Withybush General Hospital

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

OBJECTIVES: To describe hysterectomies practised in 1994 and 1995: the patients, their surgery and short term outcomes. DESIGN: One of two large cohorts, with prospective follow up, recruited to compare the outcomes of endometrial destruction with those of hysterectomy. SETTING: England, Wales and Northern Ireland. POPULATION: All women who had hysterectomies for non-malignant indications carried out during a 12-month period. METHODS: Gynaecologists in NHS and independent hospitals were asked to report cases. Follow up data were obtained at outpatient follow up approximately six weeks post-surgery. MAIN OUTCOME MEASURES: Indication for surgery, method of hysterectomy, ovarian status post-surgery, surgical complications. RESULTS: 37,298 cases were reported which is estimated to reflect about 45% of hysterectomies performed during the period studied. The median age was 45 years, and the most common indication for surgery was dysfunctional uterine bleeding (46%). Most hysterectomies were carried out by consultants (55%). The proportions of women having abdominal, vaginal or laparoscopically-assisted hysterectomy were 67%, 30% and 3%, respectively. Forty-three percent of women had no ovaries conserved after surgery. The median length of stay was five days. The overall operative complication rate was 3.5%, and highest for the laparoscopic techniques. The overall post-operative complication rate was 9%. One percent of these was regarded as severe, with the highest rate for severe in the laparoscopic group (2%). There were no operative deaths; 14 deaths were reported within the six-week post-operative period: a crude mortality rate soon after surgery of 0.38 per thousand (95% CI 0.25-0.64). CONCLUSIONS: This large study describes women who undergo hysterectomy in the UK, and presents results on early complications associated with the surgery. Operative complications occurred in one in 30 women, and post-operative complications in at least one in 10. Laparoscopic techniques tend to be associated with higher complication rates than other methods.

Between 1996 and 2003, 186 cases of hepatitis E were serologically diagnosed. Of these, 17 (9%) were not associated with recent travel abroad. Patients were >55 years old (range, 56-82 years old) and tended to be male (76%). Two patients presented with fulminant hepatitis. A total of 129 (69%) cases were associated with recent travel to countries where hepatitis E virus (HEV) is hyperendemic. Compared with patients with travel-associated disease, patients with non-travel-associated disease were more likely to be older, living in coastal or estuarine areas, not of South Asian ethnicity, and infected by genotype 3 strains of HEV. The genotype 3 subgenomic nucleotide sequences were unique and closely related to those from British pigs. Patients infected by HEV indigenous to England and Wales tended to belong to a distinct demographic group, there were multiple sources of infection, and pigs might have been a viral reservoir.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

Autistic women are overrepresented among people in treatment for Anorexia Nervosa (AN). The current study aimed to: (1) better understand how AN develops and persists in autistic individuals from the perspective of autistic women, parents and healthcare professionals; (2) derive a theoretical model of restrictive eating difficulties in autism. We conducted 44 semi-structured interviews and used Thematic Analysis to identify patterns of meaning across the data. Themes related to sensory sensitivities, social interaction and relationships, sense of self and identity, difficulties with emotions, thinking styles, and a need for control and predictability. We developed a model of potential autism-specific mechanisms underlying restrictive eating difficulties. This study generated novel insights, which have the potential to inform treatment adaptations following empirical testing.

BACKGROUND: The use of prophylactic radiotherapy to prevent procedure-tract metastases (PTMs) in malignant pleural mesothelioma remains controversial, and clinical practice varies worldwide. We aimed to compare prophylactic radiotherapy with deferred radiotherapy (given only when a PTM developed) in a suitably powered trial. METHODS: We did a multicentre, open-label, phase 3, randomised controlled trial in 22 UK hospitals of patients with histocytologically proven mesothelioma who had undergone large-bore pleural interventions in the 35 days prior to recruitment. Eligible patients were randomised (1:1), using a computer-generated sequence, to receive immediate radiotherapy (21 Gy in three fractions within 42 days of the pleural intervention) or deferred radiotherapy (same dose given within 35 days of PTM diagnosis). Randomisation was minimised by histological subtype, surgical versus non-surgical procedure, and pleural procedure (indwelling pleural catheter vs other). The primary outcome was the incidence of PTM within 7 cm of the site of pleural intervention within 12 months from randomisation, assessed in the intention-to-treat population. This trial is registered with ISRCTN, number ISRCTN72767336. FINDINGS: Between Dec 23, 2011, and Aug 4, 2014, we randomised 203 patients to receive immediate radiotherapy (n=102) or deferred radiotherapy (n=101). The patients were well matched at baseline. No significant difference was seen in PTM incidence in the immediate and deferred radiotherapy groups (nine [9%] vs 16 [16%]; odds ratio 0·51 [95% CI 0·19-1·32]; p=0·14). The only serious adverse event related to a PTM or radiotherapy was development of a painful PTM within the radiotherapy field that required hospital admission for symptom control in one patient who received immediate radiotherapy. Common adverse events of immediate radiotherapy were skin toxicity (grade 1 in 50 [54%] and grade 2 in four [4%] of 92 patients vs grade 1 in three [60%] and grade 2 in two [40%] of five patients in the deferred radiotherapy group who received radiotherapy for a PTM) and tiredness or lethargy (36 [39%] in the immediate radiotherapy group vs two [40%] in the deferred radiotherapy group) within 3 months of receiving radiotherapy. INTERPRETATION: Routine use of prophylactic radiotherapy in all patients with mesothelioma after large-bore thoracic interventions is not justified. FUNDING: Research for Patient Benefit Programme from the UK National Institute for Health Research.

The Al ‘Ays ophiolite complex in Saudi Arabia is an example of an ophiolite that contains anomalous concentrations of all six platinum group elements (PGE) in podiform chromitite with maximum values of 2,570 ppb Pt, 6,870 ppb Pd, 840 ppb Rh, 5,800 ppb Ru, 6,200 ppb Ir, and 3,300 ppb Os. Smooth chondrite-normalized PGE profiles indicate igneous PGE ratios. These suggest that in situ alteration of the PGM caused only minor mobility of PGE during secondary modification of the mineralogy. Thus the geochemistry of the igneous concentration processes can be examined despite the mineralogical changes caused by subsequent alteration. &#13;\n&#13;\nThree main types of PGE mineralization are observed that are defined by their relative abundances of individual PGE. Type 1 has Ru &gt; both Pt and Pd, with negative-slope chondrite-normalized profiles. Type 2 has Ru &lt; either Pt or Pd, (Pt+Pd)/Ir ratios of 1 to 5, and convex upward chondrite-normalized profiles. Type 3 has Ru &lt; either Pt or Pd, (Pt+Pd)/Ir ratios of 5 to 60, positive-slope chondrite-normalized profiles and is associated with elevated Cu and Ni concentrations. The unaltered centers of chromite grains in the chromitite within this complex have an unusually large range of composition; for example, Cr2O3 varies from 39 to 69 wt percent. PGE mineralization types 1, 2, and 3 are related to the composition of the chromite. Type 1 occurs across the range of chromitite compositions from 39 to 69 wt percent Cr2O3, type 2 occurs in chromitite having a range of 53 to 61 wt percent Cr2O3 , and type 3 occurs in chromitite having a range of 39 to 51 wt percent Cr2O3. &#13;\n&#13;\nThe PGE form a great variety of platinum group minerals (PGM) and they differ among the three types of PGE mineralization. Type 1 is characterized by euhedral Os, Ir, and Ru (IPGE) alloys and laurite, both commonly enclosed in chromite, as well as members of the irarsite hollingworthite solid-solution series and Pt-IPGE-bearing PGM, both commonly interstitial to the chromite grains. Type 2 PGE enrichment is characterized by IPGE-, Pt- and Rh-bearing PGM. Type 3 PGE enrichment hosts predominantly Pd- and Pt-bearing PGM associated with Ni- and Cu-bearing minerals. Where exposed to the serpentinization process, the PGM are altered to alloys, arsenides, antimonides, and oxides that form irregular shapes or may form pseudomorphs of former PGM. They are commonly associated with Ni- and Cu-bearing minerals, including ruthanian pentlandite, millerite, arsenides, and PGE-bearing awaruite. &#13;\n&#13;\nMantle melting and subsequent crystallization were at an optimum to concentrate PGE in the Al ‘Ays ophiolite complex. Crystallization of IPGE, commonly prior to chromite crystallization and latterly with some Pt and Rh, occurred across the range of chromitite composition. Crystallization of Pd with some remaining Pt occurred during sulfur saturation in chromitite formed from a more evolved magma. We propose that this crystallization was from a magma that was enriched in PGE because the degree of mantle melting was just sufficient to extract the PGE, but not dilute them in a melt that includes further mantle melting. This feature is likely to be common to other PGE-rich ophiolite complexes such as in Shetland in the United Kingdom, Leka in Norway, Thetford in Canada, Pindos in Greece, Tropoja in Albania and in New Caledonia. If equilibrium partial melting had continued in Al ‘Ays, then the magma would have been diluted by subsequent PGE-poor melt. This would have prevented sulfur saturation until much higher in the sequence, producing Pt- and Pd-bearing base metal sulfides in the crustal wehrlite and gabbro, as has occurred in the Cyprus and Oman ophiolites.

The third edition of Fundamentals of Anaesthesia is the gold standard text for the Primary FRCA, encapsulating the basic principles of modern anaesthesia in one easily accessible volume. Written and edited by a team of expert contributors with extensive FRCA examination experience, Fundamentals of Anaesthesia, 3rd edition deliberately blends the expertise of invited authors in an unrivalled consistency of style more akin to that of a single author text. Deliberate use of authors with a more general anaesthesia background ties in well with the education of anaesthetists in their early years. The third edition is fully updated, with a number of completely new chapters. Presentation of information is clear and concise, with extensive use of tables, colour illustrations, summary boxes of key information and bullet lists. This Highly Commended award winning textbook is a unique revision aid for the Primary FRCA and an essential companion for all exam candidates.

BACKGROUND AND PURPOSE: There are no previously published studies of the long-term outcome of stroke in sub-Saharan Africa. Our goal was to determine the case fatality, time to and cause of death, and recovery in a hospital cohort of stroke patients in The Gambia. METHODS: For 1 year beginning April 1, 1990, any patient presenting to the Royal Victoria Hospital (Banjul) with a diagnosis of stroke or having a stroke as an inpatient was recruited. After a standardized assessment, patients were followed up at 1 month, 6 months, and 3 to 4 years to assess recovery or, for those who died, record the date and likely cause of death. RESULTS: Mean age of the 106 patients (70 men) was 58 years (range, 20 to 93 years). By 1 and 6 months, 29 (27%) and 47 (44%), respectively, had died, with only 27 (25%) surviving to final follow-up (4 patients not traced). Death occurred in hospital in 43 patients (57%). Cause of death was the initial stroke in 46 (61%), further stroke in 5 (7%), infection in 9 (12%), miscellaneous in 8 (11%) (only 1 vascular), and unknown in 7 (9%). On Cox regression analysis, incontinence in the first 24 hours, sensory inattention, and impaired gag reflex on admission were significant predictors of mortality. Predictors of recovery were similar to those of developed countries. CONCLUSIONS: Despite the young mean age, there was a high case fatality rate. The main cause of death was the stroke itself, and ischemic heart disease was very rare.

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.

Anti tumour necrosis factor (anti-TNF) drugs increase the risk of serious respiratory infection and impair protective immunity following pneumococcal and influenza vaccination. Here we report SARS-CoV-2 vaccine-induced immune responses and breakthrough infections in patients with inflammatory bowel disease, who are treated either with the anti-TNF antibody, infliximab, or with vedolizumab targeting a gut-specific anti-integrin that does not impair systemic immunity. Geometric mean [SD] anti-S RBD antibody concentrations are lower and half-lives shorter in patients treated with infliximab than vedolizumab, following two doses of BNT162b2 (566.7 U/mL [6.2] vs 4555.3 U/mL [5.4], p <0.0001; 26.8 days [95% CI 26.2 - 27.5] vs 47.6 days [45.5 - 49.8], p <0.0001); similar results are also observed with ChAdOx1 nCoV-19 vaccination (184.7 U/mL [5.0] vs 784.0 U/mL [3.5], p <0.0001; 35.9 days [34.9 - 36.8] vs 58.0 days [55.0 - 61.3], p value < 0.0001). One fifth of patients fail to mount a T cell response in both treatment groups. Breakthrough SARS-CoV-2 infections are more frequent (5.8% (201/3441) vs 3.9% (66/1682), p = 0.0039) in patients treated with infliximab than vedolizumab, and the risk of breakthrough SARS-CoV-2 infection is predicted by peak anti-S RBD antibody concentration after two vaccine doses. Irrespective of the treatments, higher, more sustained antibody levels are observed in patients with a history of SARS-CoV-2 infection prior to vaccination. Our results thus suggest that adapted vaccination schedules may be required to induce immunity in at-risk, anti-TNF-treated patients.

BACKGROUND: We report a population-based comparison of psychosexual health 5 years after contrasting amounts of surgical treatments for heavy periods [dysfunctional uterine bleeding (DUB)]. Women's fears about sexual function after hysterectomy might not be unfounded. The psychosexual problems may return and/or develop with time. The removal of ovaries at the time of hysterectomy is associated with greater deterioration of self-reported sexual function. Surgical menopause significantly impairs sexual wellbeing. We failed to observe uniform beneficial effects of hormone replacement therapy (HRT) on reported psychosexual health. OBJECTIVE: To compare self-reported bothersome sexual function; loss of interest in sex, difficulty in becoming sexually excited and vaginal dryness 5 years after surgical management of DUB [transcervical endometrial resection/ablation (TCRE) or subtotal and total hysterectomy, with and without prophylactic bilateral oophorectomy (BO)]. DESIGN: Prospective cohort study up to 5 years post-surgery for DUB, TCRE or hysterectomy, with or without BO. SETTING: Over 400 NHS and private hospitals in England, Northern Ireland and Wales. COHORT: Of 11,325 women who responded to the 5-year questionnaire, over 9500 (84%) were valid cases, and over 8900 (94%) did complete the questions relating to psychosexual function. Most were between the ages of 39 and 45 years, married or cohabiting. MAIN OUTCOMES: Self-reported experience of bother, recorded as 'some', 'severe' and 'extreme', to questions on (1) libido loss, (2) difficulty with sexual arousal, and (3) vaginal dryness during the past 4 weeks, 5 years after surgery. RESULTS: Five years after surgery for DUB, the crude and adjusted prevalence of psychosexual problems was higher after hysterectomy than after TCRE. Amongst the women with concurrent BO, the age- and HRT-adjusted odds ratios for extreme psychosexual problems were increased by 80% (libido loss), 82% (difficult sex arousal) and 69% (vaginal dryness) compared with TCRE. CONCLUSIONS: Five years after hysterectomy more women reported having bothersome psychosexual function than did the women who had a less invasive operation. Hormone therapy, although related to surgical method, did not reduce this long-term detrimental effect. The odds were particularly high amongst women with concurrent BO. Women should be advised that they might be at higher risk of psychosexual problems following hysterectomy, compared with a less invasive procedure.

Movements of native brown trout, Salmo trutta , 1 + and older, were limited with up to 93% of recaptured marked fish occupying sites where previously caught. Movements &gt; 50 m were rare with the majority &lt; 15 m. Between sampling occasions, the population could be separated into a static component and a smaller mobile component but there was no evidence of a permanently mobile group. The proportion of mobile native fish increased after stocking with hatchery‐reared trout. Displaced native trout (1 + and older) showed the ability to home from 75 m upstream to 111 m downstream of a release site.

ABSTRACT Medetomidine (10, 20, 40 μg/kg) was used as a premedicant before thiopentone, halothane and nitrous oxide anaesthesia in 60 dogs undergoing a variety of elective surgical and diagnostic procedures at the University of Liverpool Small Animal Hospital. The efficacy of the sedation produced by the three dose groups was evaluated using a sedation scoring system which is presented. Induction of anaesthesia was accomplished using 1–25 per cent thiopentone sodium administered slowly to effect. The mean dose of thiopentone required for intubation following 10 μ‐g/kg medetomidine (group 1) was 6–9 mg/kg (SD ± 2–3 mg/kg), following 20 μ‐g/kg medetomidine (group 2) was 4–5 mg/kg (SD ± 1–6 mg/kg) and following 40 μg/kg (group 3) was 2–4 mg/kg (SD ± 2–5 mg/kg). Induction of anaesthesia was generally smooth and significant apnoea (greater than 45 seconds) was not noted. Anaesthesia was maintained in all cases using halothane vapourised in a one part oxygen to two parts nitrous oxide mixture, delivered to the patient via a suitable non‐breathing circuit (Magill, Bain or T Piece). At the conclusion of the procedure, atipamezole (50, 100, 200 μg/kg) was administered intramuscularly to half of the dogs in each group (10 dogs). Dogs receiving atipamezole recovered rapidly and smoothly to sternal recumbency, group 1 taking 8‐5 minutes (SD ± 2–7 minutes), group 2 taking 11‐8 minutes (SD ± 3–6 minutes), and group 3 taking 12‐6 minutes (sd ± 4–5 minutes). When atipamezole was not administered a dose dependent increase in recumbency time occurred.

Prescribed fire can potentially reduce carbon emissions from unplanned fires. This potential will differ among ecosystems owing to inherent differences in the efficacy of prescribed burning in reducing unplanned fire activity (or ‘leverage’, i.e. the reduction in area of unplanned fire per unit area of prescribed fire). In temperate eucalypt forests, prescribed burning leverage is relatively low and potential for mitigation of carbon emissions from unplanned fires via prescribed fire is potentially limited. Simulations of fire regimes accounting for non-linear patterns of fuel dynamics for three fuel types characteristic of eucalypt forests in south-eastern Australia supported this prediction. Estimated mean annual fuel consumption increased with diminishing leverage and increasing rate of prescribed burning, even though average fire intensity (prescribed and unplanned fires combined) decreased. The results indicated that use of prescribed burning in these temperate forests is unlikely to yield a net reduction in carbon emissions. Future increases in burning rates under climate change may increase emissions and reduce carbon sequestration. A more detailed understanding of the efficacy of prescribed burning and dynamics of combustible biomass pools is required to clarify the potential for mitigation of carbon emissions in temperate eucalypt forests and other ecosystems.

OBJECTIVE: To investigate the impact on outcome of delay between referral and diagnosis in colorectal cancer (CRC). PATIENTS AND METHODS: One hundred and fifty-four patients were studied after excluding from a consecutive series of 411 with CRC, those with factors known to affect the prognosis that may also have affected the speed of diagnosis. These were advanced disease, emergency admission or surgery, referral with diagnosis already made, and tumours treated by colonoscopic polypectomy alone. Possible causative factors were compared between early and late diagnosis groups. For assessment of symptom risk, the Department of Health criteria were used. RESULTS: Forty-four patients had Referral to Diagnosis Interval (RDI) > or = 50 days ('Late'), and 110 had RDI < 50 days ('Early'). In the Late group there were only 2 deaths from cancer and 93.7% cancer-specific five year survival (c5ys), compared with 22 and 65.3%, respectively, in the Early one (P = 0.007). There were more Duke's A cases in the Late group (38.6%vs 15.2%, P = 0.006), but this did not fully explain the improved survival. Comparisons for each Duke's Stage showed improved c5ys for Late Duke's B ones (100% of 16 vs 60.3% of 54, P = 0.039). Late patients had more low risk symptoms than Early ones, both overall (31.8%vs 13.7%, P = 0.013) and in Duke's B cases (56%vs 15.3%, P = 0.003). Tumours were smaller in the Late group (length 35.3 vs 41.6 mm, P= 0.04); this difference was confined to the Duke's A patients and sigmoid tumours. Late sigmoid tumours were not only shorter (32.4 vs 45.9 mm, P = 0.02) but also were all cured (c5ys 100% of 18 vs 60.3% of 23, P = 0.011). There were no differences between Late and Early groups in: age (mean 69.9 years), sex (male 57.7%), date of diagnosis (mean December 1998), ASA comorbidity index (mean 1.9), number of lymph nodes found in the operative specimen (mean 8.6), or histological grading (moderate differentiation 94.4%). CONCLUSION: In the context of modern rapid access clinics, symptomatic CRC patients with delay between referral and diagnosis (even if this is several months or occasionally more than a year) have less aggressive tumours and markedly better long-term cure rate than their earlier diagnosed counterparts. Attempts to speed up further the diagnosis would be a waste of time and resources, being unlikely to make an appreciable difference to the overall cure rate.

AIM: Our aim was to undertake a systematic review of the comparison of the methods used to train staff in clinical skills. METHODS: The only studies considered were those that compared two different training methods and contained defined outcome measures. The skills of intubation, venous cannulation and central venous line insertion were chosen as representative of the type of physical skills taught to clinicians. RESULTS: Only nine papers met the eligibility criteria with most papers evaluating a single teaching method. A wide range of teaching methods were used, including lectures, computer-based teaching, manikins and video assisted feedback. The studies included nurses, doctors, paramedics and medical students. CONCLUSIONS: Although no clear conclusions can be drawn from the studies, it appears that the teaching methods used have little effect on outcomes. In contrast, better outcomes are associated with workplace-based training and a course which provides repeated episodes of training spaced out over a period of weeks/months with the facility for practice of the skill. These findings are important as many current clinical skills training courses do not use the techniques associated with better outcomes.

BACKGROUND: Colonoscopy is the gold standard investigation for large bowel disease. With the increase in demand, pressure is on clinics to shorten lengths of time per procedure in addition to maintaining high levels of patient safety. Analgesia has always been the mainstay of adequate pain relief, but it leads to prolonged recovery and lengths of hospital stay, in addition to increased risk of cardio-respiratory side effects. N2O/O2 mixtures have been used for its effective analgesic effect and short half life and provides an alternative method of sedation for colonoscopy procedures. OBJECTIVES: The primary objective was to compare the overall effectiveness of nitrous oxide mixtures to other types of pain relief used during colonoscopy procedures to provide adequate pain/discomfort relief.The secondary objective was to compare between nitrous oxide and other types of pain relief with respect to hospitalisation/recovery time, side effects, patients and endoscopists satisfaction, and colonoscopy completion rates. SEARCH STRATEGY: The following electronic databases were searched: Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE (1966- present), EMBASE (1980 - present), and the Internet (Google Scholar). SELECTION CRITERIA: Randomised controlled trials which compared nitrous oxide to placebo or active comparators for patients undergoing elective colonoscopic procedures. Patients with known underlying causes of pain/discomfort were excluded. DATA COLLECTION AND ANALYSIS: Seven randomised trials were included. Each trial compared a nitrous oxide/oxygen mixture to a placebo or sedation +- other analgesic drugs on patients undergoing elective colonoscopic procedures. The results of these studies were analysed and discussed. MAIN RESULTS: There were a total of 547 patients included.There were 257 patients randomised to receive the N2O/O2 mixture (7 studies), while 225 patients received some form of sedation with or without other analgesia (6 studies), and 65 patients received a placebo (3 studies).Four studies showed that N2O/O2 is as good in controlling pain/discomfort as conventional methods, while one showed sedation was better and another study showed N2O/O2 was better.Six of the studies showed that N2O/O2 groups had quicker recovery times and shorter lengths of hospital stays while one study showed that there was no difference between the two groups.Two studies showed that N2O/O2 was safer while one reported that sedation was safer. AUTHORS' CONCLUSIONS: Nitrous oxide is as efficient and safer than various pain relief methods used during colonoscopy procedures, but further trials are necessary.