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A prevailing belief among researchers is that burnout is a work-specific syndrome induced by intractable job stress. The validity of this belief, however, remains unclear. This cross-sectional study compared burnout with two general conditions, nonspecific psychological distress (NSPD) and exhaustion, in terms of (a) causal attributions to work and (b) associations with 11 job variables (e.g., job satisfaction). The study involved 813 individuals employed in Norway (70.5 % female). Burnout was assessed with the Burnout Assessment Tool; NSPD, with the K6; and exhaustion, with the Karolinska Exhaustion Disorder Scale. Results showed that only 27.7 % of participants with burnout symptoms attributed these symptoms to work. The proportions of individuals ascribing their symptoms to work were similar for NSPD (26.9 %) and exhaustion (27.5 %). The higher one's burnout score, the higher the likelihood of attributing one's burnout, NSPD, and exhaustion symptoms to work. Overall, burnout shared more variance with job variables than did NSPD and exhaustion. Coworker support, job security, and job autonomy constituted notable exceptions. In multiple regression analyses, seven of the 11 job variables predicted NSPD; five predicted burnout and exhaustion. An a posteriori analysis of a nationally balanced quota sample of 591 U.S. employees (48.2 % female) replicated our main finding-only 35.9 % of participants attributed their burnout symptoms to work. This study invites stakeholders to exercise more caution when making etiological inferences about burnout. Assuming that symptoms experienced at work are necessarily caused by work may hinder our ability to mitigate these symptoms. Our findings further question work-centric views of burnout., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Following implantation of an implantable cardioverter defibrillator (ICD), patients are temporarily restricted from private motor vehicle driving and permanently prohibited from professional driving. We aimed to investigate the impact of driving restrictions following ICD implantation and in case of ICD shock on employment, daily living activities, driving concerns and driving behavior., Methods and Results: Data were retrieved from a nationwide survey on driving restrictions in Danish ICD patients, distributed in 2017 to all patients ≥18 years implanted with a first-time ICD from 2013-2016 (n=3913). Responses were linked with data from nationwide registers. The response rate was 71% (final analyzable population n=2741, 83% male, median age 67 years, 316 had experienced an ICD shock, and 911 patients reported receipt of driving restrictions of minimum 1 month). Among active professional drivers (n=175), 33% had lost their job as a direct consequence of the driving restrictions. Of those working prior to ICD implantation (n=465), 47% reported being limited in maintaining employment due to private driving restrictions. Among those restricted from driving minimum 1 month, 26% reported the restrictions overall had substantially impeded their daily living. Factors associated with substantial impediment were age <65 years (OR 1.84 [95% CI 1.35-2.52]), higher income (OR 1.47 [95% CI 1.05-2.05]) and driving ≥7 hours/week pre-implantation (OR 1.66 [95% CI 1.23-2.24]). Being nervous about driving or altering driving habits was reported by 3-7%., Conclusion: Both professional and private driving restrictions affect the ability to maintain employment and have a negative impact on ICD recipients' daily living activities., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Interleukin (IL)-17A contributes to hypertension in preclinical models. T helper 17 and dendritic cells are activated by NaCl, which could involve the epithelial Na + channel (ENaC). We hypothesized that the ENaC blocker amiloride reduces plasma IL-17A and related cytokines in patients with hypertension. Concentrations of IL-17A, IFN-γ, TNF, IL-6, IL-1β, and IL-10 were determined by immunoassays in plasma from two patient cohorts before and after amiloride treatment: 1 ) patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension ( n = 69, amiloride 5-10 mg/day for 8 wk) and 2 ) patients with hypertension and type 1 diabetes mellitus (T1DM) ( n = 29) on standardized salt intake (amiloride 20-40 mg/day, 2 days). Plasma and tissue from ANG II-hypertensive mice with T1DM treated with amiloride (2 mg/kg/day, 4 days) were analyzed. The effect of amiloride and benzamil on macrophage cytokines was determined in vitro. Plasma cytokines showed higher concentrations (IL-17A ∼40-fold) in patients with T2DM compared with T1DM. In patients with T2DM, amiloride had no effect on IL-17A but lowered TNF and IL-6. In patients with T1DM, amiloride had no effect on IL-17A but increased TNF. In both cohorts, blood pressure decline and plasma K + increase did not relate to plasma cytokine changes. In mice, amiloride exerted no effect on IL-17A in the plasma, kidney, aorta, or left cardiac ventricle but increased TNF in cardiac and kidney tissues. In lipopolysaccharide-stimulated human THP-1 macrophages, amiloride and benzamil (from 1 nmol/L) decreased TNF, IL-6, IL-10, and IL-1β. In conclusion, inhibition of ENaC by amiloride reduces proinflammatory cytokines TNF and IL-6 but not IL-17A in patients with T2DM, potentially by a direct action on macrophages. NEW & NOTEWORTHY ENaC activity may contribute to macrophage-derived cytokine release, since amiloride exerts anti-inflammatory effects by suppression of TNF and IL-6 cytokines in patients with resistant hypertension and type 2 diabetes and in THP-1-derived macrophages in vitro.

This review delves into the application and effectiveness of Very Brief Advice (VBA) for smoking cessation in Denmark's healthcare system. Despite some evidence, VBA's support remains limited, adopted by only a few hospitals and overlooked by many healthcare professionals. To enhance cessation efforts, we recommend elevating its status from optional to mandatory. Underlining VBA's significance as a referral catalyst is pivotal to ensuring its sustained influence within the broader cessation strategy., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

Background: EMIT-1 is a national, observational, single-arm trial designed to assess the value of the Prosigna, Prediction Analysis of Microarray using the 50 gene classifier (PAM50)/Risk of Recurrence (ROR), test as a routine diagnostic tool, examining its impact on adjuvant treatment decisions, clinical outcomes, side-effects and cost-effectiveness. Here we present the impact on treatment decisions., Patients and Methods: Patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative pT1-pT2 lymph node-negative early breast cancer (EBC) were included. The Prosigna test and standard histopathology assessments were carried out. Clinicians' treatment decisions were recorded before (pre-Prosigna) and after (post-Prosigna) the Prosigna test results were disclosed., Results: Of 2217 patients included, 2178 had conclusive Prosigna results. The pre-Prosigna treatment decisions were: no systemic treatment (NT) in 27% of patients, endocrine treatment alone (ET) in 38% and chemotherapy (CT) followed by ET (CT + ET) in 35%. Post-Prosigna treatment decisions were 25% NT, 51% ET and 24% CT + ET, respectively. Adjuvant treatment changed in 28% of patients, including 21% change in CT use. Among patients assigned to CT + ET pre-Prosigna, 45% were de-escalated to ET post-Prosigna. Of patients assigned to ET, 12% were escalated to CT + ET and 8% were de-escalated to NT; of those assigned to NT, 18% were escalated to ET/CT + ET. CT was more frequently recommended for patients aged ≤50 years. In the subgroup with pT1c-pT2 G2 and intermediate Ki67 (0.5-1.5× local laboratory median Ki67 score), the pre-Prosigna CT treatment decision varied widely across hospitals (3%-51%). Post-Prosigna, the variability of CT use was markedly reduced (8%-24%). The correlation between Ki67 and ROR score within this subgroup was poor (r = 0.25-0.39). The median ROR score increased by increasing histological grade, but the ROR score ranges were wide (for G1 0-79, G2 0-90, G3 16-94)., Conclusion: The Prosigna test result changed adjuvant treatment decisions in all EBC clinical risk groups, markedly decreased the CT use for patients categorized as higher clinical risk pre-Prosigna and reduced treatment decision discrepancies between hospitals., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To investigate the metabolic, cardiovascular, and neuropsychological phenotype, quality of life (QoL), and hormonal regulation in individuals with congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired synthesis of cortisol in the adrenal cortex and, if untreated compensatory hyperandrogenism. CAH is associated with an increased cardiovascular and metabolic morbidity, possibly due to overtreatment with glucocorticoids, leading to weight gain, insulin resistance, and metabolic syndrome., Design, Participants, Measurements: Thirty-seven individuals with CAH and 33 age- and sex-matched controls were evaluated at a single centre at Aarhus University Hospital with echocardiography, electrocardiogram, 24-h blood pressure, biochemistry, anthropometrics, and autism spectrum, anxiety, depression, personality, cognitive failures, and QoL were assessed using questionnaires., Results: CAH individuals had lower height than controls (170.5 vs. 182.9 cm in males and 160.2 vs. 170.1 cm in females, p < 0.01). Compared with female controls, females with CAH had higher haemoglobin (8.8 vs. 8.2 mmol/L, p = 0.003) and BMI (29.7 vs. 25.5 kg/m 2 , p = 0.006), reduced insulin sensitivity (HOMA-IR): 2.7 vs. 1.9, p = 0.018), prolonged E-wave deceleration time (193 vs. 174 cm, p = 0.015), and E/é ratios (5.4 vs. 4.5, p = 0.017), and lower self-reported QoL. Males with CAH had more cognitive complaints (p = 0.034) and higher autistic scores (19.9 vs. 14.9; p = 0.068) compared with male controls. More individuals with CAH than controls reported writing problems., Conclusion: A sex-specific comorbidity profile is evident in CAH, with females presenting with decreased metabolic and overall self-reported health, whereas males with CAH presented with increased cognitive complaints and autistic traits., (© 2024 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

This review summarises the present knowledge of prophylactic progesterone and preterm birth. Preterm birth (less-than 37 weeks) is a leading cause of neonatal mortality and morbidity worldwide. The incidence varies globally but remains low in the Nordic countries (5-6%). Prediction and prevention are complicated due to diverse aetiology, but obstetric history and cervical length can improve prediction. Prophylactic vaginal progesterone initiated between 12 and 24 weeks of gestation is recommended to reduce preterm birth less-than 33-35 weeks in singleton pregnancies with a history of preterm birth or with a short cervix (less-than 25 mm) and can be considered for twin pregnancies with the same risk factors., (Published under Open Access CC-BY-NC-BD 4.0. https://creativecommons.org/licenses/by-nc-nd/4.0/.)

We present a lightweight tool for clonotyping and measurable residual disease (MRD) assessment in monoclonal lymphoproliferative disorders. It is a translational method that enables computational detection of rearranged immunoglobulin heavy chain gene sequences.•The swigh-score clonotyping tool emphasizes parallelization and applicability across sequencing platforms.•The algorithm is based on an adaptation of the Smith-Waterman algorithm for local alignment of reads generated by 2nd and 3rd generation of sequencers.For method validation, we demonstrate the targeted sequences of immunoglobulin heavy chain genes from diagnostic bone marrow using serial dilutions of CD138+ plasma cells from a patient with multiple myeloma. Sequencing libraries from diagnostic samples were prepared for the three sequencing platforms, Ion S5 (Thermo Fisher Scientific), MiSeq (Illumina), and MinION (Oxford Nanopore), using the LymphoTrack assay. Basic quality filtering was performed, and a Smith-Waterman-based swigh-score algorithm was developed in shell and C for clonotyping and MRD assessment using FASTQ data files. Performance is demonstrated across the three different sequencing platforms., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Aim: This systematic review and meta-analysis sought i) to provide an overview of the incidence of delirium following open cardiac surgery and ii) to investigate how incidences of delirium are associated with different assessment tools., Methods and Results: A systematic search of studies investigating delirium following open cardiac surgery were conducted in Medline (Ovid), EMBASE, PsycINFO, CiNAHL and the Cochrane Database. Only studies with patients diagnosed or screened with a validated tool were included. Studies published from 2005 to 2021 were included in the meta-analysis.Of 7,126 individual studies retrieved, 106 met the inclusion criteria for the meta-analysis, hereof 31% of high quality. The weighted pooled incidence of delirium following open cardiac surgery across all studies was 23% (95% CI 20-26%), however we found a considerable heterogeneity (I2 = 99%), which could not be explained by subgroups or further sensitivity analyses. The most commonly applied screening tool for delirium is CAM/CAM-ICU. The lowest estimates of delirium were found by applying the Delirium Observation Scale (incidence 14%, 95% CI 8-20%), and the highest estimates in studies using "other" screening tools (Organic Brain Symptom Scale, Delirium Symptom Interview) pooled incidence of 43%, (95% CI 19 - 66%), however, only two studies applied these., Conclusion: Delirium following open cardiac surgery remains a complication with a high incidence of overall 23%, when applying a validated tool for screening or diagnosis. Nevertheless, this systematic review and meta-analyses highlight the significant inconsistency in current evidence regarding assessment tools and regimens., Registration: Prospero CRD42020215519., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

In a recent issue of Nature Chemical Biology, Folger et al. demonstrated a high-throughput approach for engineering peptide bond forming domains from non-ribosomal peptide synthesis. A non-ribosomal peptide synthetase module from surfactin biosynthesis was reprogrammed to accept a fatty acid substrate into peptide biosynthesis, thus illustrating the potential of this approach for generating novel bioactive peptides., Competing Interests: Declaration of interests The authors declare no competing interests., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Cytochrome-P450-mediated cross-linking of ribosomally encoded peptides (RiPPs) is rapidly expanding and displays great potential for biocatalysis. Here, we demonstrate that active site engineering of the biarylitide cross-linking enzyme P450 Blt enables the formation of His-X-Tyr and Tyr-X-Tyr cross-linked peptides, thus showing how such P450s can be further exploited to produce alternate cyclic tripeptides with controlled cross-linking states.

Antibiotics are central to modern medicine, and yet they are mainly the products of intra and inter-kingdom evolutionary warfare. To understand how nature evolves antibiotics around a common mechanism of action, we investigated the origins of an extremely valuable class of compounds, lipid II targeting glycopeptide antibiotics (GPAs, exemplified by teicoplanin and vancomycin), which are used as last resort for the treatment of antibiotic resistant bacterial infections. Using a molecule-centred approach and computational techniques, we first predicted the nonribosomal peptide synthetase assembly line of paleomycin, the ancestral parent of lipid II targeting GPAs. Subsequently, we employed synthetic biology techniques to produce the predicted peptide and validated its antibiotic activity. We revealed the structure of paleomycin, which enabled us to address how nature morphs a peptide antibiotic scaffold through evolution. In doing so, we obtained temporal snapshots of key selection domains in nonribosomal peptide synthesis during the biosynthetic journey from ancestral, teicoplanin-like GPAs to modern GPAs such as vancomycin. Our study demonstrates the synergy of computational techniques and synthetic biology approaches enabling us to journey back in time, trace the temporal evolution of antibiotics, and revive these ancestral molecules. It also reveals the optimisation strategies nature has applied to evolve modern GPAs, laying the foundation for future efforts to engineer this important class of antimicrobial agents., (© 2023. The Author(s).)

Lymphoid malignancies are characterized by clonal cell expansion, often identifiable by unique immunoglobulin rearrangements. Heavy (IGH) and light-chain gene usage offers diagnostic insights and enables sensitive residual disease detection via next-generation sequencing. With its adaptable throughput and variable read lengths, Oxford Nanopore thirdgeneration sequencing now holds promise for clonotyping. This study analyzed CD138+ plasma-cell DNA from eight multiple myeloma patients, comparing clonotyping performance between Nanopore sequencing, Illumina MiSeq, and Ion Torrent S5. We demonstrated clonotype consistency across platforms through Smith-Waterman local alignment of nanopore reads. The mean clonal percentage of IGH V and J gene usage in the CD138+ cells was 69% for Nanopore, 67% for S5, and 76% for MiSeq. When aligned with known clonotypes, clonal cells averaged a 91% similarity, exceeding 85%. In summary, Nanopore sequencing, with its capacity for generating millions of high-quality reads, proves effective for detecting clonal IGH rearrangements. This versatile platform offers the potential for measuring residual disease down to a sensitivity level of 10 -6 at a lower cost, marking a significant advancement in clonotyping techniques., Competing Interests: The authors have no financial or nonfinancial interests to disclose., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

The current advances and success of next-generation sequencing hold the potential for the transition of cancer cytogenetics toward comprehensive cytogenomics. However, the conventional use of short reads impedes the resolution of chromosomal aberrations. Thus, this study evaluated the detection and reproducibility of extensive copy number alterations and chromosomal translocations using long-read Oxford Nanopore Technologies whole-genome sequencing compared with short-read Illumina sequencing. Using the mantle cell lymphoma cell line Granta-519, almost 99% copy-number reproducibility at the 100-kilobase resolution between replicates was demonstrated, with 98% concordance to Illumina. Collectively, the performance of copy number calling from 1.5 million to 7.5 million long reads was comparable to 1 billion Illumina-based reads (50× coverage). Expectedly, the long-read resolution of canonical translocation t(11;14)(q13;q32) was superior, with a sequence similarity of 89% to the already published CCND1/IGH junction (9× coverage), spanning up to 69 kilobases. The cytogenetic profile of Granta-519 was in general agreement with the literature and karyotype, although several differences remained unresolved. In conclusion, contemporary long-read sequencing is primed for future cytogenomics or sequencing-guided cytogenetics. The combined strength of long- and short-read sequencing is apparent, where the high-precision junctional mapping complements and splits paired-end reads. The potential is emphasized by the flexible single-sample genomic data acquisition of Oxford Nanopore Technologies with the high resolution of allelic imbalances using Illumina short-read sequencing., (Copyright © 2023 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Introduction: Radical cystectomy is a complex surgery with better outcomes reported when performed at high-volume centers. This may lead to patients traveling farther for care. We examined the impact of travel distance on clinical outcomes., Methods: A total of 220 patients undergoing radical cystectomy from 2015-2021 were retrospectively reviewed. Distance traveled to the treatment center by patient zip codes was classified as <12.5 miles, 12.5-49.9 miles, and ≥50 miles. Multivariable logistic regression was used to assess complications, readmissions, 90-day mortality, and length of stay by distance traveled. Time to treatment based on distance traveled was compared., Results: A total of 220 patients underwent radical cystectomy with complete 90-day follow-up. Of the patients 38.6% (85/220) were readmitted; 62.5% (53/85) presented to the treatment center or were transferred. All patients readmitted to an outside hospital traveled ≥12.5 miles ( P < .001). Patients with high-grade complications were likely to be transferred to the treatment center with only 23.7% (9/38) definitively managed by outside hospital. Patients traveling >12.5 miles with low-grade complications were more likely to be managed at an outside hospital (57.5%, P = .01). There was no difference in time to initiation of neoadjuvant chemotherapy ( P = .99) or time to radical cystectomy following neoadjuvant chemotherapy ( P = .23) by distance traveled. For 49 muscle-invasive bladder cancer patients proceeding directly to surgery without neoadjuvant chemotherapy, time from diagnosis to radical cystectomy was increased if traveling >12.5 miles ( P = .04)., Conclusions: Increased travel distance did not impact early postoperative outcomes. Distance traveled may impact access to care, such as time to surgery or location of readmission to the treatment center postoperatively.

Introduction: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma in the western world. It is highly heterogeneous with a variable clinical course, but curable with chemo-immunotherapy in up to 70% of all cases. The lymphoma presents in lymph nodes and/or extranodal lymphoid tissue, and the diagnosis is based on invasive procedures for histopathologic evaluation., Methods: In this technical study, we evaluated cell-free DNA (cfDNA) from blood plasma to detect clonal B cells in patients with DLBCL using rearranged immunoglobulin heavy chain gene as targets by next-generation sequencing. Clonal B cell sequences and frequencies were determined from blood plasma cfDNA and cellular DNA from matched excised lymphoma tissues and mononuclear cells isolated from diagnostic bone marrow and blood samples from 15 patients., Results: We showed that identical clonal rearrangements could be detected in blood plasma and excised lymphoma tissue and that plasma cfDNA was superior in detecting clonal rearrangements compared to blood or bone marrow-derived cellular DNA., Conclusion: These findings consolidate the role of blood plasma as a reliable and easily accessible source for detecting neoplastic cells in DLBCL., (© 2023 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Immunodeficient mice engrafted with psoriatic human skin are widely used for the preclinical evaluation of new drug candidates. However, the T-cell activity, including the IL23/IL17 pathway, declines in the graft over time after engraftment, which likely affects the study data. Here, we investigated whether the T-cell activity could be sustained in xenografted psoriatic skin by local stimulation of T cells or systemic injection of autologous CD4 + T cells. We surgically transplanted human psoriatic skin from 5 untreated patients onto female NOG mice. Six days after surgery, mice received an intraperitoneal injection of autologous human CD4 + T cells, a subcutaneous injection under the grafts of a T-cell stimulation cocktail consisting of recombinant human IL2, human IL23, antihuman CD3, and antihuman CD28, or saline. Mice were euthanized 21 d after surgery and spleens and graft biopsies were collected for analysis. Human T cells were present in the grafts, and 60% of the grafts maintained the psoriatic phenotype. However, neither local T-cell stimulation nor systemic injection of autologous CD4 + T cells affected the protein levels of human IL17A, IL22, IFN γ, and TNF α in the grafts. In conclusion, NOG mice seem to accept psoriatic skin grafts, but the 2 approaches studied here did not affect human T-cell activity in the grafts. Therefore, NOG mice do not appear in this regard to be superior to other immunodeficient mice used for psoriasis xenografts.

Sleep is often severely disturbed in hospitalized patients due to multiple factors such as noise, pain, and an unfamiliar environment. Since sleep is important for patient recovery, safe strategies to improve sleep in hospitalized patients are warranted. Music interventions have been found to improve sleep in general, and the aim of this systematic review is to assess the effect of music on sleep among hospitalized patients. We searched 5 databases to identify randomized controlled trials evaluating the effect of music interventions on sleep in hospitalized patients. Ten studies including a total of 726 patients matched the inclusion criteria. The sample sizes ranged from 28 to 222 participants per study. The music interventions varied in how the music was chosen as well as duration and time of day. However, in most studies, participants in the intervention group listened to soft music for 30 minutes in the evening. Our meta-analysis showed that music improved sleep quality compared to standard treatment (standardized mean difference 1.55 [95% CI 0.29-2.81], z = 2.41; p = 0.0159). Few studies reported other sleep parameters, and only one study used polysomnography for objective sleep measurement. No adverse events were reported in any of the trials. Hence, music may constitute a safe and low-cost adjunctive intervention to improve sleep in hospitalized patients. Prospero registration number: CRD42021278654., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Sex chromosome abnormalities (SCAs) are chromosomal disorders with either a complete or partial loss or gain of sex chromosomes. The most frequent SCAs include Turner syndrome (45,X), Klinefelter syndrome (47,XXY), Trisomy X syndrome (47,XXX), and Double Y syndrome (47,XYY). The phenotype seen in SCAs is highly variable and may not merely be due to the direct genomic imbalance from altered sex chromosome gene dosage but also due to additive alterations in gene networks and regulatory pathways across the genome as well as individual genetic modifiers. This review summarizes the current insight into the genomics of SCAs. In addition, future directions of research that can contribute to decipher the genomics of SCA are discussed such as single-cell omics, spatial transcriptomics, system biology thinking, human-induced pluripotent stem cells, and animal models, and how these data may be combined to bridge the gap between genomics and the clinical phenotype.

TINF2 encodes the TINF2 protein, which is a subunit in the shelterin complex critical for telomere regulation. Three recent studies have associated six truncating germline variants in TINF2 that have previously been associated with a cancer predisposition syndrome (CPS) caused by elongation of the telomeres. This has added TINF2 to the long telomere syndrome genes, together with other telomere maintenance genes such as ACD , POT1 , TERF2IP , and TERT . We report a clinical study of 102 Danish patients with multiple primary melanoma (MPM) in which a germline truncating variant in TINF2 (p.(Arg265Ter)) was identified in four unrelated participants. The telomere lengths of three variant carriers were >90% percentile. In a routine diagnostic setting, the variant was identified in two more families, including an additional MPM patient and monozygotic twins with thyroid cancer and other cancer types. A total of 10 individuals from six independent families were confirmed carriers, all with cancer history, predominantly melanoma. Our findings suggest a major role of TINF2 in Danish patients with MPM. In addition to melanoma, other cancers in the six families include thyroid, renal, breast, and sarcoma, supporting a CPS in which melanoma, thyroid cancer, and sarcoma predominate. Further studies are needed to establish the full spectrum of associated cancer types and characterize lifetime cancer risk in carriers., Competing Interests: The authors declare no competing interests., (© 2023.)

The effect of exercise on disease development in hypertrophic cardiomyopathy (HCM) genotype-positive individuals is unresolved. Our objective was to test the effect of exercise training initiated before phenotype development on cardiac fibrosis, morphology, and function in a mouse model of HCM. Genotype-positive Myh6 R403Q mice exposed to cyclosporine A (CsA) for induction of HCM (HCM mice) were allocated to high-intensity interval treadmill running or sedentary behavior for 6 wk. CsA was initiated from week 4 of the protocol. Cardiac imaging and exercise testing were performed at weeks 0 , 3 , and 6 . After protocol completion, arrhythmia provocation was performed in isolated hearts, and left ventricles (LVs) were harvested for molecular biology and histology. Exercised HCM mice ran farther and faster and exhibited attenuated left atrial (LA) dilatation compared with sedentary mice. Exercised HCM mice had no difference in fibrosis compared with sedentary HCM mice despite lower expression of key extracellular matrix (ECM) genes collagen 1 and 3, fibronectin, and lysyl oxidase, accompanied by increased activation of Akt, GSK3b, and p38. Exercise did not have negative effects on LV function in HCM mice. Our findings indicate mild beneficial effects of exercise initiated before HCM phenotype development, specifically lower ECM gene expression and LA dilatation, and importantly, no detrimental effects. NEW & NOTEWORTHY Genotype-positive hypertrophic cardiomyopathy (HCM) mice had beneficial effects of exercise initiated before phenotype development. Exercised HCM mice had increased exercise capacity, smaller left atria, no increase in hypertrophy, or reduction of function, and a similar degree of fibrosis despite reduction of central extracellular matrix (ECM) genes, including collagens, compared with sedentary HCM mice.

In this work, we developed a method using precession electron diffraction data to map the residual elastic strain at the nano-scale. The diffraction pattern of each pixel was first collected and denoised. Template matching was then applied using the center spot as the mask to identify the positions of the diffraction disks. Statistics of distances between the selected diffracted disks enable the user to make an informed decision on the reference and to generate strain maps. Strain mapping on an unstrained single crystal sapphire shows the standard deviation of strain measurement is 0.5%. With this method, we were able to successfully measure and map the residual elastic strain in VO 2 on sapphire and martensite in a Ni 50.3 Ti 29.7 Hf 20 shape memory alloy. This approach does not require the user to select a "strain-free area" as a reference and can work on datasets even with the crystals oriented away from zone axes. This method is expected to provide a robust and more accessible alternative means of studying the residual strain of various material systems that complements the existing algorithms for strain mapping., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Multiple myeloma, a mature B-cell neoplasm, is the second most common hematologic malignancy. Despite advancements in treatment, the disease remains incurable, with more than 100,000 annual deaths worldwide. As recommended by the International Myeloma Working Group, measurable residual disease (MRD) should be addressed at a 10 -5 sensitivity level or beyond for practical purposes. Next-generation sequencing (NGS) has provided new opportunities with deep sequencing of clonal rearrangements of the immunoglobulin heavy chain (IGH) locus in B-cell malignancies. Although the ability to resolve one cancerous cell in a million other B cells is becoming attractive as a prognostic indicator in sustained patients who are MRD-negative, reaching consistent sensitivity levels is challenging because of sample stochasticity and the substantial amount of deoxyribonucleic acid (DNA) required for library preparation. Thus, in the presented study, we implemented ultra-deep sequencing of rearranged IGH to investigate the reproducibility and consistency aimed at the 10 -5 sensitivity level. In this controlled setup, our data provided stable MRD detection of 1.2 clonal cells per 100,000 analyzed cells and longitudinal reproducibility. We also demonstrated a low false-negative rate using 4-5 replicates and 700-800 ng DNA per sequencing replicate. In conclusion, adding an internal control to the replicates enabled clonal cell normalization for MRD evaluation as a stable reference. These findings may guide MRD-level reporting and comparisons between laboratories., Competing Interests: Conflict of Interest Disclosure The authors do not have any conflicts of interest to declare in relation to this work., (Copyright © 2023 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Human immune system (HIS) mouse models can be valuable when cross-reactivity of drug candidates to mouse systems is missing. However, no HIS mouse models of psoriasis have been established. In this study, it was investigated if imiquimod (IMQ) induced psoriasis-like skin inflammation was driven by human immune cells in human FMS-related tyrosine kinase 3 ligand (hFlt3L) boosted (BRGSF-HIS mice). BRGSF-HIS mice were boosted with hFlt3L prior to two or three topical applications of IMQ. Despite clinical skin inflammation, increased epidermal thickness and influx of human immune cells, a human derived response was not pronounced in IMQ treated mice. However, the number of murine neutrophils and murine cytokines and chemokines were increased in the skin and systemically after IMQ application. In conclusion, IMQ did induce skin inflammation in hFlt3L boosted BRGSF-HIS mice, although, a limited human immune response suggest that the main driving cellular mechanisms were of murine origin., Competing Interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: P.K.F.C, and M.H.H.-H. are former employees of LEO Pharma A/S. J.K., B.C.M. are employees of LEO Pharma A/S. J.L. is an employee of Bioneer A/S. A.K.H. declares that he has collaborated with the pharmaceutical industry and received funding from Novo Nordisk A/S, Lundbeck A/S, and LEO Pharma A/S for research projects, as described on https://ivh.ku.dk/english/employees/?pure=en/persons/107126. He did not receive funding for the present project. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Christensen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Xenografting of psoriasis skin onto immune deficient mice has been widely used to obtain proof-of-principle of new drug candidates. However, the lack of human T-cell activity in the grafts limits the use of the model. Here, we show that xenografting of lesional skin from psoriasis patients onto human IL-2 NOG mice results in increased numbers of human CD3+ cells in the grafts, axillary lymph nodes and blood from human IL-2 NOG mice compared to C.B-17 scid and NOG mice. In addition, disease relevant human cytokine levels were higher in graft lysates and serum from human IL-2 NOG mice. However, the epidermis was lacking and no efficacy of ustekinumab, a human anti-P40 antibody targeting both IL-12 and IL-23, was shown. Thus, despite the sustained T-cell activity, the model needs further investigations and validation to capture more aspects of psoriasis., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: P.K.F.C. and M.H.H.-H. are former employees of LEO Pharma A/S. J.K is an employee of LEO Pharma A/S. J.L. is an employee of Bioneer A/S. K.E. is an employee of Amniotics AB. A.K.H. declares that he has collaborated with pharmaceutical industry and received funding from this source, as well as he is the owner of a diabetes related patent as described on https://ivh.ku.dk/english/employees/?pure=en/persons/107126. S.S. declares that he has collaborated with the pharmaceutical industry and received funding from this source as described on https://ivh.ku.dk/english/employees/?pure=en/persons/102444. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Christensen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Prostate cancer (PrCa) is one of the most genetically driven solid cancers with heritability estimates as high as 57%. Men of African ancestry are at an increased risk of PrCa; however, current polygenic risk score (PRS) models are based on European ancestry groups and may not be broadly applicable. The objective of this study was to construct an African ancestry-specific PrCa PRS (PRState) and evaluate its performance., Methods: African ancestry group of 4,533 individuals in ELLIPSE consortium was used for discovery of African ancestry-specific PrCa SNPs. PRState was constructed as weighted sum of genotypes and effect sizes from genome-wide association study (GWAS) of PrCa in African ancestry group. Performance was evaluated using ROC-AUC analysis., Results: We identified African ancestry-specific PrCa risk loci on chromosomes 3, 8, and 11 and constructed a polygenic risk score (PRS) from 10 African ancestry-specific PrCa risk SNPs, achieving an AUC of 0.61 [0.60-0.63] and 0.65 [0.64-0.67], when combined with age and family history. Performance dropped significantly when using ancestry-mismatched PRS models but remained comparable when using trans-ancestry models. Importantly, we validated the PRState score in the Million Veteran Program (MVP), demonstrating improved prediction of PrCa and metastatic PrCa in individuals of African ancestry., Conclusions: African ancestry-specific PRState improves PrCa prediction in African ancestry groups in ELLIPSE consortium and MVP. This study underscores the need for inclusion of individuals of African ancestry in gene variant discovery to optimize PRSs and identifies African ancestry-specific variants for use in future studies., (© 2022. The Author(s).)

A fully provided, hypocaloric, carbohydrate-reduced high-protein (CRHP) diet compared to a hypocaloric conventional diabetes (CD) diet for 6 weeks improved glycemic control to a greater extent in face of an intended 6% weight loss in individuals with type 2 diabetes mellitus (T2DM). The present 24-week extension of that study reports on the efficacy of CRHP and CD diets in a real-life setting. Sixty-five individuals with T2DM who completed the initial 6-week fully provided diet period (% energy from carbohydrate, protein, and fat was 30/30/40 in CRHP, and 50/17/33 in CD) continued a free-living, dietician guided 24-week period of which 59 individuals completed. The CRHP compared to CD group reported a 4% lower carbohydrate intake and had higher urea excretion by 22% (both p ≤ 0.05) at week 30, suggesting less difference in carbohydrate and protein intake between groups during the 24-week extension compared to week 6. The loss of body weight during the initial 6 weeks was maintained in both groups during the 24-week extension (-5.5 ± 4.5 and -4.6 ± 4.8 kg) as well as HbA 1c (-8.4 ± 6.2 and -8.4 ± 6.9 mmol/mol) with no significant differences between groups. The additional benefits on glucoregulation harnessed by carbohydrate restriction under full diet provision for 6 weeks combined with titrated weight loss could not be maintained in a real-life setting of self-prepared diet aiming on similar diets for 6 months.

Systemic treatment with hedgehog inhibitors (HHis) is available to treat basal cell carcinomas but their utility is limited by adverse effects. Topical delivery methods may reduce adverse effects, but successful topical treatment depends on sufficient skin uptake, biological response, and time in tumor tissue. The aim of this review was to evaluate the current status of topical HHi delivery for BCCs and discuss barriers for translating systemic HHis into topical treatments. A literature search identified 16 preclinical studies and 7 clinical trials on the topical delivery of 12 HHis that have been clinically tested on BCCs. Preclinical studies on drug uptake demonstrated that novel formulations, and delivery- and pre-treatment techniques enhanced topical HHi delivery. Murine studies showed that the topical delivery of sonidegib, itraconazole, vitamin D₃ and CUR-61414 led to biological responses and tumor remission. In clinical trials, only topical patidegib and sonidegib led to at least a partial response in 26/86 BCCs and 30/34 patients, respectively. However, histological clearance was not observed in the samples analyzed. In conclusion, the incomplete clinical response could be due to poor HHi uptake, biodistribution or biological response over time. Novel topical delivery techniques may improve HHi delivery, but additional research on cutaneous pharmacokinetics and biological response is needed.

Glycopeptide antibiotics (GPAs), which include vancomycin and teicoplanin, are important last-resort antibiotics used to treat multidrug-resistant Gram-positive bacterial infections. Whilst second-generation GPAs - generated through chemical modification of natural GPAs - have proven successful, the emergence of GPA resistance has underlined the need to develop new members of this compound class. Significant recent advances have been made in GPA research, including gaining an in-depth understanding of their biosynthesis, improving titre in production strains, developing new derivatives via novel chemical modifications and identifying a new mode of action for structurally diverse type-V GPAs. Taken together, these advances demonstrate significant untapped potential for the further development of GPAs to tackle the growing threat of multidrug-resistant bacteria., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become a treatment option for fit patients with mantle cell lymphoma (MCL). However, these patients often relapse within few years, potentially caused by contaminating lymphoma cells within the reinfused stem cell product (SCP). Studies have shown that measurable residual disease, also termed minimal residual disease (MRD), following ASCT predicts shorter survival. Using next-generation sequencing, we explore whether the diagnostic MCL clonotype is present within the infused SCP. MRD was detected in 4/17 of the SCPs, ranging 4-568 clonal cells/100,000 cells. With a median survival of 17 months, 3/4 of patients with MRD+ graft succumbed from MCL relapse versus 2/13 in the MRD- fraction. Patients receiving MRD+ grafts had increased risk of mortality, and thus screening of SCPs may be important for clinical decision-making., Competing Interests: The authors have nothing to disclose., (© 2022 The Authors. Published by Elsevier Ltd.)

Purpose: To investigate the association between prenatal exposures and anthropometric data and cardiovascular risk factors including retinal arteriolar wall-to-lumen ratio in adolescence., Methods: This longitudinal observational study included all 1445 adolescents from the Copenhagen Child Cohort 2000 who attended the 2016-2017 examination. Outcome measures included retinal arteriolar wall-to-lumen ratio, height, body mass index, waist-to-hip ratio, body composition measured by bioimpedance, and blood pressure. Information on prenatal exposures (birth weight, gestational age, maternal smoking during pregnancy) as well as sex, parental age, household income and parental educational levels were obtained from national registries. Associations between exposures and outcome measures were analyzed using general linear models., Results: Maternal smoking during pregnancy was associated with a higher retinal arteriolar wall-to-lumen ratio (0.004 or 1.9%, P = 0.009) at age 16/17 years, an association driven exclusively by the female participants (0.008 or 3.7%, P < 0.0001). Maternal smoking during pregnancy was also associated to higher body-mass index (1.43 kg/m 2 , P < 0.0001), waist-to-hip ratio (0.02, P < 0.0001) and fat mass index (0.93 kg/m 2 , P < 0.0001). Birth weight, gestational age, and parental age had no detectable impact on retinal arteriolar wall-to-lumen ratios., Conclusion: Prenatal exposure to tobacco smoking is associated with a higher risk of obesity and, predominantly in girls, to a greater retinal arteriolar wall thickness, which suggests that maternal smoking may induce an unfavorable cardiovascular and metabolic risk profile in the child., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Context: Women with Turner syndrome (TS) suffer from hypergonadotropic hypogonadism, causing a deficit in gonadal hormone secretion. As a consequence, these women are treated with estrogen from the age of 12 years, and later in combination with progesterone. However, androgens have been given less attention., Objective: To assess sex hormone levels in women with TS, both those treated and those nontreated with hormone replacement therapy (HRT), and investigate the impact of HRT on sex hormone levels., Methods: At Aarhus University Hospital, 99 women with TS were followed 3 times from August 2003 to February 2010. Seventeen were lost during follow-up. Control group 1 consisted of 68 healthy age-matched control women seen once during this period. Control group 2 consisted of 28 young, eumenorrheic women sampled 9 times throughout the same menstrual cycle. Serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17β-estradiol, estrone sulfate, DHEAS, testosterone, free androgen index, androstenedione, 17-OH progesterone, and sex hormone-binding globulin (SHBG) were analyzed., Results: All androgens, 17-OH progesterone, and sex hormone-binding globulin (SHBG) were 30% to 50% lower in TS compared with controls (P < 0.01). FSH, LH, and estrone sulfate were more than doubled in women with TS compared with controls (P < 0.02). Using principal component analysis, we describe a positive correlation between women with TS receiving HRT, elevated levels of SHBG, and decreased levels of androgens., Conclusion: The sex hormone profile in TS reveals a picture of androgen deficiency, aggravated further by HRT. Conventional HRT does not normalize estradiol levels in TS., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cytochrome P450 enzymes (P450s) are a superfamily of monooxygenases that utilize a cysteine thiolate-ligated heme moiety to perform a wide range of demanding oxidative transformations. Given the oxidative power of the active intermediate formed within P450s during their active cycle, it is remarkable that these enzymes can avoid auto-oxidation and retain the axial cysteine ligand in the deprotonated-and thus highly acidic-thiolate form. While little is known about the process of heme incorporation during P450 folding, there is an overwhelming preference for one heme orientation within the P450 active site. Indeed, very few structures to date contain an alternate heme orientation, of which two are OxyA homologs from glycopeptide antibiotic (GPA) biosynthesis. Given the apparent preference for the unusual heme orientation shown by OxyA enzymes, we investigated the OxyA homolog from kistamicin biosynthesis (OxyA kis ), which is an atypical GPA. We determined that OxyA kis is highly sensitive to oxidative damage by peroxide, with both UV and EPR measurements showing rapid bleaching of the heme signal. We determined the structure of OxyA kis and found a mixed population of heme orientations present in this enzyme. Our analysis further revealed the possible modification of the heme moiety, which was only present in samples where the alternate heme orientation was present in the protein. These results suggest that the typical heme orientation in cytochrome P450s can help prevent potential damage to the heme-and hence deactivation of the enzyme-during P450 catalysis. It also suggests that some P450 enzymes involved in GPA biosynthesis may be especially prone to oxidative damage due to the heme orientation found in their active sites., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Greule, Izoré, Machell, Hansen, Schoppet, De Voss, Charkoudian, Schittenhelm, Harmer and Cryle.)

Introduction: Engagement in meaningful everyday life occupations is linked to well-being. However, people with dementia are often deprived of engagement. As a response, a Danish Dementia Town was established with the intention of transforming care services to improve opportunities for meaningful engagement. The evidence-based The meaningful occupational engagement intervention for people with dementia (MOED) intervention was developed and implemented in dementia town to enhance meaningful occupational engagement. The purpose of this paper is to evaluate the content, impact and implementation process of MOED., Method: To evaluate MOED, we applied a program theory-based qualitative approach, building on participant observations and informal conversations with people with dementia ( n = 7) and staff ( n = 9). Data were analysed from a hermeneutic approach to gain an in-depth understanding of how MOED influenced meaningful occupational engagement and to evaluate the implementation process., Findings: The main theme 'Engagement in meaningful occupations - a conditional and fragile process' emerged along with three subthemes: 'Creating an everyday space of meaning: Conditions of the intervention', 'Occupational engagement as an opportunity to blossom: Impact of the intervention' and 'Professional identity, culture and reflections: Contextual barriers to changes to working practice'. Together, the subthemes illustrate how engagement in meaningful occupations arose. However, opportunities to engage in meaningful occupations were fragile, as they depended on various factors within the context., Conclusion: Engagement in meaningful occupations emerged when MOED was applied in accordance with the program theory, as it seemed to create spaces where people with dementia could engage in meaningful occupations and they could blossom over time. However, MOED was only partially implemented in accordance with the developed program theory, as several contextual barriers influenced the sustainability of the intervention. MOED showed potential to support improvement in dementia care activity programmes to enhance opportunities to engage in meaningful occupations in everyday life for people living with dementia.

Mantle cell lymphoma (MCL) is a rare B cell malignancy. The classical MCL subtype is positive for translocation t(11;14), SOX11 expression, and characterized as a mature B cell neoplasm. While it is evident that differentiated B lymphocytes comprise the principal constituent of this malignancy, the possibility of an immature component involving immature progenitor, precursor, or even multipotent stem cells exists. It is now known that many hematologic malignancies are preceded by clonal hematopoiesis or a premalignant phase, which may involve early progenitors, and that such mutations can persist following treatment. Here, we thematically review and discuss the existing evidence pointing to an immature contribution of MCL in some cases. With the ongoing transition towards comprehensive genomic profiling, it is now possible to thoroughly investigate whether an immature genomic profile accompanies the morphologically lymphoblastic appearance of the blastoid subtype. This profile may include the expression of genes related to the pre-B cell receptor or genes required for the development and differentiation of B cell progenitors and precursors, such as transcription factor, SOX4, and the terminal transferase, DNTT. Research into the likely immature component of MCL is motivated by the relevance in treatment strategies because such cells potentially constitute a reservoir with increased resistance. In conclusion, further evidence on the concept, and definition, of lymphoma progenitors, precursors, or stem cell involvement in MCL is highly warranted., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The popliteal tendon and muscle are major stabilizers of the human and dog knee, more specifically the postero-lateral corner. Injury to this complex causes posterior knee pain, and it is generally associated with other injured structures such as the lateral collateral ligament, lateral meniscus, and/or the cranial cruciate ligament. The popliteal complex is poorly reported in the horse, and its specific function has not been determined. Nevertheless, it is likely that it is similar to that of other species, and that injury to it could have similar clinical repercussions. Lameness due to stifle pathology is a serious clinical entity in sport horses. One of the cardinal diagnostic tools in lameness exams is ultrasonography; however, a comprehensive technique to examine the popliteal complex (tendon and muscle) in the horse has not been reported. The objective of the study was to develop a systematic ultrasound technique of the equine popliteal complex that allows identification of the insertion and variations of the popliteal tendon (PopT), as well as examination of the popliteal muscle (PopM). Comparison between anatomical variants among horses was studied in order to identify possible significant differences. For this, 10 university teaching horses were used, hence 20 stifles were examined, several times. With the ultrasound technique presented here, the PopT and PopM are consistently examined. The developed technique allows reliable examination of the popliteal complex in the horse, and it could be included during standard ultrasound examination of equine stifle.

Clonal hematopoiesis (CH) denotes somatic mutations in genes related to myeloid neoplasms present at any variant allele frequency (VAF). Clonal hematopoiesis is associated with increasing age and with a factor 6 increase in the risk of developing therapy-related myeloid neoplasms (tMNs) following autologous stem cell transplantation (ASCT). However, the impact of specific mutations on progression from CH to tMN has yet to be unraveled, and it remains unclear whether mutations directly impact or even drive the development of tMN. We performed deep sequencing in longitudinal samples from a cohort of 12 patients with either multiple myeloma or lymphoma who developed tMN following ASCT. Nine patients had one or more mutations that could be tracked longitudinally. Seven patients had clonal expansion from time of ASCT to diagnosis of tMN. Of these, six patients had CH at VAF < 2% at baseline. The median VAF of non-DNMT3A clones increased from 1% (IQR 0.7%-10.0%) at time of ASCT to 37% (IQR 17%-47%) at tMN diagnosis (P = 0.002), while DNMT3A clones showed quiescent trajectories (P = 0.625). Our data provide evidence to support the hypothesis that the development of tMN following ASCT is likely instigated by CH present at VAFs as low as 0.5%, detectable years before tMN onset., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Next-generation sequencing (NGS) is an excellent methodology for measuring residual disease in acute myeloid leukemia and surveying several subclones simultaneously. There is little experience with interpretation of differential clonal responses to therapy. We hypothesized that differential clonal response could best be studied in patients with residual disease at the time of response evaluation. We performed targeted panel sequencing of paired diagnostic and first treatment evaluation samples in 69 patients with residual disease by morphology or measurable residual disease (MRD) level >0.02. Five patients had a rising clone at the time of evaluation. In a representative case, the rising clone was present only in the putative healthy stem cells (CD45 low CD34 + CD38 - CD123 - CD7 - ) and not in the putative leukemic stem cells (CD34 + CD38 - CD123 + CD7 + ) cells, thus indicating nonmalignant clonal hematopoiesis. In contrast, 17 of 43 evaluable patients exhibited a differential response in genes related to the leukemic clone. Twenty-six of 43 patients exhibited a clonal response that followed the overall treatment response. Patients with a differential response had better event-free survival (EFS) and overall survival (OS) than those in whom the clonal response followed the overall response (log-rank test, EFS: p = 0.045, OS: p = 0.050). This indicates that when following multiple leukemia-related clones, the less chemotherapy-responsive clone could, in some cases, have lower relapse potential, contrary to what is known when using standard mutation or fusion transcript-based disease surveillance. In conclusion, our results confirm the potential of refining MRD assessments by following multiple clones and warrants further studies on the precise interpretations of multiclone NGS-MRD assays., Competing Interests: Conflict of interest disclosure HBO received research funding from Jazz Pharmaceuticals and provided consultancy services to Pfizer, Jazz Pharmaceuticals, and Abbvie. MM and SK are employees at Munich Leukemia Laboratory. WK and TH are owners of Munich Leukemia Laboratory. The remaining authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

The literature about eye, ear, nose, skin, and nervous system disorders in women with Turner syndrome is equivocal. Impaired vision and hearing in women with Turner syndrome have been described, and case reports of Turner syndrome girls suffering from epilepsy have been published, but no large population-based-studies have explored the occurrence of any of these disorders. We aimed to investigate the risk of admission with disorders related to the eye, ear, nose, skin, and nervous system, compared with background females, and the impact of hormone replacement therapy on these conditions. 1,156 females with TS diagnosed during 1960-2014 were identified using the Danish Cytogenetic Central Registry and linked with personal-level data from the National Patient Registry and the Medication Statistics Registry. Statistics Denmark randomly identified 115,577 age-matched background females. Negative binomial regression was used to analyze hospital discharge diagnoses, reporting incidence rate ratios (IRR). Women with Turner syndrome have an increased risk of developing eye disorders (IRR 4.3 (95% CI 3.5-5.4), including cataract, glaucoma, ocular movement, and accommodation. The risk of ear disorders (IRR 35.0 (27.9-43.9)) and nose (IRR 2.2 (1.4-3.6)) was increased in women with Turner syndrome, due to otitis media, cholesteatoma, and hearing loss. Disorders of the nervous system such as epilepsy were increased IRR 6.2 (2.4-15.9), along with skin conditions IRR 2.2 (95%CI 1.7-2.7) like psoriasis, atopic dermatitis, and ingrown nails., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)

Introduction: To improve the outcomes of dyspnoeic patients, it is potentially important to determine the influence of uncertain diagnostic aetiology and to characterise this patient group. A change in diagnosis from emergency department (ED) contact to hospital discharge (i.e., a discordant diagnosis) served as a surrogate measure for an uncertain diagnostic aetiology. This study investigated the association between a change in diagnosis from ED contact to hospital discharge and length of stay (LOS), readmission and mortality in patients whose chief complaint was dyspnoea. The study also characterises the group of patients found to have a discordant diagnosis., Methods: This cohort study was based on data from all ED contacts at Aarhus University Hospital from 1 July 2016 to 30 June 2017. Patients triaged with dyspnoea and subsequently admitted to an inpatient unit were included., Results: Concordant contacts had an average LOS of 3.63 days, whereas discordant contacts had an average LOS of 4.65 days; the adjusted relative difference was 1.28 (95% CI: 1.10-1.48). Readmission, whether at seven or 30 days, was not significantly different between the groups. The 30-day mortality was 5% in the concordant and 10% in the discordant group, with an adjusted OR of 2.32 (95% CI: 1.08-4.96)., Conclusions: We found an association between a change in diagnosis and longer LOS, and between a change in diagnosis and 30-day mortality. The effort made to achieve diagnostic certainty in the ED may have an impact lasting throughout the entire hospital stay., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Background: Emergency department (ED) patients present with complaints and not diagnoses. Characterization and risk stratification based on chief complaint can therefore help clinicians improve ED workflow and clinical outcome. In this study we investigated the 30-day mortality and readmission among ED patients based on chief complaint., Methods: In this cohort study we retrieved routinely collected data from electronic medical records and the Danish Civil Registration System of all ED contacts from July 1, 2016 through June 30, 2017. All patients triaged with one chief complaint using the Danish Emergency Process Triage system were included. Patients with minor injuries were excluded. The chief complaint assigned by the triaging nurse was used as exposure, and 30-day mortality and 30-day readmission were the primary outcomes. Logistic regression was used to determine crude and adjusted ORs with reference to the remaining study population., Results: A total of 41 470 patients were eligible. After exclusion of minor injuries and patients not triaged, 19 325 patients were included. The 30-day mortality and 30-day readmission differed significantly among the chief complaints. The highest 30-day mortality was observed among patients presenting with altered level of conscousness (ALOC) (8.4%, OR=2.0, 95% CI 1.3 to 3.1) and dyspnea (8.0%, OR=2.1, 95% CI 1.6 to 2.6). 30-day readmission was highest among patients presenting with fever/infection (11.7%, OR=1.9, 95% CI 1.4 to 2.4) and dyspnea (11.2%, OR=1.7, 95% CI 1.4 to 2.0)., Discussion: Chief complaint is associated with 30-day mortality and readmission in a mixed ED population. ALOC and dyspnea had the highest mortality; fever/infection and dyspnea had the highest readmission rate. This knowledge may assist in improving and optimizing symptom-based initial diagnostic workup and treatment, and ultimately improve workflow and clinical outcome., Level of Evidence: Level III., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To examine cone density in relation to gestational and morphological parameters in the Copenhagen Child Cohort (CCC2000)., Methods: The macula was imaged using adaptive optics in 1,296 adolescents aged 16-17 years. Axial length and distance visual acuity were determined. Absolute and angular cone photoreceptor density were analysed for an 80 × 80-pixel area, 2 degrees temporal to the fovea. Association with axial length was analysed with linear regression. Correlation with visual acuity was described with a Pearson correlation coefficient. Associations of cone density with gestational parameters, maternal smoking, sex and age were analysed using multiple regression adjusted for axial length., Results: Mean absolute cone density was 30,007 cones/mm 2 (SD ± 3,802) and mean angular cone density was 2,383 cones/deg 2 (SD ± 231). Peri- and postnatal parameters, sex and age had no statistically significant effect on cone density (p > 0.05). Absolute cone density decreased with longer axial length (-2,855 cones/mm 2 per mm or -9.7% per mm, p < 0.0001). For angular density, which included a correction for the geometrical enlargement of the eye with axial length, a decrease with axial length was detectable, but it was small (-20 cones/deg 2 per mm or -0.84% per mm, p = 0.009)., Conclusions: The decrease in cone density per unit solid angle with increasing axial length was small, less than 1 percent per mm, indicating that expansion of the posterior pole during the development of refraction takes place without a clinically significant loss of cones. Perinatal parameters, within the spectrum presented by the study population, had no detectable effect on cone density., (© 2021 The Authors Ophthalmic and Physiological Optics © 2021 The College of Optometrists.)

Next-generation sequencing (NGS) of whole genomes has become more accessible to biomedical researchers as the sequencing price continues to drop, and more laboratories have NGS facilities or have access to a core facility. However, the rapid and robust development of practical bioinformatics pipelines partly depends on convenient access to data for the testing of algorithms. Publicly available data sets constitute a part of this strategy. Here, we provide a triplicate whole-genome paired-end sequencing data set, consisting of 1.38 billion raw sequencing reads derived from saliva DNA from a single anonymous male Caucasian donor, with the average sequencing depths aimed at 30x for two of the samples and 4x for a low-coverage sample. The raw number of single nucleotide variants were 3.3-4 million and the median variant read depth of GATK4-passed variants in three samples was 22, 18, and 10. 81% of all variants were found in two or three of the samples, whereas 19% were singletons. The karyotype was evaluated as 46,XY with no apparent copy-number variation. The data set is provided without restrictions for research, educational or commercial purposes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships which have or could be perceived to have influenced the work reported in this article. Funding was provided by the first author. Disclaimer: The provided data presentation is deliberately descriptive. It is not a regular scientific paper., (© 2021 The Author(s). Published by Elsevier Inc.)