A candidate super-Earth planet orbiting near the snow line of Barnard's star.

Barnard's star is a red dwarf, and has the largest proper motion (apparent motion across the sky) of all known stars. At a distance of 1.8 parsecs1, it is the closest single star to the Sun; only the three stars in the α Centauri system are closer. Barnard's star is also among the least magnetically active red dwarfs known2,3 and has an estimated age older than the Solar System. Its properties make it a prime target for planetary searches; various techniques with different sensitivity limits have been used previously, including radial-velocity imaging4-6, astrometry7,8 and direct imaging9, but all ultimately led to negative or null results. Here we combine numerous measurements from high-precision radial-velocity instruments, revealing the presence of a low-amplitude periodic signal with a period of 233 days. Independent photometric and spectroscopic monitoring, as well as an analysis of instrumental systematic effects, suggest that this signal is best explained as arising from a planetary companion. The candidate planet around Barnard's star is a cold super-Earth, with a minimum mass of 3.2 times that of Earth, orbiting near its snow line (the minimum distance from the star at which volatile compounds could condense). The combination of all radial-velocity datasets spanning 20 years of measurements additionally reveals a long-term modulation that could arise from a stellar magnetic-activity cycle or from a more distant planetary object. Because of its proximity to the Sun, the candidate planet has a maximum angular separation of 220 milliarcseconds from Barnard's star, making it an excellent target for direct imaging and astrometric observations in the future.

Acute impact of aerobic exercise on local cutaneous thermal hyperaemia.

Little is known about the acute changes in cutaneous microvascular function that occur in response to exercise, the accumulation of which may provide the basis for beneficial chronic cutaneous vascular adaptations. Therefore, we examined the effects of acute exercise on cutaneous thermal hyperaemia. Twelve healthy, recreationally active participants (11 male, 1 female) performed 30-minute cycling at 50 % (low-intensity exercise, LOW) or 75 % (high-intensity exercise, HIGH) maximum heart rate. Laser Doppler flowmetry (LDF) and rapid local skin heating were used to quantify cutaneous thermal hyperaemia before (PRE), immediately following (IMM) and 1-h (1HR) after exercise. Baseline, axon reflex peak, axon reflex nadir, plateau, maximum skin blood flow responses to rapid local heating (42 °C for 30-min followed by 44 °C for 15-min) at each stage were assessed and indexed as cutaneous vascular conductance [CVC = flux / mean arterial blood pressure (MAP), PU·mm Hg-1], and expressed as a percentage of maximum (%CVCmax). Exercise increased heart rate (HR), MAP and skin blood flow (all P < 0.001), and to a greater extent during HIGH (all P < 0.001). The axon reflex peak and nadir were increased immediately and 1-h after exercise (all comparisons P < 0.01 vs. PRE), which did not differ between intensities (peak: P = 0.34, axon reflex nadir: P = 0.91). The endothelium-dependent plateau response was slightly elevated after exercise (P = 0.06), with no effect of intensity (P = 0.58) nor any interaction effect (P = 0.55). CONCLUSION: Exercise increases cutaneous microvascular axonal responses to local heating for up to 1-h, suggesting an augmented sensory afferent function post-exercise. Acute exercise may only modestly affect endothelial function in cutaneous microcirculation.

Comparison of paediatric infectious disease deaths in public sector health facilities using different data sources in the Western Cape, South Africa (2007-2021).

BACKGROUND: Routinely collected population-wide health data are often used to understand mortality trends including child mortality, as these data are often available more readily or quickly and for lower geographic levels than population-wide mortality data. However, understanding the completeness and accuracy of routine health data sources is essential for their appropriate interpretation and use. This study aims to assess the accuracy of diagnostic coding for public sector in-facility childhood (age < 5 years) infectious disease deaths (lower respiratory tract infections [LRTI], diarrhoea, meningitis, and tuberculous meningitis [TBM]) in routine hospital information systems (RHIS) through comparison with causes of death identified in a child death audit system (Child Healthcare Problem Identification Programme [Child PIP]) and the vital registration system (Death Notification [DN] Surveillance) in the Western Cape, South Africa and to calculate admission mortality rates (number of deaths in admitted patients per 1000 live births) using the best available data from all sources. METHODS: The three data sources: RHIS, Child PIP, and DN Surveillance are integrated and linked by the Western Cape Provincial Health Data Centre using a unique patient identifier. We calculated the deduplicated total number of infectious disease deaths and estimated admission mortality rates using all three data sources. We determined the completeness of Child PIP and DN Surveillance in identifying deaths recorded in RHIS and the level of agreement for causes of death between data sources. RESULTS: Completeness of recorded in-facility infectious disease deaths in Child PIP (23/05/2007-08/02/2021) and DN Surveillance (2010-2013) was 70% and 69% respectively. The greatest agreement in infectious causes of death were for diarrhoea and LRTI: 92% and 84% respectively between RHIS and Child PIP, and 98% and 83% respectively between RHIS and DN Surveillance. In-facility infectious disease admission mortality rates decreased significantly for the province: 1.60 (95% CI: 1.37-1.85) to 0.73 (95% CI: 0.56-0.93) deaths per 1000 live births from 2007 to 2020. CONCLUSION: RHIS had accurate causes of death amongst children dying from infectious diseases, particularly for diarrhoea and LRTI, with declining in-facility admission mortality rates over time. We recommend integrating data sources to ensure the most accurate assessment of child deaths.

Point of care ultrasound: Current and future directions for Acute Medicine.

Point of care ultrasound (POCUS) represents an exciting tool for current and future acute care practitioners. POCUS has come a long way in a short space of time and its widespread implementation may well be one of the biggest changes seen in acute medicine across the next decade. This narrative review explores the increasing evidence base for the accuracy of POCUS use in various acute scenarios, whilst also addressing current gaps in the evidence and areas for potential future POCUS development.

IMPARTER, Phase 1 of an intervention to improve patients' understanding of gene expression profiling tests in breast cancer.

PURPOSE: To compare participants' knowledge about gene expression profiling (GEP) tests and recurrence risks after reading an information leaflet with that following viewing of an information film. METHODS: Using a randomised cross-over design, at time-point one (T1), women aged 45-75 years without breast cancer either read leaflets or watched information films about Oncotype DX or Prosigna tests. Participants answered nine questions assessing knowledge (maximum score 18). Next-day information in the opposite modality was provided and knowledge re-assessed. Additional questions probed which format was easiest to understand, participants' preferences for film or leaflet and their reasons for these. RESULTS: 120 women participated (60 received OncotypeDX films and leaflets; 60 received the Prosigna versions). T1 mean knowledge scores were higher following film viewing (13.37) compared with that after reading leaflets (9.25) (mean difference 4.1; p < 0.0001; 95% CI 3.2, 5.0). When participants read leaflets first and subsequently viewed films, all increased their scores (mean + 6.08, from T1 of 9.25, p < 0.0001; 95% CI 5.44, 6.72). When films were viewed first, followed by leaflets, (36/60, 60%), participants' scores declined (mean-1.55 from T1 of 13.37, p < 0.001; 95% CI -2.32, -0.78). A majority of participants expressed preferences for the films (88/120, 73.3%) irrespective as to whether they described OncotypeDX or Prosigna. Reasons included the clarity, ease of understanding, visual material and reassuring voice-over. CONCLUSION: Discussions between oncologists and patients about recurrence risk results can be challenging. Information leaflets may aid understanding but often employ complex language. Information films significantly improved knowledge and were preferred by participants.

The search for a unifying diagnosis involving neurological, endocrine and immune dysfunction: a case report of a novel presentation of DAVID syndrome.

BACKGROUND: We report a novel presentation of deficit in anterior pituitary function with variable immune deficiency (DAVID) syndrome in a healthy young girl presenting in Addisonian crisis with raised intracranial pressure. Nearly all cases of DAVID syndrome described in the literature have presented with recurrent infections and variable immunodeficiency. Pseudotumour cerebri has not been reported in DAVID syndrome to date. CASE PRESENTATION: A four-year-old girl represented to hospital with vomiting, confusion and diplopia after ten days of tiredness, neck and abdominal pain, and headache. Her cranial nerve examination demonstrated a right abducens nerve palsy and papilloedema, and she was found to have ketotic hypoglycaemia and hypocortisolaemia secondary to adrenocorticotrophic hormone (ACTH) deficiency. Her neuroimaging was consistent with pseudotumour cerebri, and her lumbar puncture opening pressure confirmed raised intracranial pressure (30-40 cmH2O). Cerebrospinal fluid analysis was normal. The patient's symptoms improved with hydrocortisone replacement and acetazolamide, but the raised intracranial pressure recurred after acetazolamide was discontinued. She was subsequently found to have panhypogammaglobulinaemia, and DAVID syndrome was diagnosed. Genetic testing demonstrated a truncating mutation in the NFKB2 gene c.2557C > T, p.(Arg853*). CONCLUSIONS: This case demonstrates pseudotumour cerebri as a novel neurological presentation of DAVID syndrome, highlights the rare association between adrenal insufficiency and intracranial hypertension, and shows the challenges in diagnosing isolated ACTH deficiency. We emphasise that cortisol should be checked in pre-pubertal children with pseudotumour cerebri and a diagnosis of DAVID syndrome considered in those presenting with low cortisol and neurological symptoms.

The humanistic burden of vitiligo: a systematic literature review of quality-of-life outcomes.

Despite historical mischaracterization as a cosmetic condition, patients with the autoimmune disorder vitiligo experience substantial quality-of-life (QoL) burden. This systematic literature review of peer-reviewed observational and interventional studies describes comprehensive evidence for humanistic burden in patients with vitiligo. PubMed, EMBASE, Scopus and the Cochrane databases were searched through February 10, 2021, to qualitatively assess QoL in vitiligo. Two independent reviewers assessed articles for inclusion and extracted data for qualitative synthesis. A total of 130 included studies were published between 1996 and 2021. Geographical regions with the most studies were Europe (32.3%) and the Middle East (26.9%). Dermatology-specific instruments, including the Dermatology Life Quality Index (DLQI; 80 studies) and its variants for children (CDLQI; 10 studies) and families (FDLQI; 4 studies), as well as Skindex instruments (Skindex-29, 15 studies; Skindex-16, 4 studies), were most commonly used to measure humanistic burden. Vitiligo-specific instruments, including the Vitiligo-specific QoL (VitiQoL; 11 studies) instrument and 22-item Vitiligo Impact Scale (VIS-22; 4 studies), were administered in fewer studies. Among studies that reported total scores for the overall population, a majority revealed moderate or worse effects of vitiligo on patient QoL (DLQI, 35/54 studies; Skindex, 8/8 studies; VitiQoL, 6/6 studies; VIS-22, 3/3 studies). Vitiligo also had a significant impact on the QoL of families and caregivers; 4/4 studies reporting FDLQI scores indicated moderate or worse effects on QoL. In general, treatment significantly (P < 0.05) improved QoL, but there were no trends for types or duration of treatment. Among studies that reported factors significantly (P ≤ 0.05) associated with reduced QoL, female sex and visible lesions and/or lesions in sensitive areas were most common. In summary, vitiligo has clinically meaningful effects on the QoL of patients, highlighting that greater attention should be dedicated to QoL decrement awareness and improvement in patients with vitiligo.

Vitiligo prevalence and quality of life among adults in Europe, Japan and the USA.

BACKGROUND: Vitiligo, an autoimmune disorder characterised by skin depigmentation, is associated with reduced quality of life (QoL). Vitiligo may be under-reported, in part because of misconceptions that it is a cosmetic disease. OBJECTIVES: This survey sought to characterise vitiligo prevalence and explore the relationship between sociodemographic and clinical characteristics with QoL in a population-based, multinational study. METHODS: Participants aged ≥18 years were recruited via an online panel in Europe, Japan and the USA to answer questions regarding skin disorders they may have experienced. Those reporting vitiligo (diagnosed or undiagnosed) or vitiligo signs (experiencing loss of skin colour but unaware of vitiligo and not diagnosed) were included in the analyses of vitiligo prevalence. Participants who self-reported physician-diagnosed vitiligo were given a broader survey to characterise disease progression, management and QoL (as measured with the Vitiligo-specific QoL [VitiQoL] instrument). RESULTS: The total estimated vitiligo prevalence among 35 694 survey participants (Europe, n = 18 785; USA, n = 8517; Japan, n = 8392) was 1.3% (diagnosed, 0.6%; undiagnosed, 0.4%; vitiligo signs, 0.3%). Among 219 patients formally diagnosed with vitiligo (Europe, n = 150; USA, n = 48; Japan, n = 21), total VitiQoL scores were associated with age (P = 0.00017), disease extent (P < 0.0001), disease progression (P < 0.0001), disease management (P < 0.0001) and time since diagnosis (P = 0.0015). Behaviour scores varied based on skin phototype (P = 0.024) and ethnicity (P = 0.048). Higher total VitiQoL scores were reported in patients with head lesions (P = 0.027) and those with head and hand and/or wrist lesions (P = 0.018). Substantial high concern (rated 8-10 on an 11-point Likert scale) for lesions was found across all body areas and varied with geographical region. CONCLUSIONS: The vitiligo prevalence rate may be higher than previously reported, with a substantial proportion attributed to people who have not received a formal diagnosis. Among formally diagnosed patients with vitiligo, QoL was most severely impacted by more progressive and higher extent of disease.

The effect of handedness on mental rotation of hands: a systematic review and meta-analysis.

Body-specific mental rotation is thought to rely upon internal representations of motor actions. Handedness is a source of distinctly different motor experience that shapes the development of such internal representations. Yet, the influence of handedness upon hand mental rotation has never been systematically evaluated. Five databases were searched for studies evaluating hand left/right judgement tasks in adults. Two independent reviewers performed screening, data extraction, and critical appraisal. Eighty-seven datasets were included, with 72 datasets pooled; all had unclear/high risk of bias. Meta-analyses showed that right-handers were faster, but not more accurate, than left-handers at hand mental rotation. A unique effect of handedness was found on performance facilitation for images corresponding to the dominant hand. Meta-analyses showed that right-handers were quicker at identifying images of right hands than left hands-a dominance advantage not evident in left-handers. Differing hand representations (more lateralised hand dominance in right-handers) likely underpin these findings. Given potential differences between hand preference and motor performance, future research exploring their distinct contributions to mental rotation is warranted.

Incidence and treatment of positive pelvic sidewall lymph nodes in patients with rectal cancer.

AIM: The involvement of pelvic sidewall (PSW) lymph nodes in rectal cancer is a marker of locally advanced disease and poor prognosis. Eastern countries generally advocate lateral lymph node dissection (LLND) over the Western approach of neoadjuvant chemoradiotherapy and more limited surgery. The aim of this study was to evaluate how these advanced cancers were treated in three UK Health Boards. METHODOLOGY: This was a retrospective review of three colorectal multidisciplinary team meetings from 2008 to 2016. All patients with rectal cancer and suspicious PSW lymph nodes on pretreatment MRI were included. RESULTS: There were 153 (6.2%) patients who met the inclusion criteria from a total of 2461 diagnosed rectal cancers. There was significant variability between the three centres with surgical intervention ranging from 59.2% to 84.4%, P = 0.015. There were 81 patients who had neoadjuvant chemoradiotherapy prior to surgery; of these 67 (82.7%) still had positive PSW nodes on the restaging MRI, but only 13 (19.4%) had LLND. There was no difference in local recurrence (15.3% vs 11.8%, P = 0.66), 5-year overall survival (69.2% vs 80.1%, P = 0.16) or 5-year disease-free survival (69.2% vs 79.4%, P = 0.72) between patients having LLND and those receiving standard neoadjuvant treatment followed by total mesorectal excision surgery. CONCLUSIONS: This study has demonstrated that rectal cancer patients with PSW positive nodal disease have advanced disease, mostly of the lower rectum, and receive a highly heterogeneous spectrum of therapies, even within a relatively small geographical area. Greater accuracy in our preoperative staging is needed to select those patients who will benefit from LLND surgery.

Temporary faecal diversion in ileocolic resection for Crohn's disease: is there an impact on long-term surgical recurrence?

AIM: Temporary faecal diversion after ileocolic resection (ICR) for Crohn's disease reduces postoperative anastomotic complications in high-risk patients. The aim of this study was to assess if this approach also reduces long-term surgical recurrence. METHOD: This was a multicentre retrospective review of prospectively maintained databases. Patient demographics, medical and surgical details were collected by three specialist centres. All patients had undergone an ICR between 2000 and 2012. The primary end-point was surgical recurrence. RESULTS: Three hundred and twelve patients (80%) underwent an ICR without covering ileostomy (one stage). Seventy-seven (20%) had undergone an ICR with end ileostomy/double-barrel ileostomy/enterocolostomy followed by closure (two stage). The median follow-up was 105 months [interquartile range (IQR) 76-136 months]. The median time to ileostomy closure was 9 months (IQR 5-12 months). There was no significant difference in surgical recurrence between the one- and two-stage groups (18% vs 16%, P = 0.94). We noted that smokers (20% vs 34%, P = 0.01) and patients with penetrating disease (28% vs 52%, P < 0.01) were more likely to be defunctioned. A reduced recurrence rate was observed in the small high-risk group of patients who were smokers with penetrating disease behaviour treated with a two-stage strategy (0/10 vs 4/7, P = 0.12). CONCLUSION: Despite having higher baseline risk factors, the results in terms of rate of surgical recurrence over 9 years are similar for patients having a two-stage compared with a one-stage procedure.

Symposium review: Colostrum management and calf nutrition for profitable and sustainable dairy farms.

Multistate dairy management research project NC-2042, which is part of the National Institute of Food and Agriculture, has devoted an ongoing objective to calf and heifer nutrition and management. Within this objective, colostrum research has been a priority due to continued opportunities to improve this area on US dairy farms. Research has focused on heating colostrum to reduce bacterial populations and pathogens while increasing IgG absorption. Research also identified other proteins that are reduced when heating colostrum. Studies indicated an apparent upper limit to IgG absorption from colostrum fed to calves. Additional studies have shed light on absorption of IgG from colostrum replacers and evaluated the use of lactoferrin and sodium bicarbonate in both maternal colostrum and colostrum replacers. Milk replacer formulation, feeding strategies, and the effect of calfhood nutrition on future performance have also been researched. Finally, water quality and its effect on calves and heifers have been studied. This review focuses on research done by multistate research project NC-2042 member states in the area of colostrum and calf nutrition and management.

HPV may not play a role in all lacrimal transitional cell papilloma.

BACKGROUND: Tumours of the lacrimal duct apparatus (LDA) are rare and heterogenous but knowledge of their aetiology is important for the rhinologist. A link between transitional cell papilloma/carcinoma (TCP/TCC) and human papilloma virus (HPV) has been suggested in previous studies. We aimed to add to this body of evidence by submitting 16 LDA tumour samples from our tertiary referral centre for HPV analysis. METHODOLOGY: All LDA tumour samples stored in the University College London tissue bank were submitted for HPV analysis by centralised nucleic acid extraction and HPV genotyping via a sensitive polymerase chain reaction (PCR). RESULTS: Only one of six transitional cell papillomas tested positive for HPV. Two of three transitional cell carcinomas returned HPV 16 positive results. Two inverted papillomas submitted were also HPV positive. CONCLUSIONS: Previously published literature has suggested a strong link between HPV and neoplasia of the lacrimal system. HPV has previously been demonstrated in all TCP and TCC. This is in contrast to our data, particularly for transitional cell papilloma where, in the largest sample of transitional cell papilloma in the literature thus far, we did not find a strong association with HPV. This casts doubt on the role of HPV in the papillomatous process in the lacrimal apparatus.

Adjuvant radiotherapy after local excision of rectal cancer.

BACKGROUND: Local excision is now accepted as a standard treatment option for certain patients with early rectal cancer. However, there is a higher risk of local recurrence than after radical surgery with total mesorectal excision. Adjuvant radiotherapy after local excision may reduce this excess risk, and yet retain the benefits of local excision, with rectal preservation. METHODS: A review of the literature pertaining to the use of adjuvant radiotherapy after local excision of rectal cancer and a discussion of current practice. RESULTS: We first considered local excision as a treatment option for early rectal cancer, looking at technical developments and the risks and benefits of organ preservation, in particular, the advantages for quality of life and the risk of leaving residual disease which may result in local recurrence. We then looked at reported outcomes for studies using adjuvant radiotherapy after local excision. Few of the studies routinely used modern endoscopic methods of local excision and only the recent used chemoradiation. Local recurrence rates after adjuvant radiotherapy have improved over time, with rates of around 3.5% in the recent studies. Adverse effects of adjuvant radiotherapy are not commonly described, but generally, they are relatively mild when described. We then discussed current practice regarding adjuvant radiotherapy, including pathological criteria, discussion of local recurrence risk with the patient and the importance of a surveillance regime to detect any recurrence at an early stage. CONCLUSION: We conclude that the current state of knowledge regarding adjuvant radiotherapy after local excision suggests a potential role in decreasing the risk of local recurrence but further studies are required to better define this effect, clarify which patients will gain the most benefit from this pathway, and identify those who should avoid exposure to the risks of radiotherapy.

Radiotherapy after local excision of rectal cancer may offer reduced local recurrence rates.

AIM: Early rectal cancer can be managed effectively with local excision, which is now the standard of care for many T1 lesions. However, the presence of unexpected adverse histopathological factors may indicate an increased risk of local recurrence, prompting consideration of completion radical surgery. Many patients are unfit or prefer to avoid radical surgery, relying instead on surveillance and early detection of recurrent disease. Recently, radiotherapy has shown promise as an adjuvant therapy in this group. This study assesses local recurrence rates after local excision with adjuvant radiotherapy at a single centre. METHOD: This was a retrospective review of a prospective database of all patients undergoing transanal endoscopic microsurgery (TEM) in a single institution. Data covering a 10-year period were analysed. RESULTS: Of 197 patients undergoing TEM for rectal cancer, 33 (17%) had adjuvant radiotherapy because of adverse histopathological features. At 3.2 years' median follow-up, there were three instances of local recurrence (9.1%). Estimated local recurrence at 1 and 3 years was 0% and 6.9%, compared to 16.8% and 21.2% in a propensity-score-matched group who were followed by surveillance alone. Local recurrence was diagnosed at a median of 23 months post-TEM in the radiotherapy group, compared to 8 months in the matched group. CONCLUSION: Radiotherapy after TEM is associated with a trend towards a reduced rate of local recurrence, even for high-risk disease. Radiotherapy would appear to offer a viable alternative to radical completion surgery in the presence of unforeseen adverse histopathological features, as long as a meticulous surveillance programme is in place.

Relationships between protein and energy consumed from milk replacer and starter and calf growth and first-lactation production of Holstein dairy cows.

The objective was to determine relationships between protein and energy consumed from milk replacer and starter and calf growth and first-lactation production of Holstein heifer calves. Milk replacer and starter protein intake and metabolizable energy (ME) intake data were collected from 4,534 Holstein heifer calves for growth and 3,627 Holstein cows for production from birth year of 2004 through 2014. Calves from 3 commercial dairy farms were assigned to 45 different calf research trials at the University of Minnesota Southern Research and Outreach Center, Waseca, Minnesota, from 3 to 195 d of life. Calves were moved to heifer growers at 6 mo of age, and calves were returned to their farm of birth a few weeks before calving. Most calves (85%) were fed a 20% crude protein and 20% fat milk replacer at a rate of 0.57 kg/calf daily. Metabolizable energy and protein consumed from milk replacer and starter were calculated for each individual calf for 6 and 8 wk of age. Mixed model analyses were conducted to determine the effect of protein and energy consumed from both milk replacer and starter on calf growth and first-lactation 305-d production of milk, fat, and protein, adjusting for herd, season of birth, year, average daily gain (ADG), and calf trial. Calves with ADG >0.80 kg/d consumed more combined protein and ME than calves with lower ADG. Protein and ME intake from calf starter affected growth more than protein and ME intake from milk replacer because most calves were fed the same fixed amount of milk replacer. Calves born during the fall and winter had greater combined protein and ME intake than calves born during the spring and summer. Milk replacer protein and ME intake did not have a relationship with first-lactation 305-d milk, fat, and protein production. However, starter protein and ME intake during the first 6 and 8 wk of age had a significant positive relationship with first-lactation 305-d milk, fat, and protein production. Consequently, combined protein and combined ME intake had a positive effect on 305-d milk, fat, and protein production. Variance in protein and ME intake was high, suggesting that additional factors affect calf growth during the first 8 wk of life and milk production in first lactation.

Label-invariant models for the analysis of meta-epidemiological data.

Rich meta-epidemiological data sets have been collected to explore associations between intervention effect estimates and study-level characteristics. Welton et al proposed models for the analysis of meta-epidemiological data, but these models are restrictive because they force heterogeneity among studies with a particular characteristic to be at least as large as that among studies without the characteristic. In this paper we present alternative models that are invariant to the labels defining the 2 categories of studies. To exemplify the methods, we use a collection of meta-analyses in which the Cochrane Risk of Bias tool has been implemented. We first investigate the influence of small trial sample sizes (less than 100 participants), before investigating the influence of multiple methodological flaws (inadequate or unclear sequence generation, allocation concealment, and blinding). We fit both the Welton et al model and our proposed label-invariant model and compare the results. Estimates of mean bias associated with the trial characteristics and of between-trial variances are not very sensitive to the choice of model. Results from fitting a univariable model show that heterogeneity variance is, on average, 88% greater among trials with less than 100 participants. On the basis of a multivariable model, heterogeneity variance is, on average, 25% greater among trials with inadequate/unclear sequence generation, 51% greater among trials with inadequate/unclear blinding, and 23% lower among trials with inadequate/unclear allocation concealment, although the 95% intervals for these ratios are very wide. Our proposed label-invariant models for meta-epidemiological data analysis facilitate investigations of between-study heterogeneity attributable to certain study characteristics.

Meta-analysis of the prognostic value of CpG island methylator phenotype in rectal cancer.

PURPOSE: The pathological and prognostic importance of CpG island methylator phenotype (CIMP) in rectal cancer, as a sub-population of colorectal cancer, is unknown. A meta-analysis was preformed to estimate the prognostic significance of CIMP in rectal cancer. METHODS: A systematic search was performed of PubMed, Embase, MEDLINE, PubMed Central, and Cochrane electronic databases for articles pertaining to CIMP and rectal cancer. Articles were analysed and data extracted according to PRISMA standards. RESULTS: Six studies including 1529 patients were included in the analysis. Following dichotomisation, the prevalence of CIMP-positive tumours was 10 to 57%, with a median of 12.5%. Meta-analysis demonstrated the pooled odds ratio for all-cause death for CIMP-positive tumours vs CIMP-negative tumours was 1.24 (95% CI 0.88-1.74). Z test for overall effect was 1.21 (p = 0.23). Heterogeneity between the studies was low (X2 5.96, df 5, p = 0.31, I2 = 16%). A total of 15 different loci were used for assessing CIMP across the studies, with a median of 6.5 loci (range 5-8). CONCLUSIONS: No significant association between CIMP and poor outcomes in rectal cancer was demonstrated. There was a high degree of heterogeneity in CIMP assessment methodologies and in study populations. Rectal cancer datasets were frequently not extractable from larger colorectal cohorts, limiting analysis.

Inflammatory cell ratios predict major septic complications following rectal cancer surgery.

INTRODUCTION: The inflammatory response is known to have an important role in tumourigenesis and the response to treatment. Previous studies have demonstrated that inflammatory cell ratios such as the neutrophil-to-lymphocyte ratio (NLR) can predict survival and recurrence following surgery for various cancers. The objective of this study was to demonstrate if pre-operative NLR has a role in predicting post-operative septic complications in patients undergoing rectal cancer surgery. METHODOLOGY: Consecutive patients undergoing scheduled resection for rectal cancer in a tertiary centre from July 2007 to Dec 2015 were included. Data was gathered from a prospectively held database of rectal cancer. Normally distributed data were compared with paired t tests (mean ± standard error in the mean (SEM)), and proportions were compared with Fisher's exact test. A p value of < 0.05 was considered statistically significant. RESULTS: Three hundred fourteen patients were identified in this study. Sixty nine (22.0%) patients had a major septic complication following surgery for rectal cancer, which was associated with a poor survival outcome (p < 0.01) Both pre and post-operative NLR and PLR (platelet lymphocyte ratio) were associated with post-operative septic complications (both p < 0.01). A pre-operative NLR threshold level of 4 was chosen from ROC analysis, and this provided a relatively specific test to predict post-operative septic complications in these patients (specificity = 83.7%, negative predictive value (NPV) = 74.8%). DISCUSSION: In this study, the pre-operative NLR and PLR were both predictive of major post-operative septic complications. A pre-operative NLR of less than 4 was strongly negative predictor of post-operative complications in rectal cancer surgery. It can be regarded as a predictive and prognostic factor for these patients.

Modern management of T1 rectal cancer by transanal endoscopic microsurgery: a 10-year single-centre experience.

AIM: Minimally invasive, organ-sparing surgery has been used increasingly for early rectal cancer in recent years. However, local recurrence remains a concern. This study presents a 10-year single-centre experience of recurrence after local excision for T1 rectal cancer. METHOD: Data were collected prospectively on all patients undergoing local excision by transanal endoscopic microsurgery (TEM) in a single institution. Data covering a 10-year period were analysed. RESULTS: In all, 192 patients underwent TEM for rectal cancer; 70 of these had T1 tumour in the TEM specimen and did not have preoperative radiotherapy. Four were managed with completion surgery following TEM and a further six had radiotherapy; 60 underwent surveillance alone. Local recurrence occurred in six patients; three underwent salvage surgery. Estimated local recurrence at 3 years was 7.2% for the surveillance alone group. CONCLUSIONS: Local recurrence rates were lower than previous studies. Better preoperative assessment, more effective local excision surgery and postoperative radiotherapy may be contributory factors to a better-than-predicted outcome. Local excision should be offered as part of standard of care for T1 rectal cancer in the presence of good preoperative selection and meticulous surveillance.