Administration of a tropomyosin receptor kinase inhibitor attenuates sarcoma-induced nerve sprouting, neuroma formation and bone cancer pain

Pain often accompanies cancer and most current therapies for treating cancer pain have significant unwanted side effects. Targeting nerve growth factor (NGF) or its cognate receptor tropomyosin receptor kinase A (TrkA) has become an attractive target for attenuating chronic pain

Participant Feedback in the Evaluation of Novel Stroke Rehabilitation Technologies

Purpose: Stroke participant perspectives are used to evaluate a novel rehabilitation system employing electrical stimulation (ES) technology combined with robotic assistance and virtual reality. The broader implications of such feedback for future technological development are discussed. Method: While supported by a robot, ES was applied to the triceps and anterior deltoid muscles of 5 chronic stroke participants with upper limb impairment to assist them in completing functional, virtual reality tracking tasks. Advanced ES controllers adjusted the amount of ES applied on each attempt to improve accuracy and maximise voluntary effort. The system was evaluated in terms of participants’ perspectives, expressed during a semi-structured interview, and clinical outcome measures. Results: The rehabilitation system was well accepted by participants and viewed positively, despite mixed opinions regarding effectiveness. Feedback demonstrated an alignment in participants’ perceptions of reduced impairment and clinical outcomes, in which a significant (p < 0.001) mean change of 9.3 in Fugl-Meyer scores was observed. Participant feedback also provided insight into individual differences observed in clinical outcomes. From our findings six key issues regarding effectiveness, muscles trained, system flexibility and portability, possible discomfort and the value of participant perspectives emerged that may be relevant for researchers developing new rehabilitation technologies. Conclusion: Participant feedback via a semi-structured interview provided important insight into the usability and effectiveness of using this system as a platform for upper limb stroke rehabilitation

Vaginal progesterone to reduce preterm birth among HIV-infected pregnant women in Zambia: a feasibility study protocol

Abstract Background Women infected with HIV have a risk of preterm birth (PTB) that is twice that among uninfected women, and treatment with antiretroviral therapy (ART) may further increase this risk. Progesterone supplementation reduces the risk of preterm delivery in women who have a shortened cervix in the midtrimester. We propose to study the feasibility of a trial of vaginal progesterone (VP) to prevent PTB among HIV-infected women receiving ART in pregnancy. Given low adherence among women self-administering vaginal study product in recent microbicide trials, we plan to investigate whether adequate adherence to VP can be achieved prior to launching a full-scale efficacy trial. Methods and design One hundred forty HIV-infected pregnant women in Lusaka, Zambia, will be randomly allocated to daily self-administration of either VP or matched placebo, starting between 20 and 24 gestational weeks. The primary outcome will be adherence, defined as the proportion of participants who achieve at least 80% use of study product, assessed objectively with a validated dye stain assay that confirms vaginal insertion of returned single-use applicators. Secondary outcomes will be study uptake, retention, and preliminary efficacy. We will concurrently perform semi-structured interviews with participants enrolled in the study and with women who decline enrollment to assess the acceptability of VP to prevent PTB and of enrollment to a randomized controlled trial. Discussion We hypothesize that VP could prevent PTB among women receiving ART in pregnancy. In preparation for a trial to test this hypothesis, we plan to assess whether participants will be adherent to study product and protocol. Trial registration ClinicalTrial.gov, NCT02970552

A CURE on the Evolution of Antibiotic Resistance in <i>Escherichia coli</i> Improves Student Conceptual Understanding

We developed labs on the evolution of antibiotic resistance to assess the costs and benefits of replacing traditional laboratory exercises in an introductory biology course for majors with a course-based undergraduate research experience (CURE). To assess whether participating in the CURE imposed a cost in terms of exam performance, we implemented a quasi-experiment in which four lab sections in the same term of the same course did the CURE labs, while all other students did traditional labs. To assess whether participating in the CURE impacted other aspects of student learning, we implemented a second quasi-experiment in which all students either did traditional labs over a two-quarter sequence or did CURE labs over a two-quarter sequence. Data from the first experiment showed minimal impact on CURE students' exam scores, while data from the second experiment showed that CURE students demonstrated a better understanding of the culture of scientific research and a more expert-like understanding of evolution by natural selection. We did not find disproportionate costs or benefits for CURE students from groups that are minoritized in science, technology, engineering, and mathematics

Upper limb and eye movement coordination during reaching tasks in people with stroke

Purpose: To enhance understanding of the relationship between upper limb and eye movements during reaching tasks in people with stroke. Methods: Eye movements were recorded from 10 control participants and 8 chronic stroke participants during a visual orienting task (Experiment 1) and a series of reaching tasks (Experiment 2). Stroke participants completed the reaching tasks using (i) their less impaired upper limb, (ii) their more impaired upper limb without support, and (iii) their more impaired upper limb, with support (SaeboMAS gravitational support and/or electrical stimulation). Participants were tested individually and completed both experiments in the same session. Results: Oculomotor control and the coordination between the upper limb and the oculomotor system were found to be intact in stroke participants when no limb movements were required, or when the less impaired upper limb was used. However, when the more impaired upper limb was used, success and accuracy in reaching decreased and patterns of eye movements changed, with an observed increase in eye movements to the limb itself. With upper limb support, patterns of hand-eye coordination were found to more closely resemble those of the control group. Conclusion: Deficits in upper limb motor systems result in changes in patterns of eye movement behavior during reaching tasks. These changes in eye movement behavior can be modulated by providing upper limb support. -Implications for Rehabilitation -Deficits in upper limb motor systems can result in changes in patterns of eye movement behavior during reaching tasks. -Upper limb support can reduce deficits in hand-eye coordination. -Stroke rehabilitation outcomes should consider motor and oculomotor performance

General practitioner contributions to achieving sustained healthcare for offenders: a qualitative study

Abstract Background: Offenders frequently have substantial healthcare needs and, like many other socially marginalised groups, often receive healthcare in inverse proportion to their needs. Improved continuity of healthcare over time could contribute to addressing these needs. General Practitioners need to be able to support people with complex social and medical problems, even in systems that are not specifically designed to manage individuals with such degrees of complexity. We aimed to examine offenders’ perspectives on factors that contributed to, or worked against, creating and sustaining their access to healthcare. Methods: From a sample of 200 participants serving community or prison sentences in South West (SW) and South East (SE) England, who were interviewed about their health care experiences as part of the Care for Offenders: Continuity of Access (COCOA) study, we purposively sampled 22 participants for this sub-study, based on service use. These interviews were transcribed verbatim. A thematic analytic approach initially applied 5 a priori codes based on access and different components of continuity. Data were then examined for factors that contributed to achieving and disrupting access and continuity. Results: Participants described how their own life situations and behaviours contributed to their problems in accessing healthcare and also identified barriers created by existing access arrangements. They also highlighted how some General Practitioners used their initiative and skills to ‘workaround’ the system, and build positive relationships with them; feeling listened to and building trust were particularly valued, as was clear communication. Limitations faced by General Practitioners included a lack of appropriate services to refer people to, where the offender patients would meet the access criteria, and disagreements regarding medication prescriptions. Conclusions: General Practitioners can make a positive contribution to supporting access to healthcare for an under-served population by facilitating more flexible and less formal access arrangements, by using their relationship skills, and by problem-solving. General Practitioners should recognise their potential to transform people’s experience of healthcare whilst working in imperfect systems, particularly with vulnerable and marginalised groups who have complex medical and social needs

Five endometrial cancer risk loci identified through genome-wide association analysis.

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r(2) = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.I.T. is supported by Cancer Research UK and the Oxford Comprehensive Biomedical Research Centre. T.H.T.C. is supported by the Rhodes Trust and the Nuffield Department of Medicine. Funding for iCOGS infrastructure came from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692 and C8197/A16565), the US National Institutes of Health (R01 CA128978, U19 CA148537, U19 CA148065 and U19 CA148112), the US Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Susan G. Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. SEARCH recruitment was funded by a programme grant from Cancer Research UK (C490/A10124). Stage 1 and stage 2 case genotyping was supported by the NHMRC (552402 and 1031333). Control data were generated by the WTCCC, and a full list of the investigators who contributed to the generation of the data is available from the WTCCC website. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by UK Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02; funding for this project was provided by the Wellcome Trust under award 085475. NSECG was supported by the European Union's Framework Programme 7 CHIBCHA grant and Wellcome Trust Centre for Human Genetics Core Grant 090532/Z/09Z, and CORGI was funded by Cancer Research UK. BCAC is funded by Cancer Research UK (C1287/A10118 and C1287/A12014). OCAC is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07) and the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/ng.356

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant