Sex differences in plasma clozapine and norclozapine concentrations in clinical practice and in relation to body mass index and plasma glucose concentrations: a retrospective survey

Background Clozapine is widely prescribed and, although effective, can cause weight gain and dysglycemia. The dysmetabolic effects of clozapine are thought to be more prevalent in women with this gender on average attaining 17 % higher plasma clozapine concentrations than men. Methods We investigated the relationship between dose, body mass index (BMI), plasma glucose concentration, and plasma clozapine and N-desmethylclozapine (norclozapine) concentrations in 100 individuals with a severe enduring mental illness. Results Mean (10th/90th percentile) plasma clozapine concentrations were higher for women [0.49 (0.27–0.79) mg/L] compared with men [0.44 (0.26–0.70) mg/L] (F = 2.2; p = 0.035). There was no significant gender difference in the prescribed clozapine dose. BMI was significantly higher in women [mean (95 % CI) = 34.5 (26.0–45.3)] for females compared with 32.5 (25.2–41.0) for males. Overall, BMI increased by 0.7 kg/m 2 over a mean follow-up period of 210 days. A lower proportion, 41 % of women had a fasting blood glucose ≤6.0 mmol/L (<6.0 mmol/L is defined by the International Diabetes Federation as normal glucose handling), compared with 88 % of men (χ2  = 18.6, p < 0.0001). Conclusions We have shown that mean BMI and blood glucose concentrations are higher in women prescribed clozapine than in men. Women also tended to attain higher plasma clozapine concentrations than men. The higher BMI and blood glucose in women may relate to higher tissue exposure to clozapine, as a consequence of sex differences in drug metabolism

The perception and management of risk in UK office property development

Risk is an ever-present aspect of business, and risk taking is necessary for profit and economic progress. Speculative property development is popularly perceived as a 'risky business' yet, like other entrepreneurs, developers have opportunities to manage the risks they face; techniques include phasing and joint ventures. The associated areas of investment portfolio risk, development risk analysis and construction risk management have all been addressed by research. This article presents new knowledge about how developers perceive risks and the means they subsequently adopt to manage them. The developers of office projects across the UK were sent questionnaires by post. Respondents were asked about their perceptions of risks at the first appraisal stage and currently and about the risk management techniques that they had adopted. In-depth interviews with a selection of respondents were then used to discuss and augment the findings. Developers were most concerned about market-based risks at both stages. Concern about production-orientated risks was lower and fell significantly between the two stages. A fixed price contract was the most common risk management technique. Risk management techniques were used more often outside London and the South East. Developer type affects both the perception and management of risk. While developers do manage risk, decisions are made on the basis of professional and business experience. These findings should help development companies manage risk in a more objective and analytical way

Multifocal osteoclast-rich tumour in Paget bone disease and conventional giant cell tumour, two genetically distinct entities? Sequencing from a single case

Paget disease of bone is a metabolic disorder with a strong genetic component, characterised by pronounced disorganised bone remodelling. Complications of this disease include an increased risk of developing bone neoplasms. Here, we describe the case of a 60-year-old Italian patient with Paget disease of bone, presenting with an osteoclast-rich tumour. Our analysis of this entity, based on the clinical, morphological and genetic data (whole exome sequencing), suggests that osteoclast-rich lesions in Paget disease of bone are genetically distinct from classical giant cell tumour of bone. We discuss the importance of differentiating these osteoclast-rich lesions

Type Inference for Deadlock Detection in a Multithreaded Polymorphic Typed Assembly Language

We previously developed a polymorphic type system and a type checker for a multithreaded lock-based polymorphic typed assembly language (MIL) that ensures that well-typed programs do not encounter race conditions. This paper extends such work by taking into consideration deadlocks. The extended type system verifies that locks are acquired in the proper order. Towards this end we require a language with annotations that specify the locking order. Rather than asking the programmer (or the compiler's backend) to specifically annotate each newly introduced lock, we present an algorithm to infer the annotations. The result is a type checker whose input language is non-decorated as before, but that further checks that programs are exempt from deadlocks

Brown Tumors Belong to the Spectrum of KRAS-driven Neoplasms

Brown tumors are rare and generally self-limiting mass lesions of bone occurring in the context of hyperparathyroidism. Although commonly regarded as endocrine-driven tumor-like lesions, we detected pathogenic hotspot KRAS mutations in 10/16 brown tumors (62%) with similar frequencies found in cases affecting the peripheral and axial skeleton. Pathogenic mutations in other driver genes of the RAS-MAPK pathway were not identified. Our findings suggest brown tumors to represent true neoplasms driven by the activation of the RAS-MAPK signaling pathway. The frequent regression of brown tumors after normalization of hyperparathyroidism points to a second hit mediated by endocrine stimulation to be required for tumor development. Our findings underline the pathogenic relation of brown tumors to nonossifying fibroma and giant cell granuloma of the jaws which both appear histologically similar to brown tumors and are also driven by RAS-MAPK signaling pathway activation

Quantum inequalities and `quantum interest' as eigenvalue problems

Quantum inequalities (QI's) provide lower bounds on the averaged energy density of a quantum field. We show how the QI's for massless scalar fields in even dimensional Minkowski space may be reformulated in terms of the positivity of a certain self-adjoint operator - a generalised Schroedinger operator with the energy density as the potential - and hence as an eigenvalue problem. We use this idea to verify that the energy density produced by a moving mirror in two dimensions is compatible with the QI's for a large class of mirror trajectories. In addition, we apply this viewpoint to the `quantum interest conjecture' of Ford and Roman, which asserts that the positive part of an energy density always overcompensates for any negative components. For various simple models in two and four dimensions we obtain the best possible bounds on the `quantum interest rate' and on the maximum delay between a negative pulse and a compensating positive pulse. Perhaps surprisingly, we find that - in four dimensions - it is impossible for a positive delta-function pulse of any magnitude to compensate for a negative delta-function pulse, no matter how close together they occur.Comment: 18 pages, RevTeX. One new result added; typos fixed. To appear in Phys. Rev.

Quantum interest in two dimensions

The quantum interest conjecture of Ford and Roman asserts that any negative-energy pulse must necessarily be followed by an over-compensating positive-energy one within a certain maximum time delay. Furthermore, the minimum amount of over-compensation increases with the separation between the pulses. In this paper, we first study the case of a negative-energy square pulse followed by a positive-energy one for a minimally coupled, massless scalar field in two-dimensional Minkowski space. We obtain explicit expressions for the maximum time delay and the amount of over-compensation needed, using a previously developed eigenvalue approach. These results are then used to give a proof of the quantum interest conjecture for massless scalar fields in two dimensions, valid for general energy distributions.Comment: 17 pages, 4 figures; final version to appear in PR

Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease

Maple syrup urine disease (MSUD) is an inherited disorder of branched-chain amino acid metabolism presenting with lifethreatening cerebral oedema and dysmyelination in affected individuals. Treatment requires life-long dietary restriction and monitoring of branched-chain amino acids to avoid brain injury. Despite careful management, children commonly suffer metabolic decompensation in the context of catabolic stress associated with non-specific illness. The mechanisms underlying this decompensation and brain injury are poorly understood. Using recently developed mouse models of classic and intermediate maple syrup urine disease, we assessed biochemical, behavioural and neuropathological changes that occurred during encephalopathy in these mice. Here, we show that rapid brain leucine accumulation displaces other essential amino acids resulting in neurotransmitter depletion and disruption of normal brain growth and development. A novel approach of administering norleucine to heterozygous mothers of classic maple syrup urine disease pups reduced branched-chain amino acid accumulation in milk as well as blood and brain of these pups to enhance survival. Similarly, norleucine substantially delayed encephalopathy in intermediate maple syrup urine disease mice placed on a high protein diet that mimics the catabolic stress shown to cause encephalopathy in human maple syrup urine disease. Current findings suggest two converging mechanisms of brain injury in maple syrup urine disease including: (i) neurotransmitter deficiencies and growth restriction associated with branchedchain amino acid accumulation and (ii) energy deprivation through Krebs cycle disruption associated with branched-chain ketoacid accumulation. Both classic and intermediate models appear to be useful to study the mechanism of brain injury and potential treatment strategies for maple syrup urine disease. Norleucine should be further tested as a potential treatment to prevent encephalopathy in children with maple syrup urine disease during catabolic stress

Subclassification of epithelioid sarcoma with potential therapeutic impact

Epithelioid sarcoma is a rare and aggressive mesenchymal tumour, the genetic hallmark of which is the loss of expression of SMARCB1, a key member of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodelling complex. Hampered by its rarity, epithelioid sarcoma has received little research attention and therapeutic options for this disease remain limited. SMARCB1-deficient tumours also include malignant rhabdoid tumour, atypical teratoid and rhabdoid tumour, epithelioid malignant peripheral nerve sheath tumour, and poorly differentiated chordoma. Histologically, it can be challenging to distinguish epithelioid sarcoma from malignant rhabdoid tumour and other SMARCB1-deficient tumours, whereas methylation profiling shows that they represent distinct entities and facilitates their classification. Methylation studies on SMARCB1-deficient tumours, although not including epithelioid sarcomas, reported methylation subgroups which resulted in new clinical stratification and therapeutic approaches. In addition, emerging evidence indicates that immunotherapy, including immune checkpoint inhibitors, represents a promising therapeutic strategy for SMARCB1-deficient tumours. Here, we show that some epithelioid sarcomas share methylation patterns of malignant rhabdoid tumours indicating that this could help to distinguish these entities and guide treatment. Using gene expression data, we also showed that the immune environment of epithelioid sarcoma is characterised by a predominance of CD8+ lymphocytes and M2 macrophages. These findings have potential implications for the management of patients with epithelioid sarcoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Coadministration of Anti-Viral Monoclonal Antibodies With Routine Pediatric Vaccines and Implications for Nirsevimab Use: A White Paper

Routine childhood vaccinations are key for the protection of children from a variety of serious and potentially fatal diseases. Current pediatric vaccine schedules mainly cover active vaccines. Active vaccination in infants is a highly effective approach against several infectious diseases; however, thus far, for some important viral pathogens, including respiratory syncytial virus (RSV), vaccine development and license by healthcare authorities have not been accomplished. Nirsevimab is a human-derived, highly potent monoclonal antibody (mAb) with an extended half-life for RSV prophylaxis in all infants. In this manuscript, we consider the potential implications for the introduction of an anti-viral mAb, such as nirsevimab, into the routine pediatric vaccine schedule, as well as considerations for coadministration. Specifically, we present evidence on the general mechanism of action of anti-viral mAbs and experience with palivizumab, the only approved mAb for the prevention of RSV infection in preterm infants, infants with chronic lung disease of prematurity and certain infants with hemodynamically significant heart disease. Palivizumab has been used for over two decades in infants who also receive routine vaccinations without any alerts concerning the safety and efficacy of coadministration. Immunization guidelines (Advisory Committee on Immunization Practices, Joint Committee on Vaccination and Immunization, National Advisory Committee on Immunization, Centers for Disease Control and Prevention, American Academy of Pediatrics, The Association of the Scientific Medical Societies in Germany) support coadministration of palivizumab with routine pediatric vaccines, noting that immunobiologics, such as palivizumab, do not interfere with the immune response to licensed live or inactivated active vaccines. Based on the mechanism of action of the new generation of anti-viral mAbs, such as nirsevimab, which is highly specific targeting viral antigenic sites, it is unlikely that it could interfere with the immune response to other vaccines. Taken together, we anticipate that nirsevimab could be concomitantly administered to infants with routine pediatric vaccines during the same clinic visit