The gravitationally unstable gas disk of a starburst galaxy 12 billion years ago.

Galaxies in the early Universe that are bright at submillimetre wavelengths (submillimetre-bright galaxies) are forming stars at a rate roughly 1,000 times higher than the Milky Way. A large fraction of the new stars form in the central kiloparsec of the galaxy1-3, a region that is comparable in size to the massive, quiescent galaxies found at the peak of cosmic star-formation history4 and the cores of present-day giant elliptical galaxies. The physical and kinematic properties inside these compact starburst cores are poorly understood because probing them at relevant spatial scales requires extremely high angular resolution. Here we report observations with a linear resolution of 550 parsecs of gas and dust in an unlensed, submillimetre-bright galaxy at a redshift of z = 4.3, when the Universe was less than two billion years old. We resolve the spatial and kinematic structure of the molecular gas inside the heavily dust-obscured core and show that the underlying gas disk is clumpy and rotationally supported (that is, its rotation velocity is larger than the velocity dispersion). Our analysis of the molecular gas mass per unit area suggests that the starburst disk is gravitationally unstable, which implies that the self-gravity of the gas is stronger than the differential rotation of the disk and the internal pressure due to stellar-radiation feedback. As a result of the gravitational instability in the disk, the molecular gas would be consumed by star formation on a timescale of 100 million years, which is comparable to gas depletion times in merging starburst galaxies5.

Cystic Fibrosis screen positive, inconclusive diagnosis (CFSPID) to Cystic Fibrosis: Detecting disease with serial assessments.

We present the case of a child given a CFSPID designation in early life who was later reclassified as having CF based on a combination of recurrent respiratory symptoms and CFTR functional testing, despite normal sweat chloride levels. Here we demonstrate the importance of monitoring these children, each time reviewing the diagnosis based on updated understanding of individual CFTR mutation phenotypes or clinical findings inconsistent with the designation. This case identifies situations in which the CFSPID designation should be challenged, and gives an approach for this when CF is suspected.

PrEP Use, Sexual Behaviour, and PrEP Adherence Among Men who have Sex with Men Living in Wales Prior to and During the COVID-19 Pandemic.

We examined PrEP use, condomless anal sex (CAS), and PrEP adherence among men who have sex with men (MSM) attending sexual health clinics in Wales, UK. In addition, we explored the association between the introduction of measures to control transmission of SARS-CoV-2 on these outcomes. We conducted an ecological momentary assessment study of individuals in receipt of PrEP in Wales. Participants used an electronic medication cap to record PrEP use and completed weekly sexual behaviour surveys. We defined adherence to daily PrEP as the percentage of CAS episodes covered by daily PrEP (preceded by ≥ 3 days of PrEP and followed by ≥ 2 days). Sixty participants were recruited between September 2019 and January 2020. PrEP use data prior to the introduction of control measures were available over 5785 person-days (88%) and following their introduction 7537 person-days (80%). Data on CAS episodes were available for 5559 (85%) and 7354 (78%) person-days prior to and following control measures respectively. Prior to the introduction of control measures, PrEP was taken on 3791/5785 (66%) days, there were CAS episodes on 506/5559 (9%) days, and 207/406 (51%) of CAS episodes were covered by an adequate amount of daily PrEP. The introduction of pandemic-related control measures was associated with a reduction in PrEP use (OR 0.44, 95%CI 0.20-0.95), CAS (OR 0.35, 95%CI 0.17-0.69), and PrEP adherence (RR = 0.55, 95%CI 0.34-0.89) and this may have implications for the health and wellbeing of PrEP users and, in addition to disruption across sexual health services, may contribute to wider threats across the HIV prevention cascade.

Therapeutic yoga reduces pro-tumorigenic cytokines in cancer survivors.

INTRODUCTION: Chronic inflammation can remain many years after the completion of cancer treatment and is associated with cancer recurrence. The purpose of this study was to examine how a 16-week therapeutic yoga program (TYP) modulates the cytokine profile in heterogeneous cancer survivors. METHODS: Eligible participants were 18 years of age or older and clinically diagnosed with cancer. Consenting participants were asked to attend three, 75-min sessions weekly of TYP with meditation. Seventeen patients provided blood samples at baseline and end of study. Eight cytokines (interferon (IFN)-γ; interleukin (IL)-1b, IL-1ra, IL-4, IL-6, IL-8, IL-10; and tumor necrosis factor (TNF)-α), three receptors (sIL-6R, sTNFRI, sTNFRII), and C-reactive protein (CRP) were quantified. RESULTS: Patients were 59.6 ± 7.3 years old; over half (56%) were overweight or obese BMI ≥ 25 kg/m2); majority were female (71%) and breast cancer survivors (65%), of which 44% were Hispanic. Marked reductions were observed in all cytokines except IL-4, with significant reductions (p < 0.05) found in IL-1b (- 13%) and IL-1ra (- 13%). No significant changes were observed in soluble cytokine receptors or CRP. CONCLUSIONS: TYP led to significant reduction in circulating cytokines associated with chronic inflammation in a heterogeneous sample of cancer survivors.

Standardising clinical outcomes measures for adult clinical trials in Fabry disease: A global Delphi consensus.

BACKGROUND: Recent years have witnessed a considerable increase in clinical trials of new investigational agents for Fabry disease (FD). Several trials investigating different agents are currently in progress; however, lack of standardisation results in challenges to interpretation and comparison. To facilitate the standardisation of investigational programs, we have developed a common framework for future clinical trials in FD. METHODS AND FINDINGS: A broad consensus regarding clinical outcomes and ways to measure them was obtained via the Delphi methodology. 35 FD clinical experts from 4 continents, representing 3389 FD patients, participated in 3 rounds of Delphi procedure. The aim was to reach a consensus regarding clinical trial design, best treatment comparator, clinical outcomes, measurement of those clinical outcomes and inclusion and exclusion criteria. Consensus results of this initiative included: the selection of the adaptative clinical trial as the ideal study design and agalsidase beta as ideal comparator treatment due to its longstanding use in FD. Renal and cardiac outcomes, such as glomerular filtration rate, proteinuria and left ventricular mass index, were prioritised, whereas neurological outcomes including cerebrovascular and white matter lesions were dismissed as a primary or secondary outcome measure. Besides, there was a consensus regarding the importance of patient-related outcomes such as general quality of life, pain, and gastrointestinal symptoms. Also, unity about lysoGb3 and Gb3 tissue deposits as useful surrogate markers of the disease was obtained. The group recognised that cardiac T1 mapping still has potential but requires further development before its widespread introduction in clinical trials. Finally, patients with end-stage renal disease or renal transplant should be excluded unless a particular group for them is created inside the clinical trial. CONCLUSION: This consensus will help to shape the future of clinical trials in FD. We note that the FDA has, coincidentally, recently published draft guidelines on clinical trials in FD and welcome this contribution.

Effect of non-vitamin-K oral anticoagulants on stroke severity compared to warfarin: a meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: In addition to lowering stroke risk, warfarin use is also associated with reduced stroke severity in patients with atrial fibrillation and acute ischaemic stroke. It was sought to determine whether the effect of non-vitamin-K oral anticoagulants (NOACs), compared to warfarin, differed by stroke severity. METHODS: Phase III randomized controlled trials with participants who were randomized to receive NOACs or warfarin for stroke prevention in the setting of non-valvular atrial fibrillation were identified. Stroke was classified into two categories, fatal or disabling stroke and non-disabling stroke, and meta-analyses were completed for both outcomes and for comparative case fatality of stroke amongst trials. RESULTS: Five randomized controlled trials met our inclusion criteria. In clinical trials evaluating the NOACs usually prescribed in clinical practice (four trials), acute stroke was reported in 1403 (1.86%) participants, 787 (1.04%) in the NOAC group [386 (0.51%) fatal or disabling, 401 (0.53%) non-disabling] and 616 (0.82%) in the warfarin group [367 (0.49%) fatal or disabling, 249 (0.33%) non-disabling]. On meta-analysis NOACs were significantly superior to warfarin for fatal or disabling stroke (odds ratio [OR] 0.77; 95% confidence interval [CI] 0.66-0.89, I2  = 21%) and non-disabling stroke (OR 0.85; 95% CI 0.73-0.98, I2  = 2%). The case fatality of stroke was no different between groups (OR 0.90, 95% CI 0.75-1.13, I2  = 0%), but the point estimate favoured NOACs. CONCLUSION: In phase III trials of NOACs, for prevention of stroke in atrial fibrillation, NOACs are associated with a lower risk of both fatal/disabling and non-disabling stroke compared to warfarin.

Phase-field modeling of constrained interactive fungal networks.

Fungi develop structures that interact with their surroundings and evolve adaptively in the presence of geometrical constraints, finding optimal solutions for complex combinatorial problems. The pathogenic fungus Ophiocordyceps constitutes a perfect model for the study of constrained interactive networks. Modeling these networks is challenging due to the highly coupled physics involved and their interaction with moving boundaries. In this work, we develop a computational phase-field model to elucidate the mechanics of the emerging properties observed in fungal networks. We use a variational approach to derive the equations governing the evolution in time of the mycelium biomass and the nutrients in the medium. We present an extensive testing of our model, reproduce growing and decaying phenomena, and capture spatial and temporal scales. We explore the variables interplay mechanism that leads to different colony morphologies, and explain abrupt changes of patterns observed in the laboratory. We apply our model to simulate analogous processes to the evolution of Ophiocordyceps as it grows through confined geometry and depletes available resources, demonstrating the suitability of the formulation to study this class of biological networks.

Genotyping of long term persistent Staphylococcus aureus in bovine subclinical mastitis.

Bovine mastitis affects dairy cattle worldwide and Staphylococcus aureus is one of the most common microorganisms involved in subclinical and chronic disease. Superantigens, such as enterotoxins contribute to S. aureus persistence and pathogenicity in this disease. Subclinical and chronic mastitis cases were diagnosed and S. aureus isolates from sub-clinical cases were investigated for carriage of virulence and antibiotic resistance genes that may contribute to long-term carriage and infection. Over a 12-month period, 116 S. aureus strains were recovered from 68 cows with subclinical mastitis. Classical enterotoxin genes (sea-see) were detected in 24.1% of isolates, and pvl and tsst-1 were identified in 3.4% and 46.6% the isolates, respectively. 18.1% that were persistent isolates were identified and characterized by pulsed field gel electrophoresis (PFGE), MLST, spa typing. Four isolates were methicillin-resistant S. aureus (MRSA) and belonged to SCCmec type I. Molecular typing showed that the agrI group was the most frequent, and a rare isolate was positive for both agrI and agrIII groups. Molecular characterization revealed the persistence of the spa type t10856 (ST133, clonal complex CC133, agr I), in a single animal for nine months and the persistence t605 (ST126, CC126) colonizing four animals for four months. These strains have been described recently in other herds in the same region, indicating their transmissibility and clonal expansion. We conclude that animals with subclinical mastitis are an important and somewhat overlooked reservoir for transmission within and between herds, and may carry virulence and antibiotic resistance genes contributing to persistent colonization, hinder the control of mastitis and may cause risks to the public health.

Neurological effects of glucocerebrosidase gene mutations.

The association between Gaucher disease (GD) and Parkinson disease (PD) has been described for almost two decades. In the biallelic state (homozygous or compound heterozygous) mutations in the glucocerebrosidase gene (GBA) may cause GD, in which glucosylceramide, the sphingolipid substrate of the glucocerebrosidase enzyme (GCase), accumulates in visceral organs leading to a number of clinical phenotypes. In the biallelic or heterozygous state, GBA mutations increase the risk for PD. Mutations of the GBA allele are the most significant genetic risk factor for idiopathic PD, found in 5%-20% of idiopathic PD cases depending on ethnicity. The neurological consequences of GBA mutations are reviewed and the proposition that GBA mutations result in a disparate but connected range of clinically and pathologically related neurological features is discussed. The literature relating to the clinical, biochemical and genetic basis of GBA PD, type 1 GD and neuronopathic GD is considered highlighting commonalities and distinctions between them. The evidence for a unifying disease mechanism is considered.

Management goals for type 1 Gaucher disease: An expert consensus document from the European working group on Gaucher disease.

Gaucher Disease type 1 (GD1) is a lysosomal disorder that affects many systems. Therapy improves the principal manifestations of the condition and, as a consequence, many patients show a modified phenotype which reflects manifestations of their disease that are refractory to treatment. More generally, it is increasingly recognised that information as to how a patient feels and functions [obtained by patient- reported outcome measurements (PROMs)] is critical to any comprehensive evaluation of treatment. A new set of management goals for GD1 in which both trends are reflected is needed. To this end, a modified Delphi procedure among 25 experts was performed. Based on a literature review and with input from patients, 65 potential goals were formulated as statements. Consensus was considered to be reached when ≥75% of the participants agreed to include that specific statement in the management goals. There was agreement on 42 statements. In addition to the traditional goals concerning haematological, visceral and bone manifestations, improvement in quality of life, fatigue and social participation, as well as early detection of long-term complications or associated diseases were included. When applying this set of goals in medical practice, the clinical status of the individual patient should be taken into account.

Fludrocortisone-a treatment for tubulopathy post-paediatric renal transplantation: A national paediatric nephrology unit experience.

Calcineurin inhibitors post-renal transplantation are recognized to cause tubulopathies in the form of hyponatremia, hyperkalemia, and acidosis. Sodium supplementation may be required, increasing medication burden and potentially resulting in poor compliance. Fludrocortisone has been beneficial in addressing tubulopathies in adult studies, with limited paediatric data available. A retrospective review of data from an electronic renal database from December 2014 to January 2016 was carried out. Forty-seven post-transplant patients were reviewed with 23 (49%) patients on sodium chloride or bicarbonate. Nine patients, aged 8.3 years (range 4.9-16.4), commenced fludrocortisone 22 months (range 1-80) after transplant and were followed up for 9 months (range 2-20). All patients stopped sodium bicarbonate; all had a reduction or no increase in total daily doses of sodium chloride. Potassium levels were significantly lower on fludrocortisone, 5.2 vs 4.5 mmol/L, P = .04. No difference was noted in renal function (eGFR 77.8 vs 81.7 mL/min/1.73 m2 , P = .45) and no significant increase in systolic blood pressure (z-scores 0.99 vs 0.85, P = .92). No side effects secondary to treatment with fludrocortisone were reported. A significant proportion of renal transplant patients were on sodium supplementation and fludrocortisone reduced sodium supplementation without significant effects on renal function or blood pressure. Fludrocortisone appears to be safe and effective for tubulopathies in children post-transplantation.

Refining the Definitions of Biochemical and Clinical Cure for Primary Aldosteronism Using the Primary Aldosteronism Surgical Outcome (PASO) Classification System.

INTRODUCTION: Determination of outcomes after adrenalectomy for primary aldosteronism (PA) is limited by the lack of standardized definitions of cure. The Primary Aldosteronism Surgical Outcomes (PASO) group recently established new consensus definitions for biochemical and clinical cure of PA. We hypothesize that utilization of PASO definitions will better stratify patient outcomes after surgery compared to original and current criteria utilized to document cure. MATERIALS AND METHODS: Patients undergoing adrenalectomy for PA from 1996 to 2016 were studied. Clinical data were reviewed. Three different sets of criteria (original, current, and PASO) were evaluated for differences in documentation of cure. Demographic data were reported as median (range). Comparisons were made using the Mann-Whitney U test; p < 0.05 is significant. RESULTS: A total of 314 patients with PA were identified. Ninety patients (60 males) elected to proceed with surgery. In Group 1 (35 patients), 30 patients had clinical follow-up and 29 (97%) were cured using original criteria. In Group 2 (55 patients), cure was recorded in 98% when original criteria for cure were applied, 89% cured applying current criteria, and 6% had complete biochemical and clinical cure by PASO criteria. Aldosterone rose 3.6 ng/dL (0.1-34.8) in five patients during extended follow-up, with two patients changing from complete to partial or missing biochemical success. CONCLUSION: Significant heterogeneity exists in outcomes criteria utilized to document cure or clinical improvement after adrenalectomy for primary aldosteronism. Aldosterone levels change over time after adrenalectomy. PASO definitions of cure appear to allow for improved stratification of short- and long-term outcomes.

Zombie-ant fungi across continents: 15 new species and new combinations within Ophiocordyceps. I. Myrmecophilous hirsutelloid species.

Ophiocordyceps species infecting ants - the so-called zombie-ant fungi - comprise one of the most intriguing and fascinating relationships between microbes and animals. They are widespread within tropical forests worldwide, with relatively few reports from temperate ecosystems. These pathogens possess the ability to manipulate host behaviour in order to increase their own fitness. Depending on the fungal species involved the infected ants are manipulated either to leave the nest to ascend understorey shrubs, to die biting onto vegetation, or descend from the canopy to die at the base of trees. Experimental evidence has demonstrated that the behavioural change aids spore dispersal and thus increases the chances of infection, because of the existing behavioural immunity expressed inside ant colonies that limits fungal development and transmission. Despite their undoubted importance for ecosystem functioning, these fungal pathogens are still poorly documented, especially regarding their diversity, ecology and evolutionary relationships. Here, we describe 15 new species of Ophiocordyceps with hirsutella-like asexual morphs that exclusively infect ants. These form a monophyletic group that we identified in this study as myrmecophilous hirsutelloid species. We also propose new combinations for species previously described as varieties and provide for the first time important morphological and ecological information. The species proposed herein were collected in Brazil, Colombia, USA, Australia and Japan. All species could readily be separated using classic taxonomic criteria, in particular ascospore and asexual morphology.

Genomic innovations, transcriptional plasticity and gene loss underlying the evolution and divergence of two highly polyphagous and invasive Helicoverpa pest species.

BACKGROUND: Helicoverpa armigera and Helicoverpa zea are major caterpillar pests of Old and New World agriculture, respectively. Both, particularly H. armigera, are extremely polyphagous, and H. armigera has developed resistance to many insecticides. Here we use comparative genomics, transcriptomics and resequencing to elucidate the genetic basis for their properties as pests. RESULTS: We find that, prior to their divergence about 1.5 Mya, the H. armigera/H. zea lineage had accumulated up to more than 100 more members of specific detoxification and digestion gene families and more than 100 extra gustatory receptor genes, compared to other lepidopterans with narrower host ranges. The two genomes remain very similar in gene content and order, but H. armigera is more polymorphic overall, and H. zea has lost several detoxification genes, as well as about 50 gustatory receptor genes. It also lacks certain genes and alleles conferring insecticide resistance found in H. armigera. Non-synonymous sites in the expanded gene families above are rapidly diverging, both between paralogues and between orthologues in the two species. Whole genome transcriptomic analyses of H. armigera larvae show widely divergent responses to different host plants, including responses among many of the duplicated detoxification and digestion genes. CONCLUSIONS: The extreme polyphagy of the two heliothines is associated with extensive amplification and neofunctionalisation of genes involved in host finding and use, coupled with versatile transcriptional responses on different hosts. H. armigera's invasion of the Americas in recent years means that hybridisation could generate populations that are both locally adapted and insecticide resistant.

Heteromeric α/ß glycine receptors regulate excitability in parvalbumin-expressing dorsal horn neurons through phasic and tonic glycinergic inhibition.

KEY POINTS: Spinal parvalbumin-expressing interneurons have been identified as a critical source of inhibition to regulate sensory thresholds by gating mechanical inputs in the dorsal horn. This study assessed the inhibitory regulation of the parvalbumin-expressing interneurons, showing that synaptic and tonic glycinergic currents dominate, blocking neuronal or glial glycine transporters enhances tonic glycinergic currents, and these manipulations reduce excitability. Synaptically released glycine also enhanced tonic glycinergic currents and resulted in decreased parvalbumin-expressing interneuron excitability. Analysis of the glycine receptor properties mediating inhibition of parvalbumin neurons, as well as single channel recordings, indicates that heteromeric α/ß subunit-containing receptors underlie both synaptic and tonic glycinergic currents. Our findings indicate that glycinergic inhibition provides critical control of excitability in parvalbumin-expressing interneurons in the dorsal horn and represents a pharmacological target to manipulate spinal sensory processing. ABSTRACT: The dorsal horn (DH) of the spinal cord is an important site for modality-specific processing of sensory information and is essential for contextually relevant sensory experience. Parvalbumin-expressing inhibitory interneurons (PV+ INs) have functional properties and connectivity that enables them to segregate tactile and nociceptive information. Here we examine inhibitory drive to PV+ INs using targeted patch-clamp recording in spinal cord slices from adult transgenic mice that express enhanced green fluorescent protein in PV+ INs. Analysis of inhibitory synaptic currents showed glycinergic transmission is the dominant form of phasic inhibition to PV+ INs. In addition, PV+ INs expressed robust glycine-mediated tonic currents; however, we found no evidence for tonic GABAergic currents. Manipulation of extracellular glycine by blocking either, or both, the glial and neuronal glycine transporters markedly decreased PV+ IN excitability, as assessed by action potential discharge. This decreased excitability was replicated when tonic glycinergic currents were increased by electrically activating glycinergic synapses. Finally, we show that both phasic and tonic forms of glycinergic inhibition are mediated by heteromeric α/ß glycine receptors. This differs from GABAA receptors in the dorsal horn, where different receptor stoichiometries underlie phasic and tonic inhibition. Together these data suggest both phasic and tonic glycinergic inhibition regulate the output of PV+ INs and contribute to the processing and segregation of tactile and nociceptive information. The shared stoichiometry for phasic and tonic glycine receptors suggests pharmacology is unlikely to be able to selectively target each form of inhibition in PV+ INs.

Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System.

In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from five different donors cultured in a perfused three-dimensional human liver microphysiological system, and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro-in vivo translation. For each donor, metabolic depletion profiles of six compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol, and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability [lactate dehydrogenase (LDH) release, albumin, and urea production]. Drug depletion data were analyzed with mixed-effects modeling. Substantial interdonor variability was observed with respect to gene expression levels, drug metabolism, and other measured hepatocyte functions. Specifically, interdonor variability in intrinsic metabolic clearance ranged from 24.1% for phenacetin to 66.8% for propranolol (expressed as coefficient of variation). Albumin, urea, LDH, and cytochrome P450 mRNA levels were identified as significant predictors of in vitro metabolic clearance. Predicted clearance values from the liver microphysiological system were correlated with the observed in vivo values. A population physiologically based pharmacokinetic model was developed for lidocaine to illustrate the translation of the in vitro output to the observed pharmacokinetic variability in vivo. Stochastic simulations with this model successfully predicted the observed clinical concentration-time profiles and the associated population variability. This is the first study of population variability in drug metabolism in the context of a microphysiological system and has important implications for the use of these systems during the drug development process.

Hedgehog pathway overexpression in pancreatic cancer is abrogated by new-generation taxoid SB-T-1216.

The Hedgehog pathway is one of the major driver pathways in pancreatic ductal adenocarcinoma. This study investigated prognostic importance of Hedgehog signaling pathway in pancreatic cancer patients who underwent a radical resection. Tumors and adjacent non-neoplastic pancreatic tissues were obtained from 45 patients with histologically verified pancreatic cancer. The effect of experimental taxane chemotherapy on the expression of Hedgehog pathway was evaluated in vivo using a mouse xenograft model prepared using pancreatic cancer cell line Paca-44. Mice were treated by experimental Stony Brook Taxane SB-T-1216. The transcript profile of 34 Hedgehog pathway genes in patients and xenografts was assessed using quantitative PCR. The Hedgehog pathway was strongly overexpressed in pancreatic tumors and upregulation of SHH, IHH, HHAT and PTCH1 was associated with a trend toward decreased patient survival. No association of Hedgehog pathway expression with KRAS mutation status was found in tumors. Sonic hedgehog ligand was overexpressed, but all other downstream genes were downregulated by SB-T-1216 treatment in vivo. Suppression of HH pathway expression in vivo by taxane-based chemotherapy suggests a new mechanism of action for treatment of this aggressive tumor.

Continuous subcutaneous insulin infusion (CSII) therapy at Derby Teaching Hospitals: sustained benefits in glucose control.

AIM: In the short term, continuous subcutaneous insulin infusion (CSII) has been associated with improved glycaemic control, reduced hypoglycaemia and improved quality of life (QOL). However, limited data are available on its long-term benefits, particularly in the UK. We aimed to assess the impact of CSII on longer term outcomes. METHOD: Patient-level data were obtained for CSII users at Derby Teaching Hospitals, UK. Patient confidence and satisfaction questionnaires using the Likert scale were used to assess confidence in self-management. Comparative statistics were conducted using Pearson's chi-square and Student's t-tests. RESULTS: Some 258 CSII users were identified (60.1% female, mean age 43.9 ± 13.4 years). Overall, there was significant decrease in HbA1c from 78 mmol/mol (9.3 ± 2.0%) at baseline, to 69 mmol/mol (8.5 ± 1.3%) at 6 months [mean difference (md): -0.64; 95% confidence interval (95% CI): -0.91 to -0.37; P < 0.0001]; which was sustained at 6 years of follow-up (HbA1c : 66 mmol/mol, 8.2 ± 1.3%; md: -1.07%; 95% CI: -1.45 to -0.69; P < 0.0001). One hundred and twenty-one patients (47%) responded to the survey, of whom 95 (78.5%) reported a reduction in the frequency of hypoglycaemia; 102 (84.3%) were satisfied with the quality of care received in the insulin pump service. CONCLUSION: CSII therapy led to a sustained long-term improvement in glycaemic control in addition to a reduction in self-reported hypoglycaemia.

Reduced pro-inflammatory responses to Staphylococcus aureus bloodstream infection and low prevalence of enterotoxin genes in isolates from patients on haemodialysis.

Patients with end-stage renal failure undergo regular haemodialysis (HD) and often develop episodes of Staphylococcus aureus bloodstream infection (BSI), which can re-occur. However, clinically, patients on HD, with S. aureus BSI, respond well to treatment, rarely developing overt signs of sepsis. We investigated the contributions of bacterial virulence and cytokine responses to the clinical course of S. aureus BSI in HD and non-HD patients. Seventy patients were recruited, including 27 (38.6 %) patients on HD. Isolates were spa-typed and virulence and antimicrobial resistance gene carriage was investigated using DNA microarray analysis. Four inflammatory cytokines, IL-6, RANTES, GROγ and leptin, were measured in patient plasma on the day of diagnosis and after 7 days. There was no significant difference in the prevalence of genotypes or antimicrobial resistance genes in S. aureus isolates from HD compared to non-HD patients. The enterotoxin gene cluster (containing staphylococcal enterotoxins seg, sei, sem, sen, seo and seu) was significantly less prevalent among BSI isolates from HD patients compared to non-HD patients. Comparing inflammatory cytokine response to S. aureus BSI in HD patients to non-HD patients, IL-6 and GROγ were significantly lower (p = 0.021 and p = 0.001, respectively) in HD patients compared to other patients on the day of diagnosis and RANTES levels were significantly lower (p = 0.025) in HD patients on day 7 following diagnosis. Lowered cytokine responses in HD patients and a reduced potential for super-antigen production by infecting isolates may partly explain the favourable clinical responses to episodes of S. aureus BSI in HD patients that we noted clinically.

Acceptability and benefit of rectal irrigation in patients with Low Anterior Resection Syndrome: a qualitative study.

AIM: Low Anterior Resection Syndrome (LARS) following rectal cancer surgery impairs the patient's quality of life (QoL). Rectal Irrigation has been demonstrated to be effective for anterior resection syndrome but many surgeons do not suggest it as a treatment. This feasibility study aimed to explore treatment acceptability and the benefit of rectal irrigation in patients who developed LARS following an anterior resection for rectal cancer. METHODS: This was a qualitative study, involving semi-structured interviews. Twenty-one patients diagnosed with LARS following anterior resection for rectal cancer in a single tertiary centre were offered rectal irrigation as a treatment option. Qualitative interviews (n=17) were conducted at baseline to explore patient reported impact of LARS on QoL, treatment acceptability and factors influencing the decision to accept/decline treatment. Follow up interviews were carried out at six months for the treatment group only (n=12), to assess its practicality and impact on QoL. RESULTS: Qualitative interview findings suggest rectal irrigation is an acceptable method of treatment for LARS. Participants who perceived their symptoms to be more severe or poorly controlled were most likely to consider rectal irrigation as a treatment option. The patients who completed treatment reported improvements in their QoL, the ability to control the time of defaecation being the key benefit CONCLUSION: Clinicians should consider offering rectal irrigation as a treatment option to patients presenting with bowel dysfunction following anterior resection as it can improve symptoms. Patients who perceive that their symptoms are severe are more likely to consider treatment. This article is protected by copyright. All rights reserved.