A novel targeting probe for fluorescent guided surgery in colorectal cancer resections

Background Tailoring the extent of colorectal cancer surgical resection on an individual basis would improve patient outcomes, but to achieve this goal, staging of the disease, particularly lymph node status, must be improved. Sentinel lymph node mapping has been effective in other tumours types but is ineffective in colorectal cancer. Near infra-red fluorophores are of interest in fluorescent guided surgery, but lack the ability to target the specific tissue of interest. The aim of this research is to develop a targeted near infra-red based probe to identify tumour and lymph node metastases. Methods Immunofluorescence was used to determine appropriate target and control recognition molecules in addition to appropriate target and control cell lines. Semiconducting organic polymer CN-PPV nanoparticles were produced utilising a self-assembly method and characterised over time. The selected target and control recognition molecules were conjugated to non-functionalised (NPs) and maleimide functionalised (MNPs) semiconducting organic polymer CN-PPV nanoparticles and cell binding, as well as cell toxicity, were evaluated in vitro. Results Both the target anti-CEA recognition molecules bound specifically to the target cell lines and not to controls. Characterisation of the NPs and MNPs displayed physical stability over time as well as demonstrating negligible adverse cytotoxic effects. Conjugation of both target and control antibody recognition molecules to the MNP led to non-specific binding of the conjugate to control cell lines. The target affimer recognition molecule NP conjugates demonstrated increased binding to target cell lines (42%, p<0.0001) and little non-specific binding to control cell lines (14%, p=0.3348). Conclusions Fluorescent guided surgery is a promising route for intraoperative stratification of colorectal cancer resections if an accurate probe were to be developed. I have shown that the semiconducting organic polymer nanoparticle used in this research possesses the attributes required of a clinical probe for fluorescent guided surgery. However, it requires modification with an appropriate recognition molecule to accurately target colorectal cancer tissue. The affimer NP conjugate is a more promising candidate for this role than its antibody MNP counterpart

Witness: The Modern Writer as Witness

Editor\u27s Note [Excerpt] Magic can mean many different things, especially for writers. Magic can be an illusion, a sleight of hand designed to trick onlookers into believing the impossible. Or magic can be a supernatural force in a world of harsh reality, a set of beliefs that sits just outside the realms of organized religion and advanced technology. Wizards and demons, Las Vegas entertainers and houngans --they all practice a kind of sorcery. For poets and prose writers, though, magic affords an opportunity for us to stretch the limitations of the physical world in search of new themes, settings, and characters. Magic is a door we eagerly walk through to reach new lands. We at Witness have thoroughly enjoyed the process of selecting the themed works we have collected here, mainly because the idea of enchantment is inspiring. There is the possibility of positive charms; there is a chance for dark witchery. And sometimes the spell cast by a character is nebulous, difficult to categorize. It’s arguable that we cherish these incantations the most, since they leave us in a state of wonderment bordering on disorientation. Yes, magic can also leave us bewildered and thankful for the bewilderment.https://digitalscholarship.unlv.edu/witness/1001/thumbnail.jp

Haemophilus influenzae type b reemergence after combination immunization

An increase in Haemophilus influenzae type b (Hib) in British children has been linked to the widespread use of a diphtheria/tetanus/acellular pertussis combination vaccine (DTaP-Hib). We measured anti-polyribosyl-ribitol phos- phate antibody concentration and avidity before and after a Hib booster in 176 children 2–4 years of age who had received 3 doses of DTP-Hib (either DT whole cell pertus- sis-Hib or DTaP-Hib) combination vaccine in infancy. We also measured pharyngeal carriage of Hib. Antibody con- centrations before and avidity indices after vaccination were low (geometric mean concentration 0.46μg/mL, 95% confidence interval [CI] 0.36–0.58; geometric mean avidity index 0.16, 95% CI 0.14–0.18) and inversely related to the number of previous doses of DTaP-Hib (p = 0.02 and p<0.001, respectively). Hib was found in 2.1% (95% CI 0.7%–6.0%) of study participants. Our data support an association between DTaP-Hib vaccine combinations and clinical Hib disease through an effect on antibody concen- tration and avidit

Clinical and Genetic Evaluation of People with or at Risk of Hereditary ATTR Amyloidosis: An Expert Opinion and Consensus on Best Practice in Ireland and the UK

Hereditary transthyretin-mediated amyloidosis (hATTR) is challenging to diagnose early owing to the heterogeneity of clinical presentation, which differs according to the TTR gene variant and its penetrance in each individual. The TTR variants seen most frequently in the UK and Ireland (T80A, V142I and V50M) differ to those commonly occurring in other geographic locations and warrant a specific consideration for diagnosis and genetic testing. In addition, recent availability of treatment for this condition has reinforced the need for a more consistent approach to the management of patients, including access to specialist services, genetic testing and counselling, and clinical investigation for families living in the UK and Ireland. A multidisciplinary panel of experts from the UK and Ireland was convened to identify the current challenges, provide recommendations, and develop a consensus for the diagnosis and screening of people with, or at risk of, hATTR. Over a series of meetings, experts shared their current practices and drafted, refined and approved a consensus statement. This consensus statement provides recommendations for three different groups: (1) people with symptoms raising a possibility of hATTR amyloidosis; (2) people with biopsy-confirmed hATTR amyloidosis; and (3) people without symptoms who may have hATTR amyloidosis (i.e. relatives of people with identified TTR variants). For each group, recommendations are made for the required steps for the diagnosis and follow-up of symptomatic patients, and for guidance on the specialist support for counselling and pre-symptomatic genetic testing of at-risk individuals. This guidance is intended to be practical and based on available evidence. The aim is for regional amyloid specialist centres to provide timely diagnosis, clinical screening, and treatment for individuals and their families with hATTR amyloidosis

Reproducibility in Radiomics: A Comparison of Feature Extraction Methods and Two Independent Datasets

Radiomics involves the extraction of information from medical images that are not visible to the human eye. There is evidence that these features can be used for treatment stratification and outcome prediction. However, there is much discussion about the reproducibility of results between different studies. This paper studies the reproducibility of CT texture features used in radiomics, comparing two feature extraction implementations, namely the MATLAB toolkit and Pyradiomics, when applied to independent datasets of CT scans of patients: (i) the open access RIDER dataset containing a set of repeat CT scans taken 15 min apart for 31 patients (RIDER Scan 1 and Scan 2, respectively) treated for lung cancer; and (ii) the open access HN1 dataset containing 137 patients treated for head and neck cancer. Gross tumor volume (GTV), manually outlined by an experienced observer available on both datasets, was used. The 43 common radiomics features available in MATLAB and Pyradiomics were calculated using two intensity-level quantization methods with and without an intensity threshold. Cases were ranked for each feature for all combinations of quantization parameters, and the Spearman’s rank coefficient, rs, calculated. Reproducibility was defined when a highly correlated feature in the RIDER dataset also correlated highly in the HN1 dataset, and vice versa. A total of 29 out of the 43 reported stable features were found to be highly reproducible between MATLAB and Pyradiomics implementations, having a consistently high correlation in rank ordering for RIDER Scan 1 and RIDER Scan 2 (rs &gt; 0.8). 18/43 reported features were common in the RIDER and HN1 datasets, suggesting they may be agnostic to disease site. Useful radiomics features should be selected based on reproducibility. This study identified a set of features that meet this requirement and validated the methodology for evaluating reproducibility between datasets

Understanding the models of community hospital rehabilitation activity (MoCHA): a mixed method study

Introduction To understand the variation in performance between community hospitals, our objectives are: to measure the relative performance (cost efficiency) of rehabilitation services in community hospitals; to identify the characteristics of community hospital rehabilitation that optimise performance; to investigate the current impact of community hospital in-patient rehabilitation for older people on secondary care and the potential impact if community hospital rehabilitation was optimised to best practice nationally; to examine the relationship between the configuration of intermediate care and secondary care bed use; and to develop toolkits for commissioners and community hospital providers to optimise performance. Methods and analysis Four linked studies will be performed. Study 1: Cost efficiency modelling will apply econometric techniques to datasets from the NHS Benchmarking Network surveys of community hospital and intermediate care. This will identify community hospitals’ performance and estimate the gap between high and low performers. Analyses will determine the potential impact if the performance of all community hospitals nationally was optimised to best performance, and examine the association between community hospital configuration and secondary care bed use. Study 2: A national community hospital survey gathering detailed cost data and efficiency variables will be performed. Study 3: In-depth case studies of three community hospitals, two high and one low performing, will be undertaken. Case studies will gather routine hospital and local health economy data. Ward culture will be surveyed. Content and delivery of treatment will be observed. Patients and staff will be interviewed. Study 4: Co-designed web-based quality improvement toolkits for commissioners and providers will be developed, including indicators of performance and the gap between local and best community hospitals performance. Ethics and dissemination Publications will be in peer reviewed journals, reports will be distributed through stakeholder organisations. Ethical approval was obtained from the Bradford Research Ethics committee (reference: 15/YH/0062)

Privileged Structure: Novel Indane Scaffolds as Potential Anticancer and Anti-Inflammatory Agents

The identification and use of “privileged structures” can increase the reliability and shorten the process in the drug discovery and drug design (a-b). Indane scaffolds occur in various natural products and they constitute the privileged structure that is ubiquitous in many biologically and pharmaceutically active molecules (c-e). Our research group has been working on the synthesis and pharmacological activity of nature identical and synthetically modified indanes and indanones for 20 years. In the current study, the molecular design is centred on elaboration of a fern derived bioactive pharmacophore. The fern is used in traditional Taiwanese medicine to treat inflammation, allergy, stomach cramps and fever (f). Using a synthetic approach we have designed a novel chemical scaffold which can be modified to inhibit angiogenesis and 5-lipoxygenase activity. The parent scaffold and a number of strategically modified derivatives were initially screened using the Zebra fish (Danio rerio) model of tumour angiogenesis (g). This screen led to the identification of two lead molecules, which were then further evaluated in in vitro cell lines and colorectal explants. Results from these experiments establish that the lead compounds affect inter-segmental vessel formation. These molecules also inhibit cell invasion and tube formation. When evaluated in ex vivo colorectal cancer explants where the molecules significantly affected angiogenic and inflammatory protein secretions. These small molecules also alter gene expression. Modification of the scaffold can inhibit 5-lipoxygenase activity. These data suggest that the new scaffold may have significant potential in the treatment of angiogenesis and inflammatory related diseases

Promoting smoking cessation during pregnancy: A feasibility and pilot trial of a digital storytelling intervention delivered via text?messaging

ObjectiveSmoking during pregnancy causes risks to mother and infant health. We investigated the feasibility and likely success of SKIP-IT, a narrative and picture-based smoking cessation intervention delivered via text messages.MethodsA feasibility and pilot trial. We aimed to recruit 70 pregnant women who smoked, randomised to usual care alone, or usual care and the SKIP-IT intervention, between 12 weeks of pregnancy and 6 weeks post due-date. Outcomes assessed were recruitment, retention, acceptability of, and engagement with the intervention, smoking behaviour, intentions, perceived risk, and self-efficacy.ResultsOf 312 women initially approached by smoking cessation services only 54 (17%) agreed to be contacted by the research team. Twenty were then either ineligible or uncontactable and 28 (82%) participated. Most women reported texts to be entertaining and helpful. The proportion of women not smoking at follow-up was lower in the intervention group, but numbers were too small to draw conclusions about effectiveness.ConclusionThe intervention was acceptable, but difficulty in making initial and follow-up contacts meant our methods were unfeasible for a larger trial.Practice implicationsDigital Storytelling interventions could help women quit smoking, but further research is required to identify alternative methods for studies with pregnant women who smoke

The Impact of Delayed Switch to Second-Line Antiretroviral Therapy on Mortality, Depending on Definition of Failure Time and CD4 Count at Failure

Little is known about the functional relationship of delaying second-line treatment initiation for human immunodeficiency virus–positive patients and mortality, given a patient’s immune status. We included 7,255 patients starting antiretroviral therapy during 2004–2017, from 9 South African cohorts, with virological failure and complete baseline data. We estimated the impact of switch time on the hazard of death using inverse probability of treatment weighting of marginal structural models. The nonlinear relationship between month of switch and the 5-year survival probability, stratified by CD4 count at failure, was estimated with targeted maximum likelihood estimation. We adjusted for measured time-varying confounding by CD4 count, viral load, and visit frequency. Five-year mortality was estimated to be 10.5% (95% CI: 2.2, 18.8) for immediate switch and to be 26.6% (95% CI: 20.9, 32.3) for no switch (51.1% if CD4 count was <100 cells/mm3). The hazard of death was estimated to be 0.37 (95% CI: 0.30, 0.46) times lower if everyone had been switched immediately compared with never. The shorter the delay in switching, the lower the hazard of death—delaying 30–59 days reduced the hazard by 0.53 (95% CI: 0.43, 0.65) times and 60–119 days by 0.58 (95% CI: 0.49, 0.69) times, compared with no switch. Early treatment switch is particularly important for patients with low CD4 counts at failure

PROPEL: implementation of an evidence based pelvic floor muscle training intervention for women with pelvic organ prolapse: a realist evaluation and outcomes study protocol

Abstract Background Pelvic Organ Prolapse (POP) is estimated to affect 41%–50% of women aged over 40. Findings from the multi-centre randomised controlled “Pelvic Organ Prolapse PhysiotherapY” (POPPY) trial showed that individualised pelvic floor muscle training (PFMT) was effective in reducing symptoms of prolapse, improved quality of life and showed clear potential to be cost-effective. However, provision of PFMT for prolapse continues to vary across the UK, with limited numbers of women’s health physiotherapists specialising in its delivery. Implementation of this robust evidence from the POPPY trial will require attention to different models of delivery (e.g. staff skill mix) to fit with differing care environments. Methods A Realist Evaluation (RE) of implementation and outcomes of PFMT delivery in contrasting NHS settings will be conducted using multiple case study sites. Involving substantial local stakeholder engagement will permit a detailed exploration of how local sites make decisions on how to deliver PFMT and how these lead to service change. The RE will track how implementation is working; identify what influences outcomes; and, guided by the RE-AIM framework, will collect robust outcomes data. This will require mixed methods data collection and analysis. Qualitative data will be collected at four time-points across each site to understand local contexts and decisions regarding options for intervention delivery and to monitor implementation, uptake, adherence and outcomes. Patient outcome data will be collected at baseline, six months and one year follow-up for 120 women. Primary outcome will be the Pelvic Organ Prolapse Symptom Score (POP-SS). An economic evaluation will assess the costs and benefits associated with different delivery models taking account of further health care resource use by the women. Cost data will be combined with the primary outcome in a cost effectiveness analysis, and the EQ-5D-5L data in a cost utility analysis for each of the different models of delivery. Discussion Study of the implementation of varying models of service delivery of PFMT across contrasting sites combined with outcomes data and a cost effectiveness analysis will provide insight into the implementation and value of different models of PFMT service delivery and the cost benefits to the NHS in the longer term