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Objectives Currently, NICE recommends the use of faecal immunochemical test (FIT) at faecal haemoglobin concentrations (f-Hb) of 10 μg Hb/g faeces to stratify for colorectal cancer (CRC) risk in symptomatic populations. This f-Hb cut-off is advised across all analysers, despite the fact that a direct comparison of analyser performance, in a clinical setting, has not been performed. Methods Two specimen collection devices (OC-Sensor, OC-S; HM-JACKarc, HM-J) were sent to 914 consecutive individuals referred for follow up due to their increased risk of CRC. Agreement of f-Hb around cut-offs of 4, 10 and 150 µg Hb/g faeces and CRC detection rates were assessed. Two OC-S devices were sent to a further 114 individuals, for within test comparisons. Results A total of 732 (80.1%) individuals correctly completed and returned two different FIT devices, with 38 (5.2%) CRCs detected. Median f-Hb for individuals diagnosed with and without CRC were 258.5 and 1.8 µg Hb/g faeces for OC-S and 318.1 and 1.0 µg Hb/g faeces for HM-J respectively. Correlation of f-Hb results between OC-S/HM-J over the full range was rho=0.74, p Conclusions We found large variations in f-Hb when different FIT devices were used, but a smaller variation when the same FIT device was used. Our data suggest that analyser-specific f-Hb cut-offs are applied with regard to clinical decision making, especially at lower f-Hb.

AIM We introduced primary care access to faecal immunochemical testing (FIT) as a stratification tool for symptomatic patients considered to be at risk of colorectal cancer (CRC) prior to urgent referral. We aimed to evaluate clinical and pathway outcomes during the first 6 months of this novel approach. METHOD FIT was recommended for all patients who consulted their general practitioner with lower gastrointestinal symptoms other than rectal bleeding and rectal mass. We undertook a retrospective audit of the results of FIT, related clinical outcomes and resource utilization on prospectively logged cases between November 2017 and May 2018. RESULTS Of the 1862 FIT kits dispatched by post 91.4% were returned, with a median return time of 7 days (range 2-110 days); however, 1.3% of returned kits could not be analysed. FIT results ≥ 150.0 μg haemoglobin (Hb)/g faeces identified patients with a significantly higher risk of CRC (30.9% vs 1.4%, chi-square 167.1, P

Background New national guidance on urgent referral for investigation of colorectal cancer included faecal occult blood testing in 2015. A service evaluation of faecal immunochemical testing (FIT) and anaemia as risk stratification tools in symptomatic patients suspected of having CRC was undertaken. Methods Postal FIT was incorporated into the colorectal cancer 2-week wait (2WW) pathway for all patients without rectal bleeding in 2016. Patients were investigated in the 2WW pathway as normal, and outcomes of investigations were recorded prospectively. Anaemia was defined as a haemoglobin level below 120 g/l in women and 130 g/l in men. Results FIT kits were sent to 1106 patients, with an 80·9 per cent return rate; 810 patients completed investigations and 40 colorectal cancers were diagnosed (4·9 per cent). FIT results were significantly higher in patients with anaemia (median (i.q.r.) 4·8 (0·8-34·1) versus 1·2 (0-6·4) μg Hb/g faeces in those without anaemia; P

ObjectiveService evaluation of GP access to Faecal Immunochemical Test (FIT) for colorectal cancer (CRC) detection in Nottinghamshire and use of FIT for “rule out”, “rule in” and “first test selection”.DesignRetrospective audit of FIT results, CRC outcomes and resource utilisation before and after introduction of FIT in Primary Care in November 2017. Data from the new pathway up to December 2018 was compared with previous experience.ResultsBetween November 2017 and December 2018, 6747 GP FIT test requests yielded 5733 FIT results, of which 4082 (71.2%) were [less than]4.0 μg Hb/g faeces, 579 (10.1%) were 4.0–9.9 μg Hb/g faeces, 836 (14.6%) were 10.0–149.9 μg Hb/g faeces, and 236 (4.1%) were ≥150.0 μg Hb/g faeces. The proportion of “rule out” results [less than]4.0 μg Hb/g faeces was significantly higher than in the Getting FIT cohort (71.2% vs 60.4%, Chi squared 42.8, p [less than] 0.0001) and the proportion of “rule in” results ≥150.0 μg Hb/g faeces was significantly lower (4.1% vs 8.1%, Chi squared 27.3,P [less than] 0.0001).There was a 33% rise in urgent referrals across Nottingham overall during the evaluation period. 2 CRC diagnoses were made in 4082 patients who had FIT[less than]4.0 μg Hb/g faeces. 58.4% of new CRC diagnoses associated with a positive FIT were early stage cancers (Stage I and II). The proportion of all CRC diagnoses that follow an urgent referral s rose after introduction of FIT.ConclusionsFIT allows GP's to select a more appropriate cohort for urgent investigation without a large number of missed diagnoses. FIT appears to promise a “stage migration” effect which may ultimately improve CRC outcomes.

Background A novel pathway incorporating faecal immunochemical testing (FIT) for rapid colorectal cancer diagnosis (RCCD) was introduced in 2017. This paper reports on the service evaluation after 2 years of pathway implementation. Methods The RCCD protocol was based on FIT, blood results and symptoms to stratify adult patients in primary care. Two-week-wait (2WW) investigation was indicated for patients with rectal bleeding, rectal mass and faecal haemoglobin (fHb) level of 10 µg Hb/g faeces or above or 4 µg Hb/g faeces or more in the presence of anaemia, low ferritin or thrombocytosis, in all other symptom groups. Patients with 100 µg Hb/g faeces or above had expedited investigation . A retrospective audit of colorectal cancer detected between 2017 and 2019 was conducted, fHb thresholds were reviewed and critically assessed for cancer diagnoses. Results In 2 years, 14788 FIT tests were dispatched with 13361 (90.4 per cent) completed returns. Overall, fHb was less than 4 µg Hb/g faeces in 9208 results (68.9 per cent), 4–9.9 µg Hb/g in 1583 (11.8 per cent), 10–99.9 µg Hb/g in 1850 (13.8 per cent) and 100 µg Hb/g faeces or above in 720 (5.4 per cent). During follow-up (median 10.4 months), 227 colorectal cancers were diagnosed. The cancer detection rate was 0.1 per cent in patients with fHb below 4 µg Hb/g faeces, 0.6 per cent in those with fHb 4–9.9 µg Hb/g faeces, 3.3 per cent for fHb 10–99.9 µg Hb/g faeces and 20.7 per cent for fHb 100 µg Hb/g faeces or above. The detection rate in the cohort with 10–19.9 µg Hb/g faeces was 1.4 per cent, below the National Institute for Health and Care Excellence threshold for urgent referral. The colorectal cancer rate in patients with fHb below 20 µg Hb/g faeces was less than 0.3 per cent. Conclusion Use of FIT to "rule out" urgent referral from primary care misses a small number of cases. The threshold for referral may be adjusted with blood results to improve stratification ., We present outcome data from a service evaluation that demonstrates clinical effectiveness and safety. This strategy may be crucial to overcoming the effects of the Coronavirus pandemic on 2WW and urgent pathways.

Aging is associated with a gradual decline of cellular proteostasis, giving rise to devastating protein misfolding diseases, such as Alzheimer disease (AD) or Parkinson disease (PD). These diseases often exhibit a complex pathology involving non-cell autonomous proteotoxic effects, which are still poorly understood. Using Caenorhabditis elegans we investigated how local protein misfolding is affecting neighboring cells and tissues showing that misfolded PD-associated SNCA/α-synuclein is accumulating in highly dynamic endo-lysosomal vesicles. Irrespective of whether being expressed in muscle cells or dopaminergic neurons, accumulated proteins were transmitted into the hypodermis with increasing age, indicating that epithelial cells might play a role in remote degradation when the local endo-lysosomal degradation capacity is overloaded. Cell biological and genetic approaches revealed that inter-tissue dissemination of SNCA was regulated by endo- and exocytosis (neuron/muscle to hypodermis) and basement membrane remodeling (muscle to hypodermis). Transferred SNCA conformers were, however, inefficiently cleared and induced endo-lysosomal membrane permeabilization. Remarkably, reducing INS (insulin)-IGF1 (insulin-like growth factor 1) signaling provided protection by maintaining endo-lysosomal integrity. This study suggests that the degradation of lysosomal substrates is coordinated across different tissues in metazoan organisms. Because the chronic dissemination of poorly degradable disease proteins into neighboring tissues exerts a non-cell autonomous toxicity, this implies that restoring endo-lysosomal function not only in cells with pathological inclusions, but also in apparently unaffected cell types might help to halt disease progression. Abbreviations: AD: Alzheimer disease; BM: basement membrane; BWM: body wall muscle; CEP: cephalic sensilla; CLEM: correlative light and electron microscopy; CTNS-1: cystinosin (lysosomal protein) homolog; DA: dopaminergic; DAF-2: abnormal dauer formation; ECM: extracellular matrix; FLIM: fluorescence lifetime imaging microscopy; fps: frames per second; GFP: green fluorescent protein; HPF: high pressure freezing; IGF1: insulin-like growth factor 1; INS: insulin; KD: knockdown; LMP: lysosomal membrane permeabilization; MVB: multivesicular body; NOC: nocodazole; PD: Parkinson disease; RFP: red fluorescent protein; RNAi: RNA interference; sfGFP: superfolder GFP; SNCA: synuclein alpha; TEM: transmission electron microscopy; TNTs: tunneling nanotubes; TCSPC: time correlated single photon counting; YFP: yellow fluorescent protein.

A hallmark common to many age-related neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS), is that patients develop proteinaceous deposits in their central nervous system (CNS). The progressive spreading of these inclusions from initially affected sites to interconnected brain areas is reminiscent of the behavior of bona fide prions in transmissible spongiform encephalopathies (TSEs), hence the term prion-like proteins has been coined. Despite intensive research, the exact mechanisms that facilitate the spreading of protein aggregation between cells, and the associated loss of neurons, remain poorly understood. As population demographics in many countries continue to shift to higher life expectancy, the incidence of neurodegenerative diseases is also rising. This represents a major challenge for healthcare systems and patients’ families, since patients require extensive support over several years and there is still no therapy to cure or stop these diseases. The model organism Caenorhabditis elegans offers unique opportunities to accelerate research and drug development due to its genetic amenability, its transparency, and the high degree of conservation of molecular pathways. Here, we will review how recent studies that utilize this soil dwelling nematode have proceeded to investigate the propagation and intercellular transmission of prions and prion-like proteins and discuss their relevance by comparing their findings to observations in other model systems and patients.

Introduction Latest NICE guidance (NG12) on criteria warranting urgent referral for investigation for colorectal cancer (CRC) includes the use of faecal occult blood testing. We present an interim analysis of the ‘Getting FIT’ project – a service evaluation of faecal immunochemical testing (FIT) in symptomatic patients suspected of having CRC. Method In September 2016 we incorporated FIT into our Straight to test (STT) pathway with the support of our local commissioners. GPs were given access to FIT for eligible low risk patients using a specific referral form vetted by the STT team. In two week wait (2WW) referrals, excluding those for rectal bleeding, a FIT kit is posted to patients. STT patients received a vetting telephone call and were told they shall receive a FIT test. Patients are investigated as normal and FIT results, when available, used for prioritisation within our 2WW pathway. Anaemia was defined as haemoglobin We present the results of kits analysed on the OC Sensor according to manufacturer’s protocols (EIKEN OC-Sensor io) expressed in µgHb/gFaeces. Patient outcomes are prospectively recorded on our STT database. Data on patients who returned kits between 6/9/16 and 10/2/17 are included. Results 17 of 19 (89.5%) GP requests and 348 of 441 (78.9%) 2WW kits were returned. Median time for kit return was 7 days (Range 2–24 days) with 94.9% of returned kits received within 14 days. 343 kits yielded results that were analysable and of 325 patients undergoing investigation 14 had confirmed CRC (4.3%). FIT results were significantly higher in patients who were anaemic compared to non-anaemic patients (MannWhitney p 24.9% of FIT samples yielded a zero result, 68.6% a faecal haemoglobin 150 µgHb/gFaeces. Conclusion We report a high return rate for FIT within a 2WW pathway and a turnaround time of Disclosure of Interest None Declared

Background Telehealth has been promoted as an adjunct to managing patients with long-term conditions. It has been used in various settings and for different disease groups. However, robust evidence for the efficacy of telehealth is currently lacking.Objectives To evaluate the impact of a telehealth service on emergency admissions and emergency department (ED) attendances.Methods We evaluated a telehealth service providing supported self-management to patients that was implemented in Nottingham City. Two groups of patients (‘graduates’ of the Nottingham telehealth service and service ‘decliners’) were compared for two periods; 2009 (pre-service implementation) and 2011. Eighty-nine pairs of graduates and decliners were identified who were matched for age and sex. The number and cost of emergency admissions and ED attendances for these patients were then collated and analysed.Results Graduates had significantly fewer emergency admissions and ED attendances compared with decliners in 2011. However, differences of a similar magnitude in emergency admissions and ED attendances were found in 2009. Telehealth service users were likely to be qualitatively different from decliners, reflecting a degree of self-selection. This suggests that decliners were more likely to have a confounding reason for not engaging with telehealth, such as greater disease severity.Conclusions This service review found no evidence that the Nottingham telehealth service has had a significant impact on secondary care utilisation in the short term. Longer term follow up is needed to establish conclusively whether telehealth initiatives like the Nottingham telehealth service does lead to tangible patient benefits and provide value for money.

A soluble form of the kidney membrane metalloendopeptidase, meprin, is present in urine. Urinary meprin is expressed in BALB/C mice with the Mep-1 alpha/alpha genotype (high meprin, expressing meprin-alpha and meprin-beta ) but not in BALB.K mice of the Mep-1b/b genotype (that only express meprin-beta ). Western blotting with antisera specific to the meprin-alpha and the meprin-beta subunits established that the only form of meprin present in urine samples was derived from meprin-alpha. This form of meprin is partially active, and comprises at least three variants by non-reducing SDS/PAGE and by zymography and two protein bands on reducing SDS/PAGE. Sequencing of these two bands established that the N-terminus of the larger protein band begins with the pro-peptide sequence of the alpha-subunit (VSIKH..), whereas the smaller band possessed the mature meprin N-terminal sequence (NAMRDP..). Trypsin is able to remove the pro-peptide, with a concomitant activation in proteolytic activity. After deglycosylation, the size of the pro- and mature forms of urinary meprin are consistent with cleavage in the region of the X-I boundary. There is a pronounced sexual dimorphism in urinary meprin expression. Females secrete a slightly larger form, and its proteolytic activity is about 50% of that released by males. The urinary meprin is therefore a naturally occurring secreted form of this membrane-bound metalloendopeptidase and is more likely to be generated by alternative processing pathways than by specific release mechanisms.