Financial toxicity and health-related quality of life in long-term survivors of acute promyelocytic leukaemia.

OBJECTIVES: We aimed to investigate the association between financial toxicity (FT) and the health-related quality of life profile of long-term survivors of acute promyelocytic leukaemia (APL) treated within a universal healthcare system. METHODS: We evaluated FT using the financial difficulties item of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). We also compared the prevalence of clinically important problems and symptoms between the survivors of APL with or without FT, using evidence-based thresholds for the EORTC QLQ-C30. A multivariable logistic regression analysis was performed to explore potential risk factors associated with FT. RESULTS: Overall, 352 long-term survivors of APL, with a median age of 53.9 years and a median time since diagnosis of 12.2 years, were analysed. Of these, 71 (20.2%) reported having FT. The prevalence of clinically important problems and symptoms was generally higher across most EORTC QLQ-C30 scales for those survivors who reported FT. The three largest differences between patients with and without FT were observed for emotional functioning (+35.4 percentage points), dyspnoea (+33.1 percentage points) and physical functioning (+27.0 percentage points). The presence of FT was independently associated with having comorbidities and not receiving a salary/pension. CONCLUSIONS: These findings suggest that even many years after being diagnosed, one-fifth of long-term survivors of APL experience FT. Interventions to assist with employment may be critical to minimise the risk of FT in the most vulnerable survivors.

How to hit the allergy target: A critical appraisal of intralymphatic immunotherapy with practical recommendations on ultrasound-guided injections.

BACKGROUND: Intralymphatic immunotherapy (ILIT) represents a promising novel approach treating allergic diseases. However, no standardized procedures or recommendations have been established or reported, despite the recognized fact that treatment efficacy relies on the ability to inject the allergen intranodally. OBJECTIVE: We aim to provide a critical appraisal of ILIT as a method of allergen immunotherapy and to deliver practical recommendations for accurate ILIT. METHODS: One hundred and seventy-three ILIT injections were performed in 28 (47%) women and 32 (53%) men with median age of 29 years (21-59). The injections were ultrasound-guided and recorded for retrospective analysis with respect to injection location, needle visibility, medication release, and patient characteristics. RESULTS: The results show that the correct positioning of the needle within the lymph node (LN) was most critical. If the whole length of the needle bevel was not inserted into the LN, substance backflush into the interstitium was observed. Selecting a more superficial LN and inserting the needle at a smaller angle towards the LN significantly improved needle visibility in the ultrasound. Longitudinal results showed that continuous practice significantly correlated with improved needle visibility and more accurate ILIT injections. CONCLUSION: Based on our results and practical experience, we propose several recommendations for LN selection and the correct handling of ultrasound probe and needle. We are confident that ILIT standardization and training will be important as to meet the goals of good safety and efficacy of ILIT.

Partial Fourier in the presence of respiratory motion in prostate diffusion-weighted echo planar imaging.

PURPOSE: To investigate the effect of respiratory motion in terms of signal loss in prostate diffusion-weighted imaging (DWI), and to evaluate the usage of partial Fourier in a free-breathing protocol in a clinically relevant b-value range using both single-shot and multi-shot acquisitions. METHODS: A controlled breathing DWI acquisition was first employed at 3 T to measure signal loss from deep breathing patterns. Single-shot and multi-shot (2-shot) acquisitions without partial Fourier (no pF) and with partial Fourier (pF) factors of 0.75 and 0.65 were employed in a free-breathing protocol. The apparent SNR and ADC values were evaluated in 10 healthy subjects to measure if low pF factors caused low apparent SNR or overestimated ADC. RESULTS: Controlled breathing experiments showed a difference in signal coefficient of variation between shallow and deep breathing. In free-breathing single-shot acquisitions, the pF 0.65 scan showed a significantly (p < 0.05) higher apparent SNR than pF 0.75 and no pF in the peripheral zone (PZ) of the prostate. In the multi-shot acquisitions in the PZ, pF 0.75 had a significantly higher apparent SNR than 0.65 pF and no pF. The single-shot pF 0.65 scan had a significantly lower ADC than single-shot no pF. CONCLUSION: Deep breathing patterns can cause intravoxel dephasing in prostate DWI. For single-shot acquisitions at a b-value of 800 s/mm2, any potential risks of motion-related artefacts at low pF factors (pF 0.65) were outweighed by the increase in signal from a lower TE, as shown by the increase in apparent SNR. In multi-shot acquisitions however, the minimum pF factor should be larger, as shown by the lower apparent SNR at low pF factors.

General population normative values for the EORTC QLQ-C30 by age, sex, and health condition for the French general population.

BACKGROUND: General population normative values for the widely used health-related quality of life (HRQoL) measure EORTC QLQ-C30 support the interpretation of trial results and HRQoL of patients in clinical practice. Here, we provide sex-, age- and health condition-specific normative values for the EORTC QLQ-C30 in the French general population. METHODS: French general population data was collected in an international EORTC project. Online panels with quota samples were used to recruit sex and age groups. Number and type of comorbidities were assessed. Descriptive statistics were used to calculate general population values for each QLQ-C30 scale, separately for sex, age, and presence of one- and more chronic health conditions. A multivariate linear regression model has been developed to allow estimating the effect of sex, age, and the presence for one- and more chronic health conditions on EORTC QLQ-C30 scores. Data was weighted according to United Nation statistics adjusting for the proportion of sex and age groups. RESULTS: In total, 1001 French respondents were included in our analyses. The weighted mean age was 47.9 years, 514 (51.3%) participants were women, and 497 (52.2%) participants reported at least one health condition. Men reported statistically significant better scores for Emotional Functioning (+9.6 points, p = 0.006) and Fatigue (-7.8 point; p = 0.04); women reported better profiles for Role Functioning (+8.7 points; p = 0.008) and Financial Difficulty (-7.8 points, p = 0.011). According to the regression model, the sex effect was statistically significant in eight scales; the effect of increasing age had a statistically significant effect on seven of the 15 EORTC QLQ-C30 scales. The sex- and age effect varied in its direction across the various scales. The presence of health conditions showed a strong negative effect on all scales. CONCLUSION: This is the first publication of detailed French normative values for the EORTC QLQ-C30. It aims to support the interpretation of HRQoL profiles in French cancer populations. The strong impact of health conditions on QLQ-C30 scores highlights the importance of considering the impact of comorbidities in cancer patients when interpreting HRQoL data.

Female Surgeons in Cardiac Surgery: Does the Surgeon's Gender Affect the Outcome of Routine Coronary Artery Bypass Graft and Isolated Aortic Valve Surgery?

BACKGROUND: The increasing presence of female doctors in the field of cardiac surgery has raised questions about their surgical quality compared to their male colleagues. Despite their success, female surgeons are still underrepresented in leadership positions, and biases and concerns regarding their performance persist. This study aims to examine whether female surgeons perform worse, equally well, or better than their male counterparts in commonly performed procedures that have a significant number of female patients. METHOD: A retrospective cohort of patients from 2011 to 2020 who underwent isolated coronary artery bypass graft (CABG) and aortic valve surgery was studied. To compare the surgical quality of men and women, a 1:1 propensity score matching (two groups of 680 patients operated by men and women, respectively, factors: age, logarithm of EuroSCORE (ES), elective, urgent or emergent surgery, isolated aortic valve, or isolated CABG) was performed. Procedure time, bypass time, x-clamp time, hospital stay, and early mortality were compared. RESULTS: After propensity score matching between surgeons of both sexes, patients operated by males (PoM) did not differ from patients operated by females (PoF) in mean age (PoM: 66.72 ± 9.33, PoF: 67.24 ± 9.19 years, p = 0.346), log. ES (PoM: 5.58 ± 7.35, PoF: 5.53 ± 7.26, p = 0.507), or urgency of operation (PoM: 43.09% elective, 48.97% urgent, 7.94% emergency, PoF: 40.88% elective, 55.29% urgent, 3.83% emergency, p = 0.556). This was also the case for male and female patients separately. Female surgeons had higher procedure time (PoM: 224.35 ± 110.54 min; PoF: 265.41 ± 53.60 min), bypass time (PoM: 107.46 ± 45.09 min, PoF: 122.42 ± 36.18 min), and x-clamp time (PoM: 61.45 ± 24.77 min; PoF: 72.76 ± 24.43 min). Hospitalization time (PoM: 15.96 ± 8.12, PoF: 15.98 ± 6.91 days, p = 0,172) as well as early mortality (PoM: 2.21%, PoF: 3.09%, p = 0.328) did not differ significantly. This was also the case for male and female patients separately. CONCLUSION: Our study reveals that in routine heart surgery, the gender of the surgeon does not impact the success of the operation or the early outcome of patients. Despite taking more time to perform procedures, female surgeons demonstrated comparable surgical outcomes to their male counterparts. It is possible that women's inclination for thoroughness contributes to the longer duration of procedures, while male surgeons may prioritize efficiency. Nevertheless, this difference in duration did not translate into significant differences in primary outcomes following routine cardiac surgery. These findings highlight the importance of recognizing the equal competence of female surgeons and dispelling biases regarding their surgical performance.

Toward a more patient-centered drug development process in clinical trials for patients with myelodysplastic syndromes/neoplasms (MDS): Practical considerations from the International Consortium for MDS (icMDS).

Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health-related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient-reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high-quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS-focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time-to-event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision-making for this patient population.

Shoulder and Knee Arthroscopy Access Point: Prospective Comparison of Sonographic and Palpatory Detection - Which Method is Better for Novices?

Purpose Arthroscopy is one of the most common interventions in orthopedics. Hence it is important to train users early in order to ensure the safest possible identification of access portals (AP). This prospective study aimed to compare a palpatory (PalpMethod) with a sonographic (SonoMethod) method for AP location in the shoulder and knee joints. Materials and Methods The study included trainee doctors (n=68) attending workshops (lasting approx. 90 minutes). In these workshops a teaching video initially demonstrated the PalpMethod and SonoMethod of AP identification. An experienced operator first marked the access portals on the test subject with a UV pen (determined ideal point [DIP]). Adhesive film was then affixed to the puncture regions. Subsequently participants marked on shoulders and knees first the point determined by palpation, then the point determined by sonography. Analysis involved DIP visualization with a UV lamp and employed a coordinate system around the central DIP. In addition, participants completed an evaluation before and after the workshop. Results The analysis included 324 measurements (n=163 shoulders and n= 161 knees). The majority of participants had not previously attended any courses on manual examination (87.9%) or musculoskeletal ultrasound (93.9%). Overall, the markings participants made on the shoulder using the SonoMethod were significantly closer to the DIP than those made by the PalpMethod (Palp 18.8mm ± 14.5mm vs. Sono 11.2mm ± 7.2mm; p<0.001). On the knee, however, the markings made by the PalpMethod were significantly closer to the DIP overall (Palp 8.0mm ± 3.2mm vs. Sono 12.8mm ± 5.2mm; p<0.001). Conclusion The results show that the SonoMethod produces more accurate markings on the shoulder, while the PalpMethod is superior for the knee.

Origin and Early Evolution of Hydrocharitaceae and the Ancestral Role of Stratiotes.

The combined morphological features of Stratiotes (Hydrocharitaceae) pollen, observed with light and electron microscopy, make it unique among all angiosperm pollen types and easy to identify. Unfortunately, the plant is (and most likely was) insect-pollinated and produces relatively few pollen grains per flower, contributing to its apparent absence in the paleopalynological record. Here, we present fossil Stratiotes pollen from the Eocene of Germany (Europe) and Kenya (Africa), representing the first reliable pre-Pleistocene pollen records of this genus worldwide and the only fossils of this family discovered so far in Africa. The fossil Stratiotes pollen grains are described and compared to pollen from a single modern species, Stratiotes aloides L. The paleophytogeographic significance and paleoecological aspects of these findings are discussed in relation to the Hydrocharitaceae fossil records and molecular phylogeny, as well as the present-day distribution patterns of its modern genera.

Protein insertion into the inner membrane of mitochondria: routes and mechanisms.

The inner membrane of mitochondria contains hundreds of different integral membrane proteins. These proteins transport molecules into and out of the matrix, they carry out multifold catalytic reactions and they promote the biogenesis or degradation of mitochondrial constituents. Most inner membrane proteins are encoded by nuclear genes and synthesized in the cytosol from where they are imported into mitochondria by translocases in the outer and inner membrane. Three different import routes direct proteins into the inner membrane and allow them to acquire their appropriate membrane topology. First, mitochondrial import intermediates can be arrested at the level of the TIM23 inner membrane translocase by a stop-transfer sequence to reach the inner membrane by lateral insertion. Second, proteins can be fully translocated through the TIM23 complex into the matrix from where they insert into the inner membrane in an export-like reaction. Carriers and other polytopic membrane proteins embark on a third insertion pathway: these hydrophobic proteins employ the specialized TIM22 translocase to insert from the intermembrane space (IMS) into the inner membrane. This review article describes these three targeting routes and provides an overview of the machinery that promotes the topogenesis of mitochondrial inner membrane proteins.

The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.

Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER mitochondria encounter structure (ERMES) and Tom70, together with Djp1 and Lam6, are part of two parallel and partially redundant ER-to-mitochondria delivery routes. When ER-to-mitochondria transfer is prevented by loss of these two contact sites, many precursors of mitochondrial inner membrane proteins are left stranded on the ER membrane, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.

Missing nurses cause missed care: is that it? Non-trivial configurations of reasons associated with missed care in Austrian hospitals - a qualitative comparative analysis.

BACKGROUND: Errors of omissions affect the quality of nursing care in hospitals. The Missed Nursing Care Model explains that the reasons for missed care are linked with 1) demand for patient care, 2) labor resource allocation, 3) material resource allocation, and 4) relationship and communication factors. Scientific evidence points to a lack of adequate nursing staffing as the most important factor triggering missed care. However, it remains unclear how the different theoretical reasons for missed care are interlinked with reports on missed care from the perspective of nurses in acute care settings. The aim of this study was to explore non-trivial configurations of reasons for missed care that are associated with missed care interventions from the perspective of nurses working in general units in Austrian hospitals. METHODS: A cross-sectional study was conducted. Data collection was performed using the revised MISSCARE-Austria questionnaire. Our sample consisted of 401 nurses who provided complete data. Data were analyzed using qualitative comparative analysis. Configurational models of contextual factors, reasons for missed care, and missed nursing interventions were analyzed. RESULTS: In our study contextual factors were not consistent precursors of the reasons for missed care. Missed care was consistently present when the demand for patient care was high. A lack of labor resources, in combination with the other known reasons for missed care, was consistently observed when missed care occurred. Different configurations of reasons were found to be non-trivially associated with different types and frequencies of missed care. CONCLUSIONS: To understand the complexity of the causal mechanisms of missed care, complexity theory may be necessary. Accordingly, a theoretical framework that acknowledges that complex systems, such as missed care, are composed of multiple interacting causal components must be further developed to guide new methodical approaches to enlighten its causal mechanisms.

The impact of unilateral pulmonary artery stenosis on right ventricular to pulmonary arterial coupling in patients with transposition of the great arteries.

BACKGROUND: Unilateral pulmonary artery (PA) stenosis is common in the transposition of the great arteries (TGA) after arterial switch operation (ASO) but the effects on the right ventricle (RV) remain unclear. AIMS: To assess the effects of unilateral PA stenosis on RV afterload and function in pediatric patients with TGA-ASO. METHODS: In this retrospective study, eight TGA patients with unilateral PA stenosis underwent heart catheterization and cardiac magnetic resonance (CMR) imaging. RV pressures, RV afterload (arterial elastance [Ea]), PA compliance, RV contractility (end-systolic elastance [Ees]), RV-to-PA (RV-PA) coupling (Ees/Ea), and RV diastolic stiffness (end-diastolic elastance [Eed]) were analyzed and compared to normal values from the literature. RESULTS: In all TGA patients (mean age 12 ± 3 years), RV afterload (Ea) and RV pressures were increased whereas PA compliance was reduced. RV contractility (Ees) was decreased resulting in RV-PA uncoupling. RV diastolic stiffness (Eed) was increased. CMR-derived RV volumes, mass, and ejection fraction were preserved. CONCLUSION: Unilateral PA stenosis results in an increased RV afterload in TGA patients after ASO. RV remodeling and function remain within normal limits when analyzed by CMR but RV pressure-volume loop analysis shows impaired RV diastolic stiffness and RV contractility leading to RV-PA uncoupling.

Reduction of ADC bias in diffusion MRI with deep learning-based acceleration: A phantom validation study at 3.0 T.

PURPOSE: Further acceleration of DWI in diagnostic radiology is desired but challenging mainly due to low SNR in high b-value images and associated bias in quantitative ADC values. Deep learning-based reconstruction and denoising may provide a solution to address this challenge. METHODS: The effects of SNR reduction on ADC bias and variability were investigated using a commercial diffusion phantom and numerical simulations. In the phantom, performance of different reconstruction methods, including conventional parallel (SENSE) imaging, compressed sensing (C-SENSE), and compressed SENSE acceleration with an artificial intelligence deep learning-based technique (C-SENSE AI), was compared at different acceleration factors and flip angles using ROI-based analysis. ADC bias was assessed by Lin's Concordance correlation coefficient (CCC) followed by bootstrapping to calculate confidence intervals (CI). ADC random measurement error (RME) was assessed by the mean coefficient of variation (CV¯) and non-parametric statistical tests. RESULTS: The simulations predicted increasingly negative bias and loss of precision towards lower SNR. These effects were confirmed in phantom measurements of increasing acceleration, for which CCC decreased from 0.947 to 0.279 and CV¯ increased from 0.043 to 0.439, and of decreasing flip angle, for which CCC decreased from 0.990 to 0.063 and CV¯ increased from 0.037 to 0.508. At high acceleration and low flip angle, C-SENSE AI reconstruction yielded best denoised ADC maps. For the lowest investigated flip angle, CCC = {0.630, 0.771 and 0.987} and CV¯={0.508, 0.426 and 0.254} were obtained for {SENSE, C-SENSE, C-SENSE AI}, the improvement by C-SENSE AI being significant as compared to the other methods (CV: p = 0.033 for C-SENSE AI vs. C-SENSE and p < 0.001 for C-SENSE AI vs. SENSE; CCC: non-overlapping CI between reconstruction methods). For the highest investigated acceleration factor, CCC = {0.479,0.926,0.960} and CV¯={0.519,0.119,0.118} were found, confirming the reduction of bias and RME by C-SENSE AI as compared to C-SENSE (by trend) and to SENSE (CV: p < 0.001; CCC: non-overlapping CI). CONCLUSION: ADC bias and random measurement error in DWI at low SNR, typically associated with scan acceleration, can be effectively reduced by deep-learning based C-SENSE AI reconstruction.

Conformational and Electronic Variations in 1,2- and 1,5a-Cyclophellitols and their Impact on Retaining α-Glucosidase Inhibition.

Glycoside hydrolases (glycosidases) take part in myriad biological processes and are important therapeutic targets. Competitive and mechanism-based inhibitors are useful tools to dissect their biological role and comprise a good starting point for drug discovery. The natural product, cyclophellitol, a mechanism-based, covalent and irreversible retaining ß-glucosidase inhibitor has inspired the design of diverse α- and ß-glycosidase inhibitor and activity-based probe scaffolds. Here, we sought to deepen our understanding of the structural and functional requirements of cyclophellitol-type compounds for effective human α-glucosidase inhibition. We synthesized a comprehensive set of α-configured 1,2- and 1,5a-cyclophellitol analogues bearing a variety of electrophilic traps. The inhibitory potency of these compounds was assessed towards both lysosomal and ER retaining α-glucosidases. These studies revealed the 1,5a-cyclophellitols to be the most potent retaining α-glucosidase inhibitors, with the nature of the electrophile determining inhibitory mode of action (covalent or non-covalent). DFT calculations support the ability of the 1,5a-cyclophellitols, but not the 1,2-congeners, to adopt conformations that mimic either the Michaelis complex or transition state of α-glucosidases.

Transbronchial cryobiopsy followed by as-needed surgical lung biopsy versus immediate surgical lung biopsy for diagnosing interstitial lung disease (the COLD study): a randomised controlled trial.

BACKGROUND: An adequate diagnosis for interstitial lung disease (ILD) is important for clinical decision making and prognosis. In most patients with ILD, an accurate diagnosis can be made by clinical and radiological data assessment, but in a considerable proportion of patients, a lung biopsy is required. Surgical lung biopsy (SLB) is the most common method to obtain tissue, but it is associated with high morbidity and even mortality. More recently, transbronchial cryobiopsy has been introduced, with fewer adverse events but a lower diagnostic yield than SLB. The aim of this study is to compare two diagnostic strategies: a step-up strategy (transbronchial cryobiopsy, followed by SLB if the cryobiopsy is insufficiently informative) versus immediate SLB. METHODS: The COLD study was a multicentre, randomised controlled trial in six hospitals across the Netherlands. We included patients with ILD with an indication for lung biopsy as assessed by a multidisciplinary team discussion. Patients were randomly assigned in a 1:1 ratio to the step-up or immediate SLB strategy, with follow-up for 12 weeks from the initial procedure. Patients, clinicians, and pathologists were not masked to the study treatment. The primary endpoint was unexpected chest tube drainage, defined as requiring any chest tube after transbronchial cryobiopsy, or prolonged (>24 h) chest tube drainage after SLB. Secondary endpoints were diagnostic yield, in-hospital stay, pain, and serious adverse events. A modified intention-to-treat analysis was performed. This trial is registered with the Dutch Trial Register, NL7634, and is now closed. FINDINGS: Between April 8, 2019, and Oct 24, 2021, 122 patients with ILD were assessed for study participation; and 55 patients were randomly assigned to the step-up strategy (n=28) or immediate SLB (n=27); three patients from the immediate SLB group were excluded. Unexpected chest tube drainage occurred in three of 28 patients (11%; 95% CI 4-27%) in the step-up group, and the number of patients for whom the chest tube could not be removed within 24 h was 11 of 24 patients (46%; 95% CI 2-65%) in the SLB group, with an absolute risk reduction of 35% (11-56%; p=0·0058). In the step-up strategy, the multidisciplinary team diagnostic yield after transbronchial cryobiopsy alone was 82% (64-92%), which increased to 89% (73-96%) when subsequent SLB was performed after inconclusive transbronchial cryobiopsy. In the immediate surgery strategy, the multidisciplinary team diagnostic yield was 88% (69-97%). Total in-hospital stay was 1 day (IQR 1-1) in the step-up group versus 5 days (IQR 4-6) in the SLB group. One (4%) serious adverse event occurred in step-up strategy versus 12 (50%) in the immediate SLB strategy. INTERPRETATION: In ILD diagnosis, if lung tissue assessment is required, a diagnostic strategy starting with transbronchial cryobiopsy, followed by SLB when transbronchial cryobiopsy is inconclusive, appears to result in a significant reduction of patient burden and in-hospital stay with a similar diagnostic yield versus immediate SLB. FUNDING: Netherlands Organisation for Health Research and Development (ZonMW) and Amsterdam University Medical Centers.

Soluble B-cell maturation antigen in lacrimal fluid as a potential biomarker and mediator of keratopathy in multiple myeloma.

Belantamab mafodotin (belantamab) is a first-in-class anti-BCMA antibody-drug conjugate approved for the treatment of triple-class refractory multiple myeloma. It provides a unique therapeutic option for patients ineligible for CAR-T and bispecific antibody therapy, and/or patients progressing on anti-CD38 treatment where CAR-T and bispecifics might be kept in reserve. Wider use of the drug can be challenged by its distinct ocular side effect profile, including corneal microcysts and keratopathy. While dose reduction has been the most effective way to reduce these toxicities, the underlying mechanism of this BCMA off-target effect remains to be characterized. In this study, we provide the first evidence for soluble BCMA (sBCMA) in lacrimal fluid and report on its correlation with tumor burden in myeloma patients. We confirm that corneal cells do not express BCMA, and show that sBCMA-belantamab complexes may rather be internalized by corneal epithelial cells through receptor-ligand independent pinocytosis. Using an hTcEpi corneal cell-line model, we show that the pinocytosis inhibitor EIPA significantly reduces belantamab-specific cell killing. As a proof of concept, we provide detailed patient profiles demonstrating that, after belantamab-induced cell killing, sBCMA is released into circulation, followed by a delayed increase of sBCMA in the tear fluid and subsequent onset of keratopathy. Based on the proposed mechanism, pinocytosis-induced keratopathy can be prevented by lowering the entry of sBCMA into the lacrimal fluid. Future therapeutic concepts may therefore consist of belantamab-free debulking therapy prior to belantamab consolidation and/or concomitant use of gamma-secretase inhibition as currently evaluated for belantamab and nirogacestat in ongoing studies.

Motion-induced phase-corrected homodyne reconstruction for partial Fourier single-shot diffusion-weighted echo planar imaging of the liver.

Partial Fourier encoding is popular in single-shot (ss) diffusion-weighted (DW) echo planar imaging (EPI) because it enables a shorter echo time (TE) and, hence, improves the signal-to-noise-ratio. Motion during diffusion encoding causes k-space shifting and dispersion, which compromises the quality of the homodyne reconstruction. This work provides a comprehensive understanding of the artifacts in homodyne reconstruction of partial Fourier ss-DW-EPI data in the presence of motion-induced phase and proposes the motion-induced phase-corrected homodyne (mpc-hdyne) reconstruction method to ameliorate these artifacts. Simulations with different types of motion-induced phase were performed to provide an understanding of the potential artifacts that occur in the homodyne reconstruction of partial Fourier ss-DW-EPI data. To correct for the artifacts, the mpc-hdyne reconstruction is proposed. The algorithm recenters k-space, updates the partial Fourier factor according to detected global k-space shifts, and removes low-resolution nonlinear phase before the conventional homodyne reconstruction. The mpc-hdyne reconstruction is tested on both simulation and in vivo data. Motion-induced phase can cause signal overestimation, worm artifacts, and signal loss in partial Fourier ss-DW-EPI data with the conventional homodyne reconstruction. Simulation and in vivo data showed that the proposed mpc-hdyne reconstruction ameliorated artifacts, yielding higher quality DW images compared with conventional homodyne reconstruction. Based on the understanding of the artifacts in homodyne reconstruction of partial Fourier ss-DW-EPI data, the mpc-hdyne reconstruction was proposed and showed superior performance compared with the conventional homodyne reconstruction on both simulation and in vivo data.

Student ultrasound education - current views and controversies.

As an extension of the clinical examination and as a diagnostic and problem-solving tool, ultrasound has become an established technique for clinicians. A prerequisite for high-quality clinical ultrasound practice is adequate student ultrasound training. In light of the considerable heterogeneity of ultrasound curricula in medical studies worldwide, this review presents basic principles of modern medical student ultrasound education and advocates for the establishment of an ultrasound core curriculum embedded both horizontally and vertically in medical studies.

A Dutch paediatric palliative care guideline: a systematic review and evidence-based recommendations for symptom treatment.

BACKGROUND: Children with life-threatening and life-limiting conditions can experience high levels of suffering due to multiple distressing symptoms that result in poor quality of life and increase risk of long-term distress in their family members. High quality symptom treatment is needed for all these children and their families, even more so at the end-of-life. In this paper, we provide evidence-based recommendations for symptom treatment in paediatric palliative patients to optimize care. METHODS: A multidisciplinary panel of 56 experts in paediatric palliative care and nine (bereaved) parents was established to develop recommendations on symptom treatment in paediatric palliative care including anxiety and depression, delirium, dyspnoea, haematological symptoms, coughing, skin complaints, nausea and vomiting, neurological symptoms, pain, death rattle, fatigue, paediatric palliative sedation and forgoing hydration and nutrition. Recommendations were based on evidence from a systematic literature search, additional literature sources (such as guidelines), clinical expertise, and patient and family values. We used the GRADE methodology for appraisal of evidence. Parents were included in the guideline panel to ensure the representation of patient and family values. RESULTS: We included a total of 18 studies that reported on the effects of specific (non) pharmacological interventions to treat symptoms in paediatric palliative care. A few of these interventions showed significant improvement in symptom relief. This evidence could only (partly) answer eight out of 27 clinical questions. We included 29 guidelines and two textbooks as additional literature to deal with lack of evidence. In total, we formulated 221 recommendations on symptom treatment in paediatric palliative care based on evidence, additional literature, clinical expertise, and patient and family values. CONCLUSION: Even though available evidence on symptom-related paediatric palliative care interventions has increased, there still is a paucity of evidence in paediatric palliative care. We urge for international multidisciplinary multi-institutional collaboration to perform high-quality research and contribute to the optimization of symptom relief in palliative care for all children worldwide.