Assessing systolic and diastolic reserves in male and female mice.

Cardiac reserve is a widely used health indicator and prognostic tool. Although it is well established how to assess cardiac reserve clinically, in preclinical models, it is more challenging lacking standardization. Furthermore, although cardiac reserve incorporates both systolic (i.e., contractile reserve) and diastolic (i.e., relaxation reserve) components of the cardiac cycle, less focus has been placed on diastolic reserve. The aim of our study was to determine which technique (i.e., echocardiography, invasive hemodynamic, and Langendorff) and corresponding parameters can be used to assess the systolic and diastolic reserves in preclinical models. Healthy adult male and female CD-1 mice were administered dobutamine and evaluated by echocardiography and invasive hemodynamic, or Langendorff to establish systolic and diastolic reserves. Here, we show that systolic reserve can be assessed using all techniques in vivo and in vitro. Yet, the current indices available are ineffective at capturing diastolic reserve of healthy mice in vivo. When assessing systolic reserve, sex affects the dose response of several commonly used echocardiography parameters [i.e., fractional shortening (FS), ejection fraction (EF)]. Taken together, this study improves our understanding of how sex impacts the interpretation assessment of cardiac reserve and establishes for the first time that in healthy adult mice, the diastolic reserve cannot be assessed by currently established methods in vivo.NEW & NOTEWORTHY Cardiac reserve is a globally used health indicator and prognostic tool that is used by clinicians and preclinical scientists. In physiology, we have a long-standing appreciation of how to assess systolic reserve but lack insight into sex differences and have no frame of reference for measuring diastolic reserve to certainty across cardiac techniques or the influence of sex. Here, we show that the primary means for assessing diastolic reserve is incorrect. Furthermore, we provided proof and clarity on how to correctly measure systolic and diastolic reserve capacities. We also highlight the imperative of sex differences to the measures of both systolic and diastolic reserves using several techniques (i.e., echocardiography, invasive hemodynamics, and Langendorff) in mice.

GP access to FIT increases the proportion of colorectal cancers detected on urgent pathways in symptomatic patients in Nottingham.

OBJECTIVE: Service 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". DESIGN: Retrospective 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. RESULTS: Between November 2017 and December 2018, 6747 GP FIT test requests yielded 5733 FIT results, of which 4082 (71.2%) were <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 <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 < 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 < 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<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. CONCLUSIONS: FIT 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.

Quantitative FIT stratification is superior to NICE referral criteria NG12 in a high-risk colorectal cancer population.

BACKGROUND: Guidelines for urgent investigation of colorectal cancer (CRC) are based on age and symptom-based criteria. This study aims to compare the diagnostic value of clinical features and faecal immunochemical test (FIT) results to identify those at a higher risk of CRC, thereby facilitating effective triage of patients. METHODS: We undertook a review of all patients referred for investigation of CRC at our centre between September 2016 and June 2018. Patients were identified using a prospectively recorded local database. We performed a logistic regression analysis of factors associated with a diagnosis of CRC. RESULTS: One-thousand-and-seven-hundred-eighty-four patients with FIT results were included in the study. Change in bowel habit (CIBH) was the most common referring clinical feature (38.3%). Patients diagnosed with CRC were significantly older than those without malignancy (74.0 years vs 68.9 years, p = 0.0007). Male patients were more likely to be diagnosed with CRC than females (6.5% vs 2.5%, Chi-squared 16.93, p < 0.0001). CRC was diagnosed in 3.5% (24/684) with CIBH compared to 8.1% (6/74) with both CIBH and iron deficiency anaemia. No individual or combination of referring clinical features was associated with an increased diagnosis of CRC (Chi-squared, 8.03, p = 0.155). Three patients with negative FIT results (< 4 µg Hb/g faeces) were diagnosed with CRC (3/1027, 0.3%). The highest proportion of cancers detected was in the ≥ 100 µg Hb/g faeces group (55/181, 30.4%). CONCLUSION: In a multivariate model, FIT outperforms age, sex and all symptoms prompting referral. FIT has greater stratification value than any referral symptoms. FIT does have value in patients with iron deficiency anaemia.

Thrombocytosis helps to stratify risk of colorectal cancer in patients referred on a 2-week-wait pathway.

PURPOSE: Primary care studies suggest that thrombocytosis (platelet counts > 400 × 109/L) is associated with an increased risk of colorectal cancer (CRC). We aimed to establish whether this marker has significant stratification value in patients seen in secondary care. METHODS: A retrospective review of 2991 patients referred to our colorectal 2-week-wait (2WW) pathway between August 2014 and August 2017. Patient demographics were recorded prospectively, and local electronic records systems were used to retrieve full blood counts (FBC) and cancer diagnoses. Patients with no recent platelet count at the time of referral or incomplete records were excluded. RESULTS: 2236 patients were included in this evaluation. There was no significant difference in the age distribution of those with thrombocytosis and those without. There were significantly more females in the thrombocytosis group (72.1% vs 53.9%, chi-squared 24.63, p < 0.0001). 130 CRCs were detected (5.8%) and patients with thrombocytosis were more likely to have CRC (OR 2.62, 95% CI 1.60-4.30). The CRC diagnosis rate was significantly higher in females with thrombocytosis (10.3% vs 2.9%, chi-squared 19.41, p < 0.0001) and males with thrombocytosis (16.1% vs 7.9%, chi-squared 4.62, p = 0.032). CONCLUSION: Thrombocytosis appears to have stratification value in the 2WW population. Further evaluation of its value alone or in combination with other stratification tests is required.

Early clinical outcomes of a rapid colorectal cancer diagnosis pathway using faecal immunochemical testing in Nottingham.

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 < 0.0001). FIT results ≥ 10.0 µg Hb/g faeces identified patients with significantly higher risk of significant noncancer bowel pathology (24.1% vs 4.9%, chi-square 73.6, P < 0.0001) and FIT results < 4.0 µg Hb/g faeces identified a group more likely to have non-CRC pathology (5.1% vs 2.4%, chi-square 3.9, P < 0.05). The CRC detection rate in 531 patients investigated after a FIT result of < 4.0 µg Hb/g faeces was 0.2%. In 899 investigated patients, a FIT result with a threshold of 4.0 µg Hb/g faeces had sensitivity 97.2% (85.5-99.9% CI), specificity 61.4% (58.1-64.7% CI), negative predictive value 99.8% (98.7-100.0% CI) and positive predictive value 9.5% (8.7-10.4% CI). CONCLUSION: A symptomatic pathway incorporating FIT is feasible and appears more clinically effective than pathways based on age and symptoms alone.

Iron therapy for preoperative anaemia.

BACKGROUND: Preoperative anaemia is common and occurs in 5% to 76% of patients preoperatively. It is associated with an increased risk of perioperative allogeneic blood transfusion, longer hospital stay, and increased morbidity and mortality. Iron deficiency is one of the most common causes of anaemia. Oral and intravenous iron therapy can be used to treat anaemia. Parenteral iron preparations have been shown to be more effective in conditions such as inflammatory bowel disease, chronic heart failure and postpartum haemorrhage due to rapid correction of iron stores. A limited number of studies has investigated iron therapy for the treatment of preoperative anaemia. The aim of this Cochrane Review is to summarise the evidence for iron supplementation, both enteral and parenteral, for the management of preoperative anaemia. OBJECTIVES: To evaluate the effects of preoperative iron therapy (enteral or parenteral) in reducing the need for allogeneic blood transfusions in anaemic patients undergoing surgery. SEARCH METHODS: We ran the search on 30 July 2018. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic and Embase (Ovid), CINAHL Plus (EBSCO), PubMed, and clinical trials registries, and we screened reference lists. We ran a top-up search on 28 November 2019; one study is now awaiting classification. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared preoperative iron monotherapy to placebo, no treatment, standard care or another form of iron therapy for anaemic adults undergoing surgery. We defined anaemia as haemoglobin values less than 13 g/dL for males and 12 g/dL for non-pregnant females. DATA COLLECTION AND ANALYSIS: Two review authors collected data and a third review author checked all collected data. Data were collected on the proportion of patients who receive a blood transfusion, the amount of blood transfused per patient (units), quality of life, ferritin levels and haemoglobin levels, measured as continuous variables at the following predetermined time points: pretreatment (baseline), preoperatively but postintervention, and postoperatively. We performed statistical analysis using the Cochrane software, Review Manager 5. We summarised outcome data in tables and forest plots. We used the GRADE approach to describe the quality of the body of evidence. MAIN RESULTS: Six RCTs, with a total of 372 participants, evaluated preoperative iron therapy to correct anaemia before planned surgery. Four studies compared iron therapy (either oral (one study) or intravenous (three studies)) with no treatment, placebo or usual care, and two studies compared intravenous iron therapy with oral iron therapy. Iron therapy was delivered over a range of periods that varied from 48 hours to three weeks prior to surgery. The 372 participants in our analysis fall far short of the 819 required - as calculated by our information size calculation - to detect a 30% reduction in blood transfusions. Five trials, involving 310 people, reported the proportion of participants who received allogeneic blood transfusions. Meta-analysis of iron therapy versus placebo or standard care showed no difference in the proportion of participants who received a blood transfusion (risk ratio (RR) 1.21, 95% confidence interval (CI) 0.87 to 1.70; 4 studies, 200 participants; moderate-quality evidence). Only one study that compared oral versus intravenous iron therapy measured this outcome, and reported no difference in risk of transfusion between groups. There was no difference between the iron therapy and placebo/standard care groups for haemoglobin level preoperatively at the end of the intervention (mean difference (MD) 0.63 g/dL, 95% CI -0.07 to 1.34; 2 studies, 83 participants; low-quality evidence). However, intravenous iron therapy produced an increase in preoperative postintervention haemoglobin levels compared with oral iron (MD 1.23 g/dL, 95% CI 0.80 to 1.65; 2 studies, 172 participants; low-quality evidence). Ferritin levels were increased by intravenous iron, both when compared to standard care ((MD 149.00, 95% CI 25.84 to 272.16; 1 study, 63 participants; low-quality evidence) or to oral iron (MD 395.03 ng/mL, 95% CI 227.72 to 562.35; 2 studies, 151 participants; low-quality evidence). Not all studies measured quality of life, short-term mortality or postoperative morbidity. Some measured the outcomes, but did not report the data, and the studies which did report the data were underpowered. Therefore, uncertainty remains regarding these outcomes. The inclusion of new research in the future is very likely to change these results. AUTHORS' CONCLUSIONS: The use of iron therapy for preoperative anaemia does not show a clinically significant reduction in the proportion of trial participants who received an allogeneic blood transfusion compared to no iron therapy. Results for intravenous iron are consistent with a greater increase in haemoglobin and ferritin when compared to oral iron, but do not provide reliable evidence. These conclusions are drawn from six studies, three of which included very small numbers of participants. Further, well-designed, adequately powered, RCTs are required to determine the true effectiveness of iron therapy for preoperative anaemia. Two studies are currently in progress, and will include 1500 randomised participants.

The impact of pre-operative intravenous iron on quality of life after colorectal cancer surgery: outcomes from the intravenous iron in colorectal cancer-associated anaemia (IVICA) trial.

Anaemia is associated with a reduction in quality of life, and is common in patients with colorectal cancer . We recently reported the findings of the intravenous iron in colorectal cancer-associated anaemia (IVICA) trial comparing haemoglobin levels and transfusion requirements following intravenous or oral iron replacement in anaemic colorectal cancer patients undergoing elective surgery. In this follow-up study, we compared the efficacy of intravenous and oral iron at improving quality of life in this patient group. We conducted a multicentre, open-label randomised controlled trial. Anaemic colorectal cancer patients were randomly allocated at least two weeks pre-operatively, to receive either oral (ferrous sulphate) or intravenous (ferric carboxymaltose) iron. We assessed haemoglobin and quality of life scores at recruitment, immediately before surgery and at outpatient review approximately three months postoperatively, using the Short Form 36, EuroQoL 5-dimension 5-level and Functional Assessment of Cancer Therapy - Anaemia questionnaires. We recruited 116 anaemic patients across seven UK centres (oral iron n = 61 (53%), and intravenous iron n = 55 (47%)). Eleven quality of life components increased by a clinically significant margin in the intravenous iron group between recruitment and surgery compared with one component for oral iron. Median (IQR [range]) visual analogue scores were significantly higher with intravenous iron at a three month outpatient review (oral iron 70, (60-85 [20-95]); intravenous iron 90 (80-90 [50-100]), p = 0.001). The Functional Assessment of Cancer Therapy - Anaemia score comprises of subscales related to cancer, fatigue and non-fatigue items relevant to anaemia. Median outpatient scores were higher, and hence favourable, for intravenous iron on the Functional Assessment of Cancer Therapy - Anaemia subscale (oral iron 66 (55-72 [23-80]); intravenous iron 71 (66-77 [46-80]); p = 0.002), Functional Assessment of Cancer Therapy - Anaemia trial outcome index (oral iron 108 (90-123 [35-135]); intravenous iron 121 (113-124 [81-135]); p = 0.003) and Functional Assessment of Cancer Therapy - Anaemia total score (oral iron 151 (132-170 [69-183]); intravenous iron 168 (160-174 [125-186]); p = 0.005). These findings indicate that intravenous iron is more efficacious at improving quality of life scores than oral iron in anaemic colorectal cancer patients.

Association of breast milk fatty acids with allergic disease outcomes-A systematic review.

INTRODUCTION: Dietary polyunsaturated fatty acids (PUFAs) have immunoregulatory properties. Breast milk is rich in PUFA, and it has been hypothesized that these PUFAs may be important in the aetiology of allergic diseases. Despite a growing body of evidence, the associations between breast milk PUFA and allergic disease have not previously been systematically reviewed. METHODS: The search was performed in PubMed and EMBASE databases using breastfeeding, fatty acid and allergic disease terms. Two authors were involved in selecting papers for review according to the inclusion criteria and extracting information on study characteristics and measures of association. Only studies that reported numeric associations between concentration of breast milk fatty acids and allergic disease outcomes were included. RESULTS: A total of 18 papers met the inclusion criteria, reporting results from 15 study populations. The majority were cohort studies (n=11), with data from only two case-control and two cross-sectional studies. Sample size varied between 30 and 352 participants, and follow-up time of the cohorts varied between 3 months and 14 years. Nine studies reported on eczema, seven reported on sensitization, and only five reported on asthma/wheeze. There was heterogeneity among studies in terms of presenting the association between PUFA and allergy; therefore, estimates could not be pooled. Only a few studies observed associations between n-3 and n-6 PUFAs and allergic disease, and the magnitude of this effect varied greatly. CONCLUSIONS: There is insufficient evidence to suggest that colostrum or breast milk polyunsaturated fatty acids influence the risk of childhood allergic diseases.

Randomized clinical trial of preoperative oral versus intravenous iron in anaemic patients with colorectal cancer.

BACKGROUND: Treatment of preoperative anaemia is recommended as part of patient blood management, aiming to minimize perioperative allogeneic red blood cell transfusion. No clear evidence exists outlining which treatment modality should be used in patients with colorectal cancer. The study aimed to compare the efficacy of preoperative intravenous and oral iron in reducing blood transfusion use in anaemic patients undergoing elective colorectal cancer surgery. METHODS: Anaemic patients with non-metastatic colorectal adenocarcinoma were recruited at least 2 weeks before surgery and randomized to receive oral (ferrous sulphate) or intravenous (ferric carboxymaltose) iron. Perioperative changes in haemoglobin, ferritin, transferrin saturation and blood transfusion use were recorded until postoperative outpatient review. RESULTS: Some 116 patients were included in the study. There was no difference in blood transfusion use from recruitment to trial completion in terms of either volume of blood administered (P = 0·841) or number of patients transfused (P = 0·470). Despite this, increases in haemoglobin after treatment were higher with intravenous iron (median 1·55 (i.q.r. 0·93-2·58) versus 0·50 (-0·13 to 1·33) g/dl; P < 0·001), which was associated with fewer anaemic patients at the time of surgery (75 versus 90 per cent; P = 0·048). Haemoglobin levels were thus higher at surgery after treatment with intravenous than with oral iron (mean 11·9 (95 per cent c.i. 11·5 to 12·3) versus 11·0 (10·6 to 11·4) g/dl respectively; P = 0·002), as were ferritin (P < 0·001) and transferrin saturation (P < 0·001) levels. CONCLUSION: Intravenous iron did not reduce the blood transfusion requirement but was more effective than oral iron at treating preoperative anaemia and iron deficiency in patients undergoing colorectal cancer surgery.

Breast milk polyunsaturated fatty acids: associations with adolescent allergic disease and lung function.

BACKGROUND: It has been hypothesized that n-3 PUFA in breast milk may assist immune and lung development. There are very limited data on possible long-term effects on allergic disease and lung function. The aim was to investigate associations of n-3 and n-6 PUFA levels in colostrum and breast milk with allergic disease and lung function at ages 12 and 18 years. METHODS: Polyunsaturated fatty acids were measured in 194 colostrum samples and in 118 three-month expressed breast milk samples from mothers of children enrolled in the Melbourne Atopy Cohort (MACS) Study, a high-risk birth cohort study. Associations with allergic diseases, skin prick tests and lung function assessed at 12 and 18 years were estimated using multivariable regression. RESULTS: Higher levels of n-3 but not n-6 PUFAs in colostrum were associated with a trend towards increased odds of allergic diseases, with strong associations observed for allergic rhinitis at 12 (OR = 5.69[95% CI: 1.83,17.60] per weight%) and 18 years (4.43[1.46,13.39]) and eczema at 18 years (9.89[1.44, 68.49]). Higher levels of colostrum n-3 PUFAs were associated with reduced sensitization (3.37[1.18, 9.6]), mean FEV1 (-166 ml [-332, -1]) and FEV1 /FVC ratio (-4.6%, [-8.1, -1.1]) at 12 years. CONCLUSION: Higher levels of colostrum n-3 PUFAs were associated with increased risks of allergic rhinitis and eczema up to 18 years, and sensitization and reduced lung function at 12 years. As residual confounding may have caused these associations, they should be replicated, but these results could indicate that strategies that increase maternal n-3 PUFA intake may not aid in allergic disease prevention.

Mould-sensitized adults have lower Th2 cytokines and a higher prevalence of asthma than those sensitized to other aeroallergens.

BACKGROUND: Evidence suggests that specific allergen sensitizations are associated with different allergic diseases which may reflect different underlying immune profiles. We aimed to examine the cytokine profiles of individuals sensitized to eight common aeroallergens. METHODS: We used data from the Tasmanian Longitudinal Health Study a population-based cohort study of 45-year-olds. Serum cytokines (IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α) were measured in 1157 subjects using the LINCOplex assays. Participants underwent skin prick testing for house dust mite, cat, grasses and moulds. Multivariable linear regression was used to compare serum cytokine levels between sensitized and nonatopic subjects. RESULTS: The prevalence of allergic sensitization to any aeroallergen was 51% (95% CI 47-54). Being sensitized to any aeroallergen was strongly associated with current asthma (OR = 3.7, 95% CI 2.6-5.3), and being sensitized to any moulds was associated with a very high risk of current asthma (OR = 6.40, 95% CI 4.06-10.1). The geometric mean (GM) levels of Th2 cytokines (IL-4, IL-5 and IL-6) for adults sensitized to Cladosporium were significantly lower than the levels for nonatopic individuals (IL-4 ratio of GMs = 0.25, 95% CI 0.10-0.62, P = 0.003; IL-5 GM = 0.55, 95% CI 0.30-0.99, P = 0.05; and IL-6 GM = 0.50, 95% CI 0.24-1.07, P = 0.07). Individuals sensitized to other aeroallergens all showed elevated Th2 cytokine levels. CONCLUSION: Our study is the first large population-based study to demonstrate reduced Th2 cytokines levels in people sensitized to mould. Underlying biological mechanisms driving allergic inflammatory responses in adults sensitized to moulds may differ from those sensitized to other aeroallergens. These findings suggest that it may be necessary to tailor treatments in individuals sensitized to moulds compared with other aeroallergens in order to optimize outcomes.

Whole genome sequencing reveals genomic heterogeneity and antibiotic purification in Mycobacterium tuberculosis isolates.

BACKGROUND: Whole genome sequencing has revolutionised the interrogation of mycobacterial genomes. Recent studies have reported conflicting findings on the genomic stability of Mycobacterium tuberculosis during the evolution of drug resistance. In an age where whole genome sequencing is increasingly relied upon for defining the structure of bacterial genomes, it is important to investigate the reliability of next generation sequencing to identify clonal variants present in a minor percentage of the population. This study aimed to define a reliable cut-off for identification of low frequency sequence variants and to subsequently investigate genetic heterogeneity and the evolution of drug resistance in M. tuberculosis. METHODS: Genomic DNA was isolated from single colonies from 14 rifampicin mono-resistant M. tuberculosis isolates, as well as the primary cultures and follow up MDR cultures from two of these patients. The whole genomes of the M. tuberculosis isolates were sequenced using either the Illumina MiSeq or Illumina HiSeq platforms. Sequences were analysed with an in-house pipeline. RESULTS: Using next-generation sequencing in combination with Sanger sequencing and statistical analysis we defined a read frequency cut-off of 30% to identify low frequency M. tuberculosis variants with high confidence. Using this cut-off we demonstrated a high rate of genetic diversity between single colonies isolated from one population, showing that by using the current sequencing technology, single colonies are not a true reflection of the genetic diversity within a whole population and vice versa. We further showed that numerous heterogeneous variants emerge and then disappear during the evolution of isoniazid resistance within individual patients. Our findings allowed us to formulate a model for the selective bottleneck which occurs during the course of infection, acting as a genomic purification event. CONCLUSIONS: Our study demonstrated true levels of genetic diversity within an M. tuberculosis population and showed that genetic diversity may be re-defined when a selective pressure, such as drug exposure, is imposed on M. tuberculosis populations during the course of infection. This suggests that the genome of M. tuberculosis is more dynamic than previously thought, suggesting preparedness to respond to a changing environment.

Molecular Epidemiological Interpretation of the Epidemic of Extensively Drug-Resistant Tuberculosis in South Africa.

We show that the interpretation of molecular epidemiological data for extensively drug-resistant tuberculosis (XDR-TB) is dependent on the number of different markers used to define transmission. Using spoligotyping, IS6110 DNA fingerprinting, and DNA sequence data, we show that XDR-TB in South Africa (2006 to 2008) was predominantly driven by the acquisition of second-line drug resistance.

Malaria and immunity during pregnancy and postpartum: a tale of two species.

It is well established that pregnant women are at an increased risk of Plasmodium falciparum infection when compared to non-pregnant individuals and limited epidemiological data suggest Plasmodium vivax risk also increases with pregnancy. The risk of P. falciparum declines with successive pregnancies due to the acquisition of immunity to pregnancy-specific P. falciparum variants. However, despite similar declines in P. vivax risk with successive pregnancies, there is a paucity of evidence P. vivax-specific immunity. Cross-species immunity, as well as immunological and physiological changes that occur during pregnancy may influence the susceptibility to both P. vivax and P. falciparum. The period following delivery, the postpartum period, is relatively understudied and available epidemiological data suggests that it may also be a period of increased risk of infection to Plasmodium spp. Here we review the literature and directly compare and contrast the epidemiology, clinical pathogenesis and immunological features of P. vivax and P. falciparum in pregnancy, with a particular focus on studies performed in areas co-endemic for both species. Furthermore, we review the intriguing epidemiology literature of both P. falciparum and P. vivax postpartum and relate observations to the growing literature pertaining to malaria immunology in the postpartum period.

The influence of laparoscopy on incisional hernia rates: a retrospective analysis of 1057 colorectal cancer resections.

AIM: The aim of this study was to evaluate the incidence of incisional hernia formation after laparoscopic and open surgery for colorectal cancer. METHOD: A retrospective analysis was conducted of 1057 colorectal cancer resection cases (289 laparoscopic, 768 open) performed in a single national laparoscopic training centre between January 2006 and December 2011. Clinical notes and serial computed tomography scans were reviewed, with any incisional hernia including those at a surgical incision, port site, stoma and stoma closure site identified and the size of the defect measured. RESULTS: The overall incisional hernia rate was 14.8%. There was no significant difference between the open and laparoscopic groups (14.4% vs 15.9%, P = 0.566). Excluding stoma-related hernia, 10.7% of the open group developed a surgical wound hernia, and 11.1% of the laparoscopic group developed a hernia at a port site, extraction site or surgical midline incision. There was no statistical difference between the two groups (P = 0.853). The defects were smaller in the laparoscopic group (P < 0.005). There were significantly more parastomal hernias in the laparoscopic group (40%) than in the open group (12.7%, P < 0.001). CONCLUSION: The incidence of incisional hernia formation was similar after laparoscopic or open surgery for colorectal cancer. Parastomal hernia was more frequent after laparoscopic surgery.

A randomised, controlled, crossover study to investigate the safety and response of 1R,2S-methoxamine hydrochloride (NRL001) on anal function in healthy volunteers.

AIMS: This study aimed to assess the dose and volume effects of suppository preparations and safety of NRL001 (one of four possible stereoisomers of methoxamine hydrochloride) on anal sphincter tone using rectal suppositories in healthy adult volunteers. METHODS: This was a Phase I, single-centre, randomised, double-blind, three-way crossover study during which subjects received three single doses of 1 g rectal suppositories (containing 5 or 10 mg NRL001 or matching placebo) or 2 g rectal suppositories (containing 10 or 15 mg NRL001 or matching placebo) on three separate dosing days. The outcome measures were mean anal resting pressure (MARP) variables (monitored continuously for 20-30 min before and up to 6 h after dosing), pharmacokinetics (PK) and safety assessments. RESULTS: Twenty-six subjects were dosed with study medication. Two subjects were withdrawn prematurely and were not included in the main analysis. There was a dose-dependent increase in anal sphincter tone (MARP) when comparing the 5 and 10 mg doses of NRL001; however, the 15 mg dose did not have a significantly greater effect than the 10 mg dose. Suppository size (1 or 2 g) did not appear to have an effect on sphincter tone. There was no evidence against dose proportionality for the PK variables, but the mean maximum plasma concentration (Cmax ) for the 1 g suppository group was higher than for the 2 g group. Twenty-one adverse events were reported in 8 (30.8%) subjects. A dose dependent decrease in heart rate was noted; however, there were no adverse events reported that were related to this reduction in heart rate. CONCLUSIONS: The increase in anal sphincter tone supports the potential therapeutic use of NRL001 in treating faecal incontinence, with further studies in patients required. NRL001 was well tolerated in single doses of up to 15 mg.

The feasibility and clinical efficacy of intravenous iron administration for preoperative anaemia in patients with colorectal cancer.

AIM: The study aimed to analyse the feasibility and efficacy of administration of a single intravenous iron infusion (IVI) in the preoperative optimization of colorectal cancer patients with anaemia. METHOD: Twenty patients were recruited at least 14 days before the planned date of surgery. A single 1000 mg dose of ferric carboxymaltose (Ferinject) was administered as an outpatient procedure. Blood samples were taken at recruitment prior to drug administration (REC), on the day of surgery prior to any intervention (DOS) and on the first postoperative day. Allogeneic red blood cell transfusions (ARBT) and outcomes were recorded from recruitment throughout the study period. RESULTS: There was a significant median rise in haemoglobin levels (Hb) from REC to DOS of 1.8 g/dl [interquartile range (IQR) 0.75-2.45, P < 0.001] for the entire cohort. Two patients received ARBT preoperatively, and for those not transfused preoperatively (n = 18), this incremental Hb rise remained significant (P < 0.001, median 1.65 g/dl, IQR 0.5-2.3). Of these patients, those who responded to IVI had higher erythropoietin (EPO) levels at recruitment (P < 0.01) and lower recruitment Hb values, transferrin-saturation (TSAT) and C-reactive protein (CRP) levels (P < 0.05). REC Hb (Rs = -0.62, P < 0.01), REC TSAT levels (Rs = -0.67, P < 0.01) and REC EPO (Rs = 0.69, P < 0.01) correlated with the magnitude of treatment change in Hb levels. Five patients received ARBT until the fourth postoperative day, which was significantly fewer than predicted (P < 0.05). CONCLUSION: IVI can be administered preoperatively in the outpatient clinic to colorectal cancer patients with anaemia, with associated reduction in ARBT use and increase in Hb levels.

Same-day assessment and management of urgent (2-week wait) colorectal referrals: an analysis of the outcome of 1606 patients attending an endoscopy unit-based colorectal clinic.

AIM: The Rapid Access Diagnosis and Remedy (RADAR) clinic combines 2-week wait (TWW) specialist consultation with 'straight-to-test' flexible sigmoidoscopy (FS) for left-sided 'red-flag' TWW criteria (excluding right-sided mass or iron-deficiency anaemia). The study aims were to determine the effectiveness of RADAR in differentiating colorectal cancer from benign disease and to evaluate the need for whole colonic investigation (WCI) following FS, in symptomatic patients. METHOD: Prospectively collated data of all RADAR patients from November 2005 to November 2009 were analysed, excluding patients referred internally for a FS. The local histology database was later interrogated to detect any missed cancers. RESULTS: Of 1690 patients (729 men; median (range) age: 68 (18-96) years) assessed in RADAR, 84 were excluded. Colorectal cancer (CRC) was diagnosed in 117 (7.3%). Eighty-seven cancers were diagnosed on the day of attendance and a further 13 within a week (88.9% overall). Two patients after a cancer-free FS were found to have a right-sided CRC on WCI (0.24%) and one synchronous cancer was found. No patient with a cancer-free FS having a WCI was subsequently found to have CRC at a median of 35 (12-58) months. CONCLUSION: Flexible sigmoidoscopy, in the context of an endoscopy unit TWW clinic, allows same-day diagnosis of most patients referred with left-sided symptoms, and immediate reassurance and treatment of most benign diagnoses. For these patients, the use of routine WCI following a cancer-free FS does not appear to be beneficial. Adopting this system would significantly reduce the number of barium enemas and colonoscopies currently performed.

Outcomes after biological mesh reconstruction of the pelvic floor following extra-levator abdominoperineal excision of rectum (APER).

BACKGROUND: Extra-levator abdominoperineal excision of the rectum (ELAPER) for low rectal cancer is used to avoid the adverse oncological outcomes of inadvertent perforation and a positive circumferential resection margin associated with the conventional APER technique. This wider excision creates a large defect requiring pelvic floor reconstruction, and there is still controversy regarding the best method of closure. The aim of this study is to present outcomes of biological mesh pelvic floor reconstruction following ELAPER. METHODS: Prospective data on consecutive patients having ELAPER for low rectal cancer at a single UK institution between October 2008 and March 2013 were collected. The perineum was reconstructed using a biological mesh and the short-term outcomes were evaluated, focusing particularly on perineal wound complications and perineal hernias. RESULTS: Thirty-four patients were included [median age 62 years, range 40-72 years, 27 males (79 %)]. The median operative time was 248 min (range 120-340 min). The median length of hospital stay was 9 days (range 4-20 days). There were three perineal complications (9 %) requiring surgical intervention, but no meshes were removed. There were no perineal hernias. The median length of follow-up was 21 months (range 1-54 months). The overall mortality was 9 % from distant metastases. CONCLUSIONS: Our series adds to the increasing evidence that good outcomes can be achieved for pelvic floor reconstruction with biological mesh following ELAPER without the additional use of myocutaneous flaps. The low serious complication rate, good outcomes in perineal wound healing and the absence of perineal hernias demonstrates that this is a safe and feasible procedure.

Adult serum cytokine concentrations and the persistence of asthma.

BACKGROUND: Cytokines play a pivotal role in regulating the development and persistence of the inflammatory process in asthma. Our aim was to investigate whether asthma persistence or remission is associated with a specific cytokine profile. METHODS: The Tasmanian Longitudinal Health Study followed participants from 7 to 44 years of age. Serum concentrations of interleukin (IL)-4, IL-5, IL-6, IL-8, IL-10 and tumor necrosis factor-alpha (TNF-α) were measured at age 44 years. Participants were categorized into five phenotypes (early-onset noncurrent asthma, early-onset current asthma, late-onset noncurrent asthma and late-onset current asthma). Those who had never had asthma formed the reference group. Multivariable linear regression was used to compare serum cytokine concentrations between each phenotype and the reference group. RESULTS: IL-10 concentrations were significantly lower in serum from the early-onset current asthma group than in the reference group (ratio of geometric means 0.58; 95% confidence interval 0.33-0.99; p = 0.048). IL-6 concentrations for the late-onset remitted group were also significantly lower than in the reference group (p = 0.009). The TNF-α concentrations were significantly lower for both early-and late-onset remitted asthma phenotypes when compared with the reference group. No associations were detected between serum concentrations of IL-4, IL-5 or IL-8 and these specific longitudinal asthma phenotypes. CONCLUSION: Our findings suggest a possible role for deficient IL-10 responses in the persistence of early-onset asthma. Lower IL-6 and TNF-α concentrations in serum from those with remitted asthma suggest that these proinflammatory cytokines may be actively suppressed during asthma remission.