Update on the role of bone turnover markers in the diagnosis and management of osteoporosis: a consensus paper from The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), International Osteoporosis Foundation (IOF), and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)

Purpose: the International Osteoporosis Foundation (IOF) and the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) have proposed procollagen type I N propeptide (PINP) and β isomerized C-terminal telopeptide of type I collagen (β-CTX-I) as reference bone turnover markers (BTMs) for osteoporosis. This report examines the published literature since the 2011 IOF-IFCC position paper in order to determine the clinical potential of the reference BTMs and newer markers for the prediction of fracture risk and monitoring the treatment of osteoporosis.Methods: evidence for the relationship between BTMs and subsequent fractures was gathered from prospective studies through literature review of the Medline database from years 2011 to May 2024. The impact of treatment on BTMs was also studied by examining publications in that period. Studies of the accuracy of BTMs in the assessment of bone turnover in the setting of advanced chronic kidney disease were also examined.Results: increased BTM concentrations are associated with higher fracture risk in postmenopausal women. PINP and β-CTX-I measured in blood are associated with fracture risk but their interaction with other risk factors has not been sufficiently studied limiting their incorporation into fracture risk algorithms. Treatment-induced changes in PINP and β-CTX-I account for a substantial proportion of fracture risk reduction and are useful for improving adherence; they are recommended for inclusion in studies to examine adherence in individual patients. However, total PINP (tPINP) and β-CTX-I may be elevated in CKD due to renal retention. Bone alkaline phosphatase (BALP), intact PINP (iPINP), and tartrate resistant acid phosphatase 5b (TRACP5b) show the most promise in discriminating high and low turnover bone diseases in patients with advanced CKD and for predicting fracture risk, monitoring treatment response, and assessing the risk of treatment-related complications.Conclusion: we re-affirm the use of serum/plasma tPINP and plasma β-CTX-I as reference BTMs with appropriate patient preparation and sample handling and measurement by standardized/harmonized assays in clinical studies to accumulate further data, and for monitoring treatment of osteoporosis in the setting of normal renal function in clinical practice. BALP and TRACP5b, measured by standardized assays, are recommended as reference BTMs for CKD-associated osteoporosis and should be included in observational and intervention studies to ascertain their utility for risk-evaluation, treatment initiation, and assessment of treatment response in CKD-associated osteoporosis.</p

Investigations into the flow photochemical generation of triplet aryl cations, and the development of a practicable synthesis of electroluminescent ionic 2,2’-bifluorenes

The development of an optimised experimental procedure for the synthesis of tetraimidazolium and tetrabenzimidazolium ionic 2,2’-bifluorenes is reported herein. Developed iteratively through several generations, it has improved the safety and reduced the waste associated with the ubiquitous method of preparing these and related electroluminescent compounds from the literature. This procedure has then been extended to diimidazolium species’, where an X-ray crystal structure has revealed how the triflate counterions can provide a second link between the alkylimidazolium residues and the photoluminescent core.Additionally, building upon recent work within the Harrowven group, an investigation into the flow photochemical generation of triplet aryl cations from benzyl ortho-iodophenyl ethers has produced an array of functionalised benzochromenes, including new examples and the optimisation of some that have been previously reported. Several side reactions have been examined in detail, including the alternate formation of biaryl acetamides and fluorenes. The reaction has also been extended to the synthesis of encumbered biaryls by the inclusion of ortho and ortho’ substituents on the benzyl ring

Emergency and routine presentation of neuroendocrine neoplasia in England: determinants of late presentation and survival outcomes

Objective: the time from onset of symptoms of neuroendocrine neoplasia (NEN) to diagnosis ranges between 5-7 years. Risk factors associated with this and the difference in overall survival (OS) between routine and emergency presentation (RP and EP) are not known.Design: a retrospective, population-based study.Methods: a retrospective, population-based study of gastroenteropancreatic and lung NEN registered on England’s national cancer between 2012 and 2021. Factors associated with worse OS, or emergency or late presentation (EP or LP), were evaluated using the Kaplan–Meier estimator, Cox and logistic regressions, and machine learning (ML) in two models.Results: a total of 21,345 NEN were included. 20.3% were EP. EP showed worse OS compared to RP. Factors associated with EP were male sex, advanced stage, worse deprivation, and NEC. The ML model showed EP related to advanced stage, small intestinal NEN, NEC, advanced age, deprivation, and male sex in decreasing order of importance. Factors associated with LP includedEP, male sex, and NEC. The ML model showed NEC, small intestinal NEN, advanced age, EP, and male sex are associated with LP in decreasing order of importance.Conclusion: EP is associated with poor survival. Addressing the associated factors may aid in timely diagnosis and improved surviva

Non-metal organic frameworks exhibit high proton conductivity

Porous materials such as metal-organic frameworks (MOFs) and porous organic salts are promising materials for proton conduction. Recently, we developed a new sub-class of porous materials, isoreticular non-metal organic frameworks (N-MOFs), that can be designed using crystal structure prediction (CSP). Here, two porous, isostructural and water-stable halide N-MOFs were prepared and found to show good proton conductivity of up to 1.1 x 10-1 S cm-1 at 70 °C and 90% relative humidity. Changing the halides in these N-MOF materials affects the resulting proton conductivity, as observed in previous studies involving MOFs and lead halides. Although this is the first study of proton conductivity in N-MOFs, the bromide salt, TTBT.Br, shows higher conductivity than most polycrystalline MOFs and porous organic salts, approaching that of Nafion

The ELECTRA Trial: approach to contemporary challenges in the development and implementation of double-blinded, randomised, controlled clinical trials in low-volume high-complexity surgical oncology

Background: achieving evidence-based practice change in surgery has always been challenging, with many aspects of common clinical practice evolving through lower-level studies that are susceptible to bias and confounding rather than high-quality evidence. This challenge is even more pronounced in the setting of low-volume, high-complexity surgical oncology. Additionally, when the costs of interventions or technologies are high, designing and developing such studies within financially constrained national healthcare systems becomes even more complicated, potentially widening perceived healthcare inequalities between private and publicly funded systems. However, this is precisely the area where a lack of evidence can either hinder the development of significant new clinical advances or lead to the adoption of expensive and ineffective treatments. Here, we describe the novel approaches adopted in the design, development, and implementation of the ELECTRA trial, a randomised, controlled, double-blinded feasibility study with a planned extension to a late-phase trial. Methods: the Cancer Research UK ELECTRA (NCT05877352) trial is a three-armed randomised, controlled clinical trial designed to evaluate the incremental benefit of adding intraoperative electron beam radiotherapy (IOERT) to pelvic exenteration surgery for locally advanced and locally recurrent rectal cancer. ELECTRA is double-blinded, with patients, surgeons, and oncologists unaware of whether IOERT is administered or not. The primary feasibility outcome focuses on the ability to successfully recruit and randomise participants, while the subsequent primary outcome assesses IOERT field local control. Results: we describe the collaborative process involved in developing the trial, including national and international consultations to determine the best study design and the most optimal outcome measures to evaluate. We outline the extensive patient participation and input into the study design. Given the complexity and evolving nature of the field, with no clear international standardisations, we outline the processes used to address internationally agreed definitions, radiological standardisation, surgical learning curves, quality assurance, and pathological standardisation, as well as the broader impact and benefits of these activities. Finally, we describe the novel design utilised to facilitate the involvement of national and international units with varying levels of equipoise regarding IOERT. Conclusions: historically, randomised clinical trials have not been the standard approach for evaluating surgical interventions due to their practical and methodological challenges, particularly in high-complexity, low-volume settings. Despite these difficulties, they remain the gold standard for evidence-based practice. The ELECTRA trial exemplifies a complex, innovative trial design that addresses an unmet need in a specialised area of high-complexity surgery. Using ELECTRA as an example, we highlight the genuine challenges in designing such complex trials and provide recommendations to facilitate the conduct of future well-designed surgical studies.</p

Labour pains: mothers and motherhood on the British left in the twentieth century

British left-wing politics does not know what to think about mothers. In left-wing women’s movements, motherhood has been recognised as essential and difficult; necessary for future revolutions, not least in raising future revolutionaries. In less radical circles, it has been understood as a crucial contribution to the functioning of society, often forming the basis of women’s claims to citizenship and maternalist forms of politics. On the other hand, motherhood has been seen as a ‘natural’ function of women and a private responsibility, rather than a public good or a collective act which needs comprehensive state support. The family, in this reading, is a rather conservative force, better left to social reactionaries. Mothering has added additional hurdles to the gendered obstacles women already face in pursuing politics as activists or elected representatives. Perhaps because of this, many mothers in politics have sought to downplay or distance themselves from their roles as mothers, emphasising instead their contributions as workers and activists who can be fully committed to the left cause. Feminist historians have often followed their lead and have tended to write around political mothers’ maternal roles in their scholarship. This roundtable develops themes first explored in our November 2023 workshop, generously supported by the Royal Historical Society

Associations between skeletal muscle strength and chronic kidney disease in patients with MASLD

Background: A skeletal muscle strength (SMS) decline is associated with metabolic diseases, but whether SMS also declines with chronic kidney disease (CKD) in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) is uncertain. This study examined the associations between SMS and the risk of CKD in MASLD population. Method: We performed a large-scale study with four cohorts: PERSONS and NHANES 2011–2014 cohorts for the cross-sectional investigation, and TCLSIH and UK Biobank cohorts for the longitudinal investigation. A handgrip dynamometer measured handgrip strength as a proxy for overall SMS. Participants were stratified according to CKD status [non-CKD vs. CKD (stages 1–5) groups]. Results: In the PERSONS cohort, the CKD group has a lower handgrip strength than the non-CKD group (27.14 ± 9.19 vs. 33.59 ± 11.92 kg, P &lt; 0.001). Higher handgrip strength is associated with lower odds of abnormal albuminuria or CKD (OR: 0.96, 95%CI:0.92-0.99 and OR:0.95, 95%CI: 0.91-0.99 respectively). The highest handgrip strength tertile is associated with the lowest risk of having abnormal albuminuria or CKD (compared with the lowest or middle tertile). Results are similar in NHANES cohort. Furthermore, the highest handgrip strength is independently associated with the lowest risk of incident CKD in MASLD (HR: 0.95, 95%CI: 0.92-0.99 and HR:0.99, 95%CI: 0.98-0.99 in TCLSIH and UK Biobank cohorts). In Kaplan-Meier curve analysis, the cumulative incidence of CKD is lowest in the highest handgrip strength tertile compared to the lowest or the middle tertile. Conclusions: Higher handgrip/muscle strength is independently associated with a lower risk of CKD and abnormal albuminuria in MASLD population.</p