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.

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.

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.

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.

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.

Prediction models of donor arrest and graft utilization in liver transplantation from maastricht-3 donors after circulatory death.

Shortage of organs for transplantation has led to the renewed interest in donation after circulatory-determination of death (DCDD). We conducted a retrospective analysis (2001-2009) and a subsequent prospective validation (2010) of liver Maastricht-Category-3-DCDD and donation-after-brain-death (DBD) offers to our program. Accepted and declined offers were compared. Accepted DCDD offers were divided into donors who went on to cardiac arrest and those who did not. Donors who arrested were divided into those producing grafts that were transplanted or remained unused. Descriptive comparisons and regression analyses were performed to assess predictor models of donor cardiac arrest and graft utilization. Variables from the multivariate analysis were prospectively validated. Of 1579 DCDD offers, 621 were accepted, and of these, 400 experienced cardiac arrest after withdrawal of support. Of these, 173 livers were transplanted. In the DCDD group, donor age < 40 years, use of inotropes and absence of gag/cough reflexes were predictors of cardiac arrest. Donor age >50 years, BMI >30, warm ischemia time >25 minutes, ITU stay >7 days and ALT ≥ 4× normal rates were risk factors for not using the graft. These variables had excellent sensitivity and specificity for the prediction of cardiac arrest (AUROC = 0.835) and graft use (AUROC = 0.748) in the 2010 prospective validation. These models can feasibly predict cardiac arrest in potential DCDDs and graft usability, helping to avoid unnecessary recoveries and healthcare expenditure.

Postpartum aHUS secondary to a genetic abnormality in factor H acquired through liver transplantation.

We report here a young female who underwent a successful deceased donor liver transplant for hepatic vein thrombosis. Five years after transplantation she developed postpartum atypical hemolytic uremic syndrome (aHUS). She did not recover renal function. Mutation screening of complement genes in her DNA did not show any abnormality. Mutation screening of DNA available from the donor showed a nonsense CFH mutation leading to factor H deficiency. Genotyping of the patient showed that she was homozygous for an aHUS CD46 at-risk haplotype. In this individual, the development of aHUS has been facilitated by the combination of a trigger (pregnancy), an acquired rare genetic variant (CFH mutation) and a common susceptibility factor (CD46 haplotype).

Scale-up of TB and HIV programme collaborative activities in Zambia - a 10-year review.

OBJECTIVE: To review the activities, progress, achievements and challenges of the Zambia Ministry of Health tuberculosis (TB)/HIV collaborative activities over the past decade. METHODS: Analysis of Zambia Ministry of Health National TB and HIV programme documents and external independent programme review reports pertaining to 2000-2010. RESULTS: The number of people testing for HIV increased from 37 557 persons in 2003 to 1 327 995 persons in 2010 nationally. Those receiving anti-retroviral therapy (ART) increased from 143 in 2003 to 344 304 in 2010. The national HIV prevalence estimates declined from 14.3% in 2001 to 13.5% in 2009. The proportion of TB patients being tested for HIV increased from 22.6% in 2006 to 84% in 2010 and approximately 70% were HIV positive. The proportion of the HIV-infected TB patients who: (i) started on ART increased from 38% in 2006 to 50% in 2010; (ii) commenced co-trimoxazole preventive therapy (CPT) increased from 31% in 2006 to 70% in 2010; and (iii) were successfully treated increased to an average of 80% resulting in decline of deaths from 13% in 2006 to 9% in 2010. CONCLUSIONS: The scale-up of TB/HIV collaborative programme activities in Zambia has steadily increased over the past decade resulting in increased testing for TB and HIV, and anti-retroviral (ARV) rollout with improved treatment outcomes among TB patients co-infected with HIV. Getting service delivery points to adhere to WHO guidelines for collaborative TB/HIV activities remains problematic, especially those meant to reduce the burden of TB in people living with HIV/AIDS (PLWHA).

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.

Manganese-enhanced MRI predicts the histological grade of hepatocellular carcinoma in potential surgical candidates.

AIM: To evaluate the role of manganese-enhanced magnetic resonance (Mn-MRI) in predicting tumour differentiation prior to liver transplant or resection for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: The inclusion criteria were patients with HCC who underwent Mn-MRI prior to transplantation or resection from 2001-2008. T1-weighted MRI images were acquired at 0 and 24h after manganese dipyridoxal diphosphate (MnDPDP) intravenous contrast medium and reviewed prospectively. Manganese retention at 24h was correlated with tumour differentiation and disease-free survival. RESULTS: Eighty-six patients underwent Mn-MRI (transplantation 60, resection 26); 114/125 lesions (91%) that were arterialised as evidenced at computed tomography (CT) and had manganese uptake on MRI were HCC. There were 11 false positives (9%) that were regenerative nodules. Ten of fourteen non-manganese-retaining HCC (71%) were poorly differentiated, compared with only 13/114 manganese-retaining HCC (11%) (p<0.0001). Sensitivity, specificity, positive and negative predictive values of non-retention of MnDPDP in predicting poorly differentiated tumours were 0.43, 0.96, 0.71 and 0.88. Median disease-free survival of patients with non-manganese-retaining HCC was less than for patients with manganese-retaining HCC (14±5 months versus 39±3 months, log rank p=0.025). CONCLUSION: Non-manganese-retaining HCCs are likely to be poorly differentiated and have a poor prognosis. Manganese-enhanced MRI appears to have a role in preoperative assessment of HCC and warrants further evaluation.

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.

Phenotypic expression of recurrent disease after liver transplantation.

Recurrence of the primary disease has become a major focus for transplant hepatologists both when investigating graft dysfunction and when tailoring immunosuppression to maximize graft survival. However, disease recurrence varies in penetrance, can be predictable or random, and does not always conform to the expected pattern of disease. The cholestatic hepatitis syndromes associated with hepatitis B and C are the most dramatic examples of phenotypic change. Being on immunosuppressive drugs may intensify the progression of infectious and malignant diseases, but this effect is not predictable. A significant minority of patients with each of the autoimmune diseases, counter-intuitively, get recurrent disease despite immunosuppression of a potency that is adequate to prevent rejection of the liver graft. Disease patterns emerge after liver transplantation for cryptogenic cirrhosis that shed light on the cause of the native liver disease, for example, nonalcohol-related fatty liver disease and autoimmune hepatitis. The phenotypic expression of disease recurrence can be modified by specific drugs used for immunosuppression and by HLA-antigen matching profiles. Understanding and modifying the phenotypic expression of recurrent disease after liver transplantation is a fertile area for research and continued refinement of clinical care.

Outcomes of severe pregnancy-related liver disease: refining the role of transplantation.

Severe liver disease in pregnancy is generally considered to have a favorable prognosis. The limited data available have not yielded disease-specific prognostic criteria or guidance on who should undergo liver transplantation (LT). We retrospectively evaluated 54 admissions with pregnancy-related liver disease to (1) evaluate if any admission parameters were associated with death and/or transplantation and (2) identify maternal complications. Eighteen had acute fatty liver of pregnancy and 32 had hypertension/eclampsia related disease. Seven patients (13%) died and four (7%) underwent LT. Survival rates were 43/48 if not listed for LT and 4/6 if listed. Of the four transplanted, three survived. Patients who died and/or underwent LT were more likely to have encephalopathy (p = 0.04) and hyperlactaemia (p = 0.03). Serum lactate was the best discriminant (ROC AUC 0.84). An admission lactate greater than 2.8mg/dL had 73% sensitivity and 75% specificity for predicting death or LT. The addition of encephalopathy to this parameter increased sensitivity and specificity to 90% and 86%, respectively. The King's College criteria were not effective in predicting outcome. This study confirms the overall favorable prognosis in pregnancy-related liver failure but indicates that elevated lactate levels in the presence of encephalopathy best identify patients at greatest risk of death or LT.

A simple, noninvasive test for the diagnosis of liver fibrosis in patients with hepatitis C recurrence after liver transplantation.

Recurrent hepatitis C is a common cause of graft loss in patients undergoing liver transplantation, and serial protocol liver biopsies have been used to identify patients at risk of graft loss from rapid fibrosis progression. The aim of this study was to derive a simple noninvasive index to predict fibrosis in patients with recurrent hepatitis C post-transplant. A retrospective study was performed assessing serial liver biopsies for post-transplant chronic hepatitis C infection. One hundred eighty-five patients were included in the analysis; median age 53 years (interquartile range 48-59) and 140 (76%) were male. Liver histology showed 53 (29%) had Ishak fibrosis stages F0/F1, 31 (17%) had F2, 29 (16%) had F3, 19 (10%) had F4 and 53 (29%) had F5/F6. The London Transplant Centres' (LTC) score was derived combining aspartate aminotransferase (AST IU/L), time from liver transplant (TFLT months), international normalized ratio and platelets. Diagnostic accuracy of the LTC score was assessed using area under receiver-operating characteristic (ROC) curves. The area under the ROC curve for moderate fibrosis (F >or= 2) was 0.78 (95% CI, 0.70-0.86; P < 0.0001), for advanced fibrosis (F4-6) was 0.80 (95% CI, 0.72-0.87; P < 0.0001) and for cirrhosis was 0.80 (95% CI, 0.72-0.88; P < 0.0001). An optimal cut-off value of 6.3 distinguished patients with no or mild fibrosis (F

Exploring the anthelmintic properties of Australian native shrubs with respect to their potential role in livestock grazing systems.

We measured in vitro anthelmintic activity in extracts from 85 species of Australian native shrub, with a view to identifying species able to provide a degree of worm control in grazing systems. Approximately 40% of the species showed significant activity in inhibiting development of Haemonchus contortus larvae. The most active extracts showed IC50 values of 60-300 microg/ml. Pre-incubation with polyvinylpolypyrrolidine removed the activity from some extracts, implicating tannins as the bioactive agent, while in other cases the pre-incubation had no effect, indicating the presence of other anthelmintic compounds. Plant reproductive maturity (onset of flowering or fruiting) was associated with increasing anthelmintic activity in some species. Variability was observed between plants of the same species growing in different environments, while variation between individual plants of the same species within a single field suggests the existence of distinct chemotypes. Significant activity against adult H. contortus worms in vitro was also demonstrated in a limited number of extracts tested against this life stage. Our study indicates that there is potential for Australian native shrubs to play an anthelmintic role in grazing systems, and highlights some plant biology factors which will need to be considered in order to maximize any anthelmintic effects.

Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment.

Osteonecrosis of the Jaw (ONJ) is a recently recognised and potentially highly morbid complication of bisphosphonate therapy in the setting of metastatic malignancy, including myeloma. Members of the Medical and Scientific Advisory Group of the Myeloma Foundation of Australia formulated guidelines for the management of bisphosphonates around the issue of ONJ, based on the best available evidence in June 2008. Prior to commencement of therapy, patients should have an oral health assessment and be educated about the risks of ONJ. Dental assessment should occur 6 monthly during therapy. If tooth extraction is required, sufficient time should be allowed for complete healing to occur prior to commencement of bisphosphonate. As the risk of ONJ increases with duration of bisphosphonate therapy, we recommend annual assessment of dose with modification to 3 monthly i.v. therapy or to oral therapy with clodronate for those with all but the highest risk of skeletal-related event. Established ONJ should be managed conservatively; a bisphosphonate "drug holiday" is usually indicated and invasive surgery should generally be avoided. These recommendations will assist with clinical decision making for myeloma patients who are at risk of bisphosphonate-associated ONJ.