How will public and animal health interventions drive life-history evolution in parasitic nematodes?

Infection caused by parasitic nematodes of humans and livestock can have significant health and economic costs. Treatments aimed at alleviating these costs, such as chemotherapy and vaccination, alter parasite survival and reproduction, the main selective pressures shaping life-history traits such as age to maturity, size and fecundity. Most authors have argued that the life-history evolution prompted by animal and public health programmes would be clinically beneficial, generating smaller, less fecund worms, and several mathematical models support this view. However, using mathematical models of long-lasting interventions, such as vaccination, and regularly repeated short interventions, such as drenching, we show here that the expected outcome actually depends on how mortality rates vary as a function of worm size and developmental status. Interventions which change mortality functions can exert selection pressure to either shorten or extend the time to maturity, and thus increase or decrease worm fecundity and size. The evolutionary trajectory depends critically on the details of the mortality functions with and without the intervention. Earlier optimism that health interventions would always prompt the evolution of smaller, less fecund and hence clinically less damaging worms is premature

Exploiting the neoantigen landscape for immunotherapy of pancreatic ductal adenocarcinoma

Immunotherapy approaches for pancreatic ductal adenocarcinoma (PDAC) have met with limited success. It has been postulated that a low mutation load may lead to a paucity of T cells within the tumor microenvironment (TME). However, it is also possible that while neoantigens are present, an effective immune response cannot be generated due to an immune suppressive TME. To discern whether targetable neoantigens exist in PDAC, we performed a comprehensive study using genomic profiles of 221 PDAC cases extracted from public databases. Our findings reveal that: (a) nearly all PDAC samples harbor potentially targetable neoantigens; (b) T cells are present but generally show a reduced activation signature; and (c) markers of efficient antigen presentation are associated with a reduced signature of markers characterizing cytotoxic T cells. These findings suggest that despite the presence of tumor specific neoepitopes, T cell activation is actively suppressed in PDAC. Further, we identify iNOS as a potential mediator of immune suppression that might be actionable using pharmacological avenues

Electrophysiological effects of 5-hydroxytryptamine on isolated human atrial myocytes, and the influence of chronic beta-adrenoceptor blockade

<b>1.</b> 5-Hydroxytryptamine (5-HT) has been postulated to play a proarrhythmic role in the human atria via stimulation of 5-HT<sub>4</sub> receptors. <b>2.</b> The aims of this study were to examine the effects of 5-HT on the L-type Ca<sup>2+</sup> current (<i>I</i><sub>CaL</sub>) action potential duration (APD), the effective refractory period (ERP) and arrhythmic activity in human atrial cells, and to assess the effects of prior treatment with β-adrenoceptor antagonists. <b>3.</b> Isolated myocytes, from the right atrial appendage of 27 consenting patients undergoing cardiac surgery who were in sinus rhythm, were studied using the whole-cell perforated patch-clamp technique at 37ºC. <b>4.</b> 5-HT (1 n-10 μM) caused a concentration-dependent increase in <i>I</i><sub>CaL</sub>, which was potentiated in cells from β-blocked (maximum response to 5-HT, E<sub>max</sub>=299±12% increase above control) compared to non-β-blocked patients (E<sub>max</sub>=220±6%, P<0.05), but with no change in either the potency (log EC<sub>50</sub>: -7.09±0.07 vs -7.26±0.06) or Hill coefficient (<i>n</i><sub>H</sub>: 1.5±0.6 vs 1.5±0.3) of the 5-HT concentration-response curve. <b>5.</b> 5-HT (10 μM) produced a greater increase in the APD at 50% repolarisation (APD50) in cells from β-blocked patients (of 37±10 ms, i.e. 589±197%) vs non-β-blocked patients (of 10±4 ms, i.e. 157±54%; P<0.05). Both the APD<sub>90</sub> and the ERP were unaffected by 5-HT. <b>6.</b> Arrhythmic activity was observed in response to 5-HT in five of 17 cells (29%) studied from β-blocked, compared to zero of 16 cells from the non-β-blocked patients (P<0.05). <b>7.</b> In summary, the 5-HT-induced increase in calcium current was associated with a prolonged early plateau phase of repolarisation, but not late repolarisation or refractoriness, and the enhancement of these effects by chronic β-adrenoceptor blockade was associated with arrhythmic potential

Valvuloarterial Impedence, Strain, Exercise, and AS

Background - In asymptomatic patients with severe aortic stenosis and preserved left ventricular ejection fraction, we sought to assess the incremental prognostic value of resting valvuloarterial impedence (Zva) and left ventricular global longitudinal strain (LV-GLS) to treadmill stress echocardiography. Methods and Results - We studied 504 such patients (66±12 years, 78% men, 32% with coronary artery disease who underwent treadmill stress echocardiography between 2001 and 2012. Clinical and exercise variables (% of age-sex predicted metabolic equivalents [%AGP-METs]) were recorded. Resting Zva ([systolic arterial pressure+mean aortic valve gradient]/[LV-stroke volume index]) and LV-GLS(measured offline using Velocity Vector Imaging, Siemens) were obtained from the baseline resting echocardiogram. Death was the primary outcome. There were no major adverse cardiac events during treadmill stress echocardiography. Indexed aortic valve area, Zva, and LV-GLS were 0.46±0.1 cm2/m2, 4.5±0.9 mm Hg/mL per m2 and -16±4%, respectively; only 50% achieved >100% AGP-METs. Sixty-four percent underwent aortic valve replacement. Death occurred in 164 (33%) patients over 8.9±3.6 years (2 within 30 days of aortic valve replacement). On multivariable Cox survival analysis, higher Society of Thoracic Surgeons score (hazard ratio or HR 1.06), lower % AGP-METS (HR 1.16), higher Zva (HR 1.25) and lower LV-GLS (HR 1.12) were associated with higher longer-term mortality, while aortic valve replacement (HR 0.45) was associated with improved survival (all P<0.01). Sequential addition of ZVa and LV-GLS to clinical model (Society of Thoracic Surgeons score and %AGP-METs) increased the c-statistic from 0.65 to 0.69 and 0.75, respectively, both P<0.001); findings were similar in the subgroup of patients who underwent aortic valve replacement. Conclusions - In asymptomatic patients with severe aortic stenosis undergoing treadmill stress echocardiography, LV-GLS and ZVa offer incremental prognostic value

Optimizing Peri-URban Ecosystems (PURE) to re-couple urban-rural symbiosis

Globally, rapid urbanization, along with economic development, is dramatically changing the balance of biogeochemical cycles, impacting upon ecosystem services and impinging on United Nation global sustainability goals (inter alia: sustainable cities and communities; responsible consumption and production; good health and well-being; clean water and sanitation, and; to protect and conserve life on land and below water). A key feature of the urban ecosystems is that nutrient stocks, carbon (C), nitrogen (N) and phosphorus (P), are being enriched. Furthermore, urban ecosystems are highly engineered, biogeochemical cycling of nutrients within urban ecosystems is spatially segregated, and nutrients exported (e.g. in food) from rural/peri-urban areas are not being returned to support primary production in these environments. To redress these imbalances we propose the concept of the Peri-URban Ecosystem (PURE). Through the merging of conceptual approaches that relate to Critical Zone science and the dynamics of successional climax PURE serves at the symbiotic interface between rural/natural and urban ecosystems and allow re-coupling of resource flows. PURE provides a framework for tackling the most pressing of societal challenges and supporting global sustainability goals

Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome : A 24-Week, Phase III Study

Background This study evaluated the safety and efficacy of teduglutide in pediatric patients with short bowel syndrome-associated intestinal failure (SBS-IF). Methods A 24-week, phase III trial with 2 randomized, double-blind teduglutide dose groups and a nonblinded standard of care (SOC) arm was used; patients received 0.025 mg/kg or 0.05 mg/kg teduglutide once daily. Safety end points included treatment-emergent adverse events (TEAEs) and growth parameters. The primary efficacy/pharmacodynamic end point was the number of patients who achieved a >= 20% reduction in parenteral support (PS) from baseline at week 24. Results All 59 enrolled patients completed the study (0.025 mg/kg, n = 24; 0.05 mg/kg, n = 26; SOC, n = 9). Baseline demographics and disease characteristics were comparable among groups. TEAEs were reported by 98% and 100% of patients in the teduglutide and SOC groups, respectively. The most common TEAEs in the teduglutide-treated groups were pyrexia and vomiting. The primary end point was achieved by 13 (54.2%), 18 (69.2%), and 1 (11.1%) patients who received 0.025 mg/kg teduglutide, 0.05 mg/kg teduglutide, and SOC, respectively (P <0.05 vs SOC). Both 0.025-mg/kg and 0.05-mg/kg teduglutide groups showed clinically significant reductions in PS volume (P <0.05 vs SOC), PS calories, days per week and hours per day of PS infusions, and increases in enteral nutrition and plasma citrulline at week 24 compared with baseline. Two (8.3%, 0.025 mg/kg teduglutide) and 3 patients (11.5%, 0.05 mg/kg teduglutide) achieved enteral autonomy. Conclusion The safety profile of teduglutide was similar to that reported previously in children and adults. Treatment with teduglutide was associated with significant reductions in PS for pediatric patients with SBS-IF over 24 weeks.Peer reviewe

Spatial heterogeneity and peptide availability determine CTL killing efficiency in vivo

The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. However the spleen is a heterogeneous environment and splenocytes comprise multiple cell types. Are some cell types intrinsically more susceptible to lysis than others? Quantitatively, what impacts are made by the spatial distribution of targets and effectors, and the level of peptide-MHC on the target cell surface? To address these questions we revisited the splenocyte killing assay, using CTL specific for an epitope of influenza virus. We found that at the cell population level T cell targets were killed more rapidly than B cells. Using modeling, quantitative imaging and in vitro killing assays we conclude that this difference in vivo likely reflects different migratory patterns of targets within the spleen and a heterogeneous distribution of CTL, with no detectable difference in the intrinsic susceptibilities of the two populations to lysis. Modeling of the stages involved in the detection and killing of peptide-pulsed targets in vitro revealed that peptide dose influenced the ability of CTL to form conjugates with targets but had no detectable effect on the probability that conjugation resulted in lysis, and that T cell targets took longer to lyse than B cells. We also infer that incomplete killing in vivo of cells pulsed with low doses of peptide may be due to a combination of heterogeneity in peptide uptake and the dissociation, but not internalisation, of peptide-MHC complexes. Our analyses demonstrate how population-averaged parameters in models of immune responses can be dissected to account for both spatial and cellular heterogeneity

Influenza nucleoprotein delivered with aluminium salts protects mice from an influenza virus that expresses an altered nucleoprotein sequence

Influenza virus poses a difficult challenge for protective immunity. This virus is adept at altering its surface proteins, the proteins that are the targets of neutralizing antibody. Consequently, each year a new vaccine must be developed to combat the current recirculating strains. A universal influenza vaccine that primes specific memory cells that recognise conserved parts of the virus could prove to be effective against both annual influenza variants and newly emergent potentially pandemic strains. Such a vaccine will have to contain a safe and effective adjuvant that can be used in individuals of all ages. We examine protection from viral challenge in mice vaccinated with the nucleoprotein from the PR8 strain of influenza A, a protein that is highly conserved across viral subtypes. Vaccination with nucleoprotein delivered with a universally used and safe adjuvant, composed of insoluble aluminium salts, provides protection against viruses that either express the same or an altered version of nucleoprotein. This protection correlated with the presence of nucleoprotein specific CD8 T cells in the lungs of infected animals at early time points after infection. In contrast, immunization with NP delivered with alum and the detoxified LPS adjuvant, monophosphoryl lipid A, provided some protection to the homologous viral strain but no protection against infection by influenza expressing a variant nucleoprotein. Together, these data point towards a vaccine solution for all influenza A subtypes

Safety Findings in Pediatric Patients During Long-Term Treatment With Teduglutide for Short-Bowel Syndrome-Associated Intestinal Failure : Pooled Analysis of 4 Clinical Studies

Background This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short-bowel syndrome-associated intestinal failure (SBS-IF). Methods Safety data from teduglutide-treated patients in 4 clinical trials were pooled. The completed 12-week and 24-week phase 3 core studies (NCT01952080/EudraCT 2013-004588-30 and NCT02682381/EudraCT 2015-002252-27) enrolled children aged 1-17 years with SBS-IF. Patients could elect to enroll in ongoing open-label extensions (NCT02949362/EudraCT 2016-000863-17 and NCT02954458/EudraCT 2016-000849-30). Interim data from ongoing studies were included. Results Safety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0-94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty-five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, d-lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred. Conclusion Based on integrated data from 4 clinical studies, including long-term follow-up forPeer reviewe