The Impact of SARS-COV-2 on two Colorectal Cancer screening centres.

BowelScreen paused activity in March 2020 to prioritise the response to the COVID-19 pandemic. The aim of this study was to examine the impact of this delay. Cases affected by the pause and subsequently completed were compared to the same period in 2019. Endoscopy and histology data were obtained from the BowelScreen database and patient records. One-hundred and seven colonoscopies were performed during the study period. This compared with 224 colonoscopies during the same period in 2019. Median lead time to colonoscopy in 2020 was 74 days compared to 34 days in 2019. Adenoma detection rate was 59% for both periods. Advanced adenoma and cancer detection rates were similar in both periods. While there was a marked reduction in activity and significant delays for BowelScreen patients during the first wave of the COVID-19 pandemic, this does not appear to have impacted on clinical outcomes for patients who attended for screening colonoscopy.

Phase-change-mediated transport and agglomeration of fungal spores on wheat awns.

Wheat and other staple crops are devastated by fungal diseases. Many fungal plant pathogens are spread via active or passive discharge of microscopic spores. Here, we described the unique transport of spores of the fungal pathogen Epicoccum tritici, causal agent of black sooty mould, on wheat awns. The unique multi-scale architecture of wheat awns, coupled with condensation and evaporation of dew droplets, facilitated the transport and agglomeration of spores of the fungus. First, dew droplets spontaneously transported spores from the tips of awn hairs to the neighbouring stomatal ridges, driven by gradients in Laplace pressure and surface wettability. Subsequently, spores agglomerated into dry clusters due to the Cheerios effect and evaporation, increasing the likelihood of passive spore removal via wind shear and/or rainsplash. Future plant breeding approaches should consider the development of modified spike structures, such as those without awns or awn hairs, to reduce the potential for spread of fungal plant pathogens.

Gauging mixed climate extreme value distributions in tropical cyclone regions.

In tropical cyclone (TC) regions, tide gauge or numerical hindcast records are usually of insufficient length to have sampled sufficient cyclones to enable robust estimates of the climate of TC-induced extreme water level events. Synthetically-generated TC populations provide a means to define a broader set of plausible TC events to better define the probabilities associated with extreme water level events. The challenge is to unify the estimates of extremes from synthetically-generated TC populations with the observed records, which include mainly non-TC extremes resulting from tides and more frequently occurring atmospheric-depression weather and climate events. We find that extreme water level measurements in multiple tide gauge records in TC regions, some which span more than 100 years, exhibit a behaviour consistent with the combining of two populations, TC and non-TC. We develop an equation to model the combination of two populations of extremes in a single continuous mixed climate (MC) extreme value distribution (EVD). We then run statistical simulations to show that long term records including both historical and synthetic events can be better explained using MC than heavy-tailed generalised EVDs. This has implications for estimating extreme water levels when combining synthetic cyclone extreme sea levels with hindcast water levels to provide actionable information for coastal protection.

Projected incremental changes to extreme wind-driven wave heights for the twenty-first century.

Global climate change will alter wind sea and swell waves, modifying the severity, frequency and impact of episodic coastal flooding and morphological change. Global-scale estimates of increases to coastal impacts have been typically attributed to sea level rise and not specifically to changes to waves on their own. This study provides a reduced complexity method for applying projected extreme wave changes to local scale impact studies. We use non-stationary extreme value analysis to distil an incremental change signal in extreme wave heights and associate this with a change in the frequency of events globally. Extreme wave heights are not projected to increase everywhere. We find that the largest increases will typically be experienced at higher latitudes, and that there is high ensemble model agreement on an increase (doubling of events) for the waters south of Australia, the Arabian Sea and the Gulf of Guinea by the end of the twenty-first century.

Elevated Insulin and Insulin Resistance are Associated with Altered Myelin in Cognitively Unimpaired Middle-Aged Adults.

OBJECTIVE: Insulin regulates metabolism and influences neural health. Insulin resistance (IR) and type II diabetes have been identified as risk factors for Alzheimer disease (AD). Evidence has also suggested that myelinated white matter alterations may be involved in the pathophysiology of AD; however, it is unknown whether insulin or IR affect the underlying myelin microstructure. The relationships between insulin, IR, and myelin were examined, with the hypothesis that IR would be associated with reduced myelin. METHODS: Cognitively unimpaired adults enriched for risk factors for AD underwent multicomponent driven equilibrium single pulse observation of T1 and T2 imaging, a myelin-sensitive neuroimaging technique. Linear regressions were used to test the relationship between homeostatic model assessment of IR, insulin, and myelin water fraction (MWF) as well as interactions with APOE ε4. RESULTS: Both IR and insulin level were associated with altered myelin content, wherein a significant negative association with MWF was observed in white matter regions and a positive association with MWF was observed in gray matter. CONCLUSIONS: The results suggest that insulin and IR influence white matter myelination in a cognitively unimpaired population. Additional studies are needed to determine the extent to which this may contribute to cognitive decline or vulnerability to neurodegenerative disease.

Evaluation of multiplex tandem PCR (MT-PCR) assays for the detection of bacterial resistance genes among Enterobacteriaceae in clinical urines.

Background: Increasing resistance drives empirical use of less potent and previously reserved antibiotics, including for urinary tract infections (UTIs). Molecular profiling, without culture, might better guide early therapy. Objectives: To explore the potential of AusDiagnostics multiplex tandem (MT) PCR UTI assays. Methods: Two MT-PCR assays were developed successively, seeking 8 or 16 resistance genes. Amplification was tracked in real time, with melting temperatures used to confirm product identity. Assays were variously performed on: (i) extracted DNA; (ii) cultured bacteria; (iii) urine spiked with reference strains; and (iv) bacteria harvested from clinical urines. Results were compared with those from sequencing, real-time SybrGreen PCR or phenotypic susceptibility. Results: Performance was similar irrespective of whether DNA, cultures or urines were used, with >90% sensitivity and specificity with respect to common ß-lactamases, dfr genes and aminoglycoside resistance determinants except aadA1/A2/A3, for which carriage correlated poorly with streptomycin resistance. Fluoroquinolone-susceptible and -resistant Escherichia coli (but not other species) were distinguished by the melting temperatures of their gyrA PCR products. The time from urine to results was <3 h. Conclusions: The MT-PCR assays rapidly identified resistance genes from Gram-negative bacteria in urines as well as from cultivated bacteria. Used directly on urines, this assay has the potential to guide early therapy.

Passive Antifrosting Surfaces Using Microscopic Ice Patterns.

Despite exceptional recent advances in tailoring the wettability of surfaces, to date, no engineered surface can passively suppress the in-plane growth of frost that invariably occurs in humid, subfreezing environments. Here, we show that up to 90% of a surface can exhibit passive antifrosting by using chemical or physical wettability patterns to template "ice stripes" across the surface. As ice exhibits a depressed vapor pressure relative to liquid water, these sacrificial ice stripes siphon the supersaturated water vapor to keep the intermediate surface areas dry from dew and frost. Further, we show that when these sacrificial ice stripes are elevated atop microfins, they diffusively coarsen in a suspended state above the surface. The suspended state of the coarsening ice results in a diffusive growth rate an order of magnitude slower than frost coarsening directly on a solid substrate and should also minimize its adhesive strength to the surface.

The Unyvero P55 'sample-in, answer-out' pneumonia assay: A performance evaluation.

BACKGROUND: O'Neill's recent Review on Antimicrobial Resistance expressed the view that by 2020 high-income countries should make it mandatory to support antimicrobial prescribing with rapid diagnostic evidence whenever possible. METHODS: Routine microbiology diagnosis of 95 respiratory specimens from patients with severe infection were compared with those generated by the Unyvero P55 test, which detects 20 pathogens and 19 antimicrobial resistance markers. Supplementary molecular testing for antimicrobial resistance genes, comprehensive culture methodology and 16S rRNA sequencing were performed. RESULTS: Unyvero P55 produced 85 valid results, 67% of which were concordant with those from the routine laboratory. Unyvero P55 identified more potential pathogens per specimen than routine culture (1.34 vs. 0.47 per specimen). Independent verification using 16S rRNA sequencing and culture (n = 10) corroborated 58% of additional detections compared to routine microbiology. Overall the average sensitivity for organism detection by Unyvero P55 was 88.8% and specificity was 94.9%. While Unyvero P55 detected more antimicrobial resistance markers than routine culture, some instances of phenotypic resistance were missed. CONCLUSIONS: The Unyvero P55 is a rapid pathogen detection test for lower respiratory specimens, which identifies a larger number of pathogens than routine microbiology. The clinical significance of these additional organisms is yet to be determined. Further studies are required to determine the effect of the test in practise on antimicrobial prescribing and patient outcomes.

Improving the Diagnostic Criteria for Primary Liver Graft Nonfunction in Adults Utilizing Standard and Transportable Laboratory Parameters: An Outcome-Based Analysis.

Current diagnostic criteria for primary nonfunction (PNF) of liver grafts are based on clinical experience rather than statistical methods. A retrospective, single-center study was conducted of all adults (n = 1286) who underwent primary liver transplant (LT) 2000-2008 in our center. Laboratory variables during the first post LT week were analyzed. Forty-two patients (3.7%) had 2-week graft failure. Transplant albumin, day-1 aspartate aminotransferase (AST), day-1 lactate, day-3 bilirubin, day-3 international normalized ratio (INR), and day-7 AST were independently associated with PNF on multivariate logistic regression. PNF score =(0.000280*D1AST)+ (0.361*D1 Lactate)+(0.00884*D3 Bilirubin)+(0.940*D3 INR)+(0.00153*D7 AST)-(0.0972*TxAlbumin)-4.5503. Receiver operating curve analysis showed the model area under receiver operating curve (AUROC) of 0.912 (0.889-0.932) was superior to the current United Kingdom (UK) PNF criteria of 0.669 (0.634-0.704, p < 0.0001). When applied to a validation cohort (n = 386, 34.4% patients), the model had AUROC of 0.831 (0.789-0.867) compared to the UK early graft dysfunction criteria of 0.674 (0.624-0.721). The new model performed well after exclusion of patients with marginal grafts and when modified to include variables from the first three post-LT days only (AUROC of 0.818, 0.776-0.856, p = 0.001). This model is superior to the current UK PNF criteria and is based on statistical methods. The model is also applicable to recipients of all types of grafts (marginal and nonmarginal).

Identification of bacterial pathogens and antimicrobial resistance directly from clinical urines by nanopore-based metagenomic sequencing.

OBJECTIVES: The introduction of metagenomic sequencing to diagnostic microbiology has been hampered by slowness, cost and complexity. We explored whether MinION nanopore sequencing could accelerate diagnosis and resistance profiling, using complicated urinary tract infections as an exemplar. METHODS: Bacterial DNA was enriched from clinical urines (n = 10) and from healthy urines 'spiked' with multiresistant Escherichia coli (n = 5), then sequenced by MinION. Sequences were analysed using external databases and bioinformatic pipelines or, ultimately, using integrated real-time analysis applications. Results were compared with Illumina data and resistance phenotypes. RESULTS: MinION correctly identified pathogens without culture and, among 55 acquired resistance genes detected in the cultivated bacteria by Illumina sequencing, 51 were found by MinION sequencing directly from the urines; with three of the four failures in an early run with low genome coverage. Resistance-conferring mutations and allelic variants were not reliably identified. CONCLUSIONS: MinION sequencing comprehensively identified pathogens and acquired resistance genes from urine in a timeframe similar to PCR (4 h from sample to result). Bioinformatic pipeline optimization is needed to better detect resistances conferred by point mutations. Metagenomic-sequencing-based diagnosis will enable clinicians to adjust antimicrobial therapy before the second dose of a typical (i.e. every 8 h) antibiotic.

Association of Amyloid Pathology With Myelin Alteration in Preclinical Alzheimer Disease.

IMPORTANCE: The accumulation of aggregated ß-amyloid and tau proteins into plaques and tangles is a central feature of Alzheimer disease (AD). While plaque and tangle accumulation likely contributes to neuron and synapse loss, disease-related changes to oligodendrocytes and myelin are also suspected of playing a role in development of AD dementia. Still, to our knowledge, little is known about AD-related myelin changes, and even when present, they are often regarded as secondary to concomitant arteriosclerosis or related to aging. OBJECTIVE: To assess associations between hallmark AD pathology and novel quantitative neuroimaging markers while being sensitive to white matter myelin content. DESIGN, SETTING, AND PARTICIPANTS: Magnetic resonance imaging was performed at an academic research neuroimaging center on a cohort of 71 cognitively asymptomatic adults enriched for AD risk. Lumbar punctures were performed and assayed for cerebrospinal fluid (CSF) biomarkers of AD pathology, including ß-amyloid 42, total tau protein, phosphorylated tau 181, and soluble amyloid precursor protein. We measured whole-brain longitudinal and transverse relaxation rates as well as the myelin water fraction from each of these individuals. MAIN OUTCOMES AND MEASURES: Automated brain mapping algorithms and statistical models were used to evaluate the relationships between age, CSF biomarkers of AD pathology, and quantitative magnetic resonance imaging relaxometry measures, including the longitudinal and transverse relaxation rates and the myelin water fraction. RESULTS: The mean (SD) age for the 19 male participants and 52 female participants in the study was 61.6 (6.4) years. Widespread age-related changes to myelin were observed across the brain, particularly in late myelinating brain regions such as frontal white matter and the genu of the corpus callosum. Quantitative relaxometry measures were negatively associated with levels of CSF biomarkers across brain white matter and in areas preferentially affected in AD. Furthermore, significant age-by-biomarker interactions were observed between myelin water fraction and phosphorylated tau 181/ß-amyloid 42, suggesting that phosphorylated tau 181/ß-amyloid 42 levels modulate age-related changes in myelin water fraction. CONCLUSIONS AND RELEVANCE: These findings suggest amyloid pathologies significantly influence white matter and that these abnormalities may signify an early feature of the disease process. We expect that clarifying the nature of myelin damage in preclinical AD may be informative on the disease's course and lead to new markers of efficacy for prevention and treatment trials.

Insulin Resistance is Associated with Higher Cerebrospinal Fluid Tau Levels in Asymptomatic APOEɛ4 Carriers.

BACKGROUND: Insulin resistance (IR) is linked with the occurrence of pathological features observed in Alzheimer's disease (AD), including neurofibrillary tangles and amyloid plaques. However, the extent to which IR is associated with AD pathology in the cognitively asymptomatic stages of preclinical AD remains unclear. OBJECTIVE: To determine the extent to which IR is linked with amyloid and tau pathology in late-middle-age. METHOD: Cerebrospinal fluid (CSF) samples collected from 113 participants enrolled in the Wisconsin Registry for Alzheimer's Prevention study (mean age = 60.6 years), were assayed for AD-related markers of interest: Aß42, P-Tau181, and T-Tau. IR was determined using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Linear regression was used to test the effect of IR, and APOEɛ4, on tau and amyloid pathology. We hypothesized that greater IR would be associated with higher CSF P-Tau181 and T-Tau, and lower CSF Aß42. RESULTS: No significant main effects of HOMA-IR on P-Tau181, T-Tau, or Aß42 were observed; however, significant interactions were observed between HOMA-IR and APOEɛ4 on CSF markers related to tau. Among APOEɛ4 carriers, higher HOMA-IR was associated with higher P-Tau181 and T-Tau. Among APOEɛ4 non-carriers, HOMA-IR was negatively associated with P-Tau181 and T-Tau. We found no effects of IR on Aß42 levels in CSF. CONCLUSION: IR among asymptomatic APOEɛ4 carriers was associated with higher P-Tau181 and T-Tau in late-middle age. The results suggest that IR may contribute to tau-related neurodegeneration in preclinical AD. The findings may have implications for developing prevention strategies aimed at modifying IR in mid-life.

Tensile properties in collagen-rich tissues of Quarter Horses with hereditary equine regional dermal asthenia (HERDA).

REASONS FOR PERFORMING STUDY: Hereditary equine regional dermal asthenia (HERDA) is an autosomal recessive disorder of Quarter Horses characterised by skin fragility. Horses with HERDA have a missense mutation in peptidyl-prolyl cis-trans isomerase B (PPIB), which encodes cyclophilin B and alters folding and post translational modifications of fibrillar collagen. OBJECTIVES: The study aimed to test the hypothesis that tendons, ligaments and great vessels, which, like skin, are rich in fibrillar collagen, will also have abnormal biomechanical properties in horses with HERDA. STUDY DESIGN: Ex vivo biomechanical study comparing horses with and without a diagnosis of HERDA. METHODS: Forelimb suspensory ligament, superficial and deep digital flexor tendons; withers, forelimb and abdominal skin; the main pulmonary artery and the aortic arch were harvested from 6 horses with HERDA and 6 control horses without the HERDA allele. Tissues were distracted to failure. Tensile strength (TS), elastic modulus (EM) and energy to failure (ETF) were compared. RESULTS: Horses with HERDA had significantly lower TS and EM in tendinoligamentous tissues and great vessels, respectively. The TS, EM and ETF were significantly lower in skin from horses with HERDA. Differences in TS and ETF were more extreme at the withers than at the forelimb or abdomen. CONCLUSIONS: Tendinoligamentous tissue, great vessels and skin are significantly weaker in horses with HERDA than in horses lacking the PPIB mutation, substantiating that diverse tissues with high fibrillar collagen content are abnormal in HERDA and that the HERDA phenotype is not limited to the integument.

Patient perception of skin-cancer prevention and risk after liver transplantation.

INTRODUCTION: Sun exposure is a major risk factor for the development of skin cancer. This is particularly relevant in immunosuppressed liver-transplant recipients (LTRs). Preventative strategies may help minimize the skin-cancer risk in this patient group. METHODS: We assessed 670 patients in our post-transplant clinic, using questionnaires. Patient data were collected, and we assessed whether patients had received education (such as formal talks or information from transplant coordinators or from hepatologists) on skin, sun exposure and skin cancer. In a subset of 280 of the LTRs who responded, we recorded their recall of sun-protection advice and assessed the level of patient adherence to such advice. RESULTS: The response rate was 57.5% (349/607), with a mean responder age of 51.1 years (range 19-84) and an average post-transplant time of 7.1 years (range 0-27). In the recall assessment, 37.2% reported that they were given advice about their skin, while 18.1% were seen by a dermatologist, and education on sun exposure and the risks of skin cancer was given to 65.6% and 47.9%, respectively. Over three-quarters (78%; 185/280) of the patients used mechanical sun protection (i.e. hats/clothing), while 66% reported using sunscreen; 31.8% of these used a sunscreen of the recommended sun protection factor (SPF) of > 30. Twelve patients had developed squamous cell carcinoma after a mean of 10.9 years (1-23) post-transplant; half of these had used either no sunscreen or one with an SPF of < 15. CONCLUSIONS: Despite the fact that LTRs are given information on sun-exposure and SC before and after transplantation, recall of such advice and use of sun-protection methods was only moderate, indicating that regular reinforcement of SC education is needed.

Predicting the development of acute kidney injury in liver cirrhosis--an analysis of glomerular filtration rate, proteinuria and kidney injury biomarkers.

BACKGROUND: The timely diagnosis of acute kidney injury (AKI) in liver cirrhosis is challenging. AIM: To evaluate whether quantification of glomerular filtration rate (GFR), proteinuria and kidney injury biomarkers can accurately predict the development of AKI. METHODS: A prospective cohort analysis of patients with cirrhosis was performed. Measures of baseline kidney function included serum creatinine, iohexol clearance and urine protein:creatinine ratio. Blood and urine samples were collected daily. A retrospective analysis of cystatin C GFR and neutrophil gelatinase-associated lipocalin (NGAL) measured 48 h prior to the diagnosis of AKI was undertaken to evaluate their ability to predict the development of AKI. RESULTS: Eighteen of the 34 cirrhosis patients studied developed AKI. A GFR <60 mL/min/1.73 m(2) was identified in 56% with Iohexol clearance compared to 8% using the four-variable modified diet in renal disease formula (P < 0.0001). Prediction of AKI, 48 h prior to the development of AKI with cystatin C GFR and serum NGAL concentration were similar; area under the receiver operating curve (AUROC) values 0.74 (0.51-0.97), P = 0.04 and 0.72 (0.52-0.92), P = 0.02 respectively. The development of AKI was strongly predicted by urine protein:creatinine ratio above the cut-off of >30 (equivalent to 300 mg/day of proteinuria) sensitivity 82% (57-96) and specificity 80% (52-96), AUROC 0.86 (0.73-0.98), P ≤ 0.0001. [OR 21 (3-133), P ≤ 0.002]. CONCLUSIONS: In patients with liver cirrhosis a urine protein:creatinine ratio >30 predicts AKI. Iohexol clearance and cystatin C formulae identify a greater proportion of patients with a GFR <60 mL/min/1.73 m(2), which also predicts the development of AKI.

Human liver regeneration is characterized by the coordinated expression of distinct microRNA governing cell cycle fate.

In the absence of adequate compensatory regeneration, overwhelming liver damage can cause acute liver failure (ALF) and death without emergent liver transplantation (LT). Auxiliary LT produces satisfactory outcomes in this setting, with the prospect of native liver regeneration sustaining long-term survival. Since animal models only partially recapitulate human liver regeneration, we investigated the molecular mechanisms controlling it in this unique LT setting, as an exemplar of human liver regeneration. We demonstrate coordinated changes in expression of microRNA (miRNA) during regeneration that drive proliferation, innate immunity and angiogenesis. In contrast, failed regeneration in a similar cohort is associated with distinct miRNA enforcing cell cycle inhibition and DNA methylation. The miRNA expression associated with successful or failed regeneration when recapitulated in vitro, triggered expression of cardinal regeneration-linked genes promoting cell cycle entry or inhibition, respectively. Furthermore, inhibition of miRNA 150, 663 and 503, whose downregulation is associated with successful regeneration, induced cell proliferation which a key determinant of successful regeneration. Our data indicate that human liver regeneration may be orchestrated by distinct miRNA controlling key regeneration-linked processes including hepatocyte proliferation. To our knowledge this is the first characterization of molecular processes associated with human liver regeneration.

Cyclooxygenase expression and platelet function in healthy dogs receiving low-dose aspirin.

BACKGROUND: Low-dose aspirin is used to prevent thromboembolic complications in dogs, but some animals are nonresponsive to the antiplatelet effects of aspirin ("aspirin resistance"). HYPOTHESIS/OBJECTIVES: That low-dose aspirin would inhibit platelet function, decrease thromboxane synthesis, and alter platelet cyclooxygenase (COX) expression. ANIMALS: Twenty-four healthy dogs. METHODS: A repeated measures study. Platelet function (PFA-100 closure time, collagen/epinephrine), platelet COX-1 and COX-2 expression, and urine 11-dehydro-thromboxane B(2) (11-dTXB(2)) were evaluated before and during aspirin administration (1 mg/kg Q24 hours PO, 10 days). Based on prolongation of closure times after aspirin administration, dogs were divided into categories according to aspirin responsiveness: responders, nonresponders, and inconsistent responders. RESULTS: Low-dose aspirin increased closure times significantly (62% by Day 10, P < .001), with an equal distribution among aspirin responsiveness categories, 8 dogs per group. Platelet COX-1 mean fluorescent intensity (MFI) increased significantly during treatment, 13% on Day 3 (range, -29.7-136.1%) (P = .047) and 72% on Day 10 (range, -0.37-210%) (P < .001). Platelet COX-2 MFI increased significantly by 34% (range, -29.2-270%) on Day 3 (P = .003) and 74% (range, -19.7-226%) on Day 10 (P < .001). Urinary 11-dTXB(2) concentrations significantly (P = .005, P < .001) decreased at both time points. There was no difference between aspirin responsiveness and either platelet COX expression or thromboxane production. CONCLUSIONS AND CLINICAL IMPORTANCE: Low-dose aspirin consistently inhibits platelet function in approximately one-third of healthy dogs, despite decreased thromboxane synthesis and increased platelet COX expression in most dogs. COX isoform expression before treatment did not predict aspirin resistance.