The state of an animal prior to the application of a noxious stimulus can have a profound effect on their nociceptive threshold and subsequent behaviour. In mammals, the presence of acute stress ...preceding a painful event can have an analgesic effect whereas the presence of chronic stress can result in hyperalgesia. While considerable research has been conducted on the ability of stress to modulate mammalian responses to pain, relatively little is known about fish. This is of particular concern given that zebrafish (
) are an extensively used model organism subject to a wide array of invasive procedures where the level of stress prior to experimentation could pose a major confounding factor. This study, therefore, investigated the impact of both acute and chronic stress on the behaviour of zebrafish subjected to a potentially painful laboratory procedure, the fin clip. In stress-free individuals, those subjected to the fin clip spent more time in the bottom of the tank, had reduced swimming speeds and less complex swimming trajectories; however, these behavioural changes were absent in fin-clipped fish that were first subject to either chronic or acute stress, suggesting the possibility of stress-induced analgesia (SIA). To test this, the opioid antagonist naloxone was administered to fish prior to the application of both the stress and fin-clip procedure. After naloxone, acutely stressed fin-clipped zebrafish exhibited the same behaviours as stress-free fin-clipped fish. This indicates the presence of SIA and the importance of opioid signalling in this mechanism. As stress reduced nociceptive responses in zebrafish, this demonstrates the potential for an endogenous analgesic system akin to the mammalian system. Future studies should delineate the neurobiological basis of stress-induced analgesia in fish.
For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the ...short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure.
IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 μg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562.
Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8–3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio RR 0·82 95% CI 0·66 to 1·02; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 95% CI 0·58 to 1·00; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 36%) than in the usual care group (243 43%; difference –7·00% 95% CI –12·69 to –1·32; p=0·016).
For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population.
British Heart Foundation and Pharmacosmos.
Fish are used in a variety of experimental contexts often in high numbers. To maintain their welfare and ensure valid results during invasive procedures it is vital that we can detect subtle changes ...in behaviour that may allow us to intervene to provide pain-relief. Therefore, an automated method, the Fish Behaviour Index (FBI), was devised and used for testing the impact of laboratory procedures and efficacy of analgesic drugs in the model species, the zebrafish. Cameras with tracking software were used to visually track and quantify female zebrafish behaviour in real time after a number of laboratory procedures including fin clipping, PIT tagging, and nociceptor excitation via injection of acetic acid subcutaneously. The FBI was derived from activity and distance swum measured before and after these procedures compared with control and sham groups. Further, the efficacy of a range of drugs with analgesic properties to identify efficacy of these agents was explored. Lidocaine (5 mg/L), flunixin (8 mg/L) and morphine (48 mg/L) prevented the associated reduction in activity and distance swum after fin clipping. From an ethical perspective, the FBI represents a significant refinement in the use of zebrafish and could be adopted across a wide range of biological disciplines.
Massecuite is a liquid mixture that is boiled to produce raw sugar. When formed from poor-quality sugar cane, massecuite can be difficult to boil, leading to factory shutdowns lasting several weeks. ...This “hard-to-boil” (HTB) massecuite is rich in long-chained polysaccharides and thus exhibits a rheology that is dominated by elasticity. We examine how the rheology of massecuite affects the onset of boiling by proposing an extension of classical nucleation theory that accounts for the elastic energy of fluids containing a deformable solid network. The elasticity of a fluid is shown to suppress the onset of boiling through an increase in the boiling temperature, which is calculated to be a linear function of the shear modulus. Using experimental data, the model correctly predicts that regular and HTB massecuite should and should not boil under standard operating conditions. By coupling the boiling problem to a heat transfer model, the thermo-rheological properties of HTB massecuite are shown to greatly increase the time it takes to reach the boiling temperature. We propose further experiments that can be used to validate the theoretical results obtained here.
Barrett's esophagus (BE), a common condition, is the only known precursor to esophageal adenocarcinoma (EAC). There is uncertainty about the best way to manage BE as most people with BE never develop ...EAC and most patients diagnosed with EAC have no preceding diagnosis of BE. Moreover, there have been recent advances in knowledge and practice about the management of BE and early EAC. To aid clinical decision making in this rapidly moving field, Cancer Council Australia convened an expert working party to identify pertinent clinical questions. The questions covered a wide range of topics including endoscopic and histological definitions of BE and early EAC; prevalence, incidence, natural history, and risk factors for BE; and methods for managing BE and early EAC. The latter considered modification of lifestyle factors; screening and surveillance strategies; and medical, endoscopic, and surgical interventions. To answer each question, the working party systematically reviewed the literature and developed a set of recommendations through consensus. Evidence underpinning each recommendation was rated according to quality and applicability.
The field of silicon photonics has experienced widespread adoption in the datacoms industry over the past decade, with a plethora of other applications emerging more recently such as light detection ...and ranging (LIDAR), sensing, quantum photonics, programmable photonics and artificial intelligence. As a result of this, many commercial complementary metal oxide semiconductor (CMOS) foundries have developed open access silicon photonics process lines, enabling the mass production of silicon photonics systems. On the other side of the spectrum, several research labs, typically within universities, have opened up their facilities for small scale prototyping, commonly exploiting e-beam lithography for wafer patterning. Within this ecosystem, there remains a challenge for early stage researchers to progress their novel and innovate designs from the research lab to the commercial foundries because of the lack of compatibility of the processing technologies (e-beam lithography is not an industry tool). The CORNERSTONE rapid-prototyping capability bridges this gap between research and industry by providing a rapid prototyping fabrication line based on deep-UV lithography to enable seamless scaling up of production volumes, whilst also retaining the ability for device level innovation, crucial for researchers, by offering flexibility in its process flows. This review article presents a summary of the current CORNERSTONE capabilities and an outlook for the future.
BackgroundThe prevalence of both anaemia and iron deficiency increases with age and may be higher still in patients with heart failure. Age might impair the erythropoietic response to iron. We ...analysed data from a randomised trial (IRONMAN) to determine whether the effects of intravenous (IV) iron, delivered as ferric derisomaltose (FDI), in patients with heart failure and iron deficiency were modified by age.MethodsPatients with a diagnosis of heart failure, a left ventricular ejection fraction ≤45%, and either a TSAT <20% or serum ferritin <100 µg/L were included. Haemoglobin for women had to be in the range of 9-13 g/dL and for men 9-14g/dL. Patients were randomised to receive IV ferric derisomaltose (FDI) or not. Neither the patient nor investigator was blinded. The main endpoints of interest were changes in haemoglobin at 4 months and 12 months and the primary endpoint of the trial (the rate of the composite outcome of heart failure hospitalisations or cardiovascular death expressed as events per 100 patient-years, blindly adjudicated). Analyses were conducted by intention to treat, stratified by quartile of age. A further analysis was conducted for patients with a TSAT <20%.ResultsOf 1,137 patients randomised, the median IQR age was 73 67 to 79 years. Patients in the oldest quartile were more likely to be men, were in a worse NYHA class, had a lower eGFR and haemoglobin and higher NT-proBNP, but LVEF, TSAT (16 11 to 21 %) and ferritin were similar to other quartiles. Increases in haemoglobin with FDI compared to control in the oldest quartile at 4 months (+0.7 +0.4 to +1.0 g/dL) and 12 months (+0.9 +0.5 to +1.3 g/dL) were similar to that in other quartiles. The hazard ratio for the primary endpoint in the oldest quartile was 0.66 (0.45 to 0.96), which was not significantly different from that for other age quartiles. The results were similar when restricted to patients with a TSAT <20%.ConclusionsThe increase in haemoglobin with IV FDI and its effect on the primary endpoint rate were not diminished by age.Abstract 134 Table 1BaselineQ1 age < 67 yearsQ2 age ≥67 to 73 yearsQ3 age >73 to 79 yearsQ4 age ≥79 years N= 285284283285Age (years)60 (55, 64)71 (69, 72)76 (75, 78)83 (81, 94)Women (%)85 (30)84 (30)62 (22)69 (24)NYHA II (%)178 (62)164 (58)162 (57)144 (51)NT-proBNP ng/L1203 (607, 3023)1414 (820, 2823)1686 (964, 3602)2745 (1570, 4822)TSAT (%)15 (10, 19)15 (11, 20)16 (11, 19)16 (11, 21)Ferritin ng/mL54 (28, 90)48 (28, 82)48 (31, 85)49 (30, 84)LVEF (%)30 (25, 35)35 (27, 38)35 (28, 38)34 (25, 39)eGFR mL/min/BSA64 (48, 86)54 (39, 71)47 (37, 63)44 (34, 55)Hb g/dL12.3 (11.1, 12.9)12.1 (11.3, 12.9)12.1 (11.2, 12.8)11.8 (11.1, 12.7)Follow-upUCFDIDiff*/RR**UCFDIDiff*/RR**UCFDIDiff*/RR**UCFDIDiff*/RR**Delta Hb Month 40.1 (1.1)0.8 (1.5)0.7*(0.4, 1.1)0.4 (1.2)0.7 (1.4)0.3*(-0.0, 0.6)0.2(1.3)1.0(1.3)0.8*(0.5, 1.1)0.0(1.2)0.7(1.2)0.7*(0.4, 1.0)Delta Hb Month 120.5 (1.6)1.2 (1.3)0.7*(0.3, 1.2)0.4 (1.6)0.7 (1.6)0.3*(-0.2, 0.8)0.3(1.6)0.9(1.5)0.6*(0.2, 1.1)-0.3(1.2)0.6(1.3)0.9*(0.5, 1.3)Primary Endpoint (per 100 patient years) 113 (28)91 (23)0.81**(0.50,1.33)94 (25)78 (21)0.86**(0.55,1.33)99 (25)88 (26)1.05**0.71,1.56)105 (33)79 (21)0.66**(0.45,0.96)Conflict of InterestNil
IntroductionRecent results from the IRONMAN trial add to previous data and demonstrate that correction of iron deficiency in patients with heart failure, with high dose IV iron can improve quality of ...life, and reduce the risk of heart failure hospitalisation (by around 25% in meta-analysis). Yet there are theoretical risks that IV iron administration may increase the risk from bacterial infection. A meta-analysis in 2021 (across many clinical indications) suggested an excess risk of infections with IV iron but noted most trials did not pre-specify infection as an end point, with risk of reporting bias. To answer this important question hospitalisation for infection or death due to infection were pre-specified safety endpoints in IRONMAN.MethodsIRONMAN was a prospective, randomised open-label, blinded endpoint (PROBE) event-driven trial of IV ferric derisomaltose (FDI) and usual care versus usual care alone in patients with heart failure (LVEF ≤45% ) and iron deficiency (ferritin <100 µg/L and/or TSAT <20%, provided ferritin ≤400 µg/L). Patients were enrolled if they had a current or recent hospitalisation for heart failure or elevated natriuretic peptide plasma concentration. Every four months, IV iron was administered if either ferritin was <100 µg/L or TSAT was <25% (provided ferritin ≤400 µg/L). All hospitalisations and deaths were adjudicated blindly. Given that a large part of the trial was conducted during the COVID-19 pandemic, we also evaluated COVID-19 related SAEs.Results1137 patients (26.4% women) with median (IQR) age 73 (63 to 79) years were recruited by the Ironman Study Group between Aug 2016 and Oct 2021 across 70 UK sites. Median (IQR) follow-up was 2·7 (1·8 to 3·6) years. 97% of patients consented to record linkage to national databases of deaths and hospital discharge summaries, thereby ensuring investigators were aware of all potential events. There were a similar number of hospitalisations due to infection for those assigned to ferric derisomaltose (175) and usual care (213) (p = 0.16) and infection related death (34 and 28, respectively, p = 0.43). When considering first events of hospitalisation for infection or infection death there were 120 (21.1%) events for those randomised to IV FDI and 146 (25.7%) for the usual care arm (figure). There were fewer patients with COVID related SAEs in those randomised to IV FDI (12) as compared with usual care (30), HR (95% CI) 0.40 (0.20, 0.78). p=0.007. For deaths attributed to COVID-19, 4 were seen in the IV FDI arm and 8 in the usual care arm: HR 0.51 (0.15, 1.68) p=0.27.ConclusionsThere was no excess risk of infection related hospitalisation or death in patients receiving IV ferric derisomaltose. Fewer COVID-19 related SAEs were seen in patients receiving IV FDI. Given that iron plays an important role in the T and B cell response to vaccination, further analysis needs to be done in this area.Conflict of InterestHonorarium for education from Pharmocosmos
IMPORTANCE: Ninety-day mortality rates after esophagectomy are an indicator of the quality of surgical oncologic management. Accurate risk prediction based on large data sets may aid patients and ...surgeons in making informed decisions. OBJECTIVE: To develop and validate a risk prediction model of death within 90 days after esophagectomy for cancer using the International Esodata Study Group (IESG) database, the largest existing prospective, multicenter cohort reporting standardized postoperative outcomes. DESIGN, SETTING, AND PARTICIPANTS: In this diagnostic/prognostic study, we performed a retrospective analysis of patients from 39 institutions in 19 countries between January 1, 2015, and December 31, 2019. Patients with esophageal cancer were randomly assigned to development and validation cohorts. A scoring system that predicted death within 90 days based on logistic regression β coefficients was conducted. A final prognostic score was determined and categorized into homogeneous risk groups that predicted death within 90 days. Calibration and discrimination tests were assessed between cohorts. EXPOSURES: Esophageal resection for cancer of the esophagus and gastroesophageal junction. MAIN OUTCOMES AND MEASURES: All-cause postoperative 90-day mortality. RESULTS: A total of 8403 patients (mean SD age, 63.6 9.0 years; 6641 79.0% male) were included. The 30-day mortality rate was 2.0% (n = 164), and the 90-day mortality rate was 4.2% (n = 353). Development (n = 4172) and validation (n = 4231) cohorts were randomly assigned. The multiple logistic regression model identified 10 weighted point variables factored into the prognostic score: age, sex, body mass index, performance status, myocardial infarction, connective tissue disease, peripheral vascular disease, liver disease, neoadjuvant treatment, and hospital volume. The prognostic scores were categorized into 5 risk groups: very low risk (score, ≥1; 90-day mortality, 1.8%), low risk (score, 0; 90-day mortality, 3.0%), medium risk (score, –1 to –2; 90-day mortality, 5.8%), high risk (score, −3 to −4: 90-day mortality, 8.9%), and very high risk (score, ≤−5; 90-day mortality, 18.2%). The model was supported by nonsignificance in the Hosmer-Lemeshow test. The discrimination (area under the receiver operating characteristic curve) was 0.68 (95% CI, 0.64-0.72) in the development cohort and 0.64 (95% CI, 0.60-0.69) in the validation cohort. CONCLUSIONS AND RELEVANCE: In this study, on the basis of preoperative variables, the IESG risk prediction model allowed stratification of an individual patient’s risk of death within 90 days after esophagectomy. These data suggest that this model can help in the decision-making process when esophageal cancer surgery is being considered and in informed consent.
Land Reform in Scotland Malcolm Combe, Jayne Glass, Annie Tindley
2020, 2020-02-03
eBook, Book
This interdisciplinary analysis of Scotland's perennial political hot potato – the Scottish land question – follows the latest legislative development, The Land Reform (Scotland) Act 2016. Bringing ...together leading academics and professional experts working in law, history and policy, Land Reform in Scotland delves into issues from the early modern period to present day. Individual chapters discuss some areas such as property theory and human rights which have been under-studied in relation to land reform.
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