Bioinformatic Analysis of Topoisomerase IIα Reveals Interdomain Interdependencies and Critical C-Terminal Domain Residues.

DNA Topoisomerase IIα (Top2A) is a nuclear enzyme that is a cancer drug target, and there is interest in identifying novel sites on the enzyme to inhibit cancer cells more selectively and to reduce off-target toxicity. The C-terminal domain (CTD) is one potential target, but it is an intrinsically disordered domain, which prevents structural analysis. Therefore, we set out to analyze the sequence of Top2A from 105 species using bioinformatic analysis, including the PSICalc algorithm, Shannon entropy analysis, and other approaches. Our results demonstrate that large (10th-order) interdependent clusters are found including non-proximal positions across the major domains of Top2A. Further, CTD-specific clusters of the third, fourth, and fifth order, including positions that had been previously analyzed via mutation and biochemical assays, were identified. Some of these clusters coincided with positions that, when mutated, either increased or decreased relaxation activity. Finally, sites of low Shannon entropy (i.e., low variation in amino acids at a given site) were identified and mapped as key positions in the CTD. Included in the low-entropy sites are phosphorylation sites and charged positions. Together, these results help to build a clearer picture of the critical positions in the CTD and provide potential sites/regions for further analysis.

'This is silent murder' - are we medicalising human distress caused by the reality of life as an asylum seeker in the UK?

The number of displaced people, including asylum seekers and refugees, in the UK continues to rise. This article highlights findings from two participatory community listening exercises on the topic of health of displaced people.

LIGHTSITE III: 13-Month Efficacy and Safety Evaluation of Multiwavelength Photobiomodulation in Nonexudative (Dry) Age-Related Macular Degeneration Using the Lumithera Valeda Light Delivery System.

PURPOSE: The LIGHTSITE III study evaluated multiwavelength photobiomodulation (PBM) therapy in nonexudative (dry) age-related macular degeneration (AMD) using the LumiThera Valeda Light Delivery System. METHODS: LIGHTSITE III is a randomized, controlled trial to assess the safety and effectiveness of PBM in dry AMD. Subjects were given multiwavelength PBM (590, 660, and 850 nm) or Sham treatment delivered in a series of nine sessions over 3 to 5 weeks every four months over 24 months. Subjects were assessed for efficacy and safety outcomes. Data from the 13-month analysis are presented in this report. RESULTS: A total of 100 subjects (148 eyes) with dry AMD were randomized. LIGHTSITE III met the primary efficacy best-corrected visual acuity endpoint with a significant difference between PBM (n = 91 eyes) and Sham (n = 54 eyes) groups (Between group difference: 2.4 letters (SE 1.15), CI: -4.7 to -0.1, P = 0.02) (PBM alone: 5.4 letters (SE 0.96), CI: 3.5 to 7.3, P < 0.0001; Sham alone: 3.0 letters (SE 1.13), CI: 0.7-5.2, P < 0.0001). The PBM group showed a significant decrease in new onset geographic atrophy ( P = 0.024, Fisher exact test, odds ratio 9.4). A favorable safety profile was observed. CONCLUSION: LIGHTSITE III provides a prospective, randomized, controlled trial showing improved clinical and anatomical outcomes in intermediate dry AMD following PBM therapy.

Non-Invasive Treatment of Early Diabetic Macular Edema by Multiwavelength Photobiomodulation with the Valeda Light Delivery System.

Purpose: Diabetes is associated with ocular complications including diabetic macular edema (DME). Current therapies are invasive and include repeated intravitreal injections and laser therapy. Photobiomodulation (PBM) is a treatment (Tx) that utilizes selected wavelengths of light to induce cellular benefits including reduction of inflammation and edema. This single-center, open-label, post-hoc analysis explored the utility of multiwavelength PBM in subjects with DME. Methods: Analysis included review of data from patients undergoing standard clinical care with an approved and marketed PBM medical device, the Valeda® Light Delivery System. Subjects with early-stage DME with good vision (Best-corrected visual acuity (BCVA) > 20/25, logMAR > 0.1) were evaluated in clinic and treated with one series of multiwavelength PBM (Tx delivered 3x/week over 3-4 weeks; total of 9 Tx sessions). Clinical, anatomical, and safety parameters were assessed in addition to subjective quality of life. Results: A total of 30 eyes (19 subjects) were analyzed. Subjects were predominately male (68.4%) with a mean age of 56 ± 14 years. Reductions in central retinal thickness (CRT), resolution of intraretinal fluid (IRF) and improvement in diabetic retinopathy severity scale scores were observed following PBM treatment in select patients. Baseline BCVA remained stable over the follow-up observation period of 3 months post-PBM. Approximately 64% of patients reported subjective improvements in their ocular condition and decreased influence in everyday life. Detailed OCT evaluations confirmed no safety issues related to phototoxicity up to 16 months. Conclusion: Early-stage DME subjects treated with Valeda multiwavelength PBM showed improvements in clinical and anatomical parameters. The Valeda multiwavelength PBM approach demonstrates a favorable safety profile with no signs of phototoxicity following an independent OCT review. PBM therapy may offer an alternative, non-invasive treatment strategy with a unique mechanism and modality for patients with early-stage DME.

Cross-validation of standardisation techniques at ANSTO using cobalt-60 and learnings from the presence and identification of non-gamma-ray emitting impurities.

To fulfil the technical requirements for accreditation to ISO/IEC 17025, the end-to-end validation of all processes associated with standardising 60Co, including gravimetric source dispensing, primary standardisation by the 4π(LS)ß-γ coincidence and live-timed anti-coincidence extrapolation techniques, and impurity determination were performed and documented. Pure-beta-emitting impurities in a 60Co stock solution were identified. The impact of such impurities on measurement by liquid scintillation counting and comparison in the ESIR are discussed. A fresh 60Co source was produced, standardised, and compared using the SIR.

A systematic review of models of patient engagement in the development and life cycle management of medicines.

There is currently no universally agreed code of practice for patient engagement (PE), and existing guidelines do not fully cover the scope across medicine development and subsequent life cycle management. This review conceptualises the meaning and summarises the current models of PE. A systematic literature review was conducted and analysed by thematic synthesis. Eight themes were identified as components of how to achieve meaningful PE, and five were identified for where to engage with patients in drug development. This review provides summative guidance for stakeholders intending to introduce PE and establishes a starting point for the development of a universal code of practice.

LIGHTSITE II Randomized Multicenter Trial: Evaluation of Multiwavelength Photobiomodulation in Non-exudative Age-Related Macular Degeneration.

INTRODUCTION: Photobiomodulation (PBM) represents a potential treatment for non-exudative age-related macular degeneration (AMD). PBM uses wavelengths of light to target components of the mitochondrial respiratory chain to improve cellular bioenergetic outputs. The aim of this study was to further investigate the effects of PBM on clinical, quality of life (QoL) and anatomical outcomes in subjects with intermediate stage non-exudative AMD. METHODS: The multicenter LIGHTSITE II study was a randomized clinical trial evaluating safety and efficacy of PBM in intermediate non-exudative AMD. The LumiThera Valeda® Light Delivery System delivered multiwavelength PBM (590, 660 and 850 nm) or sham treatment 3 × per week over 3-4 weeks (9 treatments per series) with repeated treatments at baseline (BL), 4 and 8 months. Subjects were enrolled with 20/32 to 20/100 best-corrected visual acuity (BCVA) and no central geographic atrophy (GA) within the central fovea (500 µm). RESULTS: LIGHTSITE II enrolled 44 non-exudative AMD subjects (53 eyes). PBM-treated eyes showed statistically significant improvement in BCVA at 9 months (n = 32 eyes, p = 0.02) with a 4-letter gain in the PBM-treated group versus a 0.5-letter gain in the sham-treated group (ns, p < 0.1) for patients that received all 27 PBM treatments (n = 29 eyes). Approximately 35.3% of PBM-treated eyes showed ≥ 5-letter improvement at 9 months. Macular drusen volume was not increased over time in the PBM-treated group but did show increases in the sham-treated group. While PBM and sham groups both showed GA lesion growth in the trial period, there was 20% less growth in the PBM group over 10 months, suggesting potential disease-modifying effects. No safety concerns or signs of phototoxicity were observed. CONCLUSION: These results confirm previous clinical testing of multiwavelength PBM and support treatment with Valeda as a novel therapy with a unique mechanism of action as a potential treatment for non-exudative AMD. TRIAL REGISTRATION: Clinicaltrial.Gov Registration Identifier: NCT03878420.

The Remarkable Outer Hair Cell: Proceedings of a Symposium in Honour of W. E. Brownell.

In 1985, Bill Brownell and colleagues published the remarkable observation that cochlear outer hair cells (OHCs) express voltage-driven mechanical motion: electromotility. They proposed OHC electromotility as the mechanism for the elusive "cochlear amplifier" required to explain the sensitivity of mammalian hearing. The finding and hypothesis stimulated an explosion of experiments that have transformed our understanding of cochlear mechanics and physiology, the evolution of hair cell structure and function, and audiology. Here, we bring together examples of current research that illustrate the continuing impact of the discovery of OHC electromotility.

Commercial weight management programmes for patients living with overweight or obesity prior to elective orthopaedic surgery: an evidence review.

BACKGROUND: Increased body mass index is associated with increased operative risk during elective joint replacement surgery. Commercial weight management programmes are designed to achieve weight loss. It is not known whether commercial weight management programmes are effective at achieving weight loss in patients awaiting planned hip or knee replacement surgery, or whether achieving significant planned weight loss prior to surgery is associated with changes in surgical outcome. METHODS: A systematic literature search of seven databases was conducted. Reference lists and grey literature were searched, including commercial weight management programme and medical association websites. Four relevant primary interventional studies were identified. RESULTS: There is weak, low-quality evidence from four small studies, of which three demonstrated that commercial weight management programmes initiated between 3 and 6 months prior to elective joint replacement surgery are associated with a statistically significant weight loss and body mass index reduction. There is a weak evidence from two studies that peri- and post-operative complications are similar between control and commercial weight management programme groups. CONCLUSION: There is a paucity of studies investigating commercial weight management programmes aiming to reduce weight in patients living with overweight or obesity awaiting total joint replacement. Further, high-quality research is urgently needed.

Duodenal volvulus: a rare cause of small bowel obstruction.

Small bowel volvulus is a rare but life-threatening emergency. Volvulus of the duodenum is even rarer without the presence of predisposing factors. The clinical presentation is vague, including abdominal pain, nausea and vomiting, prompt diagnosis of volvulus therefore relies heavily on radiographs. The treatment options lie between conservative or surgical management, where the decision is influenced by the patient and their presentation. This case is of a 100-year-old female with an extensive surgical and medical background presenting with signs of small bowel obstruction. With the help of imaging, a rare case of duodenal volvulus was diagnosed but managed conservatively due to the patient's background, age and personal wishes.

Rapid observations of ocean dynamics and stratification along a steep island coast during Hurricane María.

Hurricanes are extreme storms that affect coastal communities, but the linkages between hurricane forcing and ocean dynamics remain poorly understood. Here, we present full water column observations at unprecedented resolution from the southwest Puerto Rico insular shelf and slope during Hurricane María, representing a rare set of high-frequency, subsurface, oceanographic observations collected along an island margin during a hurricane. The shelf geometry and orientation relative to the storm acted to stabilize and strengthen stratification. This maintained elevated sea-surface temperatures (SSTs) throughout the storm and led to an estimated 65% greater potential hurricane intensity contribution at this site before eye passage. Coastal cooling did not occur until 11 hours after the eye passage. Our findings present a new framework for how hurricane interaction with insular island margins may generate baroclinic processes that maintain elevated SSTs, thus potentially providing increased energy for the storm.

The effect of intestinal microbiota dysbiosis on growth and detection of carbapenemase-producing Enterobacterales within an in vitro gut model.

BACKGROUND: Carbapenemase-producing Enterobacterales (CPE) can colonize the gut and are of major clinical concern. Identification of CPE colonization is problematic; there is no gold-standard detection method, and the effects of antibiotic exposure and microbiota dysbiosis on detection are unknown. AIM: Based on a national survey we selected four CPE screening assays in common use. We used a clinically reflective in vitro model of human gut microbiota to investigate the performance of each test to detect three different CPE strains under different, clinically relevant antibiotic exposures. METHODS: Twelve gut models were seeded with a pooled faecal slurry and exposed to CPE either before, after, concomitant with, or in the absence of piperacillin-tazobactam (358 mg/L, 3 × daily, seven days). Total Enterobacterales and CPE populations were enumerated daily. Regular screening for CPE was performed using Cepheid Xpert® Carba-R molecular test, and with Brilliance™ CRE, Colorex™ mSuperCARBA and CHROMID® CARBA SMART agars. FINDINGS: Detection of CPE when the microbiota are intact is problematic. Antibiotic exposure disrupts microbiota populations and allows CPE proliferation, increasing detection. The performances of assays varied, particularly with respect to different CPE strains. The Cepheid assay performed better than the three agar methods for detecting a low level of CPE within an intact microbiota, although performance of all screening methods was comparable when CPE populations increased in a disrupted microbiota. CONCLUSION: CPE strains differed in their dynamics of colonization in an in vitro gut model and in their subsequent response to antibiotic exposure. This affected detection by molecular and screening methods, which has implications for the sensitivity of CPE screening in healthcare settings.

Perceptual reasoning skills mediate the relationship between attention and math proficiency in individuals with a neurodevelopmental condition.

BACKGROUND: An important component of academic success in typically developing students is the development of math skills, which is associated with attention and perceptual reasoning (PR) skills. For children with a neurodevelopmental condition (NDC), the relationship is confounded by diagnostic-specific cognitive characteristics. Specifically, enhanced PR is specific to individuals with Autism Spectrum Disorder (ASD). AIMS: The purpose of this study was to test: (i) a mediation model where PR skills would mediate the relationship between attention and math proficiency for students with an NCD, and (ii) whether this mediation model is moderated by a diagnostic profile. METHODS AND PROCEDURES: One hundred and thirty-seven students with an NDC participated in a school-based study examining the effectiveness of using a standardized measure of attention in predicting math capabilities. OUTCOMES AND RESULTS: PR mediated the relationship between attention and math proficiency for students diagnosed with an NDC. However, the model was not moderated by diagnostic profile. CONCLUSIONS AND IMPLICATIONS: The results of this study provide a better understanding of the roles of higher-level cognitive ability specific to students with NDCs. Additionally, the superior PR skills demonstrated by the ASD sample further supports the research suggesting this population possesses cognitive strengths in this domain.

A non-randomised pilot study of the Solutions for Medication Adherence Problems (S-MAP) intervention in community pharmacies to support older adults adhere to multiple medications.

BACKGROUND: Older patients prescribed multiple medications commonly experience difficulties with adherence. High-quality evidence on interventions targeting older patients is lacking. Theory is rarely used to tailor adherence solutions. This study aimed to pilot test a novel intervention, developed using the Theoretical Domains Framework, which guides community pharmacists in identifying adherence barriers and delivering tailored solutions (behaviour change techniques). Key study procedures (e.g. recruitment, data collection) for a future randomised controlled trial (cRCT) were also assessed. METHODS: Using purposive sampling, this non-randomised pilot study aimed to recruit 12 community pharmacies (six in Northern Ireland; six in London, England). Pharmacists were trained to deliver the intervention to non-adherent older patients (maximum 10 per pharmacy; target n = 60-120) aged ≥ 65 years (reduced to 50 years due to recruitment challenges) and prescribed ≥ 4 regular medicines. The intervention, guided by an iPad web-application, was delivered over 3-4 face-to-face or telephone sessions, tailored to specific barriers to adherence. We assessed the feasibility of collecting adherence data (primary outcome: self-report and dispensing records), health-related quality of life (HRQOL) and unplanned hospitalisations (secondary outcomes) at baseline and 6-months. The final decision on progressing to a cRCT, using pre-defined 'stop-amend-go' criteria, is presented. RESULTS: Fifteen pharmacists from 12 pharmacies were recruited and trained. One pharmacy subsequently dropped out. Sixty patients were recruited (meeting the 'Amend' progression criteria), with 56 receiving the intervention. Adherence barriers were identified for 55 patients (98%) and a wide range of behaviour change solutions delivered (median: 5 per patient). Self-report and dispensing adherence data were available for 37 (61.7%) and 44 (73.3%) patients, respectively. HRQOL data were available for 35 (58.3%) patients. GP-reported and self-reported hospitalisations data were available for 47 (78.3%) and 23 (38.3%) patients, respectively. All progression concepts were met (nine 'Go' and three 'Amend' criteria). CONCLUSION: This study demonstrates the feasibility of key study procedures (e.g. pharmacy recruitment) and delivery of a tailored adherence intervention in community pharmacies. However, modifications are required to enhance issues identified with patient recruitment, retention and missing data. A future definitive cRCT will explore the effectiveness of the intervention. TRIAL REGISTRATION: ISRCTN, ISRCTN73831533 , Registered 12 January 2018.

The importance of the laser pulse-ablator interaction dynamics prior to the ablation plasma phase in inertial confinement fusion studies.

This work presents studies which demonstrate the importance of the very early heating dynamics of the ablator long before the ablation plasma phase begins in laser driven inertial confinement fusion (ICF) studies. For the direct-drive fusion concept using lasers, the development of perturbations during the thermo-elasto-plastic (TEP) and melting phases of the interaction of the laser pulse with the ablator's surface may act as seeding to the subsequent growth of hydro-dynamic instabilities apparent during the acceleration phase of the interaction such as for instance the Rayleigh-Taylor and the Richtmyer-Meshkov, which strongly affect the implosion dynamics of the compression phase. The multiphysics-multiphase finite-element method (FEM) simulation results are experimentally validated by advanced three-dimensional whole-field dynamic imaging of the surface of the ablator allowing for a transverse to the surface spatial resolution of only approximately 1 nm. The study shows that the TEP and melting phases of the interaction are of crucial importance since transverse perturbations of the ablator's surface can reach tens of nanometres in amplitude within the TEP and melting phases. Such perturbations are of Rayleigh type and are transferred from the ablator to the substrate from the very first moments of the interaction. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 1)'.

Correction to: Lean mass and lower limb muscle function in relation to hip strength, geometry and fracture risk indices in community-dwelling older women.

The original version of this article, published on 14 December 2018, unfortunately contained a mistake.

Development of a defined compost system for the study of plant-microbe interactions.

Plant growth promoting rhizobacteria can improve plant health by providing enhanced nutrition, disease suppression and abiotic stress resistance, and have potential to contribute to sustainable agriculture. We have developed a sphagnum peat-based compost platform for investigating plant-microbe interactions. The chemical, physical and biological status of the system can be manipulated to understand the relative importance of these factors for plant health, demonstrated using three case studies: 1. Nutrient depleted compost retained its structure, but plants grown in this medium were severely stunted in growth due to removal of essential soluble nutrients - particularly, nitrogen, phosphorus and potassium. Compost nutrient status was replenished with the addition of selected soluble nutrients, validated by plant biomass; 2. When comparing milled and unmilled compost, we found nutrient status to be more important than matrix structure for plant growth; 3. In compost deficient in soluble P, supplemented with an insoluble inorganic form of P (Ca3(PO4)2), application of a phosphate solubilising Pseudomonas strain to plant roots provides a significant growth boost when compared with a Pseudomonas strain incapable of solubilising Ca3(PO4)2. Our findings show that the compost system can be manipulated to impose biotic and abiotic stresses for testing how microbial inoculants influence plant growth.