University of Cambridge

Objective: Cribra orbitalia is believed to be a skeletal indicator of chronic anaemia, scurvy, rickets or related metabolic diseases. It has been suggested that it may be used as a proxy indicator for intestinal parasite infection, as parasites often cause anaemia today. Our aim is to investigate this association in the medieval population of Cambridge, UK. Materials: Individuals excavated from the cemeteries of the Augustinian friary and All Saints by the Castle parish church, and aged from 7 to adulthood. Methods: We undertook parasite analysis of the pelvic sediment and control samples of 46 burials with intact orbital roofs. Results: Human roundworm (Ascaris lumbricoides) and/or whipworm (Trichuris trichiura) were identified in the pelvic sediment of 22 individuals, and cribra orbitalia noted in 11 individuals. Barnards test showed no association between parasite infection and cribra orbitalia (p = .882). Conclusion: We found no association between infection and cribra orbitalia infection in this medieval adult population, calling into question this hypothesis, at least for adults. Significance: High or low cribra orbitalia prevalence in adults should not be used to infer rates of intestinal parasite infection. Limitations: The individuals in the study were over the age of 7, with no younger children. It is possible that only parasites which cause marked anaemia (such as hookworm, schistosomiasis or malaria) may cause cribra orbitalia, while less marked anaemia from roundworm and whipworm may not do so. Suggestions for Further Research: Repeating this study in younger children, when most cribra orbitalia appears to form.

Background: Improving Access to Psychological Therapies (IAPT) services address anxiety and depression in primary care, with psychotic disorders typically excluded. Our previous research found 1 in 4 patients report distressing psychotic experiences (PE) alongside common mental disorders, yet little is known about their clinical presentation and impact on recovery. Methods: We used the Community Assessment of Psychic Experiences - Positive Scale (CAPE-P15) to assess the clinical presentation and symptomatic profile of PE within IAPT settings across three National Health Service (NHS) trusts, serving a diverse population in Southern England. We identified different classes based on the reported PE frequencies using latent class analysis. Results: A total of 2,042 IAPT patients completed the CAPE-P15. The mean age was 39.8 (± 15.3) years. We identified five distinct classes of symptom profiles, findings that PE were common, especially self-referential and persecutory ideas. Prevalence and intensity increased across classes, extending to bizarre experiences and perceptual abnormalities in the fifth and least common class. Perceptual abnormalities were a strong indicator of symptom severity, with patients being the least likely to achieve recovery by the end of treatment. Limitations: Data were collected during a service evaluation. Replication of these findings across other IAPT services could prove beneficial. We did not collect information on negative PE. Conclusions: Patients seeking treatment for anxiety and depression in primary care commonly experience a wide range of positive PE. Self-referential and persecutory ideation were prevalent; perceptual abnormalities were infrequent. Providing information about prevalence and tailoring therapy may help reduce patient distress.

Achieving glass‐like ultra‐low thermal conductivity in crystalline solids with high electrical conductivity, a crucial requirement for high‐performance thermoelectric energy conversion, continues to be a formidable challenge. A careful balance between electrical and thermal transport is essential for optimizing the thermoelectric performance of a material. Despite this inherent trade‐off, the experimental realization of an ideal thermoelectric material with a “phonon‐glass electron‐crystal” (PGEC) nature has rarely been achieved. Here, we have demonstrated PGEC‐like AgSbTe 2 by tuning the atomic disorder upon Yb doping, which resulted in an outstanding thermoelectric performance with figure of merit, zT∼2.4 at 573 K. Yb‐doping induced enhanced atomic ordering decreases the overlap between the hole and phonon mean free paths and consequently leads to a PGEC‐like transport behaviour in AgSbTe 2 . We observed a two‐fold increase in electrical mobility while keeping the position of the Fermi level (E F ) nearly unchanged, which significantly increased the electrical conductivity and corroborates the enhanced crystalline nature of the AgSbTe 2 lattice upon Yb doping for electrical transport. The cation‐ordered domains, on the other hand, lead to the formation of nanoscale superstructures (∼ 2 to 4 nm) that strongly scatter heat carrying phonons, resulting in a temperature‐independent glass‐like thermal conductivity. Furthermore, we have achieved a promising output power density of 388 mWcm ⁻² in a 4‐leg device fabricated using 4 mol% Yb‐doped AgSbTe 2 as the p ‐type analogue. Our strategy paves the way for realizing high thermoelectric performance in various disordered crystals by making them amorphous to phonons while favoring crystal‐like electrical transport. This article is protected by copyright. All rights reserved

To survive, many pathogens extract heme from their host organism and break down the porphyrin scaffold to sequester the Fe ²⁺ ion via a heme oxygenase. Recent studies have revealed that...

Cancer cells adapt and survive through the acquisition and selection of molecular modifications. This process defines cancer evolution. Building on a theoretical framework based on heritable genetic changes has provided insights into the mechanisms supporting cancer evolution. However, cancer hallmarks also emerge via heritable nongenetic mechanisms, including epigenetic and chromatin topological changes, and interactions between tumor cells and the tumor microenvironment. Recent findings on tumor evolutionary mechanisms draw a multifaceted picture where heterogeneous forces interact and influence each other while shaping tumor progression. A comprehensive characterization of the cancer evolutionary toolkit is required to improve personalized medicine and biomarker discovery. Significance Tumor evolution is fueled by multiple enabling mechanisms. Importantly, genetic instability, epigenetic reprogramming, and interactions with the tumor microenvironment are neither alternative nor independent evolutionary mechanisms. As demonstrated by findings highlighted in this perspective, experimental and theoretical approaches must account for multiple evolutionary mechanisms and their interactions to ultimately understand, predict, and steer tumor evolution.

Andrew Wyllie graduated from the University of Aberdeen, becoming an academic pathologist in Aberdeen, Edinburgh and Cambridge. He was the co-discoverer of apoptotic cell death, having observed single cells dying following carcinogen exposure. Together with Alastair Currie and John Kerr, he realized the profound importance of this novel mode of cell death that showed a distinctive series of morphological changes, which he first described as a new cell death process. Wyllie and Currie introduced the term ‘apoptosis’ for this cell death process in a seminal paper in 1972. Another landmark discovery was of chromatin fragmentation in apoptosis, due to activation of an endogenous endonuclease that caused internucleosomal DNA cleavage (‘chromatin laddering’), which was the first biochemical mechanism of apoptosis described. He further characterized chromatin fragmentation in the 1980s, followed by investigations of cell surface changes to produce ‘eat-me’ signals to trigger rapid phagocytosis of the apoptotic cells and bodies, intracellular calcium ion signalling, caspase activation and other mechanisms of apoptosis. His cancer research helped identify the location of APC and generated his demonstration that apoptosis was regulated by oncogenes MYC and RAS and by tumour suppressor genes, such as TP53 . He showed how apoptosis occurred in response to DNA damage and was a key process influencing both carcinogenesis and tumour growth. Andrew made a major scientific observation that changed the understanding of how cells die in health and disease, although it took time for the scientific establishment to understand its fundamental importance. Andrew Wyllie is widely known as the ‘Father of Apoptosis’.

The paper examines pre-combustion carbon capture technology (PreCCS) for liquefied natural gas (LNG) propelled shipping from thermodynamics and energy efficiency perspectives. Various types of LNG reformers and CCS units are considered. The steam methane reformer (SMR) was found to be 20% more energy efficient than autothermal (ATR) and methane pyrolysis (MPR) reactors. Pressure swing adsorption (PSA) had a lower energy requirement than membrane separation (MEM), cryogenic separation (CS), and amine absorption (AA) in pre-combustion carbon capture, with PSA needing 0.18 kWh/kg CO2. An integrated system combining SMR and PSA was proposed using waste heat recovery (WHR) from the engine, assuming similar efficiency for LNG and H2 operation, and cooling and liquefying of the CO2 by the LNG. The SMR-PSA system without WHR had an overall efficiency of 33.4% (defined as work at the propeller divided by the total LNG energy consumption). This was improved to 41.7% with WHR and gave a 65% CO2 emission reduction. For a higher CO2 reduction, CCS from the SMR heater could additionally be employed, giving a maximum CO2 removal rate of 86.2% with 39% overall energy efficiency. By comparison, an amine-based post-engine CCS system without reforming could reach similar CO2 removal rates but with 36.6% overall efficiency. The advantages and disadvantages and technology readiness level of PreCCS for onboard operation are discussed. This study offers evidence that pre-combustion CCS can be a serious contender for maritime propulsion decarbonization. Graphical Abstract

Schizophrenia (SZ) is a prevalent mental disorder characterized by cognitive, emotional, and behavioral changes. Symptoms of SZ include hallucinations, illusions, delusions, lack of motivation, and difficulties in concentration. While the exact causes of SZ remain unproven, factors such as brain injuries, stress, and psychotropic drugs have been implicated in its development. SZ can be classified into different types, including paranoid, disorganized, catatonic, undifferentiated, and residual. Diagnosing SZ involves employing various tools, including clinical interviews, physical examinations, psychological evaluations, the Diagnostic and Statistical Manual of Mental Disorders (DSM), and neuroimaging techniques. Electroencephalography (EEG) recording is a significant functional neuroimaging modality that provides valuable insights into brain function during SZ. However, EEG signal analysis poses challenges for neurologists and scientists due to the presence of artifacts, long-term recordings, and the utilization of multiple channels. To address these challenges, researchers have introduced artificial intelligence (AI) techniques, encompassing conventional machine learning (ML) and deep learning (DL) methods, to aid in SZ diagnosis. This study reviews papers focused on SZ diagnosis utilizing EEG signals and AI methods. The introduction section provides a comprehensive explanation of SZ diagnosis methods and intervention techniques. Subsequently, review papers in this field are discussed, followed by an introduction to the AI methods employed for SZ diagnosis and a summary of relevant papers presented in tabular form. Additionally, this study reports on the most significant challenges encountered in SZ diagnosis, as identified through a review of papers in this field. Future directions to overcome these challenges are also addressed. The discussion section examines the specific details of each paper, culminating in the presentation of conclusions and findings.

Background We explored the relationships between sarcopenia (SP), osteoporosis (OP), obesity (OB), (alone and in combination) with physical frailty (PF) in a multi-ethnic, population-based study of Asians aged ≥ 60 years. Methods Participants were enrolled from the PopulatION HEalth and Eye Disease PRofile in Elderly Singaporeans Study (PIONEER) study. PF was defined using the modified Fried phenotype; SP using the Asian Working Group for Sarcopenia 2019; OP using bone mineral density scores; and OB using the fat mass index. Modified Poisson regression models investigated the associations between exposures and PF, and the relative excess rates of PF due to interactions (RERI) to determine synergistic or antagonistic interactions. Results Of the 2643 participants, 54.8% was female; and 49.8%, 25.1%, 25.0% were Chinese, Indians, and Malays, respectively. 25%, 19.0% and 6.7% participants had OB only, SP only, and OP only, respectively. A total of 356 (17.5%), 151 (7.4%) and 97 (4.8%) had osteosarcopenia (OSP), sarcopenic obesity (SOB) and osteo-obesity (OOB), respectively; while 70 (3.5%) had all 3 morbid conditions (osteosarcopenic obesity, OSO). Both SP only and OB only were strongly associated with increased rates of PF (RR: 2.53, 95% CI: 1.95, 3.29; RR: 2.05, 95% CI: 1.58, 2.66 respectively); but not OP. Those with OSP, OOB and SOB were also associated with high risks of PF (RR: 2.82, 95% CI: 2.16, 3.68; RR: 2.34, 95% CI: 1.69, 3.23; and RR: 2.58, 95% CI: 1.95, 3.41, respectively) compared to robust individuals. Critically, individuals with OSO had the highest relative risk of having PF (RR: 3.06, CI: 2.28, 4.11). Only the sarcopenia-obesity interaction was significant, demonstrating negative synergism (antagonism). The concurrent presence of SP and OB was associated with a 100% lower rate of PF compared to the sum of the relatively rates of SP only and OB only. Conclusion The prevalence of SP, OB and OP, alone and combined, is substantial in older Asians and their early identification is needed to mitigate the risk of frailty. OB may interact with SP in an antagonistic manner to moderate rates of frailty. Further longitudinal studies are needed to address causality and mechanistic underpinnings our findings.

Whirling topological textures play a key role in exotic phases of magnetic materials and are promising for logic and memory applications. In antiferromagnets, these textures exhibit enhanced stability and faster dynamics with respect to their ferromagnetic counterparts, but they are also difficult to study due to their vanishing net magnetic moment. One technique that meets the demand of highly sensitive vectorial magnetic field sensing with negligible backaction is diamond quantum magnetometry. Here we show that an archetypal antiferromagnet—haematite—hosts a rich tapestry of monopolar, dipolar and quadrupolar emergent magnetic charge distributions. The direct read-out of the previously inaccessible vorticity of an antiferromagnetic spin texture provides the crucial connection to its magnetic charge through a duality relation. Our work defines a paradigmatic class of magnetic systems to explore two-dimensional monopolar physics, and highlights the transformative role that diamond quantum magnetometry could play in exploring emergent phenomena in quantum materials.

Empirical evidence suggests fishes meet the criteria for experiencing pain beyond a reasonable doubt and zebrafish are being increasingly used in studies of pain and nociception. Zebrafish are adopted across a wide range of experimental fields and their use is growing particularly in biomedical studies. Many laboratory procedures in zebrafish involve tissue damage and this may give rise to pain. Therefore, this FELASA Working Group reviewed the evidence for pain in zebrafish, the indicators used to assess pain and the impact of a range of drugs with pain-relieving properties. We report that there are several behavioural indicators that can be used to determine pain, including reduced activity, space use and distance travelled. Pain-relieving drugs prevent these responses, and we highlight the dose and administration route. To minimise or avoid pain, several refinements are suggested for common laboratory procedures. Finally, practical suggestions are made for the management and alleviation of pain in laboratory zebrafish, including recommendations for analgesia. Pain management is an important refinement in experimental animal use and so our report has the potential to improve zebrafish welfare during and after invasive procedures in laboratories across the globe.

BACKGROUND Classification of perioperative risk is important for patient care, resource allocation, and guiding shared decision-making. Using discriminative features from the electronic health record (EHR), machine-learning algorithms can create digital phenotypes among heterogenous populations, representing distinct patient subpopulations grouped by shared characteristics, from which we can personalize care, anticipate clinical care trajectories, and explore therapies. We hypothesized that digital phenotypes in preoperative settings are associated with postoperative adverse events including in-hospital and 30-day mortality, 30-day surgical redo, intensive care unit (ICU) admission, and hospital length of stay (LOS). METHODS We identified all laminectomies, colectomies, and thoracic surgeries performed over a 9-year period from a large hospital system. Seventy-seven readily extractable preoperative features were first selected from clinical consensus, including demographics, medical history, and lab results. Three surgery-specific datasets were built and split into derivation and validation cohorts using chronological occurrence. Consensus k -means clustering was performed independently on each derivation cohort, from which phenotypes’ characteristics were explored. Cluster assignments were used to train a random forest model to assign patient phenotypes in validation cohorts. We reconducted descriptive analyses on validation cohorts to confirm the similarity of patient characteristics with derivation cohorts, and quantified the association of each phenotype with postoperative adverse events by using the area under receiver operating characteristic curve (AUROC). We compared our approach to American Society of Anesthesiologists (ASA) alone and investigated a combination of our phenotypes with the ASA score. RESULTS A total of 7251 patients met inclusion criteria, of which 2770 were held out in a validation dataset based on chronological occurrence. Using segmentation metrics and clinical consensus, 3 distinct phenotypes were created for each surgery. The main features used for segmentation included urgency of the procedure, preoperative LOS, age, and comorbidities. The most relevant characteristics varied for each of the 3 surgeries. Low-risk phenotype alpha was the most common (2039 of 2770, 74%), while high-risk phenotype gamma was the rarest (302 of 2770, 11%). Adverse outcomes progressively increased from phenotypes alpha to gamma, including 30-day mortality (0.3%, 2.1%, and 6.0%, respectively), in-hospital mortality (0.2%, 2.3%, and 7.3%), and prolonged hospital LOS (3.4%, 22.1%, and 25.8%). When combined with the ASA score, digital phenotypes achieved higher AUROC than the ASA score alone (hospital mortality: 0.91 vs 0.84; prolonged hospitalization: 0.80 vs 0.71). CONCLUSIONS For 3 frequently performed surgeries, we identified 3 digital phenotypes. The typical profiles of each phenotype were described and could be used to anticipate adverse postoperative events.

Argininosuccinate lyase (ASL) is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide (NO) biosynthesis cycle. Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide 123I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal 123I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorder with cell-autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy.

Law, like medicine, is a practiced discipline, and the practice of international law is no exception. There are different contexts in which that practice unfolds. Here, our focus is on: (1) a specific form of practice, that of “advocates,” understood widely to include counsel advising or representing a party in legal proceedings, diplomats supporting a policy directive, and civil society activists advocating for legal causes; (2) engaging in different forms of legal advocacy, which can be organized analytically under three headings: legal advice and representation, diplomacy, and campaigning; and (3) in a specific context, that of advisory opinions and, more specifically, in the conception of requests for advisory opinions. Such requests are subject to different requirements according to the institutional setting through which they are channeled, but the most prominent and complex setting is that of requests for advisory opinions by the UN General Assembly to the International Court of Justice (ICJ). This is the setting we will refer to in our essay.