A feasibility, randomised controlled trial of Club Connect: a group-based healthy brain ageing cognitive training program for older adults with major depression within an older people's mental health service.

BACKGROUND: Using the RE-AIM (reach, effectiveness, adoption, implementation, maintenance) framework, we outline steps taken to implement an evidence-based cognitive training program, Club Connect, in older adults with major depressive disorder in an Older People's Mental Health Service in Sydney, Australia. The primary aim was to explore feasibility (or 'reach'), tolerability (or 'implementation'), and acceptability (or 'adoption'). The secondary aim was to explore the most sensitive clinical outcomes and measurement tools (i.e. 'effectiveness') to inform a formal randomised controlled trial, and to explore the healthcare resources used (i.e. costs) to assist decision-making by health care managers and policy-makers in relation to future resource allocation. METHODS: Using a single blinded feasibility design, 40 participants (mean age: 76.13 years, SD: 7.45, range: 65-95 years) were randomised to either (a) Club Connect, a 10-week group-based multifaceted program, comprising psychoeducation and computer-based cognitive training, or (b) a waitlist control group. RESULTS: Implementing group-based cognitive training within a clinical setting was feasible, well tolerated and accepted by participants. Further, cognitive training, in comparison to the waiting list control, was associated with moderate to very large effect size improvements in depression, stress and inhibition (ηp2 = 0.115-0.209). We also found moderate effect size improvements on measures of daily functioning, wellbeing and cognitive flexibility. Small effect size improvements for other cognitive and psychosocial outcomes were also observed. The average cost per person participating in in the intervention was AU$607.50. CONCLUSIONS: Our findings support the feasibility of implementing group-based cognitive training into a specialised clinical (public health) setting. This trial was registered on the Australian and New Zealand Clinical Trial Registry (ACTRN12619000195156, 12/02/2019).

A Systematic Review and Meta-Analysis of Cognitive Training in Adults with Major Depressive Disorder.

Major Depressive Disorder (MDD) is common and disabling, and is linked to functional impairment and increased mortality. While current treatments for MDD are moderately effective, ultimately, up to one third of patients do not achieve full remission. Interestingly, while affective symptoms of major depression typically resolve with the depressive episode, cognitive impairment frequently persists, and has been identified as one of the most prominent predictors of illness recurrence. Additionally, MDD is well-recognised as a key risk factor for further cognitive decline and dementia. Yet, available treatments for MDD do not typically address cognitive impairment. Cognitive training, represents a promising and novel therapeutic intervention in this regard. This review systematically identified and evaluated the evidence for cognitive training in adults with MDD. Following PRISMA guidelines, eligible studies were selected according to pre-defined criteria delineating our target population (adults with clinically defined MDD), parameters for cognitive training interventions (computer-or strategy-based, clinician-facilitated), and study design (controlled trials including pre-post cognitive and psychological or functional outcome data). Of 448 studies identified, nine studies met inclusion criteria. These studies were evaluated for methodological quality and risk of bias. Despite heterogeneity, qualitative and meta-analytic synthesis of study findings revealed significant improvements in cognitive and affective outcomes following cognitive training, with moderate pooled effect sizes. Unfortunately, very few studies investigated 'far transfer' to broader domains of everyday functioning. Overall, given the strong evidence for the efficacy and value of cognitive training in this context, cognitive training should be considered as a primary therapeutic intervention in the treatment of MDD.

Constraints on Dark Matter Properties from Observations of Milky Way Satellite Galaxies.

We perform a comprehensive study of Milky Way (MW) satellite galaxies to constrain the fundamental properties of dark matter (DM). This analysis fully incorporates inhomogeneities in the spatial distribution and detectability of MW satellites and marginalizes over uncertainties in the mapping between galaxies and DM halos, the properties of the MW system, and the disruption of subhalos by the MW disk. Our results are consistent with the cold, collisionless DM paradigm and yield the strongest cosmological constraints to date on particle models of warm, interacting, and fuzzy dark matter. At 95% confidence, we report limits on (i) the mass of thermal relic warm DM, m_{WDM}>6.5 keV (free-streaming length, λ_{fs}≲10h^{-1} kpc), (ii) the velocity-independent DM-proton scattering cross section, σ_{0}<8.8×10^{-29} cm^{2} for a 100 MeV DM particle mass [DM-proton coupling, c_{p}≲(0.3 GeV)^{-2}], and (iii) the mass of fuzzy DM, m_{ϕ}>2.9×10^{-21} eV (de Broglie wavelength, λ_{dB}≲0.5 kpc). These constraints are complementary to other observational and laboratory constraints on DM properties.

Cortical inexcitability defines an adverse clinical profile in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: In amyotrophic lateral sclerosis, studies using threshold-tracking transcranial magnetic stimulation (TMS) have identified corticomotoneuronal dysfunction as a key pathogenic mechanism. Some patients, however, display no motor response at maximal TMS intensities, termed here an 'inexcitable' motor cortex. The extent to which this cortical difference impacts clinical outcomes remains unclear. The aim of this study was to determine the clinical profile of patients with inexcitability to TMS. METHODS: Motor cortex excitability was evaluated using TMS. Patients in whom a motor evoked potential could not be recorded in one or more limbs at maximal TMS intensities were classified as four-limb or partially inexcitable. Demographic information, clinical variables and survival data were analysed. RESULTS: From 133 patients, 40 were identified with inexcitability. Patients with four-limb inexcitability were younger (P = 0.03) and had lower-limb disease onset (64%), greater functional disability (P < 0.001) and faster disease progression (P = 0.02), particularly if inexcitability developed within 1 year of symptoms (P < 0.01). Patients with partial inexcitability had higher resting motor thresholds compared to the excitable cohort (P < 0.01), but averaged short-interval intracortical inhibition was similar (P = 0.5). Mean survival was reduced if inexcitability involved all limbs within 12 months of symptom onset (P = 0.04). CONCLUSION: Amyotrophic lateral sclerosis patients with inexcitability of all four limbs to TMS have a distinct clinical profile of younger age and lower-limb onset. Importantly, these patients display a more malignant disease trajectory, with faster progression, greater functional disability and reduced survival when occurring in early disease. This measure may provide an important prognostic marker in amyotrophic lateral sclerosis.

The Molecular Basis for Antigenic Drift of Human A/H2N2 Influenza Viruses.

Influenza A/H2N2 viruses caused a pandemic in 1957 and continued to circulate in humans until 1968. The antigenic evolution of A/H2N2 viruses over time and the amino acid substitutions responsible for this antigenic evolution are not known. Here, the antigenic diversity of a representative set of human A/H2N2 viruses isolated between 1957 and 1968 was characterized. The antigenic change of influenza A/H2N2 viruses during the 12 years that this virus circulated was modest. Two amino acid substitutions, T128D and N139K, located in the head domain of the H2 hemagglutinin (HA) molecule, were identified as important determinants of antigenic change during A/H2N2 virus evolution. The rate of A/H2N2 virus antigenic evolution during the 12-year period after introduction in humans was half that of A/H3N2 viruses, despite similar rates of genetic change.IMPORTANCE While influenza A viruses of subtype H2N2 were at the origin of the Asian influenza pandemic, little is known about the antigenic changes that occurred during the twelve years of circulation in humans, the role of preexisting immunity, and the evolutionary rates of the virus. In this study, the antigenic map derived from hemagglutination inhibition (HI) titers of cell-cultured virus isolates and ferret postinfection sera displayed a directional evolution of viruses away from earlier isolates. Furthermore, individual mutations in close proximity to the receptor-binding site of the HA molecule determined the antigenic reactivity, confirming that individual amino acid substitutions in A/H2N2 viruses can confer major antigenic changes. This study adds to our understanding of virus evolution with respect to antigenic variability, rates of virus evolution, and potential escape mutants of A/H2N2.

Laparoscopic versus open colorectal surgery in the acute setting (LaCeS trial): a multicentre randomized feasibility trial.

BACKGROUND: Approximately 30 000 people undergo major emergency abdominal gastrointestinal surgery annually, and 36 per cent of these procedures (around 10 800) are carried out for emergency colorectal pathology. Some 14 per cent of all patients requiring emergency surgery have a laparoscopic procedure. The aims of the LaCeS (laparoscopic versus open colorectal surgery in the acute setting) feasibility trial were to assess the feasibility, safety and acceptability of performing a large-scale definitive phase III RCT, with a comparison of emergency laparoscopic versus open surgery for acute colorectal pathology. METHODS: LaCeS was designed as a prospective, multicentre, single-blind, parallel-group, pragmatic feasibility RCT with an integrated qualitative study. Randomization was undertaken centrally, with patients randomized on a 1 : 1 basis between laparoscopic or open surgery. RESULTS: A total of 64 patients were recruited across five centres. The overall mean steady-state recruitment rate was 1·2 patients per month per site. Baseline compliance for clinical and health-related quality-of-life data was 99·8 and 93·8 per cent respectively. The conversion rate from laparoscopic to open surgery was 39 (95 per cent c.i. 23 to 58) per cent. The 30-day postoperative complication rate was 27 (13 to 46) per cent in the laparoscopic arm and 42 (25 to 61) per cent in the open arm. CONCLUSION: Laparoscopic emergency colorectal surgery may have an acceptable safety profile. Registration number: ISRCTN15681041 ( http://www.controlled-trials.com).

ANTECEDENTES: Aproximadamente 30.000 personas se someten cada año una operación de cirugía mayor urgente gastrointestinal de las cuales el 36% (~ 10.800) se realizan por patología colorrectal urgente. Aproximadamente el 14% de todos los pacientes que requieren cirugía urgente son operados mediante abordaje laparoscópico. Los objetivos del ensayo de factibilidad LaCeS (Laparoscopic versus Open Colorectal Surgery in the Acute Setting; Cirugía Colorrectal Laparoscópica versus Abierta en Urgencias) fueron evaluar la factibilidad, seguridad y aceptabilidad de realizar un ensayo clínico aleatorizado definitivo a gran escala de fase III comparando la cirugía colorrectal urgente por vía laparoscópica con el abordaje abierto. MÉTODOS: LaCeS se diseñó como un ensayo clínico prospectivo, multicéntrico, simple ciego, de grupos paralelos, pragmático, aleatorizado (factibilidad) con un estudio cualitativo integrado. La asignación al azar se realizó de forma centralizada y los pacientes se asignaron al azar en proporción 1:1 a cirugía laparoscópica o abierta. RESULTADOS: Un total de 64 pacientes fueron reclutados en 5 centros. La tasa media global estable de reclutamiento fue de 1,2 pacientes/mes. El cumplimiento inicial de los datos clínicos y de calidad de vida (HRQoL) fue del 99,8% y del 93,8%, respectivamente. La tasa de conversión de la cirugía laparoscópica a cirugía abierta fue del 39,4% (i.c. del 95%: 22,9% a 57,9%). La tasa de complicaciones postoperatorias a los 30 días fue del 27,3% (i.c. del 95%: 13,3-45,5) para la cirugía laparoscópica y del 41,9% (i.c. del 95%: 24,6-60,9) para la cirugía abierta. CONCLUSIÓN: La cirugía colorrectal urgente por vía laparoscópica puede tener un perfil de seguridad aceptable.

CBETA: First Multipass Superconducting Linear Accelerator with Energy Recovery.

Energy recovery has been achieved in a multipass linear accelerator, demonstrating a technology for more compact particle accelerators operating at higher currents and reduced energy consumption. Energy delivered to the beam during the first four passes through the accelerating structure was recovered during four subsequent decelerating passes. High-energy efficiency was achieved by the use of superconducting accelerating cavities and permanent magnets. The fixed-field alternating-gradient optical system used for the return loop successfully transported electron bunches of 42, 78, 114, and 150 MeV in a common vacuum chamber. This new kind of accelerator, an eight-pass energy recovery linac, has the potential to accelerate much higher current than existing linear accelerators while maintaining small beam dimensions and consuming much less energy per electron.

Detection of Cross-Correlation between Gravitational Lensing and γ Rays.

In recent years, many γ-ray sources have been identified, yet the unresolved component hosts valuable information on the faintest emission. In order to extract it, a cross-correlation with gravitational tracers of matter in the Universe has been shown to be a promising tool. We report here the first identification of a cross-correlation signal between γ rays and the distribution of mass in the Universe probed by weak gravitational lensing. We use data from the Dark Energy Survey Y1 weak lensing data and the Fermi Large Area Telescope 9-yr γ-ray data, obtaining a signal-to-noise ratio of 5.3. The signal is mostly localized at small angular scales and high γ-ray energies, with a hint of correlation at extended separation. Blazar emission is likely the origin of the small-scale effect. We investigate implications of the large-scale component in terms of astrophysical sources and particle dark matter emission.

Detection of CMB-Cluster Lensing using Polarization Data from SPTpol.

We report the first detection of gravitational lensing due to galaxy clusters using only the polarization of the cosmic microwave background (CMB). The lensing signal is obtained using a new estimator that extracts the lensing dipole signature from stacked images formed by rotating the cluster-centered Stokes QU map cutouts along the direction of the locally measured background CMB polarization gradient. Using data from the SPTpol 500 deg^{2} survey at the locations of roughly 18 000 clusters with richness λ≥10 from the Dark Energy Survey (DES) Year-3 full galaxy cluster catalog, we detect lensing at 4.8σ. The mean stacked mass of the selected sample is found to be (1.43±0.40)×10^{14}M_{⊙} which is in good agreement with optical weak lensing based estimates using DES data and CMB-lensing based estimates using SPTpol temperature data. This measurement is a key first step for cluster cosmology with future low-noise CMB surveys, like CMB-S4, for which CMB polarization will be the primary channel for cluster lensing measurements.

Cosmological Constraints from Multiple Probes in the Dark Energy Survey.

The combination of multiple observational probes has long been advocated as a powerful technique to constrain cosmological parameters, in particular dark energy. The Dark Energy Survey has measured 207 spectroscopically confirmed type Ia supernova light curves, the baryon acoustic oscillation feature, weak gravitational lensing, and galaxy clustering. Here we present combined results from these probes, deriving constraints on the equation of state, w, of dark energy and its energy density in the Universe. Independently of other experiments, such as those that measure the cosmic microwave background, the probes from this single photometric survey rule out a Universe with no dark energy, finding w=-0.80_{-0.11}^{+0.09}. The geometry is shown to be consistent with a spatially flat Universe, and we obtain a constraint on the baryon density of Ω_{b}=0.069_{-0.012}^{+0.009} that is independent of early Universe measurements. These results demonstrate the potential power of large multiprobe photometric surveys and pave the way for order of magnitude advances in our constraints on properties of dark energy and cosmology over the next decade.

The altered gut microbiota in adults with cystic fibrosis.

BACKGROUND: Cystic Fibrosis (CF) is an autosomal recessive disease that affects the function of a number of organs, principally the lungs, but also the gastrointestinal tract. The manifestations of cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in the gastrointestinal tract, as well as frequent antibiotic exposure, undoubtedly disrupts the gut microbiota. To analyse the effects of CF and its management on the microbiome, we compared the gut microbiota of 43 individuals with CF during a period of stability, to that of 69 non-CF controls using 454-pyrosequencing of the 16S rRNA gene. The impact of clinical parameters, including antibiotic therapy, on the results was also assessed. RESULTS: The CF-associated microbiome had reduced microbial diversity, an increase in Firmicutes and a reduction in Bacteroidetes compared to the non-CF controls. While the greatest number of differences in taxonomic abundances of the intestinal microbiota was observed between individuals with CF and the healthy controls, gut microbiota differences were also reported between people with CF when grouped by clinical parameters including % predicted FEV1 (measure of lung dysfunction) and the number of intravenous (IV) antibiotic courses in the previous 12 months. Notably, CF individuals presenting with severe lung dysfunction (% predicted FEV1 ≤ 40%) had significantly (p < 0.05) reduced gut microbiota diversity relative to those presenting with mild or moderate dysfunction. A significant negative correlation (-0.383, Simpson's Diversity Index) was also observed between the number of IV antibiotic courses and gut microbiota diversity. CONCLUSIONS: This is one of the largest single-centre studies on gut microbiota in stable adults with CF and demonstrates the significantly altered gut microbiota, including reduced microbial diversity seen in CF patients compared to healthy controls. The data show the impact that CF and it's management have on gut microbiota, presenting the opportunity to develop CF specific probiotics to minimise microbiota alterations.

Direct Measurement of the Astrophysical

We have performed the first direct measurement of the ^{38}K(p,γ)^{39}Ca reaction using a beam of radioactive ^{38}K. A proposed ℓ=0 resonance in the ^{38}K+p system has been identified at 679(2) keV with an associated strength of 120_{-30}^{+50} meV. Upper limits of 1.16 (3.5) and 8.6 (26) meV at the 68% (95%) confidence level were also established for two further expected ℓ=0 resonances at 386 and 515 keV, respectively. The present results have reduced uncertainties in the ^{38}K(p,γ)^{39}Ca reaction rate at temperatures of 0.4 GK by more than 2 orders of magnitude and indicate that Ar and Ca may be ejected in observable quantities by oxygen-neon novae. However, based on the newly evaluated rate, the ^{38}K(p,γ)^{39}Ca path is unlikely to be responsible for the production of Ar and Ca in significantly enhanced quantities relative to solar abundances.

Wide-Field Lensing Mass Maps from Dark Energy Survey Science Verification Data.

We present a mass map reconstructed from weak gravitational lensing shear measurements over 139 deg2 from the Dark Energy Survey science verification data. The mass map probes both luminous and dark matter, thus providing a tool for studying cosmology. We find good agreement between the mass map and the distribution of massive galaxy clusters identified using a red-sequence cluster finder. Potential candidates for superclusters and voids are identified using these maps. We measure the cross-correlation between the mass map and a magnitude-limited foreground galaxy sample and find a detection at the 6.8σ level with 20 arc min smoothing. These measurements are consistent with simulated galaxy catalogs based on N-body simulations from a cold dark matter model with a cosmological constant. This suggests low systematics uncertainties in the map. We summarize our key findings in this Letter; the detailed methodology and tests for systematics are presented in a companion paper.

Wild-type and mutant p53 differentially regulate NADPH oxidase 4 in TGF-ß-mediated migration of human lung and breast epithelial cells.

BACKGROUND: Transforming growth factor-beta (TGF-ß) induces the epithelial-to-mesenchymal transition (EMT) leading to increased cell plasticity at the onset of cancer cell invasion and metastasis. Mechanisms involved in TGF-ß-mediated EMT and cell motility are unclear. Recent studies showed that p53 affects TGF-ß/SMAD3-mediated signalling, cell migration, and tumorigenesis. We previously demonstrated that Nox4, a Nox family NADPH oxidase, is a TGF-ß/SMAD3-inducible source of reactive oxygen species (ROS) affecting cell migration and fibronectin expression, an EMT marker, in normal and metastatic breast epithelial cells. Our present study investigates the involvement of p53 in TGF-ß-regulated Nox4 expression and cell migration. METHODS: We investigated the effect of wild-type p53 (WT-p53) and mutant p53 proteins on TGF-ß-regulated Nox4 expression and cell migration. Nox4 mRNA and protein, ROS production, cell migration, and focal adhesion kinase (FAK) activation were examined in three different cell models based on their p53 mutational status. H1299, a p53-null lung epithelial cell line, was used for heterologous expression of WT-p53 or mutant p53. In contrast, functional studies using siRNA-mediated knockdown of endogenous p53 were conducted in MDA-MB-231 metastatic breast epithelial cells that express p53-R280K and MCF-10A normal breast cells that have WT-p53. RESULTS: We found that WT-p53 is a potent suppressor of TGF-ß-induced Nox4, ROS production, and cell migration in p53-null lung epithelial (H1299) cells. In contrast, tumour-associated mutant p53 proteins (R175H or R280K) caused enhanced Nox4 expression and cell migration in both TGF-ß-dependent and TGF-ß-independent pathways. Moreover, knockdown of endogenous mutant p53 (R280K) in TGF-ß-treated MDA-MB-231 metastatic breast epithelial cells resulted in decreased Nox4 protein and reduced phosphorylation of FAK, a key regulator of cell motility. Expression of WT-p53 or dominant-negative Nox4 decreased TGF-ß-mediated FAK phosphorylation, whereas mutant p53 (R280K) increased phospho-FAK. Furthermore, knockdown of WT-p53 in MCF-10A normal breast epithelial cells increased basal Nox4 expression, whereas p53-R280K could override endogenous WT-p53 repression of Nox4. Remarkably, immunofluorescence analysis revealed MCF-10A cells expressing p53-R280K mutant showed an upregulation of Nox4 in both confluent and migrating cells. CONCLUSIONS: Collectively, our findings define novel opposing functions for WT-p53 and mutant p53 proteins in regulating Nox4-dependent signalling in TGF-ß-mediated cell motility.

Systematic review of emergency laparoscopic colorectal resection.

BACKGROUND: Laparoscopic surgery (LS) has become standard practice for a range of elective general surgical operations. Its role in emergency general surgery is gaining momentum. This study aimed to assess the outcomes of LS compared with open surgery (OS) for colorectal resections in the emergency setting. METHODS: A systematic review was performed of studies reporting outcomes of laparoscopic colorectal resections in the acute or emergency setting in patients aged over 18 years, between January 1966 and January 2013. RESULTS: Twenty-two studies were included, providing outcomes for 5557 patients: 932 laparoscopic and 4625 open emergency resections. Median (range) operating time was 184 (63-444) min for LS versus 148 (61-231) min for OS. Median (range) length of stay was 10 (3-23) and 15 (6-33) days in the LS and OS groups respectively. The overall median (range) complication rate was 27.8 (0-33.3) and 48.3 (9-72) per cent respectively. There were insufficient data to detect differences in reoperation and readmission rates. CONCLUSION: Emergency laparoscopic colorectal resection, where technically feasible, has better short-term outcomes than open resection.

Late-onset neurological symptoms in thalidomide-exposed subjects: a study of an Australasian cohort.

BACKGROUND AND PURPOSE: Thalidomide was marketed for the treatment of morning sickness and resulted in foetal death and physical deformities. The exact mechanism of action of thalidomide in its teratogenicity is still actively debated in the literature. METHODS: This study reviewed 16 of the confirmed Australasian victims of in utero exposure to thalidomide who now presented with new-onset neurological symptoms in the fourth and fifth decades. RESULTS: Clinical neurological examination and neurophysiological investigations revealed that new symptoms were due in part to compressive neuropathies, often exacerbated by the adaptations made to accommodate the disability and poor mobility arising from the limb deformities. Other subjects were found to have musculoskeletal symptoms due to compensatory postures employed to perform tasks of daily living. CONCLUSIONS: The study provides no evidence of ongoing loss of neurons or late reactivated neural degeneration and no evidence of a generalized peripheral neuropathy. Rather, the development of new symptoms in subjects can be explained by compressive neuropathies and compensatory postures employed to perform tasks of daily living.

Fecal lactoferrin: a noninvasive fecal biomarker for the diagnosis and surveillance of pouchitis.

BACKGROUND: Fecal lactoferrin is a marker of intestinal inflammation and can be assessed with a simple qualitative immunochromatographic rapid test. OBJECTIVE: We aimed to assess the sensitivity and specificity of the test in the diagnosis of pouchitis and evaluate its clinical utility in the surveillance of inflammation of the pouch after antibiotic therapy. DESIGN: Between October 2005 and September 2009, we recruited a consecutive series of patients who had their ileal pouch examined under a general anesthetic. Distinctions between healthy and inflamed pouches were made by the use of the Pouch Disease Activity Index. Fecal samples were taken before biopsy of the pouch, and a clinician blinded to the examination findings performed the lactoferrin test. After antimicrobial treatment, a number of patients with pouchitis had a repeat examination and lactoferrin test. RESULTS: There were 85 (41 male) patients. Median age was 42 (interquartile range, 36-49) years. Twenty-four patients had pouchitis. The test was positive in all 24 patients with pouchitis and 5 patients with a healthy pouch. The sensitivity and specificity of the test for pouchitis was 100% and 92%. The positive predictive value was 82%. In 7 patients who received antibiotic treatment for their pouchitis, the test was able to accurately predict the resolution and/or persistence of pouchitis. CONCLUSION: The qualitative fecal lactoferrin rapid test is a sensitive method for the diagnosis and confirmation of resolution of pouchitis. The test provides clinicians with greater confidence in the prescription of antibiotics for suspected pouchitis and its surveillance.

Nonresectional management of colorectal cancer: multidisciplinary factors that influence treatment strategy.

AIM: Surgical resection of a primary colorectal tumour remains the treatment of choice and offers the best chance of cure. However, in some patients, resection is not achieved. There are few published data on this group of patients. The aim of this study was to evaluate this group to determine the frequency and reasons for nonresection, and to analyse the subsequent management. METHOD: A retrospective review was performed using a Trust colorectal cancer database and individual electronic patient records. Patients who presented to our unit with a diagnosis of primary colorectal cancer managed by nonresectional intervention over a 2-year period were identified. Data analysed included: patient demographics, radiological staging, histological data, nonsurgical therapy, tumour-specific complications and requirement for palliative surgical procedures. RESULTS: A total of 671 patients were identified with primary colorectal cancer. One hundred and fifty-six (23%) were managed without resection, following discussion at a multidisciplinary team meeting. Of 156 patients, histological confirmation was obtained in 131 (84%), with the remainder of the diagnoses being based on unequivocal radiological imaging and/or operative findings. Complete radiological staging was achieved in 150 (96%) patients. The predominant reasons for nonresectional management were: advanced metastatic disease (66%), significant medical comorbidity (19%) and patient refusal (6%). Fifty-nine of 156 patients (38%) subsequently received palliative chemotherapy, 9 (6%) radiotherapy and or 9 (6%) combination chemo-radiotherapy. Seventy-nine (51%) of 156 patients received no therapy other than best supportive palliative care, for reasons including significant medical comorbidity (62%) and patient refusal (19%). Following the initial decision not to resect, 68 (44%) patients did at some point undergo some form of palliative intervention (stenting, stoma or bypass) for obstruction - 44 (28%) electively and 24 (15%) as an emergency. CONCLUSION: Nonresectional management of patients with primary colorectal cancer is not an uncommon outcome following discussion at a multidisciplinary meeting. In these patients, nonsurgical palliation should be employed when necessary, though is frequently limited by comorbidity. However, subsequent surgical palliation is still required in a substantial proportion of cases.

Antigenic and genetic evolution of equine influenza A (H3N8) virus from 1968 to 2007.

Equine influenza virus is a major respiratory pathogen in horses, and outbreaks of disease often lead to substantial disruption to and economic losses for equestrian industries. The hemagglutinin (HA) protein is of key importance in the control of equine influenza because HA is the primary target of the protective immune response and the main component of currently licensed influenza vaccines. However, the influenza virus HA protein changes over time, a process called antigenic drift, and vaccine strains must be updated to remain effective. Antigenic drift is assessed primarily by the hemagglutination inhibition (HI) assay. We have generated HI assay data for equine influenza A (H3N8) viruses isolated between 1968 and 2007 and have used antigenic cartography to quantify antigenic differences among the isolates. The antigenic evolution of equine influenza viruses during this period was clustered: from 1968 to 1988, all isolates formed a single antigenic cluster, which then split into two cocirculating clusters in 1989, and then a third cocirculating cluster appeared in 2003. Viruses from all three clusters were isolated in 2007. In one of the three clusters, we show evidence of antigenic drift away from the vaccine strain over time. We determined that a single amino acid substitution was likely responsible for the antigenic differences among clusters.

Nasal cytokine responses to natural colds in asthmatic children.

BACKGROUND: The mechanisms by which viruses induce asthma exacerbations are not well understood. OBJECTIVE: We characterized fluctuations in nasal aspirate cytokines during naturally occurring respiratory viral infections in children with asthma. METHODS: Sixteen children underwent home collections of nasal aspirates when they were without cold symptoms and again during self-reported respiratory illnesses. The presence of viral infection was ascertained by multiplex PCR. Cytokines were measured using multiplex immune assay. mRNA expression for selected markers of viral infection was measured using RT-PCR. A cumulative respiratory symptom score was calculated for each day of measurement. Generalized estimated equations were used to evaluate associations between viral infection and marker elevation, and between marker elevation and symptom score. RESULTS: The 16 patients completed a total of 37 weeks of assessment (15 'well' weeks; 22 self-assessed 'sick' weeks). Viral infections were detected in 3 of the 'well' weeks and 17 of the 'sick' weeks (10 rhinovirus, three coronavirus, two influenza A, two influenza B, two respiratory syncytial virus, one parainfluenza). Compared to virus-negative well weeks, nasal aspirate IFN-γ, CXCL8/IL-8, CXCL10/IP-10, CCL5/RANTES, CCL11/eotaxin-1, CCL2/MCP-1, CCL4/MIP-1ß, CCL7/MCP-3, and CCL20/MIP3α protein levels increased during virus-positive sick weeks. Only a subset of cytokines (IFN-γ, CXCL8, CCL2, CCL4, CCL5, and CCL20) correlated with self-reported respiratory tract symptoms. While many aspirates were dilute and showed no mRNA signal, viral infection significantly increased the number of samples that were positive for IFN-λ1, IFN-λ2/3, TLR3, RIG-I, and IRF7 mRNA. CONCLUSIONS AND CLINICAL RELEVANCE: We conclude that in children with asthma, naturally occurring viral infections apparently induce a robust innate immune response including expression of specific chemokines, IFNs, and IFN-responsive genes.