Wastewater monitoring of human and avian influenza A viruses in Northern Ireland: a genomic surveillance study.

BACKGROUND: Influenza A viruses (IAVs) are significant pathogens of humans and other animals. Although endemic in humans and birds, novel IAV strains can emerge, jump species, and cause epidemics, like the latest variant of H5N1. Wastewater-based epidemiology (WBE) has been shown capable of detecting human IAVs. We aimed to assess whether whole-genome sequencing (WGS) of IAVs from wastewater is possible and can be used to discriminate between circulating strains of human and any non-human IAVs, such as those of avian origin. METHODS: Using a pan-IAV RT-quantitative PCR assay, six wastewater treatment works (WWTWs) across Northern Ireland were screened from Aug 1 to Dec 5, 2022. A nanopore WGS approach was used to sequence RT-qPCR-positive samples. Phylogenetic analysis of sequences relative to currently circulating human and non-human IAVs was performed. For comparative purposes, clinical data (PCR test results) were supplied by The Regional Virus Laboratory, Belfast Health and Social Care Trust (Belfast, Northern Ireland, UK). FINDINGS: We detected a dynamic IAV signal in wastewater from Sept 5, 2022, onwards across Northern Ireland, which did not show a clear positive relationship with the clinical data obtained for the region. Meta (mixed strain) whole-genome sequences were generated from wastewater samples displaying homology to only human and avian IAV strains. The relative proportion of IAV reads of human versus avian origin differed across time and sample site. A diversity in subtypes and lineages was detected (eg, H1N1, H3N2, and several avian). Avian segment 8 related to those found in recent H5N1 clade 2.3.4.4b was identified. INTERPRETATION: WBE affords a means to monitor circulating human and avian IAV strains and provide crucial genetic information. As such, WBE can provide rapid, cost-effective, year-round One Health surveillance to help control IAV epidemic and pandemic-related threats. However, optimisation of WBE protocols are necessary to ensure observed wastewater signals not only correlate with clinical case data, but yield information on the wider environmental pan-influenz-ome. FUNDING: Department of Health for Northern Ireland.

High absorptivity nanotextured powders for additive manufacturing.

The widespread application of metal additive manufacturing (AM) is limited by the ability to control the complex interactions between the energy source and the feedstock material. Here, we develop a generalizable process to introduce nanoscale grooves to the surface of metal powders which increases the powder absorptivity by up to 70% during laser powder bed fusion. Absorptivity enhancements in copper, copper-silver, and tungsten enable energy-efficient manufacturing, with printing of pure copper at relative densities up to 92% using laser energy densities as low as 83 joules per cubic millimeter. Simulations show that the enhanced powder absorptivity results from plasmon-enabled light concentration in nanoscale grooves combined with multiple scattering events. The approach taken here demonstrates a general method to enhance the absorptivity and printability of reflective and refractory metal powders by changing the surface morphology of the feedstock without altering its composition.

Safety protocols, precautions, and countermeasures aboard the International Space Station (ISS) to prevent ocular injury.

The International Space Station (ISS) is a $100 billion epicenter of human activity in the vacuum of space, displaying mankind's collective endeavor to explore the cosmic frontier. Even within the marvels of technological sophistication aboard the ISS, the human eye remains a highly vulnerable structure. In the absence of multiple layers of protection and risk assessments, crewmembers would face a substantial increase in vulnerability to ocular injury. Aside from stringent preflight screening criteria for astronauts, the ISS is equipped with ophthalmic medications, environmental control and life support systems (e.g., humidity regulation, carbon dioxide removal, pressurized device regulators), and radiation protection to reduce ocular injury. Moreover, additional countermeasures are currently being developed to mitigate the effects of spaceflight-associated neuro-ocular syndrome (SANS) and lunar dust toxicity for the Artemis Program missions. The success of future endeavors hinges not only on continued technological innovation, but also respecting the intricate interplay between human physiology and the extraterrestrial environments. Establishing habitations on the Moon and Mars, as well as NASA's Gateway Program (humanity's first space station around the Moon), will introduce a new set of challenges, underscoring the necessity for continuous insights into ocular health in space. We discuss the safety protocols, precautions, and countermeasures implemented on the ISS to prevent ocular injury - an aspect often overshadowed by the grandeur of space exploration.

Listening to the Voice of the Patient in RSV Research.

Patient and public involvement in research refers to patients or caregivers with disease experience contributing to the design, conduct or dissemination of results from research. Patient and public involvement has given rise to new fields in healthcare-oriented research and has the potential to transform infectious diseases through interventional trials. Our recommendations and best practices from years of organizing respiratory syncytial virus parent networks are provided.

HER2-positive grade 1 invasive carcinomas of the breast.

AIMS: The American Society of Clinical Oncology and College of American Pathologists HER2-guidelines recommend repeat testing for most grade 1 mammary carcinomas that are HER2-positive in the core biopsy. This study aimed to assess the value of repeat HER2-testing and the histological features of HER2-positive grade 1 carcinomas. METHODS AND RESULTS: A case-series of HER2-results of grade 1 carcinomas was conducted of patients with no pre-operative systemic treatment over a 5-year period. HER2-positive carcinomas had histological review. Twelve HER2-positive carcinomas were initially reported as grade 1. On review, two were reclassified as grade 2. The remaining 10 carcinomas represented 2% of the 508 grade 1 carcinomas. Eight HER2-positive grade 1 carcinomas from other years were also studied. HER2-positive carcinomas more often had marked nuclear pleomorphism (50 versus 6%) and were more often oestrogen receptor-negative (17 versus 0.8%) and progesterone receptor-negative (28 versus 8%) compared with HER2-negative grade 1 carcinomas. Six carcinomas that were HER2 3+ in the core biopsy were also 3+ on repeat assessment. Five of seven carcinomas that were 2+ amplified in the core biopsy were also HER2-positive in the excision. CONCLUSIONS: HER2-positive grade 1 carcinomas are uncommon, and more often have marked nuclear pleomorphism and lack oestrogen receptor and progesterone receptor expression compared with HER2-negative grade 1 carcinomas. A HER2-poitive result in the core biopsy was confirmed in 11 of 13 tumours that had repeat testing.

Development of a 3D-printed phantom for total skin electron therapy dose assessment.

PURPOSE: Total skin electron therapy (TSET) is a complex radiotherapy technique, posing challenges in commissioning and quality assurance (QA), especially due to significant variability in patient body shapes. Previous studies have correlated dose with factors such as obesity index, height, and gender. However, current treatment planning systems cannot simulate TSET plans, necessitating heavy reliance on QA methods using standardized anthropomorphic phantoms and in-vivo dosimetry. Given the relatively few studies on rotational techniques, comprehensive data in commissioning could streamline the process. METHODS: Developing a full-body phantom would enable a more thorough TSET commissioning process, including testing for position-specific dose distributions and comprehensive measurements across all body surfaces, unlike the typical torso-only phantoms. This was created using digital modeling software, fabricated using 3D-printing FDM technology, and filled with tissue-equivalent gelatine. The phantom was positioned at an SSD of 340 cm and irradiated with a standard rotational TSET plan using the 6E HDTSE mode on a Varian TrueBeam linac at gantry angles of ± 18° from the horizontal. The dose was measured at over 50 points across the surface using Gafchromic EBT3 film. RESULTS: Dose distributions were generally consistent with existing literature values from in-vivo dosimetry, with several position-specific differences identified, including the hands and scalp compared to conventional positions. Hotspots were observed for the mid-dorsum of the foot and nose, with areas under 80% of the dose identified as the soles of the feet, perineum, vertex of the scalp, top of the shoulder, and palm of the hand. Additionally, analysis using an interpolated dose heatmap found that 90% of the pixel area received a dose within 10% of the prescribed dose, indicating good uniformity with the commissioned technique. CONCLUSIONS: With high agreement with the current literature, a 3D-printed phantom proves effective for measuring doses in areas typically unmeasurable in TSET commissioning.

Bilateral paramedian thalamic infarction in the setting of uncontrolled atrial fibrillation with rapid ventricular response.

This case report outlines the first reported case of bilateral paramedian thalamic infarct, likely stemming from a rare artery of Percheron (AOP) variant, secondary to uncontrolled atrial fibrillation with rapid ventricular response. We underscore the importance of considering hypoperfusion due to decreased cerebral perfusion as a potential mechanism in cryptogenic AOP infarcts, challenging the conventional association with embolic etiology. This report contributes to the limited literature on AOP infarctions, emphasizing the need for heightened awareness among healthcare providers for diverse clinical presentations and potential etiologies to improve diagnosis and management, ultimately enhancing patient outcomes.

The impact of real-time feedback on ventilation quality during out-of-hospital cardiac arrest: A before-and-after study.

INTRODUCTION: Ventilations are a critical component of cardiopulmonary resuscitation (CPR). There is conflicting evidence, however, on the most appropriate method of ventilation during cardiac arrest management. Recent evidence has suggested that regardless of the optimal ventilation strategy, ventilations are often not delivered compliant with guideline recommendations. Recent technological advancements have allowed for accurate measurement and real-time feedback of ventilation rate and volume during resuscitation. Simulation studies have found significant improvements in ventilations with the use of real-time feedback during simulated cardiac arrest. The use of feedback has not been studied in clinical practice. The objective of this study was to determine whether the use of real-time feedback improves compliance with pre-defined targets for ventilation rate and volume during out-of-hospital cardiac resuscitation. METHODS: This was a before-and-after study with four paramedic services in Ontario, Canada. We enrolled adult, out-of-hospital cardiac arrest (OHCA) patients where the ZOLL Accuvent® device was utilized to measure ventilation rate and volume. In the before phase (without feedback), the Accuvent® was used to measure ventilations, however, providers were blinded to the real-time feedback. In the after phase (with feedback), the feedback dashboard was activated and providers used the real-time feedback to guide their ventilations. All other aspects of resuscitation remained consistent throughout the study. The main objective of the study was to compare the proportion of each case that was compliant with pre-defined ventilation targets with real-time feedback and without real-time feedback. We also examined the use of advanced airways on ventilation quality and examined for associations between ventilation parameters and return of circulation. RESULTS: We enrolled 412 patients in the study (191 in the before phase without feedback and 221 in the after phase with feedback). Overall, we found significant improvements in both ventilation rate and volume in the after phase (with real-time feedback) compared to the before phase (without real-time feedback). We did not find any differences in ventilation compliance with or without advanced airways, or intra-arrest or post-cardiac arrest. CONCLUSION: The use of real-time feedback was associated with an increased proportion of ventilations that were compliant with pre-defined targets during cardiac resuscitation. Further work is required to improve the use of real-time ventilation feedback, and to determine the impact of ventilations on patient outcomes.

Engineering therapeutical extracellular vesicles for clinical translation.

Cell-based therapies are revolutionizing medicine by replacing or modifying dysfunctional cells with healthy cells or engineered derivatives, offering disease reversal and cure. One promising approach is using cell-derived extracellular vesicles (EVs), which offer therapeutic benefits similar to cell transplants without the biosafety risks. Although EV applications face challenges like limited production, inadequate therapeutic loading, and poor targeting efficiency, recent advances in bioengineering have enhanced their effectiveness. Herein, we summarize technological breakthroughs in EV bioengineering over the past 5 years, highlighting their improved therapeutic functionalities and potential clinical prospects. We also discuss biomanufacturing processes, regulation, and safety considerations for bioengineered EV therapies, emphasizing the significance of establishing robust frameworks to ensure translation capability, safety, and therapeutic effectiveness for successful clinical adoption.

Revisiting surgical margins for invasive breast cancer patients treated with breast conservation therapy - Evidence for adopting a 1 mm negative width.

Clinical trials have demonstrated conclusively the non-inferiority of breast-conserving surgery followed by breast radiation therapy (BCT) compared with mastectomy for the treatment of early-stage invasive breast cancer (BC). The definition of the required surgical margin to ensure adequate removal of the cancer by BCT to obtain an acceptable low local recurrence (LR) rate remains controversial. Meta-analyses published by Houssami et al. in 2010 and 2014 demonstrated significantly lower LR rates for patients with a negative margin compared with those with positive (ink on tumour) or close (defined as ≤1 mm or ≤2 mm) margins. Neither meta-analysis addressed whether 'no ink on tumour' was adequate to define a negative margin because of a lack of data. Nevertheless, in 2014, the Society of Surgical Oncology (SSO) and the American Society for Radiation Oncology (ASTRO) with advice from pathologists reviewed these data together and published guidelines recommending that a margin of 'no ink on tumour' was sufficient to define a clear margin in BCT. Subsequently, clinical practice has varied with some national and international bodies endorsing 'no ink on tumour', whilst others have recommended a ≥1 mm margin as acceptable margins for BCT. A more recent meta-analysis conducted by Bundred and colleagues in 2022 did have sufficient data to compare 'no ink on tumour' and 1 mm and concluded that 1 mm rather than 'no ink on tumour', should be used as a minimum negative margin, and recommended that international guidelines be revised. The current review presents a balanced assessment of the evidence relating margin width and local recurrence after BCT. This review concludes that guidelines should consider re-defining a negative margin as ≥1 mm rather than 'no ink on tumour' in the context of BCT, recognising there will be variation to tailor therapy for any individual patient situation to ensure optimal patient care.

Clozapine, relapse, and adverse events: a 10-year electronic cohort study in Canada.

BACKGROUND: Clozapine is the most effective medication for treatment-resistant psychoses, but the balance of benefits and risks is understudied in real-world settings. AIMS: To examine the relative re-hospitalisation rates for mental health relapse and adverse events associated with clozapine and other antipsychotics in adult and child/youth cohorts. METHOD: Data were obtained from the Canadian Institute of Health Information for adults (n = 45 616) and children/youth (n = 1476) initially hospitalised for mental health conditions in British Columbia, Manitoba and Saskatchewan from 2008 to 2018. Patient demographics and hospitalisations were linked with antipsychotic prescriptions dispensed following the initial visit. Recurrent events survival analysis for relapse and adverse events were created and compared between clozapine and other antipsychotics. RESULTS: In adults, clozapine was associated with a 14% lower relapse rate versus other drugs (adjusted hazard ratio: 0.86, 95% CI: 0.83-0.90) over the 10-year follow-up. In the first 21 months, the relapse rate was higher for clozapine but then reversed. Over 1000 person-months, clozapine-treated adults could be expected to have 38 relapse hospitalisations compared with 45 for other drugs. In children/youth, clozapine had a 38% lower relapse rate compared with other antipsychotic medications (adjusted hazard ratio: 0.62, 95% CI: 0.49-0.78) over the follow-up period. This equates to 29 hospitalisations for clozapine and 48 for other drugs over 1000 person-months. In adults, clozapine had a higher risk for adverse events (hazard ratio: 1.34, 95% CI: 1.18-1.54) over the entire follow-up compared with other antipsychotics. This equates to 1.77 and 1.30 hospitalisations over 1000 person-months for clozapine and other drugs, respectively. CONCLUSIONS: Clozapine was associated with lower relapse overall, but this was accompanied by higher adverse events for adults. For children/youth, clozapine was associated with lower relapse all throughout and had no difference in adverse events compared with other antipsychotics.

Chronic lung inflammation and CK14+ basal cell proliferation induce persistent alveolar-bronchiolization in SARS-CoV-2-infected hamsters.

BACKGROUND: Post-acute sequalae of COVID-19 defines a wide range of ongoing symptoms and conditions long after SARS-CoV-2 infection including respiratory diseases. The histopathological changes in the lung and underlying mechanism remain elusive. METHODS: We investigated lung histopathological and transcriptional changes in SARS-CoV-2-infected male hamsters at 7, 14, 42, 84 and 120dpi, and compared with A (H1N1)pdm09 infection. FINDINGS: We demonstrated viral residue, inflammatory and fibrotic changes in lung after SARS-CoV-2 but not H1N1 infection. The most prominent histopathological lesion was multifocal alveolar-bronchiolization observed in every SARS-CoV-2 infected hamster (31/31), from 42dpi to 120dpi. Proliferating (Ki67+) CK14+ basal cells accumulated in alveoli adjacent to bronchioles at 7dpi, where they proliferated and differentiated into SCGB1A+ club cell or Tubulin+ ciliated cells forming alveolar-bronchiolization foci. Molecularly, Notch pathway significantly upregulated with intensive Notch3 and Hes1 protein expression in alveolar-bronchiolization foci at 42 and 120dpi, suggesting Notch signaling involving the persistence of alveolar-bronchiolization. This is further demonstrated by spatial transcriptomic analysis. Intriguingly, significant upregulation of some cell-growth promoting pathways and genes such as Tubb4b, Stxbp4, Grb14 and Mlf1 were spatially overlapping with bronchiolization lesion. INTERPRETATION: Incomplete resolution of SARS-CoV-2 infection in lung with viral residue, chronic inflammatory and fibrotic damage and alveolar-bronchiolization impaired respiratory function. Aberrant activation of CK14+ basal cells during tissue regeneration led to persistent alveolar-bronchiolization due to sustained Notch signaling. This study advances our understanding of respiratory PASC, sheds light on disease management and highlights the necessity for monitoring disease progression in people with respiratory PASC. FUNDING: Funding is listed in the Acknowledgements section.

A single-center retrospective series of OCT and MRI findings in pediatric MOGAD optic neuritis patients.

BACKGROUND: Whether optical computed tomography (OCT) and magnetic resonance imaging (MRI) findings are associated with final visual acuity in children with myelin oligodendrocyte glycoprotein antibody disease (MOGAD) optic neuritis is unclear. METHODS: We retrospectively reviewed the charts of pediatric patients with MOGAD optic neuritis seen at St. Louis Children's Hospital/Barnes Jewish Hospital since 2016. RESULTS: In the 12 patients in this study, presenting visual acuity was worse in the optic neuritis-affected eyes but significantly improved from presentation to follow-up, such that, at last follow-up, there was no longer a statistical difference between the affected and unaffected eyes. The number of affected eyes with nerve enhancement and the amount of optic nerve affected, as well as thickness of the retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and macula, decreased from presentation to follow-up. Ultimately, none of these variables were associated with final visual acuity. CONCLUSION: In this cohort, pediatric MOGAD optic neuritis patients had positive visual outcomes despite significant RNFL thinning and involvement of the optic nerve on MRI, leading to a lack of correlation between follow-up visual acuity and OCT and MRI measures of disease severity, respectively.

Proton therapy toxicity outcomes for localized prostate cancer: Long-term results at a comprehensive cancer center.

Background: Proton therapy (PT) has unique biologic properties with excellent clinical outcomes for the management of localized prostate cancer. Here, we aim to characterize the toxicity of PT for patients with localized prostate cancer and propose mitigation strategies using a large institutional database. Methods: We reviewed medical records of 2772 patients with localized prostate cancer treated with definitive PT between May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 849]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 117]. Descriptive statistics and Kaplan-Meier estimates assessed toxicity and freedom from biochemical relapse (FFBR). Results: Median follow-up was 7.0 years. The median dose was 78 Gy(RBE)(range: 72-79.2 Gy) in 2.0 Gy(RBE) fractions; 63 % of patients received 78 Gy(RBE) in 39 fractions, and 29 % received 76 Gy(RBE) in 38 fractions. Overall rates of late grade ≥3 GU and GI toxicity were 0.87 % and 1.01 %, respectively. Two patients developed grade 4 late GU toxicity and seven patients with grade 4 late GI toxicity. All patients experiencing severe late grade 4 toxicities were treated to 78 Gy(RBE) in 39 fractions with 80 Gy(RBE) dose to the anterior rectal wall and/or bladder neck. The 10-year FFBR rates for patients with LR to U-IR disease were compared between those treated with 76 and 78 Gy(RBE); the rates were 94.5 % (95 % confidence interval [CI] 92.4-96.0 %) and 93.2 % (95 % CI 91.3-95.7 %), respectively (log-rank p = 0.22). Conclusions: Proton therapy is associated with low rates of late grade ≥3 GU and GI toxicity. While rare, late grade 4 toxicities occurred in nine (0.3 %) patients. De-escalation to a total dose of 76 Gy(RBE) yields excellent clinical outcomes for patients with LR to U-IR disease with the potential for significant reductions in grade ≥3 late toxicity.

Remote Ischemic Conditioning Improves Cardiovascular Function in Heart Failure Patients.

Background: Recently, it has been shown that remote ischemic conditioning (RIC) can be used as a healthy regimen to reverse disease and aging. With this in mind, we are studying the consequences of RIC on cardiovascular function in heart failure patients. Methods: Forty patients with stable heart failure were prospectively enlisted and randomly divided into RIC (n = 20) and control (n = 20) groups. The RIC protocol consists of a 3-min inflation and then deflation of the blood pressure cuff attached to the upper arm to produce transient ischemia of the arm. RIC treatment was performed once daily for 1 year. NYHA class, left ventricular ejection fraction (LVEF), left atrial and ventricular dimensions were all assessed in two groups. Results: RIC was well tolerated. After 1 year of treatment, New York Heart Association (NYHA) class improved and LVEF showed a significant increase from 37.11% to 52.44% (P < 0.0001). Additionally, the dimensions of the left atrium (from 50.55 to 43.25 mm) and ventricle (from 53.04 to 50.15 mm) were significantly reduced in the RIC group. Conclusion: This study suggests that 1 year of RIC treatment as a health strategy could improve cardiovascular function in heart failure patients, leading to its widespread use in these patients.

Artificial intelligence in corneal diseases: A narrative review.

Corneal diseases represent a growing public health burden, especially in resource-limited settings lacking access to specialized eye care. Artificial intelligence (AI) offers promising solutions for automating the diagnosis and management of corneal conditions. This narrative review examines the application of AI in corneal diseases, focusing on keratoconus, infectious keratitis, pterygium, dry eye disease, Fuchs endothelial corneal dystrophy, and corneal transplantation. AI models integrating diverse imaging modalities (e.g., corneal topography, slit-lamp, and anterior segment OCT images) and clinical data have demonstrated high diagnostic accuracy, often outperforming human experts. Emerging trends include the incorporation of biomechanical data to enhance keratoconus detection, leveraging in vivo confocal microscopy for diagnosing infectious keratitis, and employing multimodal approaches for comprehensive disease analysis. Additionally, AI has shown potential in predicting disease progression, treatment outcomes, and postoperative complications in corneal transplantation. While challenges remain such as population heterogeneity, limited external validation, and the "black box" nature of some models, ongoing advancement in explainable AI, data augmentation, and improved regulatory frameworks can serve to address these limitations.

Implementation of fracture risk assessment in men with prostate cancer requiring long-term androgen deprivation therapy: a systematic scoping review using the i-PARIHS implementation framework.

PURPOSE: Androgen deprivation therapy (ADT) is a mainstay of treatment for prostate cancer (PCa) and is associated with increased risks of osteoporosis and fragility fractures. Despite international guidelines to mitigate fracture risk, osteoporosis is under-diagnosed and under-treated due to poor implementation. This scoping review aims to synthesise knowledge surrounding the implementation of guidelines to inform health service interventions to reduce fracture risk in men with PCa-taking ADT (PCa-ADT). METHOD: Four databases and additional literature were searched for studies published between January 2000 and January 2023. Studies that provided evidence influencing guidelines implementation were included. The i-PARIHS (Promoting Action on Research Implementation in Health Services) implementation framework was used to inform the narrative synthesis. RESULTS: Of the 1229 studies identified, 9 studies met the inclusion criteria. Overall, an improvement in fracture risk assessment was observed across heterogeneous study designs and outcome measures. Six studies were from Canada. Two studies involved family physicians or a community healthcare programme. Two studies incorporated patient or specialist surveys. One utilised an implementation framework. Implementation barriers included the lack of knowledge for both patients and clinicians, time constraints, unsupportive organisational structures, and challenges in transferring patient care from specialists to primary care. Effective strategies included education, novel care pathways using a multidisciplinary approach, incorporating a healthy bone prescription tool into routine care, point-of-care interventions, and bespoke clinics. CONCLUSION: There is an unmet need to provide evidence-based bone healthcare in men with PCa receiving ADT. This study highlights barriers and strategies in the implementation of fracture risk assessment for PCa-ADT patients. IMPLICATIONS FOR CANCER SURVIVORS: Primary care clinicians can play a significant role in the management of complications from long-term cancer treatment such as treatment-induced bone loss. Future studies should consult patients, families, specialists, and primary care clinicians in service re-design.