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Aims: We report on investigations exploring the P2X3‐receptor antagonist filapixant's effect on taste perception and cough‐reflex sensitivity and describe its pharmacokinetics, including its CYP3A4‐interaction potential. Methods: In a randomized, placebo‐controlled, double‐blind study, 3 × 12 healthy men (18‐45 years) were assigned (3:1) to filapixant (20, 80 or 250 mg by mouth) or placebo twice daily over 2 weeks. A single dose of midazolam (1 mg), a CYP3A4 substrate, was administered with and without filapixant. Assessments included a taste‐strips test, a taste questionnaire, cough challenge with adenosine triphosphate, adverse event reports and standard safety assessments. Results: Taste disturbances were observed mainly in the 250‐mg group: six of nine participants (67%) in this group reported hypo‐ or dysgeusia in the questionnaire; eight participants (89%) reported taste‐related adverse events. Five participants (56%) had a decrease in overall taste‐strips‐test scores ≥2 points (point estimate −1.1 points, 90% confidence interval [−3.3; 1.1]). Cough counts increased with adenosine triphosphate concentration but without major differences between treatments. Filapixant exposure increased proportionally to dose. Co‐administration of filapixant had no clinically relevant effect on midazolam pharmacokinetics. Area under the concentration‐time curve ratios and 90% confidence intervals were within 80‐125%. No serious or severe adverse events were reported. Conclusions: Overall, filapixant was safe and well tolerated, apart from mild, transient taste disturbances. Such disturbances occurred more frequently than expected based on (in vitro) receptor‐selectivity data, suggesting that other factors than P2X3:P2X2/3 selectivity might also play an important role in this context. The cough‐challenge test showed no clear treatment effect. Filapixant has no clinically relevant CYP3A4 interaction potential. [ABSTRACT FROM AUTHOR]

Background: Afferent neuronal hypersensitization via P2X3 receptor signaling has been implicated as a driver of several disorders, including refractory chronic cough, endometriosis, diabetic neuropathic pain, and overactive bladder. Eliapixant, a selective P2X3 receptor antagonist, has been in clinical development for all four disorders. Objective: This paper describes pharmacokinetic (PK) and safety data from two phase I studies of eliapixant in healthy Japanese and Chinese participants and compares those data within the two populations and with previous multiple dose data from Caucasian participants. Methods: Two separate phase I, single-center, randomized, placebo-controlled studies were conducted with healthy male participants. The Japanese study was single-blind and the Chinese study was double-blind. Eliapixant was administered as an oral amorphous solid dispersion immediate-release tablet in strengths of 25 mg, 75 mg, and 150 mg. PK characteristics after a single dose (SD) and at steady state (multiple dose [MD], twice daily), adverse events (AEs), and tolerability were evaluated. A post hoc comparison of PK characteristics after SD of eliapixant in Japanese and Chinese participants, and after MD of eliapixant in Japanese, Chinese, and Caucasian participants, was performed. Results: Overall, 36/39 participants enrolled in the Japanese/Chinese studies, respectively (mean [standard deviation] age 25.4 [6.5] and 26.7 [5.0] years, respectively). After SD administration, maximum plasma concentration (Cmax) was higher among Japanese than Chinese participants in the 25 mg and 75 mg dose groups, but comparable in the 150 mg dose group. The area under the concentration–time curve (AUC) was comparable between Japanese and Chinese participants in the 25 mg and 75 mg dose groups, but lower among Japanese participants in the 150 mg group. Half-lives after SD and MD administration were also comparable in Japanese and Chinese participants. The post hoc analysis included 26 Japanese, 30 Chinese, and 50 Caucasian participants. Comparable exposure (Cmax,md and AUC[0–12]md) was observed after MD administration of eliapixant in Chinese and/or Japanese compared with Caucasian participants (geometric mean inter-ethnic ratios close to 1). The trough plasma concentration after eliapixant 150 mg MD, which was assumed to be relevant to eliapixant efficacy, was comparable across all ethnicity groups. Most AEs reported in the Japanese (eliapixant 75 mg SD, n = 2; eliapixant 150 mg MD, n = 2) and Chinese participants (eliapixant 25 mg SD, n = 7; eliapixant 75 mg SD, n = 6; eliapixant 150 mg SD, n = 7; eliapixant 150 mg MD, n = 9; placebo SD, n = 5; placebo MD, n = 1) were of mild intensity. Higher incidences of AEs in the Chinese population were likely due to differing standards of AE reporting between investigators. Conclusion: Eliapixant was well tolerated by Japanese and Chinese participants. The inter-ethnic evaluation demonstrated similar PK characteristics across Japanese, Chinese, and Caucasian participants. Registration: ClinicalTrials.gov identifier numbers: NCT04265781 and NCT04802343. [ABSTRACT FROM AUTHOR]

MICA polymorphisms have been associated with increased incidence of acute GvHD and adverse outcome in allogeneic haematopoietic stem cell transplantation (HSCT). MICB is another expressed member of MHC class I‐related chain genes and its impact on HSCT outcome is yet to be fully defined. We typed a large cohort of patients and donors for MICB polymorphisms and investigated the impact of MICB matching on outcome after unrelated HSCT. 69.2% of the patients were 10/10 human leukocyte antigen (HLA) matched and 30.8% were 9/10 HLA matched. MICB typing was performed using a short amplicon‐based NGS typing assay on the Illumina MiSeq platform. Differences in proteins were considered as mismatches. MICA polymorphisms were identified as possible confounder and were therefore included as parameter in the multivariate analyses. Due to the strong linkage disequilibrium with the classical HLA‐genes, sub‐stratification for HLA matching status was necessary, and no effect of MICB mismatches was seen in the 10/10 HLA matched group when compared to the MICB matched cases. However, in the 9/10 HLA matched group, MICB mismatched cases showed significantly worse disease free survival (DFS), GvHD and relapse free survival (GRFS) compared to the MICB matched cases (DFS: HR 1.24, p = 0.011; GRFS: HR 1.26, p = 0.002). MICA mismatches had no impact on any outcome parameter. According to our findings, effects previously attributed to MICA differences may have been confounded by MICB polymorphisms. We show that MICB differences contribute a small but relevant effect in 9/10 HLA‐matched transplantations, which in turn highlights the possible usefulness of MICB typing in donor selection among similarly suitable 9/10 matched donors, especially when HLA‐B mismatches have to be accepted. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aims to improve the preoperative classification of nerve sheath tumors using radiomics, a method that extracts quantitative data from medical images. By analyzing MRI scans, we seek to develop a more accurate way to distinguish between different types of nerve sheath tumors before surgery. Our findings could lead to better treatment planning and outcomes for patients with these tumors. This research has the potential to enhance the diagnostic process and contribute to more personalized care for individuals with nerve sheath tumors, ultimately benefiting the medical community and patients alike. Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue tumors prevalent in neurofibromatosis type 1 (NF1) patients, posing a significant risk of metastasis and recurrence. Current magnetic resonance imaging (MRI) imaging lacks decisiveness in distinguishing benign peripheral nerve sheath tumors (BPNSTs) and MPNSTs, necessitating invasive biopsies. This study aims to develop a radiomics model using quantitative imaging features and machine learning to distinguish MPNSTs from BPNSTs. Clinical data and MRIs from MPNST and BPNST patients (2000–2019) were collected at a tertiary sarcoma referral center. Lesions were manually and semi-automatically segmented on MRI scans, and radiomics features were extracted using the Workflow for Optimal Radiomics Classification (WORC) algorithm, employing automated machine learning. The evaluation was conducted using a 100× random-split cross-validation. A total of 35 MPNSTs and 74 BPNSTs were included. The T1-weighted (T1w) MRI radiomics model outperformed others with an area under the curve (AUC) of 0.71. The incorporation of additional MRI scans did not enhance performance. Combining T1w MRI with clinical features achieved an AUC of 0.74. Experienced radiologists achieved AUCs of 0.75 and 0.66, respectively. Radiomics based on T1w MRI scans and clinical features show some ability to distinguish MPNSTs from BPNSTs, potentially aiding in the management of these tumors. [ABSTRACT FROM AUTHOR]

This study evaluated and characterized the pharmacological activity of the orally administered interleukin‐1 receptor‐associated kinase 4 (IRAK4) inhibitors BAY1834845 (zabedosertib) and BAY1830839 in healthy male volunteers. Participants received one of either IRAK4 inhibitors or a control treatment (prednisolone 20 mg or placebo) twice daily for 7 days. Localized skin inflammation was induced by topical application of imiquimod (IMQ) cream for 3 days, starting at Day 3 of treatment. The inflammatory response was evaluated by laser speckle contrast imaging (skin perfusion) and multispectral imaging (erythema). At Day 7, participants received 1 ng/kg intravenous lipopolysaccharide (LPS). Circulating inflammatory proteins, leukocyte differentiation, acute phase proteins, and clinical parameters were evaluated before and after the systemic LPS challenge. Treatment with BAY1834845 significantly reduced the mean IMQ‐induced skin perfusion response (geometric mean ratio [GMR] vs. placebo: 0.69 for BAY1834845, 0.70 for prednisolone; both p < 0.05). Treatment with BAY1834845 and BAY1830839 significantly reduced IMQ‐induced erythema (GMR vs. placebo: 0.75 and 0.83, respectively, both p < 0.05; 0.86 for prednisolone, not significant). Both IRAK4 inhibitors significantly suppressed the serum TNF‐α and IL‐6 responses (≥80% suppression vs. placebo, p < 0.05) and inhibited C‐reactive protein, procalcitonin, and IL‐8 responses to intravenous LPS. This study demonstrated the pharmacological effectiveness of BAY1834845 and BAY1830839 in suppressing systemically and locally induced inflammatory responses in the same range as prednisolone, underlining the potential value of these IRAK4 inhibitors as future therapies for dermatological or other immune‐mediated inflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: Obesity, specifically abdominal adiposity, is associated with increased risks of lung function impairment and asthma in children, but potential adverse effects among adolescents are unknown. We hypothesized that elevated amounts of specific abdominal fat depots during childhood and adolescence may lead to adverse respiratory outcomes in adolescents. Methods: In a population‐based prospective cohort study among 2877 children at 13 years, we measured specific abdominal fat depots including subcutaneous fat mass and visceral fat mass by magnetic resonance imaging. Lung function was measured by spirometry, and current asthma by a questionnaire. Conditional regression analyses were used to examine the associations of abdominal fat depots with respiratory outcomes in adolescence. Results: After adjustment for confounders and child's body mass index, higher subcutaneous and visceral fat mass index at age 13 years, independent of these measures at earlier age, were associated with lower FEV1, FEV1/FVC, and FEF75 (range Z‐score difference (95% CI): −0.10 (−0.15, −0.06) to −0.06 (−0.11, −0.01)). Also, an increase in subcutaneous and visceral fat between ages 10 and 13 years was associated with a decrease in FEV1, FEV1/FVC, and FEF75 during the same period. No associations of abdominal fat depots with asthma were observed. Conclusion: Adolescents with higher amounts of subcutaneous and visceral fat, independent of that at an earlier age and body mass index, have an increased risk of lung function impairment. [ABSTRACT FROM AUTHOR]

Purpose: Support groups might help survivors of allogeneic hematopoietic cell transplantations (HCT) to cope with medical, psychological, and social challenges. The aim of this project was (1) to establish a facilitated post-HCT support group and (2) to assess the participation behaviour. Methods: From 11/2013 until 7/2017, all adult patients who had received a HCT at our centre were invited to participate in a professionally facilitated support group. The format of the group was unstructured without any rules regarding regular attendance. The attendance was prospectively minuted by the facilitator. Reasons for non-attendance were assessed by a survey. Results: During the observation period, 53 group meetings were scheduled. Nine meetings were cancelled because of low attendance. Altogether 23 different patients (F: n=10; M: n=13) and 10 spouses (F: n=9; M: n=1) participated. Median participation was 5 [range 2–11]. With respect to all HCT patients who had the theoretical opportunity to attend, the mean participation rate was 7%. Thirteen patients and four spouses attended more than one meeting. The median count of participations among those participants was 8 [2-32]. The median interval from the first until the last participation was 16 months. The main reason reported for non-participation was the effort to get to the venue of the support group. Conclusions: To our knowledge, this is the first analysis on the attendance behaviour of the participants of a support group for HCT survivors. The results provide guidance for the organization of future support groups and indicate what participation rates can be expected and how they might be increased. [ABSTRACT FROM AUTHOR]

Background: Overactive adenosine triphosphate signaling via P2X3 homotrimeric receptors is implicated in multiple conditions. To fully understand the metabolism and elimination pathways of eliapixant, a study was conducted to assess the pharmacokinetics, mass balance, and routes of excretion of a single oral dose of the selective P2X3 receptor antagonist eliapixant, in addition to an in vitro characterization. Methods: In this single-center open-label non-randomized non-placebo-controlled phase I study, healthy male subjects (n = 6) received a single dose of 50 mg eliapixant blended with 3.7 MBq [14C]eliapixant as a PEG 400-based oral solution. Total radioactivity and metabolites excreted in urine and feces, and pharmacokinetics of total radioactivity, eliapixant, and metabolites in plasma were assessed via liquid scintillation counting and high-performance liquid chromatography-based methods coupled to radiometric and mass spectrometric detection. Metabolite profiles of eliapixant in human in vitro systems and metabolizing enzymes were also investigated. Results: After administration as an oral solution, eliapixant was rapidly absorbed, reaching maximum plasma concentrations within 2 h. Eliapixant was eliminated from plasma with a mean terminal half-life of 48.3 h. Unchanged eliapixant was the predominant component in plasma (72.6% of total radioactivity area under the curve). The remaining percentage of drug-related components in plasma probably represented the sum of many metabolites, detected in trace amounts. Mean recovery of total radioactivity was 97.9% of the administered dose (94.3–99.4%) within 14 days, with 86.3% (84.8–88.1%) excreted via feces and 11.6% (9.5–13.1%) via urine. Excretion of parent drug was minimal in feces (0.7% of dose) and urine (≈ 0.5%). In feces, metabolites formed by oxidation represented > 90% of excreted total radioactivity. The metabolites detected in the in vitro experiments were similar to those identified in vivo. Conclusion: Complete recovery of administered eliapixant-related radioactivity was observed in healthy male subjects with predominant excretion via feces. Eliapixant was almost exclusively cleared by oxidative biotransformation (> 90% of dose), with major involvement of cytochrome P450 3A4. Excretion of parent drug was of minor importance (~ 1% of dose). Clinical trial registration: ClinicalTrials.gov: NCT04487431 (registered 27 July 2020)/EudraCT number: 2020-000519-54 (registered 3 February 2020), NCT02817100 (registered 26 June 2016), NCT03310645 (registered 16 October 2017). Plain Language Summary: Eliapixant is a drug that acts on structures in the body called P2X3 receptors that are involved in several conditions, including chronic cough, overactive bladder, and endometriosis-related pain. When evaluating a new drug, it is important to know how it is being removed from the body by natural mechanisms. We performed a study in which six healthy male volunteers took a single dose of eliapixant, and we investigated what happened to the drug after it was taken. We measured the amount of eliapixant in the volunteers' blood, urine, and feces, and also measured the compounds formed when eliapixant was broken down naturally by the body ("metabolites"). We also used human cells in the laboratory to investigate how the different metabolites of eliapixant are formed. Almost three-quarters of eliapixant in the blood had not been broken down at all, while the remaining one-quarter had been converted into many different metabolites. A total of 2 weeks after taking eliapixant, almost all of it had been converted to metabolites and eliminated from the body (mostly in feces, but also a small amount in urine). The most important organ for breaking down eliapixant is the liver. The information from this study will help doctors determine whether eliapixant is likely to interfere with other drugs taken simultaneously, and whether patients with liver or kidney problems might take longer than healthy people to remove it from their bodies. [ABSTRACT FROM AUTHOR]

Introduction: Extracorporal Photophoresis (ECP) is in clinical use for steroidrefractory and steroid-dependent acute GVHD (SR-aGVHD). Based on recent Phase-III study results, ruxolitinib has become the new standard of care for SRaGVHD. Our aim was to collect comparative data between ruxolitinib and ECP in SR-aGVHD in order to improve the evidence base for clinical decision making. Methods: We asked EBMT centers if they were willing to participate in this study by completing a data form (Med-C) with detailed information on GVHD grading, -therapy, -dosing, -response and complications for each included patient. Results: 31 centers responded positively (14%) and we included all patients receiving alloSCT between 1/2017-7/2019 and treated with ECP or ruxolitinib for SR-aGVHD grades II-IV from these centers. We identified 53 and 40 patients with grades II-IV SR-aGVHD who were treated with ECP and ruxolitinib, respectively. We performed multivariate analyses adjusted on grading and type of SR-aGVHD (steroid dependent vs. refractory). At day+90 after initiation of treatment for SR-aGVHD we found no statistically significant differences in overall response. The odds ratio in the ruxolitinib group to achieve overall response vs. the ECP group was 1.13 (95% CI = [0.41; 3.22], p = 0.81). In line, we detected no statistically significant differences in overall survival, progressionfree survival, non-relapse mortality and relapse incidence. Discussion: The clinical significance is limited by the retrospective study design and the current data can’t replace prospective studies on ECP in SR-aGVHD. However, the present results contribute to the accumulating evidence on ECP as an effective treatment option in SR-aGVHD. [ABSTRACT FROM AUTHOR]

Summary: Background: Body composition between prepubertal children and adolescents varies, and it is unclear how physical activity and sedentary behaviour affect adolescent body composition. Objectives: This study aimed to examine the associations of physical activity and screen time with overall and specific fat depots in the general adolescent population. Methods: In a population‐based prospective cohort study, among 3258 adolescents aged 13 years, physical activity and screen time were assessed via self‐report questionnaires. Body mass index, dual‐energy X‐ray absorptiometry‐based measures (i.e. fat mass and lean body mass) and magnetic resonance imaging–based measures (i.e. abdominal subcutaneous and visceral fat mass) were obtained. Results: After adjusting for social‐demographic and growth‐related factors, each additional hour of daily physical activity was associated with lower fat mass, abdominal visceral fat mass and higher lean body mass (all p < 0.05). However, these associations were not observed in the longitudinal analyses. Each additional hour of daily screen time was associated with higher body mass index, fat mass, abdominal subcutaneous and visceral fat mass (all p < 0.05), which were consistent with the longitudinal analyses. Conclusion: Adolescents with higher physical activity and lower screen time had lower levels of adiposity both at the general and visceral levels. [ABSTRACT FROM AUTHOR]

Introduction: Autologous stem cell transplantation is a successful routine procedure with only a small number of non-engraftment cases, although the time to hematopoietic recovery may vary considerably across patients. While CD34 has been the decisive marker for enumerating hematopoietic stem and progenitor cells (HSPCs) for more than 30 years, the impact of CD34-positive cellular subpopulations in autologous HSPC grafts on hematopoietic reconstitution remains unclear. Methods: The two-color ISHAGE protocol represents the current gold standard for CD34+ cell enumeration but includes only the number of viable CD45+/CD34+ cells relative to the body weight of the recipient. We adapted a multicolor flow cytometry marker panel for advanced characterization of CD34 subpopulations in retained samples of autologous peripheral blood stem cell products (n = 49), which had been cryostored for a wide range from 4 to 15 years. The flow cytometric analysis included CD10, CD34, CD38, CD45, CD45RA, CD133, and viability staining with 7AAD. The findings were correlated with clinical engraftment data, including reconstitution of leukocytes, neutrophils, and platelets after transplantation (TPL). Results: We demonstrated that the identification of autologous HSPC subpopulations by flow cytometry after cryopreservation is feasible. Regarding the distribution of HSPC subpopulations, a markedly different pattern was observed in comparison to previously published data obtained using fresh autologous material. Our data revealed the largest ratio of lympho-myeloid progenitors (LMPPs) after freezing and thawing, followed by multipotent progenitors and erythroid-myeloid progenitors. A high ratio of LMPPs, representing an immature stage of differentiation, correlated significantly with early neutrophilic granulocyte and leukocyte engraftment (p = 0.025 and p = 0.003). Conversely, a large ratio of differentiated cells correlated with late engraftment of neutrophilic granulocytes (p = 0.024). Overall, successful engraftment was documented for all patients. Conclusion: We established an advanced flow cytometry panel to assess the differentiation ability of cryostored autologous peripheral blood stem cell grafts and correlated it with timely hematopoietic reconstitution. This approach represents a novel and comprehensive way to identify hematopoietic stem and progenitor subpopulations. It is a feasible way to indicate the engraftment capacity of stem cell products. [ABSTRACT FROM AUTHOR]

Purpose: To systematically review the techniques that address undersampling artifacts in accelerated quantitative magnetic resonance imaging (qMRI). Methods: A literature search was conducted using the Embase, Medline, Web of Science Core Collection, Coherence Central Register of Controlled Trials, and Google Scholar databases for studies, published before July 2022 proposing reconstruction techniques for accelerated qMRI. Studies are reviewed according to inclusion criteria, and included studies are categorized based on the methodology used. Results: A total of 292 studies included in the review are categorized. A technical overview of each category is provided, and the categories are described in a unified mathematical framework. The distribution of the reviewed studies over time, application domain, and parameters of interest is illustrated. Conclusion: An increasing trend in the number of articles that propose new techniques for accelerated qMRI reconstruction indicates the importance of acceleration in qMRI. The techniques are mostly validated for relaxometry parameters and brain scans. The categories of techniques are compared based on theoretical grounds, highlighting existing trends and potential gaps in the field. [ABSTRACT FROM AUTHOR]

"Normal" and "abnormal" are frequently used in surgical planning and to evaluate surgical results of the forefoot. However, there is no objectifiable value of metatarsophalangeal angles (MTPAs) 2–5 in the dorsoplantar (DP) view with which to objectively evaluate lesser toe alignment. We aimed to determine which angles are considered to be "normal" by orthopedic surgeons and radiologists. Thirty anonymized radiographs of feet were submitted twice in randomized order to determine the respective MTPAs 2–5. After six weeks, the anonymized radiographs and photographs of the same feet without apparent affiliation were presented again. The terms "normal," "borderline normal," and "abnormal" were assigned by the observers. Viewers considered MTP-2 alignment from 0° to −20° to be normal, and below −30° abnormal; MTP-3, 0° to −15° to be normal and below −30° abnormal; MTP-4, 0° to −10° normal and below −20° abnormal. Between 5° valgus and 15° varus was the range of MTP-5 recognized as normal. High intra-observer but low interobserver reliability with overall low correlation of clinical and radiographic aspects was observed. The assessment of the terms "normal" or "abnormal" are subject to a high degree of variation. Therefore, these terms should be used cautiously. [ABSTRACT FROM AUTHOR]

Background: Post-placement menstrual bleeding pattern changes with intrauterine contraceptives (IUCs), including levonorgestrel-releasing intrauterine systems (LNG-IUS), can be a reason for avoidance or early discontinuation. Prostaglandins play an important role in menstrual bleeding and pain. The key drivers of prostaglandin synthesis are cyclooxygenase (COX) enzymes, which are inhibited by non-steroidal anti-inflammatory drugs. In this study, we report the findings from pharmacokinetic (PK) analyses undertaken with an LNG-IUS (LNG-IUS 8) modified with an additional reservoir containing indomethacin (IND). Methods: The IND/LNG-IUS 8 is a proof-of-concept device studied in a phase II proof-of-concept/dose-finding study. IND/LNG-IUS 8 contains the same LNG content as the unmodified LNG-IUS 8 (13.5 mg) but was prepared with three different IND doses (low, 6.5 mg; middle, 12.5 mg; and high, 15.4 mg), resulting in different daily release rates. Overall, 174 healthy, premenopausal women were randomized to one of the four treatment arms (low-, middle-, high-dose IND/LNG-IUS 8 or LNG-IUS 8). Initial and residual IND and LNG content were collected and the amount of IND and LNG released in vivo over the period of use was calculated. A subset of 62 participants underwent dense blood sampling for PK analysis. Concentrations of IND and LNG in plasma were determined by validated liquid chromatography-tandem mass spectrometry methods and plotted over time. Descriptive statistics were calculated for plasma drug concentrations and PK parameters. Results: High-dose IND/LNG-IUS 8 initially released much higher levels of IND than expected based on in vitro release data, followed by a steep decline, with the reservoir emptied by 4.5 months. Middle- and low-dose IND/LNG-IUS 8 demonstrated steady sustained release of IND over time, emptying after 7.4 and 8.4 months, respectively. Peak plasma concentrations of IND for low- and middle-dose IND/LNG-IUS 8 remained below the 20% maximal inhibitory concentration (IC20) values for COX enzymes. The average daily IND release rate in vivo was 49 µg/day for low-dose and 112 µg/day for middle-dose IND/LNG-IUS 8. The IND release rate profile and IND plasma concentrations in vitro both decreased steadily over time with low- and middle-dose IND/LNG-IUS 8. The LNG release rate profile was comparable for all IND/LNG-IUS 8 dose groups and LNG-IUS 8. Conclusion: This PK study demonstrates that two different drugs can be released at different rates from an IUS designed with two drug reservoirs. Inclusion of IND does not impact the LNG PK profile. Low- and middle-dose IND/LNG-IUS 8 were associated with a systemic IND exposure that should preclude the occurrence of adverse events typically observed after oral IND dosing. Study Registration: ClinicalTrials.gov identifier number: NCT03562624 [ABSTRACT FROM AUTHOR]

Purpose: To introduce a novel imaging and parameter estimation framework for accurate multi‐shot diffusion MRI. Theory and Methods: We propose a new framework called ADEPT (Accurate Diffusion Echo‐Planar imaging with multi‐contrast shoTs) that enables fast diffusion MRI by allowing diffusion contrast settings to change between shots in a multi‐shot EPI acquisition (i.e., intra‐scan modulation). The framework estimates diffusion parameter maps directly from the acquired intra‐scan modulated k‐space data, while simultaneously accounting for shot‐to‐shot phase inconsistencies. The performance of the estimation framework is evaluated using Monte Carlo simulation studies and in‐vivo experiments and compared to that of reference methods that rely on parallel imaging for shot‐to‐shot phase correction. Results: Simulation and real‐data experiments show that ADEPT yields more accurate and more precise estimates of the diffusion metrics in multi‐shot EPI data in comparison with the reference methods. Conclusion: ADEPT allows fast multi‐shot EPI diffusion MRI without significantly degrading the accuracy and precision of the estimated diffusion maps. [ABSTRACT FROM AUTHOR]

Background and Objectives: The potent, selective P2X3 receptor antagonist eliapixant (BAY 1817080) is under development for conditions characterized by neuronal hypersensitization. As prominent food effects and limited bioavailability in the fasted state were observed with immediate-release eliapixant tablets, a novel formulation was needed. Accordingly, several novel eliapixant formulations were assessed by in vitro and animal studies in a structured way. The most promising of the formulations was then investigated in a phase I study designed to assess its pharmacokinetics, food effect, and bioavailability in healthy volunteers. Methods: In vitro non-sink dissolution tests were performed with two amorphous solid dispersion (ASD) granule prototypes compared with pure crystalline eliapixant as a surrogate for the immediate-release formulation. Subsequently, the drug exposure of novel eliapixant formulations under fed and fasted conditions in rats and dogs was assessed to confirm improvements in bioavailability versus the suspension-based formulation. A novel Kollidon VA64®-based eliapixant formulation was identified from the preclinical studies and compared with the original tablet formulation in an open-label, partially randomized, threefold, crossover phase I study, in which healthy males received single oral doses (25–400 mg, fasted/fed). Pharmacokinetic parameters, absolute bioavailability (using an intravenous [13C715N]-eliapixant microdose), relative bioavailability (novel versus original formulation), effect of food, and adverse events (AEs) were evaluated. Results: The non-sink dissolution test demonstrated that the two ASD formulations had an improved dissolution rate compared with pure crystalline eliapixant, with a Kollidon VA64-based prototype having the highest dissolution rate. Further testing of this prototype in animal studies confirmed an approximately twofold higher bioavailability compared with the suspension-based formulation. In the phase I study, 30 subjects were randomized. With the novel Kollidon VA64® formulation (400 mg; fasted), area under the concentration–time curve (AUC) and maximum plasma concentration (Cmax) were up to 3.1-fold and 1.7-fold higher, respectively, than with the original formulation (fed). AUC increased dose proportionally between 25 and 100 mg, and less than dose proportionally from 100 to 400 mg. Food had no clinically relevant effect on the novel formulation, with AUC increasing 1.3-fold and Cmax 2.1–2.4-fold (time to maximum concentration was delayed by 1.5–2.25 h). Absolute bioavailability with the novel formulation (100 mg) was 50%. AEs occurred in 57% of patients; most were mild in severity. Conclusions: The novel eliapixant formulation substantially improved bioavailability compared with immediate-release eliapixant and may be administered with/without food. Clinical Trial Registration: Clinicaltrials.gov: NCT03773068 (initial registration: 12 December 2018). [ABSTRACT FROM AUTHOR]

Introduction: Graft‐versus‐host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) and is highly influenced by the degree of HLA matching between recipient and donor. The HLA‐class Ib molecule HLA‐G has been shown to promote tolerogenicity through its interaction with inhibitory receptors found on several immunocompetent cells. We hypothesized that in an allo‐HSCT setting, HLA‐G mismatches may negatively impact the HLA‐G‐mediated tolerogenicity either due to inefficient interaction with the inhibitory receptors of the transplanted immune cells or due to direct allorecognition of mismatched HLA‐G on host cells by the immune cells of the donor. Methods: In order to explore this hypothesis, we investigated the impact of HLA‐G mismatching in 2.083 10/10 matched high resolution HLA‐typed allo‐HSCT transplants. Results: We found that the risk of chronic GvHD was significantly higher in HLA‐G‐mismatched transplant cases as compared with the HLA‐G‐matched control group (HR: 1.46, 95%CI = 1.11–1.91, p = 0.006). Sub‐analysis of the mismatch vector revealed that this effect was only detectable in the GvH (HR: 1.89, 95%CI 1.39–2.57, p < 0.001) but not the HvG direction (HR: 1.01, 95%CI = 0.63–1.63, p = 0.967). In addition, the negative impact of HLA‐G mismatching on chronic GvHD was only significant in younger patients (<30y HR: 3.02, 95%CI = 1.25–7.28, p = 0.014; >29y HR: 1.28, 95%CI = 0.94–1.72, p = 0.113). Discussion: Our results indicate that HLA‐G mismatches may contribute to the onset of chronic GvHD, especially in younger patients and should therefore be avoided when possible. [ABSTRACT FROM AUTHOR]

Aims: Neuronal hypersensitisation due to adenosine triphosphate‐dependent P2X3 receptor signalling plays a significant role in several disorders including chronic cough and endometriosis. This first‐in‐human study of eliapixant (BAY 1817080) investigated the tolerability, safety and pharmacokinetics (PK) of single doses of eliapixant, including the effect of food and coadministration with a CYP3A inhibitor on eliapixant relative bioavailability. Methods: In this randomised, double‐blind phase I study (NCT02817100), 88 healthy male subjects received single ascending doses of immediate‐release eliapixant (10–800 mg) tablets or placebo under fasted conditions, with food (low‐fat continental or high‐fat American breakfast) or with itraconazole (fasted state). PK parameters, dose proportionality, adverse events and taste assessments (taste strips; dysgeusia questionnaire) were evaluated. Results: Eliapixant had a long half‐life (23.5–58.9 h [fasted state]; 32.8–43.8 h [high‐fat breakfast]; 38.9–46.0 h [low‐fat breakfast]). Less than dose‐proportional increases in maximum plasma concentrations (Cmax) and area under the concentration–time curve from time 0 to infinity (AUC[0–inf]) were observed with ascending eliapixant doses. We observed a pronounced food effect with the high‐fat breakfast (4.1‐fold increased Cmax; 2.7‐fold increased AUC[0–inf]), a smaller food effect with the low‐fat breakfast and a mild‐to‐moderate effect of itraconazole coadministration on eliapixant (1.1–1.2‐fold increased Cmax; 1.7‐fold increased AUC from 0 to 72 h). Eliapixant was well tolerated with minimal impact on taste perception. Conclusion: The PK profile, particularly the long half‐life, and favourable tolerability with no taste‐related adverse events, supports the further development of eliapixant in disorders with underlying P2X3 receptor‐mediated neuronal hypersensitisation. [ABSTRACT FROM AUTHOR]

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COVID-19 in patients with hematological diseases is associated with a high mortality. Moreover, preventive vaccination demonstrated reduced efficacy and the knowledge on influencing factors is limited. In this single-center study, antibody levels of the SARS-CoV-2 spike protein were measured ≥ 2 weeks after 2nd COVID-19 vaccination with a concentration ≥ 0.8 U/mL considered positive. Between July and October 2021, in a total of 373 patients (median age 64 years, 44% women) with myeloid neoplasms (n = 214, 57%), lymphoid neoplasms (n = 124, n = 33%), and other diseases (n = 35, 10%), vaccination was performed with BNT162b2 (BioNTech), mRNA-1273 (Moderna), ChADOx1 (AstraZeneca), or a combination. A total of 229 patients (61%) were on active therapy within 3 months prior vaccination and 144 patients (39%) were previously treated or treatment naïve. Vaccination-related antibody response was negative in 56/373 patients (15%): in 39/124 patients with lymphoid neoplasms, 13/214 with myeloid neoplasms, and 4/35 with other diseases. Active treatment per se was not correlated with negative response. However, rituximab and BTK inhibitor treatment were correlated significantly with a negative vaccination response, whereas younger age and chronic myeloid leukemia (CML) disease were associated with positive response. In addition, 5 of 6 patients with myeloproliferative neoplasm (MPN) and negative vaccination response were on active treatment with ruxolitinib. In conclusion, a remarkable percentage of patients with hematological diseases had no response after 2nd COVID-19 vaccination. Multivariable analysis revealed important factors associated with response to vaccination. The results may serve as a guide for better protection and surveillance in this vulnerable patient cohort. [ABSTRACT FROM AUTHOR]

Background and Objective: There is no licensed treatment for refractory chronic cough; off-label therapies have limited efficacy and can produce adverse effects. Excessive adenosine triphosphate signaling via P2X3 receptors is implicated in refractory chronic cough, and selective P2X3 receptor antagonists such as eliapixant (BAY 1817080) are under investigation. The objective of the study was to investigate the safety and tolerability of ascending repeated oral doses of eliapixant in healthy volunteers. Methods: We conducted a repeated-dose, double-blind, randomized, placebo-controlled study in 47 healthy male individuals. Subjects received repeated twice-daily ascending oral doses of eliapixant (10, 50, 200, and 750 mg) or placebo for 2 weeks. The primary outcome was frequency and severity of adverse events. Other outcomes included pharmacokinetics and evaluation of taste disturbances, which have occurred with the less selective P2X3 receptor antagonist gefapixant. Results: Peak plasma concentrations of eliapixant were reached 3–4 h after administration of the first and subsequent doses. With multiple dosing, steady-state plasma concentrations were reached after ~ 6 days, and plasma concentrations predicted to achieve ≥ 80% P2X3 receptor occupancy (the level required for efficacy) were reached at 200 and 750 mg. Increases in plasma concentrations with increasing doses were less than dose proportional. After multiple dosing, mean plasma concentrations of eliapixant showed low peak–trough fluctuations and were similar for 200- and 750-mg doses. Eliapixant was well tolerated with a low incidence of taste-related adverse events. Conclusions: Eliapixant (200 and 750 mg) produced plasma concentrations that cover the predicted therapeutic threshold over 24 h, with good safety and tolerability. These results enabled eliapixant to progress to clinical trials in patients with refractory chronic cough. Clinical Trial Registration: Clinicaltrials.gov: NCT03310645 (initial registration: 16 October, 2017). Plain Language Summary: There are few effective treatments for patients with a long-term (chronic) cough. It is thought that chronic cough is caused by nerves becoming oversensitive, wrongly causing a cough when there is no need. We tested a new drug called eliapixant in 47 healthy men. Eliapixant reduces the excessive nerve signaling responsible for chronic cough. We looked for side effects of eliapixant and measured how it behaves in the body. In particular we looked for side effects relating to the sense of taste because gefapixant, a similar drug to eliapixant, can affect taste. Participants took one of four eliapixant doses or a placebo twice daily for 2 weeks. The highest levels of eliapixant in the blood were seen 3–4 h after taking the drug, and stable concentrations were seen after about 6 days. At the two highest doses, eliapixant reached concentrations in the body that should be high enough to work in patients with chronic cough. Side effects were generally similar between eliapixant and placebo. Taste-related side effects were mild and went away without needing treatment. The positive results of this study meant that eliapixant could be tested in patients with chronic cough. [ABSTRACT FROM AUTHOR]

We present a compact multi-modal and multi-scale retinal imaging instrument with an angiographic functional extension for clinical use. The system integrates scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT) and OCT angiography (OCTA) imaging modalities and provides multi-scale fields of view. For high resolution, and high lateral resolution in particular, cellular imaging correction of aberrations by adaptive optics (AO) is employed. The entire instrument has a compact design and the scanning head is mounted on motorized translation stages that enable 3D self-alignment with respect to the subject's eye by tracking the pupil position. Retinal tracking, based on the information provided by SLO, is incorporated in the instrument to compensate for retinal motion during OCT imaging. The imaging capabilities of the multi-modal and multi-scale instrument were tested by imaging healthy volunteers and patients. [ABSTRACT FROM AUTHOR]

Treatment planning of gastrointestinal stromal tumors (GISTs) includes distinguishing GISTs from other intra-abdominal tumors and GISTs' molecular analysis. The aim of this study was to evaluate radiomics for distinguishing GISTs from other intra-abdominal tumors, and in GISTs, predict the c-KIT, PDGFRA, BRAF mutational status, and mitotic index (MI). Patients diagnosed at the Erasmus MC between 2004 and 2017, with GIST or non-GIST intra-abdominal tumors and a contrast-enhanced venous-phase CT, were retrospectively included. Tumors were segmented, from which 564 image features were extracted. Prediction models were constructed using a combination of machine learning approaches. The evaluation was performed in a 100 × random-split cross-validation. Model performance was compared to that of three radiologists. One hundred twenty-five GISTs and 122 non-GISTs were included. The GIST vs. non-GIST radiomics model had a mean area under the curve (AUC) of 0.77. Three radiologists had an AUC of 0.69, 0.76, and 0.84, respectively. The radiomics model had an AUC of 0.52 for c-KIT, 0.56 for c-KIT exon 11, and 0.52 for the MI. The numbers of PDGFRA, BRAF, and other c-KIT mutations were too low for analysis. Our radiomics model was able to distinguish GISTs from non-GISTs with a performance similar to three radiologists, but less observer dependent. Therefore, it may aid in the early diagnosis of GIST, facilitating rapid referral to specialized treatment centers. As the model was not able to predict any genetic or molecular features, it cannot aid in treatment planning yet. [ABSTRACT FROM AUTHOR]

Crystallization is one of the most important phase transformations of first order. In the case of metals and alloys, the liquid phase is the parent phase of materials production. The conditions of the crystallization process control the as-solidified material in its chemical and physical properties. Nucleation initiates the crystallization of a liquid. It selects the crystallographic phase, stable or meta-stable. Its detailed knowledge is therefore mandatory for the design of materials. We present techniques of containerless processing for nucleation studies of metals and alloys. Experimental results demonstrate the power of these methods not only for crystal nucleation of stable solids but in particular also for investigations of crystal nucleation of metastable solids at extreme undercooling. This concerns the physical nature of heterogeneous versus homogeneous nucleation and nucleation of phases nucleated under non-equilibrium conditions. The results are analyzed within classical nucleation theory that defines the activation energy of homogeneous nucleation in terms of the interfacial energy and the difference of Gibbs free energies of solid and liquid. The interfacial energy acts as barrier for the nucleation process. Its experimental determination is difficult in the case of metals. In the second part of this work we therefore explore the potential of colloidal suspensions as model systems for the crystallization process. The nucleation process of colloids is observed in situ by optical observation and ultra-small angle X-ray diffraction using high intensity synchrotron radiation. It allows an unambiguous discrimination of homogeneous and heterogeneous nucleation as well as the determination of the interfacial free energy of the solid-liquid interface. Our results are used to construct Turnbull plots of colloids, which are discussed in relation to Turnbull plots of metals and support the hypothesis that colloids are useful model systems to investigate crystal nucleation. [ABSTRACT FROM AUTHOR]

The HLA-DRB3/4/5 loci are closely linked to the HLA-DRB1 gene. Mismatches in these loci occur with a frequency of about 8%–12% in otherwise 10/10 HLA-matched transplant pairs. There is preliminary evidence that these disparities may associate with increased acute graft-versus-host disease (GvHD) rates. The aim of this study was to analyze a large cohort of German patients and their donors for HLA-DRB3/4/5 compatibility and to correlate the HLA-DRB3/4/5 matching status with the outcome of unrelated hematopoietic stem cell transplantation (uHSCT). To this end, 3,410 patients and their respective donors were HLA-DRB3/4/5 and HLA-DPB1 typed by amplicon-based next-generation sequencing (NGS). All patients included received their first allogeneic transplant for malignant hematologic diseases between 2000 and 2014. Mismatches in the antigen recognition domain (ARD) of HLA-DRB3/4/5 genes were correlated with clinical outcome. HLA-DRB3/4/5 incompatibility was seen in 12.5% (n = 296) and 17.8% (n = 185) of the 10/10 and 9/10 HLA-matched cases, respectively. HLA-DRB3/4/5 mismatches in the ARD associated with a worse overall survival (OS), as shown in univariate (5-year OS: 46.1% vs. 39.8%, log-rank p = 0.038) and multivariate analyses [hazard ratio (HR) 1.25, 95% CI 1.02–1.54, p = 0.034] in the otherwise 10/10 HLA-matched subgroup. The worse outcome was mainly driven by a significantly higher non-relapse mortality (HR 1.35, 95% CI 1.05–1.73, p = 0.017). In the 9/10 HLA-matched cases, the effect was not statistically significant. Our study results suggest that mismatches within the ARD of HLA-DRB3/4/5 genes significantly impact the outcome of otherwise fully matched uHSCT and support their consideration upon donor selection in the future. [ABSTRACT FROM AUTHOR]

Objectives: Our aim was to assess the ability of semi-automatically extracted magnetic resonance imaging (MRI)–based radiomic features from tibial subchondral bone to distinguish between knees without and with osteoarthritis. Methods: The right knees of 665 females from the population-based Rotterdam Study scanned with 1.5T MRI were analyzed. A fast imaging employing steady-state acquisition sequence was used for the quantitative bone analyses. Tibial bone was segmented using a method that combines multi-atlas and appearance models. Radiomic features related to the shape and texture were calculated from six volumes of interests (VOIs) in the proximal tibia. Machine learning–based Elastic Net models with 10-fold cross-validation were used to distinguish between knees without and with MRI Osteoarthritis Knee Score (MOAKS)–based tibiofemoral osteoarthritis. Performance of the covariate (age and body mass index), image features, and combined covariate + image features models were assessed using the area under the receiver operating characteristic curve (ROC AUC). Results: Of 665 analyzed knees, 76 (11.4%) had osteoarthritis. An ROC AUC of 0.68 (95% confidence interval (CI): 0.60–0.75) was obtained using the covariate model. The image features model yielded an ROC AUC of 0.80 (CI: 0.73–0.87). The model that combined image features from all VOIs and covariates yielded an ROC AUC of 0.80 (CI: 0.73–0.87). Conclusion: Our results suggest that radiomic features are useful imaging biomarkers of subchondral bone for the diagnosis of osteoarthritis. An advantage of assessing bone on MRI instead of on radiographs is that other tissues can be assessed simultaneously. Key Points: • Subchondral bone plays a role in the osteoarthritis disease processes. • MRI radiomics is a potential method for quantifying changes in subchondral bone. • Semi-automatically extracted radiomic features of tibia differ between subjects without and with osteoarthritis. [ABSTRACT FROM AUTHOR]

Histopathological growth patterns (HGPs) are independent prognosticators for colorectal liver metastases (CRLM). Currently, HGPs are determined postoperatively. In this study, we evaluated radiomics for preoperative prediction of HGPs on computed tomography (CT), and its robustness to segmentation and acquisition variations. Patients with pure HGPs [i.e. 100% desmoplastic (dHGP) or 100% replacement (rHGP)] and a CT-scan who were surgically treated at the Erasmus MC between 2003–2015 were included retrospectively. Each lesion was segmented by three clinicians and a convolutional neural network (CNN). A prediction model was created using 564 radiomics features and a combination of machine learning approaches by training on the clinician's and testing on the unseen CNN segmentations. The intra-class correlation coefficient (ICC) was used to select features robust to segmentation variations; ComBat was used to harmonize for acquisition variations. Evaluation was performed through a 100 × random-split cross-validation. The study included 93 CRLM in 76 patients (48% dHGP; 52% rHGP). Despite substantial differences between the segmentations of the three clinicians and the CNN, the radiomics model had a mean area under the curve of 0.69. ICC-based feature selection or ComBat yielded no improvement. Concluding, the combination of a CNN for segmentation and radiomics for classification has potential for automatically distinguishing dHGPs from rHGP, and is robust to segmentation and acquisition variations. Pending further optimization, including extension to mixed HGPs, our model may serve as a preoperative addition to postoperative HGP assessment, enabling further exploitation of HGPs as a biomarker. [ABSTRACT FROM AUTHOR]

Metastatic mesenteric masses of small intestinal neuroendocrine tumors (SI-NETs) are known to often cause intestinal complications. The aim of this study was to identify patients at risk to develop these complications based on routinely acquired CT scans using a standardized set of clinical criteria and radiomics. Retrospectively, CT scans of SI-NET patients with a mesenteric mass were included and systematically evaluated by five clinicians. For the radiomics approach, 1128 features were extracted from segmentations of the mesenteric mass and mesentery, after which radiomics models were created using a combination of machine learning approaches. The performances were compared to a multidisciplinary tumor board (MTB). The dataset included 68 patients (32 asymptomatic, 36 symptomatic). The clinicians had AUCs between 0.62 and 0.85 and showed poor agreement. The best radiomics model had a mean AUC of 0.77. The MTB had a sensitivity of 0.64 and specificity of 0.68. We co nclude that systematic clinical evaluation of SI-NETs to predict intestinal complications had a similar performance than an expert MTB, but poor inter-observer agreement. Radiomics showed a similar performance and is objective, and thus is a promising tool to c orrectly identify these patients. However, further validation is needed before the transition to clinical practice. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is among the top 10 burdensome diseases, with the knee the most affected joint. Magnetic resonance imaging (MRI) allows whole-knee assessment, making it ideally suited for imaging OA, considered a multitissue disease. Three-dimensional (3D) MRI enables the comprehensive assessment of OA, including quantitative morphometry of various joint tissues. Manual tissue segmentation on 3D MRI is challenging but may be overcome by advanced automated image analysis methods including artificial intelligence (AI). This review presents examples of the utility of 3D MRI for knee OA, focusing on the articular cartilage, bone, meniscus, synovium, and infrapatellar fat pad, and it highlights several applications of AI that facilitate segmentation, lesion detection, and disease classification. [ABSTRACT FROM AUTHOR]

Lower-limb exoskeletons could improve the mobility of people with disabilities, older adults, workers, first responders, and military personnel. Despite recent advances, few products are commercially available and exoskeleton research is still often limited by hardware constraints. Many promising multi-joint assistance strategies, especially those with high-torque and high-power components, have yet to be tested because they are beyond the capabilities of current devices. To study these untested assistance strategies, we present a hip–knee–ankle exoskeleton emulator that can apply high torques and powers that match or exceed those observed in uphill running. The system has powerful off-board motors that actuate a 13.5 kg exoskeleton end effector worn by the user. It can apply up to 200 Nm of torque in hip flexion, hip extension, and ankle plantarflexion, 250 Nm of torque in knee extension, and 140 Nm of torque in knee flexion, with over 4.5 kW of power at each joint and a closed-loop torque bandwidth of at least 18 Hz in each direction of actuation. The exoskeleton is compliant in unactuated directions, adjustable for a wide range of users and comfortable during walking and running. When paired with human-in-the-loop optimization, we expect that this system will identify new assistance strategies to improve human mobility. A complete computer-aided design (CAD) model of the exoskeleton and a bill of materials are included and available for download. [ABSTRACT FROM AUTHOR]

Treatment of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains a great challenge. Aiming to evaluate the combination of venetoclax and hypomethylating agents (HMAClax) for the treatment of relapse of myeloid malignancies after alloHSCT, we retrospectively collected data from 32 patients treated at 11 German centers. Venetoclax was applied with azacitidine (n = 13) or decitabine (n = 19); 11 patients received DLI in addition. HMAClax was the first salvage therapy in 8 patients. The median number of cycles per patient was 2 (1-19). All but 1 patient had grade 3/4 neutropenia. Hospital admission for grade 3/4 infections was necessary in 23 patients (72%); 5 of these were fatal. In 30 evaluable patients, overall response rate (ORR) was 47% (14/30, 3 CR MRDneg, 5 CR, 2 CRi, 1 MLFS, 3 PR). ORR was 86% in first salvage patients versus 35% in later salvage patients (p = 0.03). In 6 patients with molecular relapse (MR), ORR was 67% versus 42% in patients with hematological relapse (HR) (n = 24, p = n.s.). After a median follow-up of 8.4 months, 25 patients (78%) had died and 7 were alive. Estimated median overall survival was 3.7 months. Median survival of patients with HMAClax for first versus later salvage therapy was 5.7 and 3.4 months (p = n.s.) and for patients with MR (not reached) compared to HR (3.4 months, p = 0.024). This retrospective case series shows that venetoclax is utilized in various different combinations, schedules, and doses. Toxicity is substantial and patients who receive venetoclax/HMA combinations for MR or as first salvage therapy derive the greatest benefit. [ABSTRACT FROM AUTHOR]

Objective To assess the association between meniscal volume, its change over time and the development of knee OA after 30 months in overweight/obese women. Methods Data from the PRevention of knee Osteoarthritis in Overweight Females study were used. This cohort included 407 women with a BMI ≥ 27 kg/m2, free of OA-related symptoms. The primary outcome measure was incident OA after 30 months, defined by one out of the following criteria: medial or lateral joint space narrowing (JSN)  ≥ 1.0 mm, incident radiographic OA [Kellgren and Lawrence (K&L)  ≥ 2], or incident clinical OA. The secondary outcomes were either of these items separately. Menisci at both baseline and follow-up were automatically segmented to obtain meniscal volume and delta-volumes. Generalized estimating equations were used to evaluate associations between the volume measures and the outcomes. Results Medial and lateral baseline and delta-volumes were not significantly associated to the primary outcome. Lateral meniscal baseline volume was significantly associated to lateral JSN [odds ratio (OR) = 0.87; 95% CI: 0.75, 0.99], while other measures were not. Medial and lateral baseline volume were positively associated to K&L incidence (OR = 1.32 and 1.22; 95% CI: 1.15, 1.50 and 1.03, 1.45, respectively), while medial and lateral delta-volume were negatively associated to K&L incidence (OR = 0.998 and 0.997; 95% CI: 0.997, 1.000 and 0.996, 0.999, respectively). None of the meniscal measures were significantly associated to incident clinical OA. Conclusion Larger baseline meniscal volume and the decrease of meniscal volume over time were associated to the development of structural OA after 30 months in overweight and obese women. [ABSTRACT FROM AUTHOR]

Introduction: Recently, we identified a huge discrepancy between the collection practice and the actual utilization of cryopreserved peripheral blood stem cells (PBSCs) for high-dose chemotherapy (HDCT) and autologous blood stem cell transplantation (ABSCT). Specifically, patients with Burkitt lymphoma, acute leukemia, and myeloproliferative neoplasms (MPN) were frequently not referred for ABSCT after successful PBSC collection. Objective: The aim of this study was to identify variables that are associated with the non-utilization of PBSC grafts. Methods: We retrospectively analyzed the collection, storage, and disposal of PBSC grafts in Burkitt lymphoma (n = 18), acute lymphoblastic leukemia (ALL, n = 22), MPN (n = 18), and acute myeloid leukemia (AML, n = 71) patients. Patients who underwent autologous PBSC collection at 2 collection and transplantation centers between 2001 and 2012 were included and followed up until 2016. Results: None of the Burkitt lymphoma patients were referred for ABSCT. Only in 1 (6%) patient, the graft was discarded after the patient's death. In all other patients (n = 17, 94%), the grafts were stored independently of the patient's status (death, n = 4, 22%; no follow-up, n = 6, 33%; no indication for ABSCT given, n = 7, 39%). In ALL patients, 4 (18%) patients underwent ABSCT after a median follow-up of 74 (1–182) months. In the remaining patients, PBSC grafts were either discarded (8 patients, 36%) or stored until the reference date (10 patients, 45%). Seven of 18 MPN patients (39%) underwent ABSCT. ABSCT was performed in 24 (34%) AML patients. In 20 (28%) patients who were not referred to ABSCT, an allogeneic transplantation (TPL) was performed. Fifteen (21%) patients received palliative care or deceased, and their grafts were discarded in all but 1 patient. Additional grafts were discarded in 21 (31%) patients and stored in 9 (13%) patients who underwent ABSCT or allogeneic TPL (n = 44). Conclusions: As the role and efficacy of autologous HDCT/ABSCT are not established in the analyzed entities, the indication for PBSC collection should be reanalyzed in regular intervals. Moreover, PBSC grafts from patients who have deceased, have insufficient grafts, or have already undergone an allogeneic TPL should be considered for disposal or (if applicable) for research use, to economize storage costs on a rational basis. [ABSTRACT FROM AUTHOR]

The lamina cribrosa (LC) is an active structure that responds to the strain by changing its morphology. Abnormal changes in LC morphology are usually associated with, and indicative of, certain pathologies such as glaucoma, intraocular hypertension, and myopia. Recent developments in optical coherence tomography (OCT) have enabled detailed in vivo studies about the architectural characteristics of the LC. Structural characteristics of the LC have been widely explored in glaucoma management. However, information about which LC biomarkers could be useful for the diagnosis, and follow-up, of other diseases besides glaucoma is scarce. Hence, this literature review aims to summarize the role of the LC in nonophthalmic and ophthalmic diseases other than glaucoma. PubMed was used to perform a systematic review on the LC features that can be extracted from OCT images. All imaging features are presented and discussed in terms of their importance and applicability in clinical practice. A total of 56 studies were included in this review. Overall, LC depth (LCD) and thickness (LCT) have been the most studied features, appearing in 75% and 45% of the included studies, respectively. These biomarkers were followed by the prelaminar tissue thickness (21%), LC curvature index (5.4%), LC global shape index (3.6%), LC defects (3.6%), and LC strains/deformations (1.8%). Overall, the disease groups showed a thinner LC (smaller LCT) and a deeper ONH cup (larger LCD), with some exceptions. A large variability between approaches used to compute LC biomarkers has been observed, highlighting the importance of having automated and standardized methodologies in LC analysis. Moreover, further studies are needed to identify the pathologies where LC features have a diagnostic and/or prognostic value. [ABSTRACT FROM AUTHOR]

T-cell epitope matching according to the TCE3 algorithm classifies HLA-DPB1 mismatches in permissive and non-permissive. This classification has been shown to be predictive for mortality and acute GvHD (aGvHD) events in large international cohorts. We retrospectively genotyped HLA-DPB1 in 3523 patients transplanted in Germany between 2000 and 2014 and in their unrelated donors using an Illumina amplicon-NGS based assay. Aim of the study was to evaluate DP-compatibility beyond the established TCE3 algorithm by assessing the combined effect of several DP-mismatch parameters on post-transplant outcome. We implemented an extended DP-mismatch assessment model where TCE3, DP allotype expression with respect to rs9277534, mismatch vector and number of mismatches were conjointly taken into consideration. In this model, non-permissive HLA-DPB1 mismatches showed significantly increased aGvHD risk if they were accompanied by two HLA-DPB1 mismatches in GvH direction (HR: 1.46) or one mismatched highly expressed patient allotype (HR: 1.53). As previously reported, non-permissive HLA-DPB1 mismatches associated with a significantly higher risk of aGvHD and non-relapse mortality (HR 1.36 and 1.21, respectively), which in turn translated into worse GvHD and relapse free survival (HR 1.13). Effects on GvL and GvHD appeared strongest in GvH-directed non-permissive mismatches. Our study results support the consideration of additional HLA-DPB1 mismatch parameters along with the established TCE3 matching algorithm for refinement of future donor selection. In particular, our findings suggest that DP non-permissiveness associated with two HLA-DPB1 mismatches or at least on highly expressed mismatched patient allotype should be avoided. [ABSTRACT FROM AUTHOR]

With the increasing size of datasets used in medical imaging research, the need for automated data curation is arising. One important data curation task is the structured organization of a dataset for preserving integrity and ensuring reusability. Therefore, we investigated whether this data organization step can be automated. To this end, we designed a convolutional neural network (CNN) that automatically recognizes eight different brain magnetic resonance imaging (MRI) scan types based on visual appearance. Thus, our method is unaffected by inconsistent or missing scan metadata. It can recognize pre-contrast T1-weighted (T1w),post-contrast T1-weighted (T1wC), T2-weighted (T2w), proton density-weighted (PDw) and derived maps (e.g. apparent diffusion coefficient and cerebral blood flow). In a first experiment,we used scans of subjects with brain tumors: 11065 scans of 719 subjects for training, and 2369 scans of 192 subjects for testing. The CNN achieved an overall accuracy of 98.7%. In a second experiment, we trained the CNN on all 13434 scans from the first experiment and tested it on 7227 scans of 1318 Alzheimer's subjects. Here, the CNN achieved an overall accuracy of 98.5%. In conclusion, our method can accurately predict scan type, and can quickly and automatically sort a brain MRI dataset virtually without the need for manual verification. In this way, our method can assist with properly organizing a dataset, which maximizes the shareability and integrity of the data. [ABSTRACT FROM AUTHOR]