Patient-reported outcomes: pathways to better health, better services, and better societies

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordWhile the use of PROs in research is well established, many challenges lie ahead as their use is extended to other applications. There is consensus that health outcome evaluations that include PROs along with clinician-reported outcomes and administrative data are necessary to inform clinical and policy decisions. The initiatives presented in this paper underline evolving recognition that PROs play a unique role in adding the patient perspective alongside clinical (e.g., blood pressure) and organizational (e.g., admission rates) indicators for evaluating the effects of new products, selecting treatments, evaluating quality of care, and monitoring the health of the population. In this paper, we first explore the use of PRO measures to support drug approval and labeling claims. We critically evaluate the evidence and challenges associated with using PRO measures to improve healthcare delivery at individual and population levels. We further discuss the challenges associated with selecting from the abundance of measures available, opportunities afforded by agreeing on common metrics for constructs of interest, and the importance of establishing an evidence base that supports integrating PRO measures across the healthcare system to improve outcomes. We conclude that the integration of PROs as a key end point within individual patient care, healthcare organization and program performance evaluations, and population surveillance will be essential for evaluating whether increased healthcare expenditure is translating into better health outcomes.Jose M. Valderas was supported by an NIHR Clinician Scientist Award (NIHR/CS/010/024)

The Top Window for dark matter

We investigate a scenario that the top quark is the only window to the dark matter particle. We use the effective Lagrangian approach to write down the interaction between the top quark and the dark matter particle. Requiring the dark matter satisfying the relic density we obtain the size of the effective interaction. We show that the scenario can be made consistent with the direct and indirect detection experiments by adjusting the size of the effective coupling. Finally, we calculate the production cross section for $t\bar t + \chi \bar \chi$ at the Large Hadron Collider (LHC), which will give rise to an interesting signature of a top-pair plus large missing energy.Comment: 17 pages including 8 figures; added references and a footnot

Cross talk of signals between EGFR and IL-6R through JAK2/STAT3 mediate epithelial–mesenchymal transition in ovarian carcinomas

Epidermal growth factor receptor (EGFR) is overexpressed in ovarian carcinomas, with direct or indirect activation of EGFR able to trigger tumour growth. We demonstrate significant activation of both signal transducer and activator of transcription (STAT)3 and its upstream activator Janus kinase (JAK)2, in high-grade ovarian carcinomas compared with normal ovaries and benign tumours. The association between STAT3 activation and migratory phenotype of ovarian cancer cells was investigated by EGF-induced epithelial–mesenchymal transition (EMT) in OVCA 433 and SKOV3 ovarian cancer cell lines. Ligand activation of EGFR induced a fibroblast-like morphology and migratory phenotype, consistent with the upregulation of mesenchyme-associated N-cadherin, vimentin and nuclear translocation of β-catenin. This occurred concomitantly with activation of the downstream JAK2/STAT3 pathway. Both cell lines expressed interleukin-6 receptor (IL-6R), and treatment with EGF within 1 h resulted in a several-fold enhancement of mRNA expression of IL-6. Consistent with that, EGF treatment of both OVCA 433 and SKOV3 cell lines resulted in enhanced IL-6 production in the serum-free medium. Exogenous addition of IL-6 to OVCA 433 cells stimulated STAT3 activation and enhanced migration. Blocking antibodies against IL-6R inhibited IL-6 production and EGF- and IL-6-induced migration. Specific inhibition of STAT3 activation by JAK2-specific inhibitor AG490 blocked STAT3 phosphorylation, cell motility, induction of N-cadherin and vimentin expression and IL6 production. These data suggest that the activated status of STAT3 in high-grade ovarian carcinomas may occur directly through activation of EGFR or IL-6R or indirectly through induction of IL-6R signalling. Such activation of STAT3 suggests a rationale for a combination of anti-STAT3 and EGFR/IL-6R therapy to suppress the peritoneal spread of ovarian cancer

'We Have the Internet in Our Hands’: Bangladeshi College Students’ Use of ICTs For Health Information

Information and Communications Technologies (ICTs) which enable people to access, use and promote health information through digital technology, promise important health systems innovations which can challenge gatekeepers’ control of information, through processes of disintermediation. College students, in pursuit of sexual and reproductive health (SRH) information, are particularly affected by gatekeeping as strong social and cultural norms restrict their access to information and services. This paper examines mobile phone usage for obtaining health information in Mirzapur, Bangladesh. It contrasts college students’ usage with that of the general population, asks whether students are using digital technologies for health information in innovative ways, and examines how gender affects this

The hypoactive corpora cavernosa with degenerative erectile dysfunction: a new syndrome

BACKGROUND: In a group of 22 patients with erectile dysfunction, vasculogenic, neurogenic, endocrinologic or psychogenic investigations failed to find a cause for their erectile dysfunction. The electro-cavernosograms of these patients recorded a diminished activity. We investigated the hypothesis that diminished corpus cavernosum electromyography activity was the cause of erectile dysfunction in these patients. METHODS: The study comprised the above mentioned 22 patients (study group, 43.8 ± 5.9 SD years) and 15 healthy volunteers (control group, 41.8 ± 5.1 SD years). The electro-cavernosograms were recorded in the flaccid, erectile and detumescent phases by 2 electrodes inserted into the corpus cavernosum. RESULTS: The electro-cavernosogram of the healthy volunteers registered in the flaccid phase regular slow waves and random action potentials. The wave variables declined significantly in the erectile phase (p < 0.01). In the study group, the slow wave variables in the flaccid phase exhibited a significant decrease (p < 0.05) compared to the healthy volunteers, and the rhythm was irregular. Erection did not occur with sildenafil administration or intracavernosal papaverine injection, and penile implant was performed. Biopsy examination showed degenerated muscle fibers, and fragmented collagen and elastic fibers with areas of fibrosis. CONCLUSION: A novel concept of the cause of erectile dysfunction was presented. Corpora cavernosa showed degenerative changes on histopathologic examination and exhibited diminished electromyography activity. They did not respond to sildenafil administration or intracavernosal papaverine injection. Penile implants were the only treatment. The condition is given the name 'hypoactive corpus cavernosum'. The cause of corpus cavernosum degenerative changes needs further study

General Analysis of Antideuteron Searches for Dark Matter

Low energy cosmic ray antideuterons provide a unique low background channel for indirect detection of dark matter. We compute the cosmic ray flux of antideuterons from hadronic annihilations of dark matter for various Standard Model final states and determine the mass reach of two future experiments (AMS-02 and GAPS) designed to greatly increase the sensitivity of antideuteron detection over current bounds. We consider generic models of scalar, fermion, and massive vector bosons as thermal dark matter, describe their basic features relevant to direct and indirect detection, and discuss the implications of direct detection bounds on models of dark matter as a thermal relic. We also consider specific dark matter candidates and assess their potential for detection via antideuterons from their hadronic annihilation channels. Since the dark matter mass reach of the GAPS experiment can be well above 100 GeV, we find that antideuterons can be a good indirect detection channel for a variety of thermal relic electroweak scale dark matter candidates, even when the rate for direct detection is highly suppressed.Comment: 44 pages, 15 Figure

Grb2 monomer-dimer equilibrium determines normal versus oncogenic function

The adaptor protein growth factor receptor-bound protein 2 (Grb2) is ubiquitously expressed in eukaryotic cells and involved in a multitude of intracellular protein interactions. Grb2 plays a pivotal role in tyrosine kinase-mediated signal transduction including linking receptor tyrosine kinases to the Ras/mitogen-activated protein (MAP) kinase pathway, which is implicated in oncogenic outcome. Grb2 exists in a constitutive equilibrium between monomeric and dimeric states. Here we show that only monomeric Grb2 is capable of binding to SOS and upregulating MAP kinase signalling and that the dimeric state is inhibitory to this process. Phosphorylation of tyrosine 160 (Y160) on Grb2, or binding of a tyrosylphosphate-containing ligand to the SH2 domain of Grb2, results in dimer dissociation. Phosphorylation of Y160 on Grb2 is readily detectable in the malignant forms of human prostate, colon and breast cancers. The self-association/dissociation of Grb2 represents a switch that regulates MAP kinase activity and hence controls cancer progression

Proteomics: in pursuit of effective traumatic brain injury therapeutics

Effective traumatic brain injury (TBI) therapeutics remain stubbornly elusive. Efforts in the field have been challenged by the heterogeneity of clinical TBI, with greater complexity among underlying molecular phenotypes than initially conceived. Future research must confront the multitude of factors comprising this heterogeneity, representing a big data challenge befitting the coming informatics age. Proteomics is poised to serve a central role in prescriptive therapeutic development, as it offers an efficient endpoint within which to assess post-TBI biochemistry. We examine rationale for multifactor TBI proteomic studies and the particular importance of temporal profiling in defining biochemical sequences and guiding therapeutic development. Lastly, we offer perspective on repurposing biofluid proteomics to develop theragnostic assays with which to prescribe, monitor and assess pharmaceutics for improved translation and outcome for TBI patients

Combining ability of summer-squash lines with different degrees of parthenocarpy and PRSV-W resistance

The aim was to assess heterosis in a set of 16 summer-squash hybrids, and evaluate the combining capacity of the respective parental lines, which differed as to the degree of parthenocarpy and resistance to PRSV-W (Papaya Ringspot Virus-Watermelon strain). The hybrids were obtained using a partial diallel cross design (4 × 4). The lines of parental group I were 1 = ABX-037G-77-03-05-01-01-bulk, 2 = ABX-037G-77-03-05-03-10-bulk, 3 = ABX-037G-77-03-05-01-04-bulk and 4 = ABX-037G-77-03-05-05-01-bulk, and of group II, 1′ = ABX-037G-77-03-05-04-08-bulk, 2′ = ABX-037G-77-03-05-02-11-bulk, 3′ = Clarice and 4′ = Caserta. The 16 hybrids and eight parental lines were evaluated for PRSV-W resistance, parthenocarpic expression and yield in randomized complete-block designs, with three replications. Parthenocarpy and the resistance to PRSV-W were rated by means of a scale from 1 to 5, where 1 = non-parthenocarpic or high resistance to PRSV-W, and 5 = parthenocarpic or high susceptibility to PRSV-W. Both additive and non-additive gene effects were important in the expression of parthenocarpy and resistance to PRSV-W. Whereas estimates of heterosis in parthenocarpy usually tended towards a higher degree, resistance to PRSV-W was towards higher susceptibility. At least one F1 hybrid was identified with a satisfactory degree of parthenocarpy, resistance to PRSV-W and high fruit-yield

Climate and southern Africa's water-energy-food nexus

In southern Africa, the connections between climate and the water-energy-food nexus are strong. Physical and socioeconomic exposure to climate is high in many areas and in crucial economic sectors. Spatial interdependence is also high, driven for example, by the regional extent of many climate anomalies and river basins and aquifers that span national boundaries. There is now strong evidence of the effects of individual climate anomalies, but associations between national rainfall and Gross Domestic Product and crop production remain relatively weak. The majority of climate models project decreases in annual precipitation for southern Africa, typically by as much as 20% by the 2080s. Impact models suggest these changes would propagate into reduced water availability and crop yields. Recognition of spatial and sectoral interdependencies should inform policies, institutions and investments for enhancing water, energy and food security. Three key political and economic instruments could be strengthened for this purpose; the Southern African Development Community, the Southern African Power Pool, and trade of agricultural products amounting to significant transfers of embedded water