Towards Physical Hybrid Systems

Some hybrid systems models are unsafe for mathematically correct but physically unrealistic reasons. For example, mathematical models can classify a system as being unsafe on a set that is too small to have physical importance. In particular, differences in measure zero sets in models of cyber-physical systems (CPS) have significant mathematical impact on the mathematical safety of these models even though differences on measure zero sets have no tangible physical effect in a real system. We develop the concept of "physical hybrid systems" (PHS) to help reunite mathematical models with physical reality. We modify a hybrid systems logic (differential temporal dynamic logic) by adding a first-class operator to elide distinctions on measure zero sets of time within CPS models. This approach facilitates modeling since it admits the verification of a wider class of models, including some physically realistic models that would otherwise be classified as mathematically unsafe. We also develop a proof calculus to help with the verification of PHS.Comment: CADE 201

Sport and transgender people: a systematic review of the literature relating to sport participation and competitive sport policies

Background Whether transgender people should be able to compete in sport in accordance with their gender identity is a widely contested question within the literature and among sport organisations, fellow competitors and spectators. Owing to concerns surrounding transgender people (especially transgender female individuals) having an athletic advantage, several sport organisations place restrictions on transgender competitors (e.g. must have undergone gender-confirming surgery). In addition, some transgender people who engage in sport, both competitively and for leisure, report discrimination and victimisation. Objective To the authors’ knowledge, there has been no systematic review of the literature pertaining to sport participation or competitive sport policies in transgender people. Therefore, this review aimed to address this gap in the literature. Method Eight research articles and 31 sport policies were reviewed. Results In relation to sport-related physical activity, this review found the lack of inclusive and comfortable environments to be the primary barrier to participation for transgender people. This review also found transgender people had a mostly negative experience in competitive sports because of the restrictions the sport’s policy placed on them. The majority of transgender competitive sport policies that were reviewed were not evidence based. Conclusion Currently, there is no direct or consistent research suggesting transgender female individuals (or male individuals) have an athletic advantage at any stage of their transition (e.g. cross-sex hormones, gender-confirming surgery) and, therefore, competitive sport policies that place restrictions on transgender people need to be considered and potentially revised

DISCO-SCA and Properly Applied GSVD as Swinging Methods to Find Common and Distinctive Processes

BACKGROUND: In systems biology it is common to obtain for the same set of biological entities information from multiple sources. Examples include expression data for the same set of orthologous genes screened in different organisms and data on the same set of culture samples obtained with different high-throughput techniques. A major challenge is to find the important biological processes underlying the data and to disentangle therein processes common to all data sources and processes distinctive for a specific source. Recently, two promising simultaneous data integration methods have been proposed to attain this goal, namely generalized singular value decomposition (GSVD) and simultaneous component analysis with rotation to common and distinctive components (DISCO-SCA). RESULTS: Both theoretical analyses and applications to biologically relevant data show that: (1) straightforward applications of GSVD yield unsatisfactory results, (2) DISCO-SCA performs well, (3) provided proper pre-processing and algorithmic adaptations, GSVD reaches a performance level similar to that of DISCO-SCA, and (4) DISCO-SCA is directly generalizable to more than two data sources. The biological relevance of DISCO-SCA is illustrated with two applications. First, in a setting of comparative genomics, it is shown that DISCO-SCA recovers a common theme of cell cycle progression and a yeast-specific response to pheromones. The biological annotation was obtained by applying Gene Set Enrichment Analysis in an appropriate way. Second, in an application of DISCO-SCA to metabolomics data for Escherichia coli obtained with two different chemical analysis platforms, it is illustrated that the metabolites involved in some of the biological processes underlying the data are detected by one of the two platforms only; therefore, platforms for microbial metabolomics should be tailored to the biological question. CONCLUSIONS: Both DISCO-SCA and properly applied GSVD are promising integrative methods for finding common and distinctive processes in multisource data. Open source code for both methods is provided

A recessively inherited risk locus on chromosome 13q22-31 conferring susceptibility to schizophrenia

We report a consanguineous family in which schizophrenia segregates in a manner consistent with recessive inheritance of a rare, partial-penetrance susceptibility allele. From 4 marriages between 2 sets of siblings who are half first cousins, 6 offspring have diagnoses of psychotic disorder. Homozygosity mapping revealed a 6.1-Mb homozygous region on chromosome 13q22.2-31.1 shared by all affected individuals, containing 13 protein-coding genes. Microsatellite analysis confirmed homozygosity for the affected haplotype in 12 further apparently unaffected members of the family. Psychiatric reports suggested an endophenotype of milder psychiatric illness in 4 of these individuals. Exome and genome sequencing revealed no potentially pathogenic coding or structural variants within the risk haplotype. Filtering for noncoding variants with a minor allele frequency of <0.05 identified 17 variants predicted to have significant effects, the 2 most significant being within or adjacent to the SCEL gene. RNA sequencing of blood from an affected homozygote showed the upregulation of transcription from NDFIP2 and SCEL. NDFIP2 is highly expressed in brain, unlike SCEL, and is involved in determining T helper (Th) cell type 1 and Th2 phenotypes, which have previously been implicated with schizophrenia

Photochemical internalisation of chemotherapy potentiates killing of multidrug-resistant breast and bladder cancer cells

Multidrug resistance (MDR) is the major confounding factor in adjuvant solid tumour chemotherapy. Increasing intracellular amounts of chemotherapeutics to circumvent MDR may be achieved by a novel delivery method, photochemical internalisation (PCI). PCI consists of the co-administration of drug and photosensitiser; upon light activation the latter induces intracellular release of organelle-bound drug. We investigated whether co-administration of hypericin (photosensitiser) with mitoxantrone (MTZ, chemotherapeutic) plus illumination potentiates cytotoxicity in MDR cancer cells. We mapped the extent of intracellular co-localisation of drug/photosensitiser. We determined whether PCI altered drug-excreting efflux pump P-glycoprotein (Pgp) expression or function in MDR cells. Bladder and breast cancer cells and their Pgp-overexpressing MDR subclones (MGHU1, MGHU1/R, MCF-7, MCF-7/R) were given hypericin/MTZ combinations, with/without blue-light illumination. Pilot experiments determined appropriate sublethal doses for each. Viability was determined by the 3-[4,5-dimethylthiazolyl]-2,5-diphenyltetrazolium bromide assay. Intracellular localisation was mapped by confocal microscopy. Pgp expression was detected by immunofluorescence and Pgp function investigated by Rhodamine123 efflux on confocal microscopy. MTZ alone (0.1–0.2 μg ml−1) killed up to 89% of drug-sensitive cells; MDR cells exhibited less cytotoxicity (6–28%). Hypericin (0.1–0.2 μM) effects were similar for all cells; light illumination caused none or minimal toxicity. In combination, MTZ /hypericin plus illumination, potentiated MDR cell killing, vs hypericin or MTZ alone. (MGHU1/R: 38.65 and 36.63% increase, P<0.05; MCF-7/R: 80.2 and 46.1% increase, P<0.001). Illumination of combined MTZ/hypericin increased killing by 28.15% (P<0.05 MGHU1/R) compared to dark controls. Intracytoplasmic vesicular co-localisation of MTZ/hypericin was evident before illumination and at serial times post-illumination. MTZ was always found in sensitive cell nuclei, but not in dark resistant cell nuclei. In illuminated resistant cells there was some mobilisation of MTZ into the nucleus. Pgp expression remained unchanged, regardless of drug exposure. Pgp efflux was blocked by the Pgp inhibitor verapamil (positive control) but not impeded by hypericin. The increased killing of MDR cancer cells demonstrated is consistent with PCI. PCI is a promising technique for enhancing treatment efficacy

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700