Explaining empirical dynamic modelling using verbal, graphical and mathematical approaches.

Empirical dynamic modelling (EDM) is becoming an increasingly popular method for understanding the dynamics of ecosystems. It has been applied to laboratory, terrestrial, freshwater and marine systems, used to forecast natural populations and has addressed fundamental ecological questions. Despite its increasing use, we have not found full explanations of EDM in the ecological literature, limiting understanding and reproducibility. Here we expand upon existing work by providing a detailed introduction to EDM. We use three progressively more complex approaches. A short verbal explanation of EDM is then explicitly demonstrated by graphically working through a simple example. We then introduce a full mathematical description of the steps involved. Conceptually, EDM translates a time series of data into a path through a multi-dimensional space, whose axes are lagged values of the time series. A time step is chosen from which to make a prediction. The state of the system at that time step corresponds to a 'focal point' in the multi-dimensional space. The set (called the library) of candidate nearest neighbours to the focal point is constructed, to determine the nearest neighbours that are then used to make the prediction. Our mathematical explanation explicitly documents which points in the multi-dimensional space should not be considered as focal points. We suggest a new option for excluding points from the library that may be useful for short-term time series that are often found in ecology. We focus on the core simplex and S-map algorithms of EDM. Our new R package, pbsEDM, enhances understanding (by outputting intermediate calculations), reproduces our results and can be applied to new data. Our work improves the clarity of the inner workings of EDM, a prerequisite for EDM to reach its full potential in ecology and have wide uptake in the provision of advice to managers of natural resources.

Non-clinical hallucinations and mental imagery across sensory modalities.

INTRODUCTION: Vivid mental imagery has been proposed to increase the likelihood of experiencing hallucinations. Typically, studies have employed a modality general approach to mental imagery which compares imagery across multiple domains (e.g., visual, auditory and tactile) to hallucinations in multiple senses. However, modality specific imagery may be a better predictor of hallucinations in the same domain. The study examined the contribution of imagery to hallucinations in a non-clinical sample and specifically whether imagery best predicted hallucinations at a modality general or modality specific level. METHODS: In study one, modality general and modality specific accounts of the imagery-hallucination relationship were contrasted through application of self-report measures in a sample of 434 students. Study two used a subsample (n = 103) to extend exploration of the imagery-hallucinations relationship using a performance-based imagery task. RESULTS: A small to moderate modality general relationship was observed between self-report imagery and hallucination proneness. There was only evidence of a modality specific relationship in the tactile domain. Performance-based imagery measures were unrelated to hallucinations and self-report imagery. CONCLUSIONS: Mental imagery may act as a modality general process increasing hallucination proneness. The observed distinction between self-report and performance-based imagery highlights the difficulty of accurately measuring internal processes.

Role of vitamin D supplementation in modifying outcomes after surgery: a systematic review of randomised controlled trials.

BACKGROUND: There is increasing evidence to suggest vitamin D plays a role in immune and vascular function; hence, it may be of biological and clinical relevance for patients undergoing major surgery. With a greater number of randomised studies being conducted evaluating the impact of vitamin D supplementation on surgical patients, it is an opportune time to conduct further analysis of the impact of vitamin D on surgical outcomes. METHODS: MEDLINE, EMBASE and the Cochrane Trials Register were interrogated up to December 2023 to identify randomised controlled trials of vitamin D supplementation in surgery. The risk of bias in the included studies was assessed using the Cochrane Risk of Bias tool. A narrative synthesis was conducted for all studies. The primary outcome assessed was overall postoperative survival. RESULTS: We screened 4883 unique studies, assessed 236 full-text articles and included 14 articles in the qualitative synthesis, comprising 1982 patients. The included studies were highly heterogeneous with respect to patient conditions, ranging from open heart surgery to cancer operations to orthopaedic conditions, and also with respect to the timing and equivalent daily dose of vitamin D supplementation (range: 0.5-7500 mcg; 20-300 000 IU). No studies reported significant differences in overall survival or postoperative mortality with vitamin D supplementation. There was also no clear evidence of benefit with respect to overall or intensive care unit length of stay. DISCUSSION: Numerous studies have reported the benefits of vitamin D supplementation in different surgical settings without any consistency. However, this systematic review found no clear evidence of benefit, which warrants the supposition that a single biological effect of vitamin D supplementation does not exist. The observed improvement in outcomes in low vitamin D groups has not been convincingly proven beyond chance findings. TRIAL REGISTRATION NUMBER: CRD42021232067.

Redo aortic valve replacement versus valve-in-valve trans-catheter aortic valve implantation: a UK propensity-matched analysis.

This study sought to compare the morbidity and mortality of redo aortic valve replacement (redo-AVR) versus valve-in-valve trans-catheter aortic valve implantation (valve-in-valve TAVI) for patients with a failing bioprosthetic valve. A multicenter UK retrospective study of redo-AVR or valve-in-valve TAVI for patients referred for redo aortic valve intervention due to a degenerated aortic bioprosthesis. Propensity score matching was performed for confounding factors. From July 2005 to April 2021, 911 patients underwent redo-AVR and 411 patients underwent valve-in-valve TAVI. There were 125 pairs for analysis after propensity score matching. The mean age was 75.2±8.5 years. In-hospital mortality was 7.2% (n=9) for redo-AVR versus 0 for valve-in-valve TAVI, p=0.002. Surgical patients suffered more post-operative complications, including intra-aortic balloon pump support (p=0.02), early re-operation (p<0.001), arrhythmias (p<0.001), respiratory and neurological complications (p=0.02 and p=0.03) and multi-organ failure (p=0.01). The valve-in-valve TAVI group had a shorter intensive care unit and hospital stay (p<0.001 for both). However, moderate aortic regurgitation at discharge and higher post-procedural gradients were more common after valve-in-valve TAVI (p<0.001 for both). Survival probabilities in patients who were successfully discharged from the hospital were similar after valve-in-valve TAVI and redo-AVR over the 6-year follow-up (log-rank p=0.26). In elderly patients with a degenerated aortic bioprosthesis, valve-in-valve TAVI provides better early outcomes as opposed to redo-AVR, although there was no difference in mid-term survival in patients successfully discharged from the hospital.

Experimental evidence of size-selective harvest and environmental stochasticity effects on population demography, fluctuations and non-linearity.

Theory and analyses of fisheries data sets indicate that harvesting can alter population structure and destabilise non-linear processes, which increases population fluctuations. We conducted a factorial experiment on the population dynamics of Daphnia magna in relation to size-selective harvesting and stochasticity of food supply. Harvesting and stochasticity treatments both increased population fluctuations. Timeseries analysis indicated that fluctuations in control populations were non-linear, and non-linearity increased substantially in response to harvesting. Both harvesting and stochasticity induced population juvenescence, but harvesting did so via the depletion of adults, whereas stochasticity increased the abundance of juveniles. A fitted fisheries model indicated that harvesting shifted populations towards higher reproductive rates and larger-magnitude damped oscillations that amplify demographic noise. These findings provide experimental evidence that harvesting increases the non-linearity of population fluctuations and that both harvesting and stochasticity increase population variability and juvenescence.

Computer-designed repurposing of chemical wastes into drugs.

As the chemical industry continues to produce considerable quantities of waste chemicals1,2, it is essential to devise 'circular chemistry'3-8 schemes to productively back-convert at least a portion of these unwanted materials into useful products. Despite substantial progress in the degradation of some classes of harmful chemicals9, work on 'closing the circle'-transforming waste substrates into valuable products-remains fragmented and focused on well known areas10-15. Comprehensive analyses of which valuable products are synthesizable from diverse chemical wastes are difficult because even small sets of waste substrates can, within few steps, generate millions of putative products, each synthesizable by multiple routes forming densely connected networks. Tracing all such syntheses and selecting those that also meet criteria of process and 'green' chemistries is, arguably, beyond the cognition of human chemists. Here we show how computers equipped with broad synthetic knowledge can help address this challenge. Using the forward-synthesis Allchemy platform16, we generate giant synthetic networks emanating from approximately 200 waste chemicals recycled on commercial scales, retrieve from these networks tens of thousands of routes leading to approximately 300 important drugs and agrochemicals, and algorithmically rank these syntheses according to the accepted metrics of sustainable chemistry17-19. Several of these routes we validate by experiment, including an industrially realistic demonstration on a 'pharmacy on demand' flow-chemistry platform20. Wide adoption of computerized waste-to-valuable algorithms can accelerate productive reuse of chemicals that would otherwise incur storage or disposal costs, or even pose environmental hazards.

Surgical factors associated with new-onset postoperative atrial fibrillation after lung resection: the EPAFT multicentre study.

PURPOSE OF THE STUDY: Postoperative atrial fibrillation (POAF) is a recognised complication in approximately 10% of major lung resections. In order to best target preoperative treatment, this study aimed at determining the association of incidence of POAF in patients undergoing lung resection to surgical and anatomical factors, such as surgical approach, extent of resection and laterality. STUDY DESIGN: Evaluation of Post-operative Atrial Fibrillation in Thoracic surgery (EPAFT): a multicentre, population-based, retrospective, cross-sectional, observational study including 1367 patients undergoing lung resections between April 2016 and March 2017. The primary outcome was the presence of POAF following resection. POAF was defined as at least one episode of symptomatic or asymptomatic AF confirmed by ECG within 7 days from the thoracic procedure or prior to discharge from the hospital. RESULTS: POAF was observed in 7.4% of patients: 3.1% in minor resection (video-assisted thoracoscopic surgery (VATS): 2.5%; thoracotomy: 3.8%), 9.0% in simple lobectomy (VATS: 7.3%, thoracotomy: 9.9%), 6.0% in complex resection (thoracotomy: 6.3%) and 11.4% in pneumonectomy. POAF was higher in left (4.0%) vs right (2.4%) minor resections, and in left (9.9%) vs right (8.3%) lobectomy, but higher in right (7.5%) complex resections, and the highest in right pneumonectomy (17.6%). No significant variations were observed as per sex, laterality or resected lobes. A positive univariable and multivariable association was observed for increasing age and increasing extent of resection, but not thoracotomy. Median (Q1-Q3) hospital stay was 9 (7-14) days in POAF and 5 (4-7) days in non-AF patients (p<0.001), with an increased cerebrovascular accident burden (p<0.001) and long-term mortality (p<0.001). CONCLUSIONS: Among patients undergoing lung resection, POAF was significantly associated with age, increasing invasiveness of approach and increasing extent of resection. In addition, POAF carried a significant long-term mortality rate and burden of cerebrovascular accident. Appropriate prophylaxis should be targeted at these groups.

Antimicrobial prophylaxis in adult cardiac surgery in the United Kingdom and Republic of Ireland.

BACKGROUND: Deep sternal wound infections are a financially costly complication of cardiac surgery with serious implications for patient morbidity and mortality. Prophylactic antimicrobials have been shown to reduce the incidence of infection significantly. In 2018, the European Association for CardioThoracic Surgery (EACTS) provided clear guidance advising that third-generation cephalosporins are the first-line prophylactic antimicrobial of choice for cardiac surgery via median sternotomy as a result of their broad spectrum of activity and association with reduced postoperative mortality. Despite this guidance, it was believed that UK practice differed from this as a consequence of national concerns surrounding cephalosporins use and Clostridioides difficile infection. METHODS: A survey was developed and distributed to all UK and Republic of Ireland (ROI) cardiac surgery centres in January 2019 to quantify this variation. RESULTS: Of the 38 centres, 34 responded. Variation existed between the antimicrobial agent used, as well as the dosage, frequency and duration of suggested regimens even among centres using the same antimicrobial agent. The most common antimicrobial prophylaxis prescribed was a combination of flucloxacillin and gentamicin (16, 47%). Followed by cefuroxime (6, 17.6%) and cefuroxime combined with a glycopeptide (4, 11.7%). In patients colonised with methicillin-resistant Staphylococcus aureus or those with penicillin allergy gentamicin combined with teicoplanin was most common (42% and 50%, respectively). DISCUSSION: This variation in antimicrobial agents and regimens may well contribute to the varying incidence of surgical site infection seen across the UK and ROI.

Functional genetic diversity in an exploited marine species and its relevance to fisheries management.

The timing of reproduction influences key evolutionary and ecological processes in wild populations. Variation in reproductive timing may be an especially important evolutionary driver in the marine environment, where the high mobility of many species and few physical barriers to migration provide limited opportunities for spatial divergence to arise. Using genomic data collected from spawning aggregations of Pacific herring (Clupea pallasii) across 1600 km of coastline, we show that reproductive timing drives population structure in these pelagic fish. Within a specific spawning season, we observed isolation by distance, indicating that gene flow is also geographically limited over our study area. These results emphasize the importance of considering both seasonal and spatial variation in spawning when delineating management units for herring. On several chromosomes, we detected linkage disequilibrium extending over multiple Mb, suggesting the presence of chromosomal rearrangements. Spawning phenology was highly correlated with polymorphisms in several genes, in particular SYNE2, which influences the development of retinal photoreceptors in vertebrates. SYNE2 is probably within a chromosomal rearrangement in Pacific herring and is also associated with spawn timing in Atlantic herring (Clupea harengus). The observed genetic diversity probably underlies resource waves provided by spawning herring. Given the ecological, economic and cultural significance of herring, our results support that conserving intraspecific genetic diversity is important for maintaining current and future ecosystem processes.

The COVID-19 ibuprofen controversy: A systematic review of NSAIDs in adult acute lower respiratory tract infections.

AIMS: In light of the recent safety concerns relating to NSAID use in COVID-19, we sought to evaluate cardiovascular and respiratory complications in patients taking NSAIDs during acute lower respiratory tract infections. METHODS: We carried out a systematic review of randomised controlled trials and observational studies. Studies of adult patients with short-term NSAID use during acute lower respiratory tract infections, including bacterial and viral infections, were included. Primary outcome was all-cause mortality. Secondary outcomes were cardiovascular, renal and respiratory complications. RESULTS: In total, eight studies including two randomised controlled trials, three retrospective and three prospective observational studies enrolling 44 140 patients were included. Five of the studies were in patients with pneumonia, two in patients with influenza, and one in a patient with acute bronchitis. Meta-analysis was not possible due to significant heterogeneity. There was a trend towards a reduction in mortality and an increase in pleuro-pulmonary complications. However, all studies exhibited high risks of bias, primarily due to lack of adjustment for confounding variables. Cardiovascular outcomes were not reported by any of the included studies. CONCLUSION: In this systematic review of NSAID use during acute lower respiratory tract infections in adults, we found that the existing evidence for mortality, pleuro-pulmonary complications and rates of mechanical ventilation or organ failure is of extremely poor quality, very low certainty and should be interpreted with caution. Mechanistic and clinical studies addressing the captioned subject are urgently needed, especially in relation to COVID-19.

Ultrasound appearance of SURGICEL® Absorbable Hemostat (oxidised cellulose) following laparoscopic resection of a splenic cyst - A potential diagnostic peril.

We present the case of a 14 year old who underwent laparoscopic marsupialisation of a splenic cyst. Postoperative ultrasound demonstrated an echogenic collection in the surgical bed that was initially misdiagnosed as an infected collection/abscess due to its sonographic appearances but was finally correctly identified as haemostatic material that had been packed into the surgical cavity. We subsequently constructed a tissue phantom containing a compressed ball of SURGICEL (r) Absorbable Hemostat and demonstrated that it showed identical sonographic appearances. Haemostatic agents such as oxidised cellulose are often packed within the operative bed to control microvascular haemorrhage. These agents can be observed on a variety of postoperative imaging modalities, in particular ultrasound and computed tomography, and may cause diagnostic error. The critical importance of understanding the details of the surgical procedure and effective communication between the surgical team and ultrasound practitioner is emphasised to minimise the risk of misdiagnosis and unnecessary further imaging and radiological/surgical intervention.

Are Pain and Fatigue in Multiple Myeloma Related to Psychosocial Factors?: A Systematic Review.

BACKGROUND: Fatigue, pain, and psychological distress have been found to be among the most significant quality of life concerns for patients with multiple myeloma. Strong links between these variables have been found in other cancer populations. OBJECTIVE: The aim of this study was to systematically review the research literature on the associations between psychosocial factors and pain and/or fatigue in patients with multiple myeloma. INTERVENTIONS/METHODS: The review followed PRISMA guidelines. A systematic search of 3 databases was conducted. Included studies were appraised for risk of bias. Data were extracted and combined in a narrative synthesis. RESULTS: The review identified 11 studies for inclusion, reporting data from a total of 2432 participants. It found consistent evidence of a medium-sized relationship between both global distress and depression on the one hand and pain and fatigue on the other. The included studies were highly varied in the psychosocial factors they investigated. CONCLUSIONS: There is good evidence that pain and fatigue are related to global distress and depression in patients with multiple myeloma. The evidence on relationships with other psychosocial factors is inconclusive. Research investigating the role of more specific psychosocial processes is called for. IMPLICATIONS FOR PRACTICE: Assessment of pain and fatigue in patients with multiple myeloma should routinely include screening for psychological distress. Interventions for psychological distress may be considered as adjuvant intervention strategies for pain and fatigue in patients with multiple myeloma.

A robotic platform for flow synthesis of organic compounds informed by AI planning.

The synthesis of complex organic molecules requires several stages, from ideation to execution, that require time and effort investment from expert chemists. Here, we report a step toward a paradigm of chemical synthesis that relieves chemists from routine tasks, combining artificial intelligence-driven synthesis planning and a robotically controlled experimental platform. Synthetic routes are proposed through generalization of millions of published chemical reactions and validated in silico to maximize their likelihood of success. Additional implementation details are determined by expert chemists and recorded in reusable recipe files, which are executed by a modular continuous-flow platform that is automatically reconfigured by a robotic arm to set up the required unit operations and carry out the reaction. This strategy for computer-augmented chemical synthesis is demonstrated for 15 drug or drug-like substances.

A graph-convolutional neural network model for the prediction of chemical reactivity.

We present a supervised learning approach to predict the products of organic reactions given their reactants, reagents, and solvent(s). The prediction task is factored into two stages comparable to manual expert approaches: considering possible sites of reactivity and evaluating their relative likelihoods. By training on hundreds of thousands of reaction precedents covering a broad range of reaction types from the patent literature, the neural model makes informed predictions of chemical reactivity. The model predicts the major product correctly over 85% of the time requiring around 100 ms per example, a significantly higher accuracy than achieved by previous machine learning approaches, and performs on par with expert chemists with years of formal training. We gain additional insight into predictions via the design of the neural model, revealing an understanding of chemistry qualitatively consistent with manual approaches.

Transapical valve-in-ring mitral valve implantation through the anterior mitral valve leaflet.

Transcatheter mitral valve implantation (TMVI) is a relatively novel intervention used to replace the mitral valve of individuals deemed too high risk or unsuitable for surgery. It is associated with a number of specific risks, including left ventricular outflow tract obstruction (LVOTO).  In this video tutorial we present the case of a 75-year-old man who was unable to undergo redo surgical repair and had a number of risk factors for LVOTO. To minimize these risks, we deployed the TMVI within the anterior mitral valve leaflet. The postoperative result was mild mitral valve regurgitation and no LVOTO.  The long-term outcome of this approach is yet to be determined but we believe this technique offers a novel method to manage a select group of patients suffering with mitral valve disease and at risk of LVOTO.

Transapical valve-in-ring mitral valve implantation through the anterior mitral valve leaflet.

Transcatheter mitral valve implantation is a relatively novel intervention that replaces the mitral valve of individuals deemed too high-risk or unsuitable for surgery. It is associated with a number of specific risks, including left ventricular outflow tract obstruction. In this report, we present the case of a 75-year-old man who was unable to undergo redo surgical repair and had a number of risk factors for left ventricular outflow tract obstruction. To minimize this risk, we deployed transcatheter mitral valve implantation within the anterior mitral valve leaflet resulting in mild mitral valve regurgitation postoperatively and no left ventricular outflow tract obstruction. Long-term durability of this approach is yet to be determined, but we believe that this intervention adds to the armamentarium of the heart team.

Collapse, Tipping Points, and Spatial Demographic Structure Arising from the Adopted Migrant Life History.

The roles of dispersal and recruitment have long been a focal point in ecology and conservation. The adopted migrant hypothesis proposes a life history in which social learning transmits migratory knowledge between generations of iteroparous fish. Specifically, juveniles disperse from the parental spawning site, encounter and recruit to a local adult population, and learn migration routes between spawning and foraging habitats by following older, experienced fish. Although the adopted migrant life history may apply to many species of pelagic marine fishes, there is scant theoretical or empirical work on the consequent population dynamics. We developed and analyzed a mathematical model of this life history in which the recruitment of juveniles depends on the relative abundance of the local populations and recruitment overlap, which measures the ease with which juveniles are recruited by a nonparental population. We demonstrate that the adopted migrant life history can maintain spatial demographic structure among local populations, that it can also predispose local populations to collapse when a tipping point is crossed, and that recovery after collapse is impaired by reduced recruitment at small local population sizes.

SCScore: Synthetic Complexity Learned from a Reaction Corpus.

Several definitions of molecular complexity exist to facilitate prioritization of lead compounds, to identify diversity-inducing and complexifying reactions, and to guide retrosynthetic searches. In this work, we focus on synthetic complexity and reformalize its definition to correlate with the expected number of reaction steps required to produce a target molecule, with implicit knowledge about what compounds are reasonable starting materials. We train a neural network model on 12 million reactions from the Reaxys database to impose a pairwise inequality constraint enforcing the premise of this definition: that on average, the products of published chemical reactions should be more synthetically complex than their corresponding reactants. The learned metric (SCScore) exhibits highly desirable nonlinear behavior, particularly in recognizing increases in synthetic complexity throughout a number of linear synthetic routes.

The impact of enhanced recovery after surgery (ERAS) protocol compliance on morbidity from resection for primary lung cancer.

OBJECTIVE: The adoption of Enhanced Recovery After Surgery programs in thoracic surgery is relatively recent with limited outcome data. This study aimed to determine the impact of an Enhanced Recovery After Surgery pathway on morbidity and length of stay in patients undergoing lung resection for primary lung cancer. METHODS: This prospective cohort study collected data on consecutive patients undergoing lung resection for primary lung cancer between April 2012 and June 2014 at a regional referral center in the United Kingdom. All patients followed a standardized, 15-element Enhanced Recovery After Surgery protocol. Key data fields included protocol compliance with individual elements, pathophysiology, and operative factors. Thirty-day morbidity was taken as the primary outcome measure and classified a priori according to the Clavien-Dindo system. Logistic regression models were devised to identify independent risk factors for morbidity and length of stay. RESULTS: A total of 422 consecutive patients underwent lung resection over a 2-year period, of whom 302 (71.6%) underwent video-assisted thoracoscopic surgery. Lobectomy was performed in 297 patients (70.4%). Complications were experienced by 159 patients (37.6%). The median length of stay was 5 days (range, 1-67), and 6 patients (1.4%) died within 30 days of surgery. There was a significant inverse relationship between protocol compliance and morbidity after adjustment for confounding factors (odds ratio, 0.72; 95% confidence interval, 0.57-0.91; P < .01). Age, lobectomy or pneumonectomy, more than 1 resection, and delayed mobilization were independent predictors of morbidity. Age, lack of preoperative carbohydrate drinks, planned high dependency unit/intensive therapy unit admission, delayed mobilization, and open approach were independent predictors of delayed discharge (length of stay >5 days). CONCLUSIONS: Increased compliance with an Enhanced Recovery After Surgery pathway is associated with improved clinical outcomes after resection for primary lung cancer. Several elements, including early mobilization, appear to be more influential than others.

Osteonecrosis of the Jaw and Rebound Hypercalcemia in Young People Treated With Denosumab for Giant Cell Tumor of Bone.

Context: Denosumab, an inhibitor of receptor activator of nuclear factor κ-B ligand, is an approved treatment of giant cell tumor of bone (GCTB) in adults and "skeletally mature" adolescents. Safety concerns include oversuppression of bone remodelling, with risk of osteonecrosis of the jaw (ONJ) and atypical femur fractures during treatment in adults and rebound hypercalcemia after treatment cessation in children. To date, ONJ has never been reported in children or adolescents. Objectives: To describe serious adverse effects during and following high-dose denosumab therapy in GCTB patients. Patients: Two adolescents (14 and 15 years) and a young adult (40 years) received fixed-dose denosumab for GCTB for 1.3 to 4 years (cumulative dose, 47 to 98 mg/kg), which was stopped because of development of ONJ in one adolescent and bilateral femoral cortical stress reactions in the young adult. All three patients developed rebound hypercalcemia with acute kidney injury 5.5 to 7 months after denosumab cessation. Results: The ONJ necessitated surgical debridement. Rebound hypercalcemia (serum calcium, 3.1 to 4.3 mmol/L) was unresponsive to hyperhydration alone, requiring repeated doses of calcitonin or intravenous bisphosphonate treatment. Hypercalcemia recurred in two patients within 4 weeks, with normal serum calcium profiles thereafter. All patients were naive to chemotherapy, radiotherapy, bisphosphonates, and corticosteroids and were metastases free, confirming the causative role of denosumab in these complications. Conclusion: These suppression-release effects of high-dose denosumab on bone remodeling raise questions about safety of fixed dosing and treatment duration. In young people, weight-adjusted dosing and safety monitoring during and after antiresorptive therapy is required.