Multimorbidity patterns and risk of hospitalisation in children: A population cohort study of 3.6 million children in England, with illustrative examples from childhood cancer survivors

Background: Population-level estimates of hospitalisation risk in children are currently limited. The study aims to characterise morbidity patterns in all children, focusing on childhood cancer survivors versus children without cancer. Methods: Employing hospital records of children aged <19 years between 1997 to 2018 in England, we characterised morbidity patterns in childhood cancer survivors compared with children without cancer. The follow-up began on the 5th anniversary of the index hospitalisation and the primary outcome was the incidence of comorbidities. Findings: We identified 3,559,439 eligible participants having 12,740,666 hospital admissions, with a mean age at study entry of 11.2 years. We identified 32,221 patients who survived for at least 5 years since their initial cancer diagnosis. During the follow-up period and within the whole population of 3.6 million children, the leading conditions for admission were (i) metabolic, endocrine, digestive renal and genitourinary conditions (84,749, 2.5%), (ii) neurological (35,833, 1.0%) and (iii) musculoskeletal or skin conditions (23,574, 0.7%), fever, acute respiratory and sepsis (22,604, 0.7%). Stratified analyses revealed that females and children from socioeconomically deprived areas had a higher cumulative incidence for morbidities requiring hospitalisation (p < 0.001). At baseline (5 years after the initial cancer diagnosis or initial hospitalisation for survivors and population comparisons, respectively), cancer survivors experienced a higher prevalence of individual conditions and multimorbidity (≥ 2 morbidities) compared with children without cancer. Cox regression analyses showed that survivors had at least a 4-fold increase in the risk of hospitalisation for conditions such as chronic eye conditions (hazard ration (HR):4.0, 95% confidence interval (CI): 3.5-4.7), fever requiring hospitalisation (HR: 4.4, 95% CI: 3.8-5.0), subsequent neoplasms (HR: 5.7, 95% CI:5.0-6.5), immunological disorders (HR: 6.5, 95% CI:4.5-9.3) and metabolic conditions (HR: 7.1, 95% CI:5.9-8.5). Interpretation: The overall morbidity burden among children was low in general; however, childhood cancer survivors experienced a higher prevalence and subsequent risk of hospitalisation for a range of morbidities. Targeted policies may be required to promote awareness on health vulnerabilities and gender disparity and to improve advocacy for healthcare in deprived communities. Funding: Wellcome Trust, National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, NIHR Great Ormond Street Hospital Biomedical Research Centre and Academy of Medical Sciences. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report

Late effects of cancer in children, teenagers and young adults: Population-based study on the burden of 183 conditions, in-patient and critical care admissions and years of life lost

Background: Children, teenagers and young adults who survived cancer are prone to developing late effects. The burden of late effects across a large number of conditions, in-patient hospitalisation and critical care admissions have not been described using a population-based dataset. We aim to systematically quantify the cumulative burden of late effects across all cancer subtypes, treatment modalities and chemotherapy drug classes. // Methods: We employed primary care records linked to hospitals, the death registry and cancer registry from 1998–2020. CTYA survivors were 25 years or younger at the time of cancer diagnosis had survived ≥5 years post-diagnosis. Year-of-birth and sex-matched community controls were used for comparison. We considered nine treatment types, nine chemotherapy classes and 183 physical and mental health late effects. Cumulative burden was estimated using mean cumulative count, which considers recurring events. Multivariable logistic regression was used to investigate the association between treatment exposures and late effects. Excess years of life lost (YLL) attributable to late effects were estimated. // Findings: Among 4,063 patients diagnosed with cancer, 3,466 survived ≥ 5 years (85%); 13,517 matched controls were identified. The cumulative burden of late effects at age 35 was the highest in survivors of leukaemia (23.52 per individual [95% CI:19.85–29.33]) and lowest in survivors of germ cell tumours (CI:6.04 [5.32–6.91]). In controls, the cumulative burden was 3.99 (CI:3.93–4.08) at age 35 years. When survivors reach age 45, the cumulative burden for immunological conditions and infections was the highest (3.27 [CI:3.01–3.58]), followed by cardiovascular conditions (3.08 [CI:1.98–3.29]). Survivors who received chemotherapy and radiotherapy had the highest disease burden compared to those who received surgery only. These patients also had the highest burden of hospitalisation (by age 45: 10.43 [CI:8.27–11.95]). Survivors who received antimetabolite chemotherapy had the highest disease and hospitalisation burden, while the lowest burden is observed in those receiving antitumour antibiotics. Regression analyses revealed that survivors who received only surgery had lower odds of developing cardiovascular (adjusted odds ratio 0.73 [CI:0.56–0.94]), haematological (aOR 0.51 [CI:0.37–0.70]), immunology and infection (aOR 0.84 [CI:0.71–0.99]) and renal (aOR 0.51 [CI:0.39–0.66]) late effects. By contrast, the opposite trend was observed in survivors who received chemo-radiotherapy. High antimetabolite chemotherapy cumulative dose was associated with increased risks of subsequent cancer (aOR 2.32 [CI:1.06–4.84]), metastatic cancer (aOR 4.44 [CI:1.29–11.66]) and renal (aOR 3.48 [CI:1.36–7.86]) conditions. Patients who received radiation dose of ≥50 Gy experienced higher risks of developing metastatic cancer (aOR 5.51 [CI:2.21–11.86]), cancer (aOR 3.77 [CI:2.22–6.34]), haematological (aOR 3.43 [CI:1.54–6.83]) and neurological (aOR 3.24 [CI:1.78–5.66]) conditions. Similar trends were observed in survivors who received more than three teletherapy fields. Cumulative burden analyses on 183 conditions separately revealed varying dominance of different late effects across cancer types, socioeconomic deprivation and treatment modalities. Late effects are associated with excess YLL (i.e., the difference in YLL between survivors with or without late effects), which was the most pronounced among survivors with haematological comorbidities. // Interpretation: To our knowledge, this is the first study to dissect and quantify the importance of late morbidities on subsequent survival using linked electronic health records from multiple settings. The burden of late effects is heterogeneous, as is the risk of premature mortality associated with late effects. We provide an extensive knowledgebase to help inform treatment decisions at the point of diagnosis, future interventional trials and late-effects screening centred on the holistic needs of this vulnerable population

Knots and Particles

Using methods of high performance computing, we have found indications that knotlike structures appear as stable finite energy solitons in a realistic 3+1 dimensional model. We have explicitly simulated the unknot and trefoil configurations, and our results suggest that all torus knots appear as solitons. Our observations open new theoretical possibilities in scenarios where stringlike structures appear, including physics of fundamental interactions and early universe cosmology. In nematic liquid crystals and 3He superfluids such knotted solitons might actually be observed.Comment: 9 pages, 4 color eps figures and one b/w because of size limit (color version available from authors

Counterflow dielectrophoresis for trypanosome enrichment and detection in blood

Human African trypanosomiasis or sleeping sickness is a deadly disease endemic in sub-Saharan Africa, caused by single-celled protozoan parasites. Although it has been targeted for elimination by 2020, this will only be realized if diagnosis can be improved to enable identification and treatment of afflicted patients. Existing techniques of detection are restricted by their limited field-applicability, sensitivity and capacity for automation. Microfluidic-based technologies offer the potential for highly sensitive automated devices that could achieve detection at the lowest levels of parasitemia and consequently help in the elimination programme. In this work we implement an electrokinetic technique for the separation of trypanosomes from both mouse and human blood. This technique utilises differences in polarisability between the blood cells and trypanosomes to achieve separation through opposed bi-directional movement (cell counterflow). We combine this enrichment technique with an automated image analysis detection algorithm, negating the need for a human operator

Addressing Missing Data in Patient-Reported Outcome Measures (PROMS) : Implications for the Use of PROMS for Comparing Provider Performance

Patient-reported outcome measures (PROMs) are now routinely collected in the English National Health Service and used to compare and reward hospital performance within a high-powered pay-for-performance scheme. However, PROMs are prone to missing data. For example, hospitals often fail to administer the pre-operative questionnaire at hospital admission, or patients may refuse to participate or fail to return their post-operative questionnaire. A key concern with missing PROMs is that the individuals with complete information tend to be an unrepresentative sample of patients within each provider and inferences based on the complete cases will be misleading. This study proposes a strategy for addressing missing data in the English PROM survey using multiple imputation techniques and investigates its impact on assessing provider performance. We find that inferences about relative provider performance are sensitive to the assumptions made about the reasons for the missing data

Primordial Black Holes: sirens of the early Universe

Primordial Black Holes (PBHs) are, typically light, black holes which can form in the early Universe. There are a number of formation mechanisms, including the collapse of large density perturbations, cosmic string loops and bubble collisions. The number of PBHs formed is tightly constrained by the consequences of their evaporation and their lensing and dynamical effects. Therefore PBHs are a powerful probe of the physics of the early Universe, in particular models of inflation. They are also a potential cold dark matter candidate.Comment: 21 pages. To be published in "Quantum Aspects of Black Holes", ed. X. Calmet (Springer, 2014

Cancer and thrombosis: Managing the risks and approaches to thromboprophylaxis

Patients with cancer are at increased risk of venous thromboembolism (VTE) compared with patients without cancer. This results from both the prothrombotic effects of the cancer itself and iatrogenic factors, such as chemotherapy, radiotherapy, indwelling central venous devices and surgery, that further increase the risk of VTE. Although cancer-associated thrombosis remains an important cause of morbidity and mortality, it is often underdiagnosed and undertreated. However, evidence is accumulating to support the use of low-molecular-weight heparins (LMWHs) in the secondary prevention of VTE in patients with cancer. Not only have LMWHs been shown to be at least as effective as coumarin derivatives in this setting, but they have a lower incidence of complications, including bleeding, and are not associated with the practical problems of warfarin therapy. Furthermore, a growing number of studies indicate that LMWHs may improve survival among patients with cancer due to a possible antitumor effect. Current evidence suggests that LMWHs should increasingly be considered for the long-term management of VTE in patients with cancer

Controls on gut phosphatisation : the trilobites from the Weeks Formation Lagerstätte (Cambrian; Utah)

Despite being internal organs, digestive structures are frequently preserved in Cambrian Lagerstätten. However, the reasons for their fossilisation and their biological implications remain to be thoroughly explored. This is particularly true with arthropods--typically the most diverse fossilised organisms in Cambrian ecosystems--where digestive structures represent an as-yet underexploited alternative to appendage morphology for inferences on their biology. Here we describe the phosphatised digestive structures of three trilobite species from the Cambrian Weeks Formation Lagerstätte (Utah). Their exquisite, three-dimensional preservation reveals unique details on trilobite internal anatomy, such as the position of the mouth and the absence of a differentiated crop. In addition, the presence of paired pygidial organs of an unknown function is reported for the first time. This exceptional material enables exploration of the relationships between gut phosphatisation and the biology of organisms. Indeed, soft-tissue preservation is unusual in these fossils as it is restricted to the digestive structures, which indicates that the gut played a central role in its own phosphatisation. We hypothesize that the gut provided a microenvironment where special conditions could develop and harboured a source of phosphorus. The fact that gut phosphatization has almost exclusively been observed in arthropods could be explained by their uncommon ability to store ions (including phosphorous) in their digestive tissues. However, in some specimens from the Weeks Formation, the phosphatisation extends to the entire digestive system, suggesting that trilobites might have had some biological particularities not observed in modern arthropods. We speculate that one of them might have been an increased capacity for ion storage in the gut tissues, related to the moulting of their heavily-mineralised carapace