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Introduction Home-based, virtually-supported care models may represent the most efficient and scalable approach to delivering prehabilitation services. However, virtual approaches to prehabilitation are understudied. This manuscript describes the protocol for an internal pilot randomised controlled trial of a virtually-delivered, multimodal prehabilitation intervention.Methods and analysis We will conduct a pragmatic, individual patient, internal pilot randomised controlled trial of home-based, virtually supported, multimodal prehabilitation compared with standard perioperative care in adults undergoing elective, inpatient thoracic, abdominal, pelvic and vascular surgery at five Canadian hospitals. Participants will be partially blinded; clinicians and outcome assessors will be fully blinded. The intervention consists of 3–12 weeks of a home-based, multimodal (exercise, nutrition and psychosocial support) prehabilitation programme supported through an online platform. The primary feasibility outcomes and their progression targets are (1) monthly recruitment of>6 participants at each centre, (2) intervention adherence of>75%, (3) retention of>90% of participants at the patient-reported primary outcome point of 30-days after surgery and (4) elicitation of patient, clinician and researcher-identified barriers to our pragmatic trial. A sample size of 144 participants will be adequate to estimate recruitment, adherence and retention rates with acceptable precision. All participants will be followed to either death or up to 1 year. As an internal pilot, if no substantive changes to the trial or intervention design are required, pilot participant outcome data will migrate, unanalysed by allocation, to the future full-scale trial.Ethics and dissemination Ethical approval has been granted by Clinical Trials Ontario (Project ID: 4479) and our ethics review board (Protocol Approval #20230399–01T). Results will be disseminated through presentations at scientific conferences, peer-reviewed publications, partner organisations and engagement of social and traditional media.Trial registration number ClinicalTrials.gov identifier NCT06042491. Protocol, V.1.2, dated 6 June 2024.

The COVID-19 pandemic increased the prevalence of mental health issues across the U.S. While therapists have been able to shift to telehealth delivery of mental healthcare, there has been a recent increase in the number of therapists on social media. Social media as a site of engagement has been feared by systems of power which regulate the ethics of therapists, and despite the influx of therapists online, these ethical guidelines remain under researched. Feminist geographers have explored theories and practices of care within different spaces, and especially in the wake of the pandemic, there is a need to conceptualize how therapists provide care within digital spaces and how this affects the delivery of mental healthcare. This study sampled 100 videos on the social media site, TikTok, for a content analysis using the hashtag #therapistsoftiktok. The videos were analyzed to uncover themes relating to how therapists provided care to the viewer. Four themes emerged in the analysis and showed that therapists provided care both directly and indirectly to the viewers. Direct care included providing psychoeducation to the viewers and offering validations/affirmations. Indirect care included normalizing therapy and humanizing the therapist, and these videos were interpreted to focus more on relationship building and addressing viewers' anxieties about therapy and therapists, which may allow viewers to engage in therapy in the future. This study identified ways that therapists are engaging in care work digitally, despite the admonishments and warnings from professional therapy boards. Ethical concerns still abound, as intimacy and relationship-building can occur across digital spaces. However, rather than simply abstaining from social media, therapists are engaging in resistant and creative ways to provide care and destigmatize mental health issues to a global audience.

Abstract Interaction of intense lasers with nm thick targets provides an attractive regime for the acceleration of ions of all types. Acceleration of heavy ions however is undermined in the presence of low charge contaminant species due to their higher charge-to-mass ratio. Here we show narrow-band acceleration of very heavy Au ions from ~15 nm Au foils driven by a sub-Petawatt laser, with spectral peaks of 1.5 ± 0.5 GeV at fluxes on the order of 1012 particles per steradian. 3D and 2D particle-in-cell simulations show a complex interplay between different acceleration mechanisms at different stages of the interaction, suggesting the spectrally peaked Au ion bunches stem from strong radiation pressure acceleration on a heavy-ion dominant plasma in the moments just before transparency, followed by an efficient acceleration due to transparency-enhanced mechanisms.

Abstract Background Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive disorder caused by mutations in the SMPD1 gene. This rarity contributes to misdiagnosis, delayed diagnosis and barriers to good care. There are no published national or international consensus guidelines for the diagnosis and management of patients with ASMD. For these reasons, we have developed clinical guidelines that defines standard of care for ASMD patients. Methods The information contained in these guidelines was obtained through a systematic literature review and the experiences of the authors in their care of patients with ASMD. We adopted the Appraisal of Guidelines for Research and Evaluation (AGREE II) system as method of choice for the guideline development process. Results The clinical spectrum of ASMD, although a continuum, varies substantially with subtypes ranging from a fatal infantile neurovisceral disorder to an adult-onset chronic visceral disease. We produced 39 conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. In addition, these guidelines have identified knowledge gaps that must be filled by future research. Conclusion These guidelines can inform care providers, care funders, patients and their carers about best clinical practice and leads to a step change in the quality of care for patients with ASMD with or without enzyme replacement therapy (ERT).

Recently it has been identified that our Moon had an extensive magnetosphere for several hundred million years soon after it was formed when the Moon was within 20 Earth Radii (RE) from the Earth. Some aspects of the interaction between the early Earth-Moon magnetospheres are investigated by mapping the interconnected field lines between the Earth and the Moon and investigating how the early lunar magnetosphere affects the magnetospheric dynamics within the coupled magnetospheres over time. So long as the magnetosphere of the Moon remains strong as it moves away from the Earth in the antialigned dipole configuration, the extent of the Earth’s open field lines decreases. As a result, at times it significantly changes the structure of the field-aligned current system, pushing the polar cusp significantly northward, and forcing magnetotail reconnection sites into the deeper tail region. In addition, the combined magnetospheres of the Earth and the Moon greatly extend the number of closed field lines enabling a much larger plasmasphere to exist and connecting the lunar polar cap with closed field lines to the Earth. That configuration supports the transfer of plasma between the Earth and the Moon potentially creating a time capsule of the evolution of volatiles with depth. This paper only touches on the evolution of the early Earth and Moon magnetospheres, which has been a largely neglected space physics problem and has great potential for complex follow-on studies using more advanced tools and due to the expected new lunar data coming in the next decade through the Artemis Program.

Summary: Introduction: Until recently, healthcare-associated E. coli bacteraemia was a neglected area of infection prevention and control (IPC), despite a 30-day mortality of 15–20%. Recently, the UK Department of Health (DH) introduced a target to reduce hospital-acquired E. coli bacteraemias by 50% over a five-year period. Following implementation of multifaceted and multidisciplinary interventions, the aim of this study was to determine its impact on achieving this target. Methods: From April 2017 to March 2022, consecutive hospital-acquired E. coli bacteraemic inpatients within Barts Health NHS Trust were prospectively studied. Using quality improvement methodology, and implementing the plan, do, study, act (PDSA) cycle at each stage, antibiotic prophylaxis for high-risk procedures were modified and ‘good practice’ interventions around medical devices introduced. Characteristics of bacteraemic patients were analysed and trends in bacteraemic episodes recorded. Statistical analysis was undertaken in Stata SE (version 16). Results: There were 770 patients and 797 episodes of hospital-acquired E. coli bacteraemias. Following a baseline of 134 episodes in 2017-18, this peaked at 194 in 2019-20 before dropping to 157 in 2020-21 and 159 in 2021-22. Most hospital-acquired E. coli bacteraemias occurred in those aged > 50, 551 (69.1%), with the highest proportion occurring in those age > 70, 292 (36.6%). Hospital-acquired E. coli bacteraemia occurred more commonly between October to December.Most episodes occurred in either medicine or care of the elderly patients, 345 (43.3%), specialist surgery, 141 (17.7%), haematology/oncology, 127 (15.9%) and patients requiring critical care, 108 (13.6%). The urinary tract, 336 (42.2%), both catheter and non-catheter associated, was the commonest sites of infection. 175 (22.0%) of E. coli bacteraemic isolates were extended spectrum beta lactamase (ESB) producing. Co-amoxiclav resistance was 315 (39.5%), ciprofloxacin resistance 246 (30.9%) and gentamicin resistance 123 (15.4%). At 7 days, 77 patients (9.7%; 95% CI 7.4–12.2%) died and by 30 days this had risen to 129 (16.2%; 95% CI 13.7–19.9%). Conclusion: Despite implementation of quality improvement (QI) interventions, it was not possible to achieve a 50% reduction from baseline although an 18% reduction was achieved from 2019-20 onwards. Our work highlights the importance of antimicrobial prophylaxis and medical device ‘good practice’. Over time, these interventions, if properly implemented, could further reduce healthcare-associated E. coli bacteraemic infection.

The soybean cyst nematode (SCN) [Heterodera glycines Ichinohe] is a devastating pathogen of soybean [Glycine max (L.) Merr.] that is rapidly becoming a global economic issue. Two loci conferring SCN resistance have been identified in soybean, Rhg1 and Rhg4; however, they offer declining protection. Therefore, it is imperative that we identify additional mechanisms for SCN resistance. In this paper, we develop a bioinformatics pipeline to identify protein–protein interactions related to SCN resistance by data mining massive-scale datasets. The pipeline combines two leading sequence-based protein–protein interaction predictors, the Protein–protein Interaction Prediction Engine (PIPE), PIPE4, and Scoring PRotein INTeractions (SPRINT) to predict high-confidence interactomes. First, we predicted the top soy interacting protein partners of the Rhg1 and Rhg4 proteins. Both PIPE4 and SPRINT overlap in their predictions with 58 soybean interacting partners, 19 of which had GO terms related to defense. Beginning with the top predicted interactors of Rhg1 and Rhg4, we implement a “guilt by association” in silico proteome-wide approach to identify novel soybean genes that may be involved in SCN resistance. This pipeline identified 1,082 candidate genes whose local interactomes overlap significantly with the Rhg1 and Rhg4 interactomes. Using GO enrichment tools, we highlighted many important genes including five genes with GO terms related to response to the nematode (GO:0009624), namely, Glyma.18G029000, Glyma.11G228300, Glyma.08G120500, Glyma.17G152300, and Glyma.08G265700. This study is the first of its kind to predict interacting partners of known resistance proteins Rhg1 and Rhg4, forming an analysis pipeline that enables researchers to focus their search on high-confidence targets to identify novel SCN resistance genes in soybean.

Abstract Background There is currently significant interest in assessing the role of oxygen in the radiobiological effects at ultra-high dose rates. Oxygen modulation is postulated to play a role in the enhanced sparing effect observed in FLASH radiotherapy, where particles are delivered at 40–1000 Gy/s. Furthermore, the development of laser-driven accelerators now enables radiobiology experiments in extreme regimes where dose rates can exceed 109 Gy/s, and predicted oxygen depletion effects on cellular response can be tested. Access to appropriate experimental enviroments, allowing measurements under controlled oxygenation conditions, is a key requirement for these studies. We report on the development and application of a bespoke portable hypoxia chamber specifically designed for experiments employing laser-driven sources, but also suitable for comparator studies under FLASH and conventional irradiation conditions. Materials and methods We used oxygen concentration measurements to test the induction of hypoxia and the maintenance capacity of the chambers. Cellular hypoxia induction was verified using hypoxia inducible factor-1α immunostaining. Calibrated radiochromic films and GEANT-4 simulations verified the dosimetry variations inside and outside the chambers. We irradiated hypoxic human skin fibroblasts (AG01522B) cells with laser-driven protons, conventional protons and reference 225 kVp X-rays to quantify DNA DSB damage and repair under hypoxia. We further measured the oxygen enhancement ratio for cell survival after X-ray exposure in normal fibroblast and radioresistant patient- derived GBM stem cells. Results Oxygen measurements showed that our chambers maintained a radiobiological hypoxic environment for at least 45 min and pathological hypoxia for up to 24 h after disconnecting the chambers from the gas supply. We observed a significant reduction in the 53BP1 foci induced by laser-driven protons, conventional protons and X-rays in the hypoxic cells compared to normoxic cells at 30 min post-irradiation. Under hypoxic irradiations, the Laser-driven protons induced significant residual DNA DSB damage in hypoxic AG01522B cells compared to the conventional dose rate protons suggesting an important impact of these extremely high dose-rate exposures. We obtained an oxygen enhancement ratio (OER) of 2.1 ± 0.1 and 2.5 ± 0.1 respectively for the AG01522B and patient-derived GBM stem cells for X-ray irradiation using our hypoxia chambers. Conclusion We demonstrated the design and application of portable hypoxia chambers for studying cellular radiobiological endpoints after exposure to laser-driven protons at ultra-high dose, conventional protons and X-rays. Suitable levels of reduced oxygen concentration could be maintained in the absence of external gassing to quantify hypoxic effects. The data obtained provided indication of an enhanced residual DNA DSB damage under hypoxic conditions at ultra-high dose rate compared to the conventional protons or X-rays.

Abstract Background Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). Method The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features of the disease. Results A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations: 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile neurological onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (70.9%) and dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score for each neurological form. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, except for ‘swallowing’ and ‘seizure’. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.4% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.9%), antidepressants (11.8%) and antacids (9.4%). Conclusion The proportion of participants at each age of neurological onset was relatively equal across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.

Abstract Background Longitudinal integrated clerkships (LICs) are an innovation in medical education that are often successfully implemented in general practice contexts. The aim of this study was to explore the experiences and perspectives of general practitioner (GP)-tutors on the impact of LICs on their practices, patients and the wider community. Methods GPs affiliated with the University of Limerick School of Medicine- LIC were invited to participate in in-depth interviews. Semi-structured interviews were conducted in person and over the phone and were based on a topic guide. The guide and approach to analysis were informed by symbiosis in medical education as a conceptual lens. Data were recorded, transcribed and analysed using an inductive thematic approach. Results Twenty-two GPs participated. Two main themes were identified from interviews: ‘roles and relationships’ and ‘patient-centred physicians’. Five subthemes were identified which were: ‘GP-role model’, ‘community of learning’, and ‘mentorship’, ‘student doctors’ and ‘serving the community’. Conclusion LICs have the potential to develop more patient-centred future doctors, who have a greater understanding of how medicine is practised in the community. The LIC model appears to have a positive impact on all stakeholders but their success hinges on having adequate support for GPs and resourcing for the practices.

Background The COVID-19 pandemic changed the way in which people were diagnosed and treated for cancer. We explored healthcare professional and patient perceptions of the main changes to colorectal cancer delivery during the COVID-19 pandemic and how they impacted on socioeconomic inequalities in care. Methods In 2020, using a qualitative approach, we interviewed patients (n = 15) who accessed primary care with colorectal cancer symptoms and were referred for further investigations. In 2021, we interviewed a wide range of healthcare professionals (n = 30) across the cancer care pathway and gathered national and local documents/guidelines regarding changes in colorectal cancer care. Results Changes with the potential to exacerbate inequalities in care, included: the move to remote consultations; changes in symptomatic triage, new COVID testing procedures/ways to access healthcare, changes in visitor policies and treatment (e.g., shorter course radiotherapy). Changes that improved patient access/convenience or the diagnostic process have the potential to reduce inequalities in care. Discussion Changes in healthcare delivery during the COVID-19 pandemic have the ongoing potential to exacerbate existing health inequalities due to changes in how patients are triaged, changes to diagnostic and disease management processes, reduced social support available to patients and potential over-reliance on digital first approaches. We provide several recommendations to help mitigate these harms, whilst harnessing the gains.

Abstract Developing compact ion accelerators using intense lasers is a very active area of research, motivated by a strong applicative potential in science, industry and healthcare. However, proposed applications in medical therapy, as well as in nuclear and particle physics demand a strict control of ion energy, as well as of the angular and spectral distribution of ion beam, beyond the intrinsic limitations of the several acceleration mechanisms explored so far. Here we report on the production of highly collimated ( $$\sim 0.2^{\circ }$$ ∼ 0 . 2 ∘ half angle divergence), high-charge (10s of pC) and quasi-monoenergetic proton beams up to $$\sim$$ ∼ 50 MeV, using a recently developed method based on helical coil targetry. In this concept, ions accelerated from a laser-irradiated foil are post-accelerated and conditioned in a helical structure positioned at the rear of the foil. The pencil beam of protons was produced by guided post-acceleration at a rate of $$\sim$$ ∼ 2 GeV/m, without sacrificing the excellent beam emittance of the laser-driven proton beams. 3D particle tracing simulations indicate the possibility of sustaining high acceleration gradients over extended helical coil lengths, thus maximising the gain from such miniature accelerating modules.

Background: People with cystic fibrosis (PWCF) have increased energy requirements. However, in recent years concerns have emerged regarding the ‘cystic fibrosis (CF) diet’ in terms of reliance on energy-dense, nutrient poor foods, which tend to be higher in saturated fat, sugar, and salt. These foods lack essential nutrients and are aetiologically linked with diet-related chronic diseases. The aim is to explore habitual dietary intakes in PWCF and (i) assess adherence to CF dietary guidelines and population specific healthy eating guidelines; (ii) derive a diet quality score and the inflammatory potential for the average diet consumed by PWCF and assess associations with patient reported outcome measures; (iii) assess drivers for current consumption patterns and enablers and barriers to eating a healthy diet. Methods: The aim is to recruit between 100-180 PWCF. A mixed methods study will be performed. Using three-day food diaries and food frequency questionnaires, aims (i) and (ii) will be addressed. The Dietary Approaches to Stop Hypertension (DASH) score and Healthy Eating Index-International (HEI-I) will derive diet quality scores. The Dietary Inflammatory Index (DII®) will ascertain inflammatory potential of the diet. Validated questionnaires will be used to report health related quality of life measures. Online focus groups and semi-structured interview with PWCF will address aim (iii). Conclusions: It is timely to revise dietary priorities and targets for CF. However, a greater understanding of what adults with CF currently consume and what they require in terms of nutrition and dietary guidance into the future is needed. In doing so, this research will help to clarify nutrition priorities and simplify the dietary aspects of CF treatment, thereby supporting adherence.

Abstract Background Computational prediction of protein function constitutes one of the more complex problems in Bioinformatics, because of the diversity of functions and mechanisms in that proteins exert in nature. This issue is reinforced especially for proteins that share very low primary or tertiary structure similarity to existing annotated proteomes. In this sense, new alignment-free (AF) tools are needed to overcome the inherent limitations of classic alignment-based approaches to this issue. We have recently introduced AF protein-numerical-encoding programs (TI2BioP and ProtDCal), whose sequence-based features have been successfully applied to detect remote protein homologs, post-translational modifications and antibacterial peptides. Here we aim to demonstrate the applicability of 4 AF protein descriptor families, implemented in our programs, for the identification enzyme-like proteins. At the same time, the use of our novel family of 3D–structure-based descriptors is introduced for the first time. The Dobson & Doig (D&D) benchmark dataset is used for the evaluation of our AF protein descriptors, because of its proven structural diversity that permits one to emulate an experiment within the twilight zone of alignment-based methods (pair-wise identity

ENTREVISTA COM O PROFESSOR DOUTOR JAMES GREEN, REALIZADA NO DIA 18 DE MAIO DE 2017, NA RESIDÊNCIA DA PROFESSORA DOUTORA LÚCIA VELLOSO MAURICIO, NA ZONA SUL DO RIO DE JANEIRO

Background Cancer is diagnosed and managed by multidisciplinary teams (MDTs) in the UK and worldwide, these teams meet regularly in MDT meetings (MDMs) to discuss individual patient treatment options. Rising cancer incidence and increasing case complexity have increased pressure on MDMs. Streamlining discussions has been suggested as a way to enhance efficiency and to ensure high-quality discussion of complex cases.Methods Secondary analysis of quantitative and qualitative data from a national survey of 1220 MDT members regarding their views about streamlining MDM discussions.Results The majority of participants agreed that streamlining discussions may be beneficial although variable interpretations of ‘streamlining’ were apparent. Agreement levels varied significantly by tumour type and occupational group. The main reason for opposing streamlining were concerns about the possible impact on the quality and safety of patient care. Participants suggested a range of alternative approaches for improving efficiency in MDMs in addition to the use of treatment protocols and pre-MDT meetings.Conclusions This work complements previous analyses in supporting the development of tumour-specific guidance for streamlining MDM discussions considering a range of approaches. The information provided about the variation in opinions between MDT for different tumour types will inform the development of these guidelines. The evidence for variation in opinions between those in different occupational groups and the reasons underlying these opinions will facilitate their implementation. The impact of any changes in MDM practices on the quality and safety of patient care requires evaluation.