A phase Ib randomized multicenter trial of isolated hepatic perfusion in combination with ipilimumab and nivolumab for uveal melanoma metastases (SCANDIUM II trial).

BACKGROUND: Uveal melanoma (UM) is a rare malignancy where 50% of patients develop metastatic disease primarily affecting the liver. Approximately 40% of patients with metastatic UM respond to one-time isolated hepatic perfusion (IHP) with high-dose melphalan. This phase I trial investigates the safety and clinical efficacy of IHP combined with ipilimumab (IPI) and nivolumab (NIVO). PATIENTS AND METHODS: Immunotherapy-naïve patients were randomized in this phase I trial to receive either IHP followed by IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) for four cycles (post-operative arm), or one cycle of preoperative IPI3/NIVO1, IHP and then three cycles of IPI3/NIVO1 (pre-post-operative arm), followed by maintenance therapy with NIVO 480 mg for 1 year. RESULTS: Eighteen patients were enrolled and randomized. Three patients did not undergo IHP as planned. In total, 11/18 patients (6 in the post-operative arm and 5 in the pre-post-operative arm) did not complete the planned four cycles of IPI3/NIVO1. Toxicity to IHP was similar in both groups, but the number of immune-related adverse events (AEs) was higher in the pre-post-operative arm. Among assessable patients, overall response rate was 57% in the post-operative arm (4/7) and 22% in the pre-post-operative arm (2/9). CONCLUSIONS: Combination therapy with IHP and IPI3/NIVO1 was associated with severe AEs. The efficacy of this combination is encouraging with high response rates. One cycle of preoperative IPI/NIVO before IHP did not show potential benefits in terms of safety or efficacy.

Quality of life gains in frail and intermediate-fit patients with multiple Myeloma: Findings from the prospective HOVON123 clinical trial.

BACKGROUND: Frailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life (HRQoL). Currently, data on changes in HRQoL of frail and intermediate-fit MM patients during active treatment and post-treatment follow-up are absent. METHODS: The HOVON123 study (NTR4244) was a phase II trial in which NDMM patients ≥ 75 years were treated with nine dose-adjusted cycles of Melphalan-Prednisone-Bortezomib (MPV). Two HRQoL instruments (EORTC QLQ-C30 and -MY20) were obtained before start of treatment, after 3 and 9 months of treatment and 6 and 12 months after treatment for patients who did not yet start second-line treatment. HRQoL changes and/or differences in frail and intermediate-fit patients (IMWG frailty score) were reported only when both statistically significant (p < 0.005) and clinically relevant (>MID). RESULTS: 137 frail and 71 intermediate-fit patients were included in the analysis. Compliance was high and comparable in both groups. At baseline, frail patients reported lower global health status, lower physical functioning scores and more fatigue and pain compared to intermediate-fit patients. Both groups improved in global health status and future perspective; polyneuropathy complaints worsened over time. Frail patients improved over time in physical functioning, fatigue and pain. Improvement in global health status occurred earlier than in intermediate-fit patients. CONCLUSION: HRQoL improved during anti-myeloma treatment in both intermediate-fit and frail MM patients. In frail patients, improvement occurred faster and, in more domains, which was retained during follow-up. This implies that physicians should not withhold safe and effective therapies from frail patients in fear of HRQoL deterioration.

Piximi - An Images to Discovery web tool for bioimages and beyond.

Deep learning has greatly accelerated research in biological image analysis yet it often requires programming skills and specialized tool installation. Here we present Piximi, a modern, no-programming image analysis tool leveraging deep learning. Implemented as a web application at Piximi.app, Piximi requires no installation and can be accessed by any modern web browser. Its client-only architecture preserves the security of researcher data by running all computation locally. Piximi offers four core modules: a deep learning classifier, an image annotator, measurement modules, and pre-trained deep learning segmentation modules. Piximi is interoperable with existing tools and workflows by supporting import and export of common data and model formats. The intuitive researcher interface and easy access to Piximi allows biological researchers to obtain insights into images within just a few minutes. Piximi aims to bring deep learning-powered image analysis to a broader community by eliminating barriers to entry.

The geographic limits and life history of the tropical brown dog tick, Rhipicephalus linnaei (Audouin, 1826), in Australia with notes on the spread of Ehrlichia canis.

The tropical brown dog tick, Rhipicephalus linnaei, is a tick of much medical, veterinary, and zoonotic importance. This tick has a nearly world-wide distribution due to its ability to survive and propagate in kennels and houses. Rhipicephalus linnaei is the vector of Ehrlichia canis, the causative agent of canine monocytic ehrlichiosis, an often debilitating disease of canids and, occasionally, humans. To prevent incursion of E. canis into Australia, dogs entering Australia have been required to have a negative immunofluorescence antibody test for E. canis. In May 2020 however, E. canis was detected in Western Australia. The detection of E. canis in Australia prompted disease investigation and concerted surveillance for R. linnaei and E. canis in regions across Australia. These investigations revealed that R. linnaei was established far beyond the previously recognised geographic range limits of this tick. In the present paper, using records from various collections, published data, and data from our network of veterinarian collaborators and colleagues, we update the current geographic range of R. linnaei in Australia. Our analyses revealed that the geographic range of R. linnaei in Australia is much wider than was previously supposed, particularly in Western Australia, and in South Australia. We also map, for the first time, where E. canis has been detected in Australia. Last, we discuss the possible routes of incursion and subsequently the factors which may have aided the spread of E. canis in Australia which led to the establishment of this pathogen in Australia.

Global assessment of the knowledge and confidence in managing allergic disorders among primary care pediatricians across Europe: An EAACI task force report.

BACKGROUND: Pediatricians are often the first point of contact for children in Primary Care (PC), but still perceive gaps in their allergy knowledge. We investigated self-perceived knowledge gaps and educational needs in pediatricians across healthcare systems in Europe so that future educational initiatives may better support the delivery of allergy services in PC. METHOD: A multinational survey was circulated to pediatricians who care for children and adolescents with allergy problems in PC by the EAACI Allergy Educational Needs in Primary Care Pediatricians Task Force from February to March 2023. A 5-point Likert scale was used to assess the level of agreement with questionnaire statements. Thirty surveys per country were the cut-off for inclusion and statistical analysis. RESULTS: In this study, 1991 respondents were obtained from 56 countries across Europe and 210 responses were from countries with a cut-off below 30 participants per country. Primary care pediatricians (PCPs) comprised 74.4% of the respondents. The majority (65.3%) were contracted to state or district health services. 61.7% had awareness of guidelines for onward allergy referral in their countries but only 22.3% were aware of the EAACI competencies document for allied health professionals for allergy. Total sample respondents versus PCPs showed 52% and 47% of them have access to allergy investigations in their PC facility (mainly specific IgE and skin prick tests); 67.6% and 58.9% have access to immunotherapy, respectively. The main barrier to referral to a specialist was a consideration that the patient's condition could be diagnosed and treated in this PC facility, (57.8% and 63.6% respectively). The main reasons for referral were the need for hospital assessment, and partial response to first-line treatment (55.4% and 59.2%, 47% and 50.7%, respectively). Learning and assessment methods preference was fairly equally divided between Traditional methods (45.7% and 50.1% respectively) and e-learning 45.5% and 44.9%, respectively. Generalist physicians (GPs) have the poorest access to allergy investigations (32.7%, p = .000). The majority of the total sample (91.9%) assess patients with allergic pathology. 868 (43.6%) and 1117 (46.1%), received allergy training as undergraduates and postgraduates respectively [these proportions in PCPs were higher (45% and 59%), respectively]. PCPs with a special interest in allergology experienced greater exposure to allergy teaching as postgraduates. GPs received the largest amount of allergy teaching as undergraduates. Identifying allergic disease based on clinical presentation, respondents felt most confident in the management of eczema/atopic dermatitis (87.4%) and rhinitis/asthma (86.2%), and least confident in allergen immunotherapy (36.9%) and latex allergy (30.8%). CONCLUSION: This study exploring the confidence of PCPs to diagnose, manage, and refer patients with allergies, demonstrated knowledge gaps and educational needs for allergy clinical practice. It detects areas in need of urgent improvement especially in latex and allergen immunotherapy. It is important to ensure the dissemination of allergy guidelines and supporting EAACI documents since the majority of PCPs lack awareness of them. This survey has enabled us to identify what the educational priorities of PCPs are and how they would like to have them met.

Surgical Training Simulators for Rhinoplasty: A Systematic Review.

Rhinoplasty training currently follows an apprenticeship model that is largely observational. Trainees have limited experience in performing maneuvers of this complex surgery. Rhinoplasty simulators can address this issue by providing trainees with the opportunity to gain surgical simulator experience that could improve technical competences in the operating room. This review amalgamates the collective understanding of rhinoplasty simulators described to date. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, PubMed, OVID Embase, OVID Medline, and Web of Science databases were all searched for original research on surgical simulators for rhinoplasty education and reviewed by independent reviewers. Articles underwent title and abstract screening, and then relevant articles underwent full-text review to extract simulator data. Seventeen studies, published between 1984 and 2021, were included for final analysis. Study participant numbers ranged from 4 to 24, and included staff surgeons, fellows, residents (postgraduate year 1-6), and medical students. Cadaveric surgical simulators comprised eight studies, of which three were with human cadavers, one study was a live animal simulator, two were virtual simulators, and six were three-dimensional (3D) models. Both animal and human-based simulators increased the confidence of trainees significantly. Significant improvement in various aspects of rhinoplasty knowledge occurred with implementation of a 3D-printed model in rhinoplasty education. Rhinoplasty simulators are limited by a lack of an automated method of evaluation and a large reliance on feedback from experienced rhinoplasty surgeons. Rhinoplasty simulators have the potential to provide trainees with the opportunity for hands-on training to improve skill and develop competencies without putting patients in harm's way. Current literature on rhinoplasty simulators largely focuses on simulator development, with few simulators being validated and assessed for utility. For wider implementation and acceptance, further refinement of simulators, validation, and assessment of outcomes is required.

The use of enhanced intrinsic feedback for motor learning in stroke survivors: Clinical trial protocol.

BACKGROUND: Stroke can lead to lasting sensorimotor deficits of the upper limb (UL) persisting into the chronic phase despite intensive rehabilitation. A major impairment of reaching after stroke is a decreased range of active elbow extension, which in turn leads to the use of compensatory movements. Retraining movement patterns relies on cognition and motor learning principles. Implicit learning may lead to better outcomes than explicit learning. Error augmentation (EA) is a feedback modality based on implicit learning resulting in improved precision and speed of UL reaching movements in people with stroke. However, accompanying changes in UL joint movement patterns have not been investigated. The objective of this study is to determine the capacity for implicit motor learning in people with chronic stroke and how this capacity is affected by post-stroke cognitive impairments. METHODS: Fifty-two subjects who have chronic stroke will practice reaching movements 3×/wk. for 9 wk. in a virtual reality environment. Participants will be randomly allocated to 1 of 2 groups to train with or without EA feedback. Outcome measures (pre-, post- and follow-up) will be: endpoint precision, speed, smoothness, and straightness and joint (UL and trunk) kinematics during a functional reaching task. The degree of cognitive impairment, lesion profile, and integrity of descending white matter tracts will be related to training outcomes. CONCLUSIONS: The results will inform us which patients can best benefit from training programs that rely on motor learning and utilize enhanced feedback. TRIAL STATUS: Ethical approval for this study was finalized in May 2022. Recruitment and data collection is actively in progress and is planned to finish in 2026. Data analysis and evaluation will occur subsequently, and the final results will be published.

Usability study of a sleeve attachment device for enhancing ease of use of metered dose inhalers in children.

BACKGROUND: Children with asthma often lack the strength to activate their pressurised metered dose inhaler (pMDI). A recently developed sleeve device that attaches to a pMDI reduces the activation force of pMDIs from 36 - 39 Newtons (N) to 12.6 N and monitors the remaining doses with a built-in counter. OBJECTIVES: To examine the usability and patient experience of the Easy Squeezy (ES) sleeve attachment device in the paediatric patient population. METHODS: This cross-over study included 40 participants aged 5 - 10 years, half of whom had previous experience in using a pMDI. The experienced participants had used a pMDI for at least 1 year, and the inexperienced participants had no experience of using a pMDI. Participants and their parents recorded their responses on the ease of use, perceptions and satisfaction with using the pMDI alone and the pMDI with the ES. RESULTS: The participants felt that it was easier for them to activate the pMDI using the ES. They liked the ES device more than the pMDI and felt happier using the ES device. The parents reported that their children would be happier using the ES and would find it easier to activate the pMDI using the ES, that the built-in counter in the ES would make it easier to keep track of the doses, and that their children would be more likely to take the ES to school and use it there compared with the pMDI. They would recommend the ES to other parents and were willing to buy the device with their own money. CONCLUSION: The paediatric participants and their parents reported that the ES made it easier for children to activate the pMDI, that the counter made it easier to keep count of the doses, and that the aesthetics of the ES could potentially remove the stigma attached to use of a pMDI.

PD-1 inhibitor therapy of basal cell carcinoma with pulmonary metastasis.

Basal cell carcinoma (BCC) may be challenging to differentiate from basaloid squamous cell carcinoma (bSCC), both clinically and histologically. BCC constitutes one of the most common tumours and metastatic behaviour is extremely rare. In contrast, bSCC is a rare entity with an increased propensity for distant metastasis. If these conditions develop into inoperable metastatic disease, the therapeutic alternatives are different, but the use of PD-1 inhibitors may be a valid option for both. Here, we report a case with complex histology with a component initially classified as bSCC with lung metastases and treated with the PD-1 inhibitor cemiplimab resulting in radiological and clinical responses. Re-examination of the lung biopsy using routine histomorphology in combination with immunohistochemical staining for cytokeratin 14, cytokeratin17 and BerEp4 has, however, revealed a histopathological pattern of BCC, which is in concordance with a similar analysis of the cutaneous primary tumour in the face that the patient underwent surgery for more than 5 years earlier.

Usability study of a sleeve attachment device for enhancing ease of use of metered dose inhalers in children

Children with asthma often lack the strength to activate their pressurised metered dose inhaler (pMDI). A recently developed sleeve device that attaches to a pMDI reduces the activation force of pMDIs from 36 - 39 Newtons (N) to 12.6 N and monitors the remaining doses with a built-in counter. Objectives. To examine the usability and patient experience of the Easy Squeezy (ES) sleeve attachment device in the paediatric patient population. Methods. This cross-over study included 40 participants aged 5 - 10 years, half of whom had previous experience in using a pMDI. The experienced participants had used a pMDI for at least 1 year, and the inexperienced participants had no experience of using a pMDI. Participants and their parents recorded their responses on the ease of use, perceptions and satisfaction with using the pMDI alone and the pMDI with the ES. Results. The participants felt that it was easier for them to activate the pMDI using the ES. They liked the ES device more than the pMDI and felt happier using the ES device. The parents reported that their children would be happier using the ES and would find it easier to activate the pMDI using the ES, that the built-in counter in the ES would make it easier to keep track of the doses, and that their children would be more likely to take the ES to school and use it there compared with the pMDI. They would recommend the ES to other parents and were willing to buy the device with their own money. Conclusion. The paediatric participants and their parents reported that the ES made it easier for children to activate the pMDI, that the counter made it easier to keep count of the doses, and that the aesthetics of the ES could potentially remove the stigma attached to use of a pMDI

Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with B-cell non-Hodgkin lymphoma.

Patients diagnosed with B-cell non-Hodgkin lymphoma (B-NHL), particularly if recently treated with anti-CD20 antibodies, are at risk of severe COVID-19 disease. Because studies evaluating humoral response to COVID-19 vaccine in these patients are lacking, recommendations regarding vaccination strategy remain unclear. The humoral immune response to BNT162b2 messenger RNA (mRNA) COVID-19 vaccine was evaluated in patients with B-NHL who received 2 vaccine doses 21 days apart and compared with the response in healthy controls. Antibody titer, measured by the Elecsys Anti-SARS-CoV-2S assay, was evaluated 2 to 3 weeks after the second vaccine dose. Patients with B-NHL (n = 149), aggressive B-NHL (a-B-NHL; 47%), or indolent B-NHL (i-B-NHL; 53%) were evaluated. Twenty-eight (19%) were treatment naïve, 37% were actively treated with a rituximab/obinutuzumab (R/Obi)-based induction regimen or R/Obi maintenance, and 44% had last been treated with R/Obi >6 months before vaccination. A seropositive response was achieved in 89%, 7.3%, and 66.7%, respectively, with response rates of 49% in patients with B-NHL vs 98.5% in 65 healthy controls (P < .001). Multivariate analysis revealed that longer time since exposure to R/Obi and absolute lymphocyte count ≥0.9 × 103/µL predicted a positive serological response. Median time to achieve positive serology among anti-CD20 antibody-treated patients was longer in i-B-NHL vs a-B-NHL. The humoral response to BNT162b2 mRNA COVID-19 vaccine is impaired in patients with B-NHL who are undergoing R/Obi treatment. Longer time since exposure to R/Obi is associated with improved response rates to the COVID-19 vaccine. This study is registered at www.clinicaltrials.gov as #NCT04746092.

Surgical data recording in the operating room: a systematic review of modalities and metrics.

INTRODUCTION: Operating room recording, via video, audio and sensor-based recordings, is increasingly common. Yet, surgical data science is a new field without clear guidelines. The purpose of this study is to examine existing published studies of surgical recording modalities to determine which are available for use in the operating room, as a first step towards developing unified standards for this field. METHODS: Medline, EMBASE, CENTRAL and PubMed databases were systematically searched for articles describing modalities of data collection in the operating room. Search terms included 'video-audio media', 'bio-sensing techniques', 'sound', 'movement', 'operating rooms' and others. Title, abstract and full-text screening were completed to identify relevant articles. Descriptive statistical analysis was performed for included studies. RESULTS: From 3756 citations, 91 studies met inclusion criteria. These studies described 10 unique data-collection modalities for 17 different purposes in the operating room. Data modalities included video, audio, kinematic and eye-tracking among others. Data-collection purposes described included surgical trainee assessment, surgical error, surgical team communication and operating room efficiency. CONCLUSION: Effective data collection and utilization in the operating room are imperative for the provision of superior surgical care. The future operating room landscape undoubtedly includes multiple modalities of data collection for a plethora of purposes. This review acts as a foundation for employing operating room data in a way that leads to meaningful benefit for patient care.

Repeatability and Reliability of Quantified Ultrasound Biomicroscopy Image Analysis of the Ciliary Body at the Pars Plicata.

Most of the ciliary body and ciliary processes of the eye cannot be directly visualized in vivo because of the posterior location of the pars plicata to the posterior chamber and iris. However, ciliary anatomy can be effectively imaged using ultrasound biomicroscopy (UBM) by placing the probe close to the limbus, perpendicular to this structure. Previous studies measuring ciliary body parameters in meridian UBM images found that these parameters were measured with poor reliability and repeatability. This study evaluates the intra-observer reliability and inter-observer agreement of a standardized protocol for measuring six ciliary parameters in transverse or quadrant UBM images that capture an entire row of ciliary processes. All six ciliary parameters have high intra-observer reliability, with ciliary body thickness, ciliary process length and ciliary process density measurements being the most consistent for each observer. The coefficient of variation for each observer ranged from 1.4%-15%. Inter-observer agreement was also high for all six parameters, with an intra-class correlation coefficient >0.8. Utilizing transverse UBM images of the pars plicata allows for consistent quantitative analysis in control subjects.

Cardiotoxicity during long-term trastuzumab use in patients with HER2-positive metastatic breast cancer: who needs cardiac monitoring?

PURPOSE: Patients with HER2-positive metastatic breast cancer (MBC) usually receive many years of trastuzumab treatment. It is unknown whether these patients require continuous left ventricular ejection fraction (LVEF) monitoring. We studied a real-world cohort to identify risk factors for cardiotoxicity to select patients in whom LVEF monitoring could be omitted. METHODS: We included patients with HER2-positive MBC who received > 1 cycle of trastuzumab-based therapy in eight Dutch hospitals between 2000 and 2014. Cardiotoxicity was defined as LVEF < 50% that declined > 10%-points and was categorized into non-severe cardiotoxicity (LVEF 40-50%) and severe cardiotoxicity (LVEF < 40%). Multivariable Cox and mixed model analyses were performed to identify risk factors associated with cardiotoxicity. Additionally, we explored the reversibility of cardiotoxicity in patients who continued trastuzumab. RESULTS: In total, 429 patients were included. Median follow-up for cardiotoxicity was 15 months (interquartile range 8-31 months). The yearly incidence of non-severe + severe cardiotoxicity in the first and second year was 11.7% and 9.1%, respectively, which decreased thereafter. The yearly incidence of severe cardiotoxicity was low (2.8%) and stable over time. In non-smoking patients with baseline LVEF > 60% and no cardiotoxicity during prior neoadjuvant/adjuvant treatment, the cumulative incidence of severe cardiotoxicity was 3.1% after 4 years of trastuzumab. Despite continuing trastuzumab, LVEF decline was reversible in 56% of patients with non-severe cardiotoxicity and in 33% with severe cardiotoxicity. CONCLUSIONS: Serial cardiac monitoring can be safely omitted in non-smoking patients with baseline LVEF > 60% and without cardiotoxicity during prior neoadjuvant/adjuvant treatment.

Chronic rhinitis in South Africa - more than just allergy!

Chronic rhinitis is a troublesome condition for sufferers. It is tempting to label all patients with chronic nasal symptoms as having allergic rhinitis (AR), but many such patients have other causes of chronic rhinitis that need a specific diagnosis and management strategy. Even when the patient fully fits the definition of AR, their condition will be best served by combining medication with ongoing patient education.

A new diagnostic work-up for defining anemia etiologies: a cohort study in patients ≥ 50 years in general practices.

BACKGROUND: To study etiologies of anemia using an extensive laboratory analysis in general practices. METHOD: An extensive laboratory analysis was performed in blood of newly diagnosed anemia patients aged ≥50 years from the general population in the city of Dordrecht area, the Netherlands. Eight laboratory-orientated etiologies of anemia were defined. Patients were assigned one or more of these etiologies on the basis of their test results. RESULTS: Blood of 4152 patients (median age 75 years; 49% male) was analyzed. The anemia etiology was unclear in 20%; a single etiology was established in 59%; and multiple etiologies in 22% of the patients. The most common etiologies were anemia of chronic disease (ACD) (54.5%), iron deficiency anemia (IDA) (19.1%) and renal anemia (13.8%). The most common single etiologies were IDA (82%) and ACD (68%), while the multiple etiologies most commonly included folic acid deficiency (94%) and suspected bone marrow disease (88%). Older age was associated with a lower incidence of IDA and a higher incidence of renal anemia. Mild anemia was more often associated with ACD and uncertain anemia, while severe anemia was mainly seen in patients with IDA. CONCLUSION: Extensive laboratory analysis in anemic patients from the general population helped clarify the etiology of anemia and revealed many various combinations of etiologies in a significant proportion of patients. Age, sex and the severity of anemia are predictive of the underlying etiology.