mechanistic understanding of these behavioural impacts, we begin by introducing a mechanistic framework which explicitly considers the drivers and ecological consequences of behavioural change, as well as the moderating role of environmental context. We then synthesise the existing literature within this framework. We find that while some behavioural impacts of invasive plants are relatively well-covered in the literature, others are supported by only a handful of studies and should be explored further in the future. We conclude by identifying priority topics for future research, which will benefit from an interdisciplinary approach uniting invasion ecology with the study of animal behaviour and cognition.

A high-stringency blueprint of the human proteome.

The Human Proteome Organization (HUPO) launched the Human Proteome Project (HPP) in 2010, creating an international framework for global collaboration, data sharing, quality assurance and enhancing accurate annotation of the genome-encoded proteome. During the subsequent decade, the HPP established collaborations, developed guidelines and metrics, and undertook reanalysis of previously deposited community data, continuously increasing the coverage of the human proteome. On the occasion of the HPP's tenth anniversary, we here report a 90.4% complete high-stringency human proteome blueprint. This knowledge is essential for discerning molecular processes in health and disease, as we demonstrate by highlighting potential roles the human proteome plays in our understanding, diagnosis and treatment of cancers, cardiovascular and infectious diseases.

The use of XLSTAT in conducting principal component analysis (PCA) when evaluating the relationships between sensory and quality attributes in grilled foods.

Multivariate statistics is a tool for examining the relationship of multiple variables simultaneously. Principal component analysis (PCA) is an unsupervised multivariate analysis technique that simplifies the complexity of data by transforming them in a few dimensions showing their trends and correlations. Interests in XLSTAT as statistical software program of choice for routine multivariate statistics has been growing due in part to its compatibility with Microsoft Excel data format. As a case of study, multivariate analysis is used to study the effects of unfiltered beer-based marination on the volatile terpenes and thiols, and sensory attributes of grilled ruminant meats. PCA was conducted to determine the correlations between the abundances of volatile terpenes and thiols and sensory attribute scores in marinated grilled meats, as well as to analyze if there was any clustering based on the type of meat and marination treatments employed.•XLSTAT PCA output successfully reduced the number of variables into 2 components that explained 90.47% of the total variation of the data set.•PCA clustered marinated and unmarinated meats based on the presence and abundances of volatile terpenes, thiols and consumer sensory attribute scores.•PCA could be applied to explore relationships between volatile compounds and sensory attributes in different food systems.

A novel next generation sequencing approach to improve sarcoma diagnosis.

Sarcoma is a rare disease affecting both bone and connective tissue and with over 100 pathologic entities, differential diagnosis can be difficult. Complementing immune-histological diagnosis with current ancillary diagnostic techniques, including FISH and RT-PCR, can lead to inconclusive results in a significant number of cases. We describe here the design and validation of a novel sequencing tool to improve sarcoma diagnosis. A NGS DNA capture panel containing probes for 87 fusion genes and 7 genes with frequent copy number changes was designed and optimized. A cohort of 113 DNA samples extracted from soft-tissue and bone sarcoma FFPE material with clinical FISH and/or RT-PCR results positive for either a translocation or gene amplification was used for validation of the NGS method. Sarcoma-specific translocations or gene amplifications were confirmed in 110 out of 113 cases using FISH and/or RT-PCR as gold-standard. MDM2/CDK4 amplification and a total of 25 distinct fusion genes were identified in this cohort of patients using the NGS approach. Overall, the sensitivity of the NGS panel is 97% with a specificity of 100 and 0% failure rate. Targeted NGS appears to be a feasible and cost-effective approach to improve sarcoma subtype diagnosis with the ability to screen for a wide range of genetic aberrations in one test.

Fistulae involving the appendix: a systematic review of the literature.

BACKGROUND: The appendix has a unique place in surgical history. Although the first ever appendicectomy involved a fistula to the skin, fistulae involving the appendix remain uncommon and can lead to unique surgical considerations. METHODS: A systematic review of the literature was performed for case reports of appendiceal fistulae. We excluded cases in which the patient had a history of appendicectomy. Cases were categorized by site and aetiology, with information regarding relative frequency and demographics obtained. RESULTS: A total of 301 case reports of fistula involving the appendix were found. The most common sites of these fistulae were to the bladder (148 cases), skin (40 cases), vasculature (19 cases), umbilicus (16 cases) and to the gastrointestinal tract. The most common aetiology in sub-analysis was appendicitis alone (150 cases), with less common causes including appendiceal adenocarcinoma (32 cases) and congenital abnormalities (18 cases). There were significantly more appendiceal fistulae in males than in females, with a ratio of 1.7:1. In patients with appendiceal adenocarcinoma as a cause for fistula, there were significantly more females than males with a ratio of 2.3:1. CONCLUSION: In conducting a systematic review of case reports of fistulae involving the appendix, we identified 301 unique case reports, with a range of different sites and aetiologies.