Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

A protocol for a pilot study to assess the feasibility of a randomised clinical trial of perioperative intravenous lidocaine on colorectal cancer outcome after surgery (FLICOR trial)

Background: Cancer recurrence after curative cancer surgery significantly impacts patients and healthcare services. Before surgery, a small number of clinically undetectable circulating tumour cells are often present. The surgical stress response promotes the distribution and proliferation of circulating tumour cells leading to cancer recurrence and metastasis. Preclinical evidence suggests that lidocaine may exert ‘anti-cancer’ effects and alleviate pro-metastatic environments. The Feasibility Study of Lidocaine Infusion During Bowel Cancer Surgery for Cancer Outcome (FLICOR) will assess the feasibility of conducting a clinical trial on perioperative intravenous lidocaine infusion for postoperative colorectal cancer outcomes. Methods: The study is a double-blinded, randomised, controlled pilot study for a full trial comparing intravenous lidocaine administration at 1.5 mg kg−1 bolus followed by 1.5 mg kg−1 h−1 infusion for 24 h with placebo in patients undergoing minimally invasive (laparoscopy or robotic) colorectal cancer surgery. The feasibility of data collection instruments will be measured, including those for future economic evaluation and clinical and patient-reported outcomes. For the exploratory outcomes, blood samples will be collected before and after surgery on days 0, 1, and 3. Recruitment is planned for two NHS Trusts over 6 months with a 12-month follow-up. Patients and clinicians will be asked for their feedback on the study process. Dissemination plan: Study data will be disseminated to trial participants, the public, and academic communities. The work will be presented at national and international conferences to stimulate interest and enthusiasm for centres to participate in the future definitive trial. This research will also be published in peer-reviewed open-access journals. Clinical trial registration: ISRCTN29594895 (ISRCTN), NCT05250791 (ClinicalTrials.gov). Protocol version number and date: 3.0, February 8, 2023

Sleep duration, chronotype, health and lifestyle factors affect cognition: a UK Biobank cross-sectional study

Objective To explore the nuanced relationship between sleep patterns, chronotype, quality and the influence of health and lifestyle factors on cognitive performance.Design, setting, participants This cross-sectional analysis used ordinary least squares regression within the UK Biobank database, assessing 26 820 participants aged 53–86 years, categorised into two cohorts: Cohort 1 (10 067 participants, 56% female; completed all four cognitive tests of Fluid Intelligence/reasoning, Pairs Matching, Reaction Time and Prospective Memory) and Cohort 2 (16 753 participants, 56% female; completed only two cognitive assessments of Pairs Matching and Reaction Time).Exposures Participant’s self-reported sleep duration, chronotype and quality. Cognitive function was assessed through standardised computerised tests. The analysis was adjusted for demographic and comorbidity covariates.Main outcomes and measures Cognitive performance scores were evaluated against sleep parameters and health and lifestyle factors including sex, age, vascular and cardiac conditions, diabetes, alcohol intake, smoking habits and body mass index.Results The regression highlighted a positive association between normal sleep duration (7–9 hours) and cognitive scores in Cohort 1 (β=0.0567, 95% CI 0.0284 to 0.0851), while extended sleep duration negatively impacted scores across both cohorts (Cohort 1: β=−0.188, 95% CI −0.2938 to −0.0822; Cohort 2: β=−0.2619, 95% CI −0.3755 to −0.1482). Chronotype distinctions, particularly intermediate and evening types, were linked to superior cognitive function. Gender, age, angina, high blood pressure, diabetes, alcohol intake and smoking emerged as significant cognitive influencers.Conclusions and relevance The study delineates a multifaceted and nuanced relationship between sleep variables, health and lifestyle factors in determining cognitive outcomes. These findings highlight the vital role of sleep quality on cognitive health

A nation in exile : Tibetan diaspora and the dynamics of long-distance nationalism.

This essay is an attempt to explore the dynamics of Tibetan nationalism in diaspora. I do this from three perspectives. First, I examine the techniques of contemporary nationalist uprisings among displaced communities, and I argue that the nature and character of the nationalism-in-exile is determined to a great extent by the cooperation between the community within Tibet and those outside it. Secondly, I analyse the situation where a displaced community keeps the nationalism agenda alive in isolation. Specifically, I argue that beyond whatever situation may be present in the territory with a contested sovereignty, those in the diaspora always pursue a policy to establish links and ties--both clandestine and open--with their counterparts and work in tandem in order to facilitate their cause. Thirdly, I argue that fears of persecution cannot be a basis to non-engagement with those living in the contested territory: nationalist struggle is very much like a war, and it cannot be fought effectively from outside. In addition, the aspirations of the community concerned is likely to be compromised if those in the diaspora are overwhelmingly concentrated in one host country. Further, although traditional-legal or charismatic leadership is a great uniting factor and crucial to the vision of the diasporic community, excessive dependence on it can significantly alter the course of the nationalist aspiration