Cortico-ponto-cerebellar pathway in rats. An anatomical study of the somatosensory cortical input to the cerebellum

Cortico-ponto-cerebellar pathway is one of the major subcortical pathways linking sensory cortical areas with distant motor regions of the brain. In this thesis I focus on the projections from the primary somatosensory cortex in order to understand the principles in the organisation of this pathway in rats. Primary somatosensory cortex in rats contains aggregates of granule cells in layer IV, named "barrels" by Woolsey and Van der Loos (1970). There are about 32 whiskers and an equal number of large cortical barrels within the posteromedial barrel subfield (PMBSF) in the primary somatosensory cortex. In addition to its cortical representation the peripheral organisation of the whiskers is replicated in other stations within the afferent pathway, the trigeminal nuclei and the thalamus. This organisation is easily identified both anatomically and physiologically. Therefore rat somatosensory system can serve as a model system to study sensory-motor integration. I mapped terminals from small regions of the primary somatosensory cortex of rats (within and surrounding the PMBSF) in the pontine nuclei using the anterograde tracers Phaseolus vulgaris leucoagglutinin, biocytin and biotinilated dextran-amine. The results demonstrate that cells in layer Vb of all the cortical barrels project to the ipsilateral pons. Most barrel columns terminate within the same set of pontine nuclei with slight medio-lateral shifts in their termination zones. The most rostral, smaller barrel columns and the cortical regions representing intervibrissal fur project bilaterally. This dichotomy is not present in corticotectal projections. Both small and large barrel columns as well as the less granular zones of the somatosensory cortex project to the deep layers of the ipsilateral superior colliculus. Retrograde tracing with fluorescent latex beads demonstrated that at least 70% of layer Vb cells in the primary somatosensory cortex in rats send collaterals to the deep layers of the superior colliculus and the pontine nuclei. Pontine nuclei project as mossy fibres onto the cerebellar cortex. These projections are predominantly contralateral but there are also ipsilateral mossy fibre terminals. Some pontine cells in cats are known to send axons that collateralise within the cerebellar white matter and supply the ipsilateral as well as the contralateral cerebellar cortex (Rosina and Provini, 1982). The experiments in the third chapter were designed to analyse whether and to what extent the axons of the pontine cells in rats, which receive somatosensory cortical inputs related to the whiskers, bifurcate. Whisker sensitive patches in lobules VII, IX and Crus I of the cerebellar cortex were injected with differently coloured fluorescent beads. Both sides of pontine nuclei contained large numbers of retrogradely labelled cells, a small percentage of which was double labelled

Faecal immunochemical tests (FIT) versus colonoscopy for surveillance after screening and polypectomy: a diagnostic accuracy and cost-effectiveness study.

OBJECTIVE: The English Bowel Cancer Screening Programme (BCSP) recommends 3 yearly colonoscopy surveillance for patients at intermediate risk of colorectal cancer (CRC) postpolypectomy (those with three to four small adenomas or one ≥10 mm). We investigated whether faecal immunochemical tests (FITs) could reduce surveillance burden on patients and endoscopy services. DESIGN: Intermediate-risk patients (60-72 years) recommended 3 yearly surveillance were recruited within the BCSP (January 2012-December 2013). FITs were offered at 1, 2 and 3 years postpolypectomy. Invitees consenting and returning a year 1 FIT were included. Participants testing positive (haemoglobin ≥40 µg/g) at years one or two were offered colonoscopy early; all others were offered colonoscopy at 3 years. Diagnostic accuracy for CRC and advanced adenomas (AAs) was estimated considering multiple tests and thresholds. We calculated incremental costs per additional AA and CRC detected by colonoscopy versus FIT surveillance. RESULTS: 74% (5938/8009) of invitees were included in our study having participated at year 1. Of these, 97% returned FITs at years 2 and 3. Three-year cumulative positivity was 13% at the 40 µg/g haemoglobin threshold and 29% at 10 µg/g. 29 participants were diagnosed with CRC and 446 with AAs. Three-year programme sensitivities for CRC and AAs were, respectively, 59% and 33% at 40 µg/g, and 72% and 57% at 10 µg/g. Incremental costs per additional AA and CRC detected by colonoscopy versus FIT (40 µg/g) surveillance were £7354 and £180 778, respectively. CONCLUSIONS: Replacing 3 yearly colonoscopy surveillance in intermediate-risk patients with annual FIT could reduce colonoscopies by 71%, significantly cut costs but could miss 30%-40% of CRCs and 40%-70% of AAs. TRIAL REGISTRATION NUMBER: ISRCTN18040196; Results

Impact of general practice endorsement on the social gradient in uptake in bowel cancer screening

This is a summary of independent research funded by the National Institute for Health. Research (NIHR)’s Programme Grants for Applied Research Programme (RP-PG-0609–10106

Biomarkers as predictors of recurrence of atrial fibrillation post ablation: an updated and expanded systematic review and meta-analysis

Background: A high proportion of patients undergoing catheter ablation (CA) for atrial fibrillation (AF) experience recurrence of arrhythmia. This meta-analysis aims to identify pre-ablation serum biomarker(s) associated with arrhythmia recurrence to improve patient selection before CA. Methods: A systematic approach following PRISMA reporting guidelines was utilised in libraries (Pubmed/Medline, Embase, Web of Science, Scopus) and supplemented by scanning through bibliographies of articles. Biomarker levels were compared using a random-effects model and presented as odds ratio (OR). Heterogeneity was examined by meta-regression and subgroup analysis. Results: In total, 73 studies were identified after inclusion and exclusion criteria were applied. Nine out of 22 biomarkers showed association with recurrence of AF after CA. High levels of N-Terminal-pro-B-type-Natriuretic Peptide [OR (95% CI), 3.11 (1.80–5.36)], B-type Natriuretic Peptide [BNP, 2.91 (1.74–4.88)], high-sensitivity C-Reactive Protein [2.04 (1.28–3.23)], Carboxy-terminal telopeptide of collagen type I [1.89 (1.16–3.08)] and Interleukin-6 [1.83 (1.18–2.84)] were strongly associated with identifying patients with AF recurrence. Meta-regression highlighted that AF type had a significant impact on BNP levels (heterogeneity R2 = 55%). Subgroup analysis showed that high BNP levels were more strongly associated with AF recurrence in paroxysmal AF (PAF) cohorts compared to the addition of non-PAF patients. Egger’s test ruled out the presence of publication bias from small-study effects. Conclusion: Ranking biomarkers based on the strength of association with outcome provides each biomarker relative capacity to predict AF recurrence. This will provide randomised controlled trials, a guide to choosing a priori tool for identifying patients likely to revert to AF, which are required to substantiate these findings

Is whole-colon investigation by colonoscopy, computerised tomography colonography or barium enema necessary for all patients with colorectal cancer symptoms, and for which patients would flexible sigmoidoscopy suffice? A retrospective cohort study

Background: For patients referred to hospital with suspected colorectal cancer (CRC), it is current standard clinical practice to conduct an examination of the whole colon and rectum. However, studies have shown that an examination of the distal colorectum using flexible sigmoidoscopy (FS) can be a safe and clinically effective investigation for some patients. These findings require validation in a multicentre study. Objectives: To investigate the links between patient symptoms at presentation and CRC risk by subsite, and to provide evidence of whether or not FS is an effective alternative to whole-colon investigation (WCI) in patients whose symptoms do not suggest proximal or obstructive disease. Design: A multicentre retrospective study using data collected prospectively from two randomised controlled trials. Additional data were collected from trial diagnostic procedure reports and hospital records. CRC diagnoses within 3 years of referral were sourced from hospital records and national cancer registries via the Health and Social Care Information Centre. Setting: Participants were recruited to the two randomised controlled trials from 21 NHS hospitals in England between 2004 and 2007. Participants: Men and women aged ≥ 55 years referred to secondary care for the investigation of symptoms suggestive of CRC. Main outcome measure: Diagnostic yield of CRC at distal (to the splenic flexure) and proximal subsites by symptoms/clinical signs at presentation. Results: The data set for analysis comprised 7380 patients, of whom 59% were women (median age 69 years, interquartile range 62–76 years). Change in bowel habit (CIBH) was the most frequently presenting symptom (73%), followed by rectal bleeding (38%) and abdominal pain (29%); 26% of patients had anaemia. CRC was diagnosed in 551 patients (7.5%): 424 (77%) patients with distal CRC, 122 (22%) patients with cancer proximal to the descending colon and five patients with both proximal and distal CRC. Proximal cancer was diagnosed in 96 out of 2021 (4.8%) patients with anaemia and/or an abdominal mass. The yield of proximal cancer in patients without anaemia or an abdominal mass who presented with rectal bleeding with or without a CIBH or with a CIBH to looser and/or more frequent stools as a single symptom was low (0.5%). These low-risk groups for proximal cancer accounted for 41% (3032/7380) of the cohort; only three proximal cancers were diagnosed in 814 low-risk patients examined by FS (diagnostic yield 0.4%). Limitations: A limitation to this study is that changes to practice since the trial ended, such as new referral guidelines and improvements in endoscopy quality, potentially weaken the generalisability of our findings. Conclusions: Symptom profiles can be used to determine whether or not WCI is necessary. Most proximal cancers were diagnosed in patients who presented with anaemia and/or an abdominal mass. In patients without anaemia or an abdominal mass, proximal cancer diagnoses were rare in those with rectal bleeding with or without a CIBH or with a CIBH to looser and/or more frequent stools as a single symptom. FS alone should be a safe and clinically effective investigation in these patients. A cost-effectiveness analysis of symptom-based tailoring of diagnostic investigations for CRC is recommended. Trial registration: Current Controlled Trials ISRCTN95152621. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 66. See the NIHR Journals Library website for further project information

Computed tomographic colonography versus colonoscopy for investigation of patients with symptoms suggestive of colorectal cancer (SIGGAR): a multicentre randomised trial

BACKGROUND: Colonoscopy is the gold-standard test for investigation of symptoms suggestive of colorectal cancer; computed tomographic colonography (CTC) is an alternative, less invasive test. However, additional investigation after CTC is needed to confirm suspected colonic lesions, and this is an important factor in establishing the feasibility of CTC as an alternative to colonoscopy. We aimed to compare rates of additional colonic investigation after CTC or colonoscopy for detection of colorectal cancer or large (?10 mm) polyps in symptomatic patients in clinical practice.METHODS: This pragmatic multicentre randomised trial recruited patients with symptoms suggestive of colorectal cancer from 21 UK hospitals. Eligible patients were aged 55 years or older and regarded by their referring clinician as suitable for colonoscopy. Patients were randomly assigned (2:1) to colonoscopy or CTC by computer-generated random numbers, in blocks of six, stratified by trial centre and sex. We analysed the primary outcome-the rate of additional colonic investigation-by intention to treat. The trial is an International Standard Randomised Controlled Trial, number 95152621.FINDINGS: 1610 patients were randomly assigned to receive either colonoscopy (n=1072) or CTC (n=538). 30 patients withdrew consent, leaving for analysis 1047 assigned to colonoscopy and 533 assigned to CTC. 160 (30.0%) patients in the CTC group had additional colonic investigation compared with 86 (8.2%) in the colonoscopy group (relative risk 3.65, 95% CI 2.87-4.65; p<0.0001). Almost half the referrals after CTC were for small (<10 mm) polyps or clinical uncertainty, with low predictive value for large polyps or cancer. Detection rates of colorectal cancer or large polyps in the trial cohort were 11% for both procedures. CTC missed 1 of 29 colorectal cancers and colonoscopy missed none (of 55). Serious adverse events were rare.INTERPRETATION: Guidelines are needed to reduce the referral rate after CTC. For most patients, however, CTC provides a similarly sensitive, less invasive alternative to colonoscopy.FUNDING: NIHR Health Technology Assessment Programme, NIHR Biomedical Research Centres funding scheme, Cancer Research UK, EPSRC Multidisciplinary Assessment of Technology Centre for Healthcare, and NIHR Collaborations for Leadership in Applied Health Research and Care

Computed tomographic colonography versus barium enema for diagnosis of colorectal cancer or large polyps in symptomatic patients (SIGGAR): a multicentre randomised trial

BACKGROUND: Barium enema (BE) is widely available for diagnosis of colorectal cancer despite concerns about its accuracy and acceptability. Computed tomographic colonography (CTC) might be a more sensitive and acceptable alternative. We aimed to compare CTC and BE for diagnosis of colorectal cancer or large polyps in symptomatic patients in clinical practice.METHODS: This pragmatic multicentre randomised trial recruited patients with symptoms suggestive of colorectal cancer from 21 UK hospitals. Eligible patients were aged 55 years or older and regarded by their referring clinician as suitable for radiological investigation of the colon. Patients were randomly assigned (2:1) to BE or CTC by computer-generated random numbers, in blocks of six, stratified by trial centre and sex. We analysed the primary outcome-diagnosis of colorectal cancer or large (?10 mm) polyps-by intention to treat. The trial is an International Standard Randomised Controlled Trial, number 95152621.FINDINGS: 3838 patients were randomly assigned to receive either BE (n=2553) or CTC (n=1285). 34 patients withdrew consent, leaving for analysis 2527 assigned to BE and 1277 assigned to CTC. The detection rate of colorectal cancer or large polyps was significantly higher in patients assigned to CTC than in those assigned to BE (93 [7.3%] of 1277 vs 141 [5.6%] of 2527, relative risk 1.31, 95% CI 1.01-1.68; p=0.0390). CTC missed three of 45 colorectal cancers and BE missed 12 of 85. The rate of additional colonic investigation was higher after CTC than after BE (283 [23.5%] of 1206 CTC patients had additional investigation vs 422 [18.3%] of 2300 BE patients; p=0.0003), due mainly to a higher polyp detection rate. Serious adverse events were rare.INTERPRETATION: CTC is a more sensitive test than BE. Our results suggest that CTC should be the preferred radiological test for patients with symptoms suggestive of colorectal cancer.FUNDING: NIHR Health Technology Assessment Programme, NIHR Biomedical Research Centres funding scheme, Cancer Research UK, EPSRC Multidisciplinary Assessment of Technology Centre for Healthcare, and NIHR Collaborations for Leadership in Applied Health Research and Care.<br/