• H,

      Cabello-Lobato, Maria Jose; Schmidt, Christine K; orcid: 0000-0002-8363-7933; email: christine.schmidt@manchester.ac.uk; Cliff, Matthew J; orcid: 0000-0002-7482-0234; email: matthew.cliff@manchester.ac.uk (2021-06-25)
      DNA double-strand breaks (DSBs) represent the most cytotoxic DNA lesions, as-if mis- or unrepaired-they can cause cell death or lead to genome instability, which in turn can cause cancer. DSBs are repaired by two major pathways termed homologous recombination and non-homologous end-joining (NHEJ). NHEJ is responsible for repairing the vast majority of DSBs arising in human cells. Defects in NHEJ factors are also associated with microcephaly, primordial dwarfism and immune deficiencies. One of the key proteins important for mediating NHEJ is XRCC4. XRCC4 is a dimer, with the dimer interface mediated by an extended coiled-coil. The N-terminal head domain forms a mixed alpha-beta globular structure. Numerous factors interact with the C-terminus of the coiled-coil domain, which is also associated with significant self-association between XRCC4 dimers. A range of construct lengths of human XRCC4 were expressed and purified, and the 1-164 variant had the best NMR properties, as judged by consistent linewidths, and chemical shift dispersion. In this work we report the H,  N and C backbone resonance assignments of human XRCC4 in the solution form of the 1-164 construct. Assignments were obtained by heteronuclear multidimensional NMR spectroscopy. In total, 156 of 161 assignable residues of XRCC4 were assigned to resonances in the TROSY spectrum, with an additional 11 resonances assigned to His-Tag residues. Prediction of solution secondary structure from a chemical shift analysis using the TALOS + webserver is in good agreement with the published X-ray crystal structures of this protein.
    • Haemoglobin and Hematinic Status Before and After Bariatric Surgery over 4 years of Follow-Up

      Shipton, Michael J.; Johal, Nicholas J.; Dutta, Neel; Slater, Christopher; Iqbal, Zohaib; Ahmed, Babur; Ammori, Basil J.; Senapati, Siba; Akhtar, Khurshid; Summers, Lucinda K. M.; et al. (Springer US, 2020-09-01)
      Abstract: Purpose: Bariatric surgery is associated with deficiencies of vitamins and minerals, and patients are routinely advised supplements postoperatively. We studied prevalence of vitamin B12, folate and iron deficiencies and anaemia before and after bariatric surgery over 4 years of follow-up. Materials and Methods: We performed a retrospective cohort analysis of 353 people with obesity, including 257 (72.8%) women, who underwent gastric bypass (252, 71.4%) or sleeve gastrectomy (101, 28.6%) at our National Health Service bariatric centre in Northwest England. Results: At baseline, mean (standard error) age was 46.0 (0.6) years, body mass index 53.1 (0.4) kg/m2, serum vitamin B12 400.2 (16.4) pg/L, folate 7.7 (0.2) μg/L, iron 12.0 (0.3) μmol/L, ferritin 118.3 (8.4) μg/L and haemoglobin 137.9 (0.8) g/L. Frequency of low vitamin B12 levels reduced from 7.5% preoperatively to 2.3% at 48 months (P < 0.038). Mean folate levels increased from baseline to 48 months by 5.3 μg/L (P < 0.001) but frequency of low folate levels increased from 4.7% preoperatively to 10.3% (P < 0.048). Ferritin levels increased from baseline to 48 months by 51.3 μg/L (P < 0.009). Frequency of low ferritin levels was greater in women (39.1%) than in men (8.9%) at baseline (P < 0.001) and throughout the study period. Haemoglobin was low in 4.6% of all patients at baseline with no significant change over the study period. Conclusion: There were notable rates of haematinic insufficiencies in bariatric surgical candidates preoperatively. Our study lends further support to regular supplementation with vitamin B12, folic acid, and iron in people undergoing bariatric surgery.
    • Haemoglobin and Hematinic Status Before and After Bariatric Surgery over 4 years of Follow-Up

      Shipton, Michael J.; Johal, Nicholas J.; Dutta, Neel; Slater, Christopher; Iqbal, Zohaib; Ahmed, Babur; Ammori, Basil J.; Senapati, Siba; Akhtar, Khurshid; Summers, Lucinda K. M.; et al. (Springer US, 2020-09-01)
      Abstract: Purpose: Bariatric surgery is associated with deficiencies of vitamins and minerals, and patients are routinely advised supplements postoperatively. We studied prevalence of vitamin B12, folate and iron deficiencies and anaemia before and after bariatric surgery over 4 years of follow-up. Materials and Methods: We performed a retrospective cohort analysis of 353 people with obesity, including 257 (72.8%) women, who underwent gastric bypass (252, 71.4%) or sleeve gastrectomy (101, 28.6%) at our National Health Service bariatric centre in Northwest England. Results: At baseline, mean (standard error) age was 46.0 (0.6) years, body mass index 53.1 (0.4) kg/m2, serum vitamin B12 400.2 (16.4) pg/L, folate 7.7 (0.2) μg/L, iron 12.0 (0.3) μmol/L, ferritin 118.3 (8.4) μg/L and haemoglobin 137.9 (0.8) g/L. Frequency of low vitamin B12 levels reduced from 7.5% preoperatively to 2.3% at 48 months (P < 0.038). Mean folate levels increased from baseline to 48 months by 5.3 μg/L (P < 0.001) but frequency of low folate levels increased from 4.7% preoperatively to 10.3% (P < 0.048). Ferritin levels increased from baseline to 48 months by 51.3 μg/L (P < 0.009). Frequency of low ferritin levels was greater in women (39.1%) than in men (8.9%) at baseline (P < 0.001) and throughout the study period. Haemoglobin was low in 4.6% of all patients at baseline with no significant change over the study period. Conclusion: There were notable rates of haematinic insufficiencies in bariatric surgical candidates preoperatively. Our study lends further support to regular supplementation with vitamin B12, folic acid, and iron in people undergoing bariatric surgery.
    • Halogens in Eclogite Facies Minerals from the Western Gneiss Region, Norway

      Hughes; orcid: 0000-0002-4363-8675; email: lewis.hughes@manchester.ac.uk; Cuthbert; orcid: 0000-0002-1029-6357; email: simon.cuthbert@agh.edu.pl; Quas-Cohen; email: alexandra.quas-cohen@postgrad.manchester.ac.uk; Ruzié-Hamilton; orcid: 0000-0002-2802-8123; email: lorraine.ruzie@manchester.ac.uk; Pawley; orcid: 0000-0002-3022-3235; email: alison.pawley@manchester.ac.uk; Droop; email: giles.droop@gmail.com; Lyon; email: Ian.Lyon@manchester.ac.uk; Tartèse; email: romain.tartese@manchester.ac.uk; Burgess; orcid: 0000-0001-7674-8718; email: ray.burgess@manchester.ac.uk (MDPI, 2021-07-14)
      Ultra-high-pressure (UHP) eclogites and ultramafites and associated fluid inclusions from the Western Gneiss Region, Norwegian Caledonides, have been analysed for F, Cl, Br and I using electron-probe micro-analysis, time-of-flight secondary ion mass spectrometry and neutron-irradiated noble gas mass spectrometry. Textures of multi-phase and fluid inclusions in the cores of silicate grains indicate formation during growth of the host crystal at UHP. Halogens are predominantly hosted by fluid inclusions with a minor component from mineral inclusions such as biotite, phengite, amphibole and apatite. The reconstructed fluid composition contains between 11.3 and 12.1 wt% Cl, 870 and 8900 ppm Br and 6 and 169 ppm I. F/Cl ratios indicate efficient fractionation of F from Cl by hydrous mineral crystallisation. Heavy halogen ratios are higher than modern seawater by up to two orders of magnitude for Br/Cl and up to three orders of magnitude for I/Cl. No correlation exists between Cl and Br or I, while Br and I show good correlation, suggesting that Cl behaved differently to Br and I during subduction. Evolution to higher Br/Cl ratios is similar to trends defined by eclogitic hydration reactions and seawater evaporation, indicating preferential removal of Cl from the fluid during UHP metamorphism. This study, by analogy, offers a field model for an alternative source (continental crust) and mechanism (metasomatism by partial melts or supercritical fluids) by which halogens may be transferred to and stored in the sub-continental lithospheric mantle during transient subduction of a continental margin.
    • Halokinetic modulation of sedimentary thickness and architecture: A numerical modelling approach

      Cumberpatch, Zoë A.; orcid: 0000-0001-8253-8418; email: zoe.cumberpatch@manchester.ac.uk; Finch, Emma; Kane, Ian A.; Pichel, Leonardo M.; Jackson, Christopher A.‐L.; Kilhams, Ben A.; Hodgson, David M.; Huuse, Mads (2021-07-03)
      Abstract: Subsurface salt flow can deform overlying strata and influence contemporaneous sedimentary systems. Studying salt‐sediment interactions is challenging in the subsurface due to poor imaging adjacent to salt, and in the field due to the dissolution of halite. Discrete Element Modelling provides an efficient and inexpensive tool to model stratigraphy and deformation around salt structures, which is advantageous over other modelling techniques as it realistically recreates brittle processes such as faulting. Six 2D experiments were run representing 4.6 Myr to determine the effect of salt growth on syn‐kinematic stratigraphy. Halokinetic deformation of stratigraphic architecture was assessed by varying sediment input rates through time. Results show the realistic formation and evolution of salt‐related faults which define a zone of halokinetic influence ca. 3 times the width of the initial diapir. Outside of this, early diapiric and syn‐kinematic stratigraphy are undeformed. Within this zone, syn‐kinematic strata are initially isolated into primary salt withdrawal basins, onlapping and thinning towards the salt‐cored high. In most models, syn‐kinematic strata eventually thin across and cover the diapir roof. Thinning rates are up to six times greater within 350 m of the diapir, compared to further afield, and typically decrease upwards (with time) and laterally (with distance) from the diapir. Outputs are compared to a subsurface example from the Pierce field, UK North Sea, which highlights the importance of considering local fluctuations in diapir rise rate. These can create stratigraphic architectures that may erroneously be interpreted to represent increases/decreases in sedimentation rate. Exposed examples, such as the Bakio diapir, northern Spain, can be used to make inferences of the expected depositional facies, below model resolution. Our models aid the prediction of sedimentary unit thickness and thinning rates and can be used to test interpretations arising from incomplete or low‐resolution subsurface and outcrop data when building geological models for subsurface energy.
    • Harnessing repeated measurements of predictor variables for clinical risk prediction: a review of existing methods

      Bull, Lucy M.; orcid: 0000-0002-3926-3030; email: lucy.bull@manchester.ac.uk; Lunt, Mark; Martin, Glen P.; Hyrich, Kimme; Sergeant, Jamie C. (BioMed Central, 2020-07-09)
      Abstract: Background: Clinical prediction models (CPMs) predict the risk of health outcomes for individual patients. The majority of existing CPMs only harness cross-sectional patient information. Incorporating repeated measurements, such as those stored in electronic health records, into CPMs may provide an opportunity to enhance their performance. However, the number and complexity of methodological approaches available could make it difficult for researchers to explore this opportunity. Our objective was to review the literature and summarise existing approaches for harnessing repeated measurements of predictor variables in CPMs, primarily to make this field more accessible for applied researchers. Methods: MEDLINE, Embase and Web of Science were searched for articles reporting the development of a multivariable CPM for individual-level prediction of future binary or time-to-event outcomes and modelling repeated measurements of at least one predictor. Information was extracted on the following: the methodology used, its specific aim, reported advantages and limitations, and software available to apply the method. Results: The search revealed 217 relevant articles. Seven methodological frameworks were identified: time-dependent covariate modelling, generalised estimating equations, landmark analysis, two-stage modelling, joint-modelling, trajectory classification and machine learning. Each of these frameworks satisfies at least one of three aims: to better represent the predictor-outcome relationship over time, to infer a covariate value at a pre-specified time and to account for the effect of covariate change. Conclusions: The applicability of identified methods depends on the motivation for including longitudinal information and the method’s compatibility with the clinical context and available patient data, for both model development and risk estimation in practice.
    • Haunting, ruination and encounter in the ordinary Anthropocene: storying the return Florida’s wild flamingos

      Fredriksen, Aurora; orcid: 0000-0003-4287-3443; email: aurora.fredriksen@manchester.ac.uk (SAGE Publications, 2021-03-21)
      In the spring of 2006 wild flamingos returned to Florida, though not to the places their kind had inhabited 100 years and more ago at the southern edge of the Everglades and the Florida Keys. Instead this group of flamingos alighted 80 miles northward in Palm Beach County’s Stormwater Treatment Area 2 (STA-2), a human-made facility for filtering anthropogenic pollutants from storm runoff. This paper takes the return of wild flamingos to Florida as a case for thinking through haunting, ruination and encounters in what I call ‘the ordinary Anthropocene’: the ongoing, everyday more-than-human relationships, actions and less-than-planetary assemblages through which the Anthropocene is sensed and lived. After setting out a case for thinking with haunting, ruination and encounter as a way of making sense in the ordinary Anthropocene, I trace three interwoven narrative threads that unspool from the encounter with the STA-2 flamingos: First, I trace the transfiguration of living wild flamingos into idealised symbols of tropical dreamworlds over the 20th century. This leads me sideways to the present-absence of flamingos in the mid-century writings of Rachel Carson and through her backwards to John J. Audubon and the genocidal ruinations of the 19th century as they flicker in the margins of his ornithological writings. I end by returning to the present, to the encounter with STA-2 flamingos in the ongoing moment of living with others in the late capitalist ecologies of south Florida. The conclusion considers what might be taken forward, into the uncertain future, from this telling.
    • Have (R)-[

      Chauveau, Fabien; orcid: 0000-0002-4177-741X; email: chauveau@cermep.fr; Becker, Guillaume; orcid: 0000-0002-1714-0267; Boutin, Hervé; orcid: 0000-0002-0029-5246; email: herve.boutin@manchester.ac.uk (2021-08-13)
      The prototypical TSPO radiotracer (R)-[ C]PK11195 has been used in humans for more than thirty years to visualize neuroinflammation in several pathologies. Alternative radiotracers have been developed to improve signal-to-noise ratio and started to be tested clinically in 2008. Here we examined the scientific value of these "(R)-[ C]PK11195 challengers" in clinical research to determine if they could supersede (R)-[ C]PK11195. A systematic MEDLINE (PubMed) search was performed (up to end of year 2020) to extract publications reporting TSPO PET in patients with identified pathologies, excluding studies in healthy subjects and methodological studies. Of the 288 publications selected, 152 used 13 challengers, and 142 used (R)-[ C]PK11195. Over the last 20 years, the number of (R)-[ C]PK11195 studies remained stable (6 ± 3 per year), but was surpassed by the total number of challenger studies for the last 6 years. In total, 3914 patients underwent a TSPO PET scan, and 47% (1851 patients) received (R)-[ C]PK11195. The 2 main challengers were [ C]PBR28 (24%-938 patients) and [ F]FEPPA (11%-429 patients). Only one-in-ten patients (11%-447) underwent 2 TSPO scans, among whom 40 (1%) were scanned with 2 different TSPO radiotracers. Generally, challengers confirmed disease-specific initial (R)-[ C]PK11195 findings. However, while their better signal-to-noise ratio seems particularly useful in diseases with moderate and widespread neuroinflammation, most challengers present an allelic-dependent (Ala147Thr polymorphism) TSPO binding and genetic stratification is hindering their clinical implementation. As new challengers, insensitive to TSPO human polymorphism, are about to enter clinical evaluation, we propose this systematic review to be regularly updated (living review). [Abstract copyright: © 2021. The Author(s).]
    • “Havens of mercy”: health, medical research, and the governance of the movement of dogs in twentieth-century America

      Kirk, Robert G. W.; orcid: 0000-0002-6541-5915; email: robert.g.kirk@manchester.ac.uk; Ramsden, Edmund (Springer International Publishing, 2021-12-02)
      Abstract: This article argues that the movement of dogs from pounds to medical laboratories played a critically important role in debates over the use of animals in science and medicine in the United States in the twentieth century, not least by drawing the scientific community into every greater engagement with bureaucratic political governance. If we are to understand the unique characteristics of the American federal legislation that emerges in the 1960s, we need to understand the long and protracted debate over the use of pound animals at the local municipal and state level between antivivisectionists, humane activists, and scientific and medical researchers. We argue that the Laboratory Animal Care Act of 1966 reflects the slow evolution of a strategy that proved most successful in local conflicts, and which would characterize a “new humanitarianism”: not the regulation of experimental practices but of the care and transportation of the animals being provided to the laboratory. Our analysis is consistent with, and draws upon, scholarship which has established the productive power of public agencies and civil society on the periphery of the American state.
    • HE4 as a Biomarker for Endometrial Cancer

      Behrouzi, Roya; email: rbehrouzi@doctors.org.uk; Barr, Chloe E.; email: Chloe.Barr@mft.nhs.uk; Crosbie, Emma J.; orcid: 0000-0003-0284-8630; email: Emma.Crosbie@manchester.ac.uk (MDPI, 2021-09-23)
      There are currently no blood biomarkers in routine clinical use in endometrial carcinoma (EC). Human epididymis protein 4 (HE4) is a glycoprotein that is overexpressed in the serum of patients with EC, making it a good candidate for use as a diagnostic and/or prognostic biomarker. HE4 is correlated with poor prognostic factors, including stage, myometrial invasion and lymph node metastases, which means it could be used to guide decisions regarding the extent of surgery and need for adjuvant therapy. Serum HE4 has also shown promise for predicting responses to progestin therapy in early-stage EC. The use of algorithms and indices incorporating serum HE4 and other biomarkers, including clinical and imaging variables, is an area of increasing interest. Serum HE4 levels rise with age and renal dysfunction, which may affect the interpretation of results. This review covers the evidence supporting the use of HE4 as an EC biomarker for diagnosis, prognosis, recurrence monitoring, and prediction of therapy response. The evidence for combining serum HE4 with other biomarkers, including clinical and imaging variables, its value as a biomarker in other biofluids and potential challenges of its clinical use are also discussed.
    • Health and healthcare in North Korea: a retrospective study among defectors

      Lee, Hayoung; Robinson, Courtland; Kim, Jaeshin; McKee, Martin; Cha, Jiho; orcid: 0000-0003-1212-5671; email: jiho.cha@manchester.ac.uk (BioMed Central, 2020-06-29)
      Abstract: Background: To gain insights into the socio-economic and political determinants of ill health and access to healthcare in North Korea. Methods: A retrospective survey using respondent-driven sampling conducted in 2014–15 among 383 North Korean refugees newly resettling in South Korea, asking about experiences of illness and utilization of healthcare while in North Korea, analyzed according to measures of political, economic and human rights indicators. Results: Although the Public Health Act claims that North Korea provides the comprehensive free care system, respondents reported high levels of unmet need and, among those obtaining care, widespread informal expenditure. Of the respondents, 55.1% (95%CI, 47.7–63.7%) had received healthcare for the most recent illness episode. High informal costs (53.8%, 95%CI, 45.1–60.8%) and a lack of medicines (39.5%, 95%CI, 33.3–47.1%) were reported as major healthcare barriers resulting in extensive self-medication with narcotic analgesics (53.7%, 95%CI, 45.7–61.2%). In multivariate logistic regressions, party membership was associated with better access to healthcare (Adjusted OR (AOR) = 2.34, 95%CI, 1.31–4.18), but household income (AOR = 0.40, 95%CI 0.21–0.78) and informal market activity (AOR = 0.29, 95%CIs 0.15–0.50) with reduced access. Respondents who could not enjoy political and economic rights were substantially more likely to report illness and extremely reduced access to care, even with life-threatening conditions. Conclusions: There are large disparities in health and access to healthcare in North Korea, associated with political and economic inequalities. The scope to use these findings to bring about change is limited but they can inform international agencies and humanitarian organizations working in this unique setting.
    • Health impacts of daily weather fluctuations: Empirical evidence from COVID-19 in U.S. counties.

      Emediegwu, Lotanna E; email: lotanna.emediegwu@manchester.ac.uk (2021-04-24)
      The emergence of the novel coronavirus has necessitated immense research efforts to understand how several non-environmental and environmental factors affect transmission. With the United States leading the path in terms of case incidence, it is important to investigate how weather variables influence the spread of the disease in the country. This paper assembles a detailed and comprehensive dataset comprising COVID-19 cases and climatological variables for all counties in the continental U.S. and uses a developed econometric approach to estimate the causal effect of certain weather factors on the growth rate of infection. The results indicate a non-linear and significant negative relationship between the individual weather measures and the growth rate of COVID-19 in the U.S. Specifically, the paper finds that a 1 °C rise in daily temperature will reduce daily covid growth rate in the U.S. by approximately 6 percent in the following week, while a marginal increase in relative humidity reduces the same outcome by 1 percent over a similar period. In comparison, a 1 m/s increase in daily wind speed will bring about an 8 percent drop in daily growth rate of COVID-19 in the country. These results differ by location and are robust to several sensitivity checks, so large deviations are unexpected. [Abstract copyright: Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.]
    • Health inequalities as a foundation for embodying knowledge within public health teaching: a qualitative study

      Mabhala, Mzwandile A.; University of Chester (BioMed Central, 2013-06-28)
      Introduction: Recent UK health policies identified nurses as key contributors to the social justice agenda of reducing health inequalities, on the assumption that all nurses understand and wish to contribute to public health. Following this policy shift, public health content within pre-registration nursing curricula increased. However, public health nurse educators (PHNEs) had various backgrounds, and some had limited formal public health training, or involvement in or understanding of policy required to contribute effectively to it. Their knowledge of this subject, their understanding and interpretation of how it could be taught, was not fully understood. Methodology This research aimed to understand how public health nurse educators’ professional knowledge could be conceptualised and to develop a substantive theory of their knowledge of teaching public health, using a qualitative data analysis approach. Qualitative in-depth semi-structured interviews (n=26) were conducted with eleven university-based PHNEs. Results Integrating public health into all aspects of life was seen as central to the knowing and teaching of public health; this was conceptualised as ‘embodying knowledge’. Participants identified the meaning of embodying knowledge for teaching public health as: (a) possessing a wider vision of health; (b) reflecting and learning from experience; and (c) engaging in appropriate pedagogical practices. Conclusion The concept of public health can mean different things to different people. The variations of meaning ascribed to public health reflect the various backgrounds from which the public health workforce is drawn. The analysis indicates that PHNEs are embodying knowledge for teaching through critical pedagogy, which involves them engaging in transformative, interpretive and integrative processes to refashion public health concepts; this requires PHNEs who possess a vision of what to teach, know how to teach, and are able to learn from experience. Their vision of public health is influenced by social justice principles in that health inequalities, socioeconomic determinants of health, epidemiology, and policy and politics are seen as essential areas of the public health curriculum. They believe in forms of teaching that achieve social transformation at individual, behavioural and societal levels, while also enabling learners to recognise their capacity to effect change.
    • Heart's Ease: Eudaimonia, Musicking in the Pandemic, and Its Implications for Music Education

      Boyce-Tillman, June; email: june.boyce-tillman@winchester.ac.uk (Frontiers Media S.A., 2021-09-09)
      This article will review the themes found in the literature on eudaimonia: ethical behaviour, a sense of meaning and purpose, autonomy – being able to make wise decisions and manage behaviour, contemplation, relationship with spirits of the ancestors and celestial beings and relationships of mutuality, respect. It will use these to critique various events online during the pandemic, such as the Embodiment conference, the SHIFT conference and the ZOOM peace choir. These developments related to music and wellbeing will be used to interrogate the purposes of music education and what might be learned from these new developments in relation to technology in relation to themes, such as values, orality and literacy, process and product.
    • Heartburn as a Marker of the Success of Acid Suppression Therapy in Chronic Cough

      Badri, H.; orcid: 0000-0002-6134-4347; email: huda.badri@manchester.ac.uk; Satia, I.; Bansal, V.; Mangi, M. A.; Tangaroonsanti, A.; DeVault, K. R.; Lee, A. S.; Houghton, L. A.; Smith, J. A. (Springer US, 2021-11-19)
      Abstract: Purpose: Gastro-oesophageal reflux disease (GORD) is commonly thought to play an important role in chronic cough and patients are often empirically treated with acid suppression therapy. We sought to investigate the response rate to acid suppression treatment in patients with and without heartburn attending two specialist cough clinics. Methods: A retrospective review of 558 consecutive patients referred to two specialist cough clinics was performed (UK and USA). Patients who were treated with acid suppression were included and their documented response to treatment was collected. Binary logistic regression was used to ascertain the value of reported heartburn in predicting the response of chronic cough to acid suppression therapy. Results: Of 558 consecutive referrals, 238 patients were excluded due to missing data or cough duration of < 8 weeks. The remaining 320 patients were predominantly female (76%), with mean age 61 yrs (± 13) and 96.8% non-smokers, with chronic cough for 36 (18–117) months. Of 72 patients with heartburn, 20 (28%) noted improvement in their cough with acid suppression, whereas of 248 without heartburn, only 35 (14%) responded. Patients reporting heartburn were 2.7 (95% C.I. 1.3–5.6) times more likely to respond to acid suppression therapy (p = 0.007). Conclusion: In specialist cough clinics, few patients report a response of their chronic cough to acid suppression therapy. Nonetheless, heartburn is a useful predictor substantially increasing the likelihood of benefit.
    • Heat shock response regulates stimulus-specificity and sensitivity of the pro-inflammatory NF-κB signalling

      Paszek, Anna; Kardyńska, Małgorzata; Bagnall, James; Śmieja, Jarosław; Spiller, David G.; Widłak, Piotr; Kimmel, Marek; Widlak, Wieslawa; email: wieslawa.widlak@io.gliwice.pl; Paszek, Pawel; orcid: 0000-0002-0363-0716; email: pawel.paszek@manchester.ac.uk (BioMed Central, 2020-05-24)
      Abstract: Background: Ability to adapt to temperature changes trough the Heat Shock Response (HSR) pathways is one of the most fundamental and clinically relevant cellular response systems. Heat Shock (HS) affects the signalling and gene expression responses of the Nuclear Factor κB (NF-κB) transcription factor, a critical regulator of proliferation and inflammation, however, our quantitative understanding of how cells sense and adapt to temperature changes is limited. Methods: We used live-cell time-lapse microscopy and mathematical modelling to understand the signalling of the NF-κB system in the human MCF7 breast adenocarcinoma cells in response to pro-inflammatory Interleukin 1β (IL1β) and Tumour Necrosis Factor α (TNFα) cytokines, following exposure to a 37–43 °C range of physiological and clinical temperatures. Results: We show that exposure to 43 °C 1 h HS inhibits the immediate NF-κB signalling response to TNFα and IL1β stimulation although uptake of cytokines is not impaired. Within 4 h after HS treatment IL1β-induced NF-κB responses return to normal levels, but the recovery of the TNFα-induced responses is still affected. Using siRNA knock-down of Heat Shock Factor 1 (HSF1) we show that this stimulus-specificity is conferred via the Inhibitory κB kinase (IKK) signalosome where HSF1-dependent feedback regulates TNFα, but not IL1β-mediated IKK recovery post HS. Furthermore, we demonstrate that through the temperature-dependent denaturation and recovery of IKK, TNFα and IL1β-mediated signalling exhibit different temperature sensitivity and adaptation to repeated HS when exposed to a 37–43 °C temperature range. Specifically, IL1β-mediated NF-κB responses are more robust to temperature changes in comparison to those induced by TNFα treatment. Conclusions: We demonstrate that the kinetics of the NF-κB system following temperature stress is cytokine specific and exhibit differential adaptation to temperature changes. We propose that this differential temperature sensitivity is mediated via the IKK signalosome, which acts as a bona fide temperature sensor trough the HSR cross-talk. This novel quantitative understanding of NF-κB and HSR interactions is fundamentally important for the potential optimization of therapeutic hyperthermia protocols. D-ESB-DSZSgbr1c4s2oumkVideo Abstract
    • Heritability of haemodynamics in the ascending aorta

      McGurk, Kathryn A.; email: K.McGurk@imperial.ac.uk; Owen, Benjamin; Watson, William D.; Nethononda, Richard M.; Cordell, Heather J.; Farrall, Martin; Rider, Oliver J.; Watkins, Hugh; Revell, Alistair; Keavney, Bernard D.; email: Bernard.Keavney@manchester.ac.uk (Nature Publishing Group UK, 2020-09-01)
      Abstract: Blood flow in the vasculature can be characterised by dimensionless numbers commonly used to define the level of instabilities in the flow, for example the Reynolds number, Re. Haemodynamics play a key role in cardiovascular disease (CVD) progression. Genetic studies have identified mechanosensitive genes with causal roles in CVD. Given that CVD is highly heritable and abnormal blood flow may increase risk, we investigated the heritability of fluid metrics in the ascending aorta calculated using patient-specific data from cardiac magnetic resonance (CMR) imaging. 341 participants from 108 British Caucasian families were phenotyped by CMR and genotyped for 557,124 SNPs. Flow metrics were derived from the CMR images to provide some local information about blood flow in the ascending aorta, based on maximum values at systole at a single location, denoted max, and a ‘peak mean’ value averaged over the area of the cross section, denoted pm. Heritability was estimated using pedigree-based (QTDT) and SNP-based (GCTA-GREML) methods. Estimates of Reynolds number based on spatially averaged local flow during systole showed substantial heritability (hPed2=41%[P=0.001], hSNP2=39%[P=0.002]), while the estimated heritability for Reynolds number calculated using the absolute local maximum velocity was not statistically significant (12–13%; P>0.05). Heritability estimates of the geometric quantities alone; e.g. aortic diameter (hPed2=29%[P=0.009], hSNP2=30%[P=0.010]), were also substantially heritable, as described previously. These findings indicate the potential for the discovery of genetic factors influencing haemodynamic traits in large-scale genotyped and phenotyped cohorts where local spatial averaging is used, rather than instantaneous values. Future Mendelian randomisation studies of aortic haemodynamic estimates, which are swift to derive in a clinical setting, will allow for the investigation of causality of abnormal blood flow in CVD.
    • Hermetia illucens (L.) (Diptera: Stratiomyidae) Odorant Binding Proteins and Their Interactions with Selected Volatile Organic Compounds: An in Silico Approach

      Scieuzo, Carmen; email: carmen.scieuzo@unibas.it; Nardiello, Marisa; email: nardiellomarisa@gmail.com; Farina, Donatella; email: donatella.farina.92@gmail.com; Scala, Andrea; email: andreascala@inwind.it; Cammack, Jonathan A.; email: jcammack_07@tamu.edu; Tomberlin, Jeffery K.; orcid: 0000-0002-0560-4466; email: jktomberlin@tamu.edu; Vogel, Heiko; orcid: 0000-0001-9821-7731; email: hvogel@ice.mpg.de; Salvia, Rosanna; orcid: 0000-0002-6661-7164; email: r.salvia@unibas.it; Persaud, Krishna; email: krishna.persaud@manchester.ac.uk; Falabella, Patrizia; orcid: 0000-0003-0304-6867; email: patrizia.falabella@unibas.it (MDPI, 2021-09-11)
      The black soldier fly (BSF), Hermetia illucens (Diptera: Stratiomyidae), has considerable global interest due to its outstanding capacity in bioconverting organic waste to insect biomass, which can be used for livestock, poultry, and aquaculture feed. Mass production of this insect in colonies requires the development of methods concentrating oviposition in specific collection devices, while the mass production of larvae and disposing of waste may require substrates that are more palatable and more attractive to the insects. In insects, chemoreception plays an essential role throughout their life cycle, responding to an array of chemical, biological and environmental signals to locate and select food, mates, oviposition sites and avoid predators. To interpret these signals, insects use an arsenal of molecular components, including small proteins called odorant binding proteins (OBPs). Next generation sequencing was used to identify genes involved in chemoreception during the larval and adult stage of BSF, with particular attention to OBPs. The analysis of the de novo adult and larval transcriptome led to the identification of 27 and 31 OBPs for adults and larvae, respectively. Among these OBPs, 15 were common in larval and adult transcriptomes and the tertiary structures of 8 selected OBPs were modelled. In silico docking of ligands confirms the potential interaction with VOCs of interest. Starting from the information about the growth performance of H. illucens on different organic substrates from the agri-food sector, the present work demonstrates a possible correlation between a pool of selected VOCs, emitted by those substrates that are attractive for H. illucens females when searching for oviposition sites, as well as phagostimulants for larvae. The binding affinities between OBPs and selected ligands calculated by in silico modelling may indicate a correlation among OBPs, VOCs and behavioural preferences that will be the basis for further analysis.
    • Herwig 7.2 release note

      Bellm, Johannes; Bewick, Gavin; Ferrario Ravasio, Silvia; Gieseke, Stefan; Grellscheid, David; Kirchgaeßer, Patrick; Loshaj, Frashër; Masouminia, Mohammad R.; Nail, Graeme; Papaefstathiou, Andreas; et al. (Springer Berlin Heidelberg, 2020-05-20)
      Abstract: A new release of the Monte Carlo event generator Herwig (version 7.2) is now available. This version introduces a number of improvements over the major version 7.0, notably: multi-jet merging with the dipole shower at LO and NLO QCD; spin correlations in both the dipole and angular-ordered parton showers; an improved choice of evolution variable in the angular-ordered parton shower; improvements to mass effects and top decays in the dipole shower, improvements to the simulation of multiple-parton interactions, including diffractive processes; a new model for baryonic colour reconnection; improvements to strangeness production; as well as a new tune of the hadronisation parameters and support for generic Lorentz structures in BSM models. This article illustrates new features of versions 7.1 and 7.2.