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Author(s): S. J. Humphray (corresponding author) [1]; K. Oliver [1]; A. R. Hunt [1]; R. W. Plumb [1]; J. E. Loveland [1]; K. L. Howe [1]; T. D. Andrews [1]; [...]

Sexual dysfunction is prevalent in both men and women. Although new pharmaceutical agents have been identified for male erectile problems, sexual desire and orgasm disorders, individuals with sexual dysfunction often seek alternative therapies, including traditional Chinese medicine. This article reviews currently used alternative therapies, such as herbal medications, L-arginine, acupuncture, biofeedback and others. Potential herb-drug interactions are also presented. [ABSTRACT FROM AUTHOR]

Objective: To examine the effects of resident and attending physician gender on the evaluation of residents in an internal medicine training program.Design: Cross-sectional study.Setting: Large urban academic internal medicine residency program.Participants: During their first 2 years of training, 132 residents (85 men, 47 women) received a total of 974 evaluations from 255 attending physicians (203 men, 52 women) from 1989 to 1995.Measurements: The primary measurements were the numerical portions of the American Board of Internal Medicine evaluation form. Separate analyses were performed for each of the nine evaluation dimensions graded on a scale of 1 to 9. The primary outcome was the difference in the average scores received by each resident from male versus female attending physicians.Results: Compared with female trainees, male residents received significantly higher scores from male attending physicians than from female attending physicians in six of the nine dimensions: clinical judgment, history, procedures, relationships, medical care, and overall. Similar trends, not reaching conventional levels of statistical significance, were observed in the other three categories: medical knowledge, physical exam, and attitude. These differences ranged from 0.24 to 0.60 points, and were primarily due to higher grading of male residents by male attending physicians than by female attending physicians.Conclusions: In one academic training program, we found a significant interaction in the grading process between the gender of internal medicine residents and the gender of their attending evaluators. This study raises the possibility that subtle aspects of gender bias may exist in medical training programs. [ABSTRACT FROM AUTHOR]

Fluoride has long been considered essential in the prevention of dental caries, however, its relationship with bone cancer remains unclear. With little improvements in survival from primary bone cancers, it is important to understand the underlying drivers. The focus of this systematic review was, therefore, to assess the association between fluoride exposure and the development of primary bone cancer. The review was conducted as per the PRISMA guidelines and was registered on PROSPERO (CRD42021296109) with a search cut-off of March 2024. In total, 14 studies, involving 8680 participants across all age groups, were identified examining the effects of fluoride exposure on humans investigated for primary bone cancer. Of the 14 studies, only two reported a positive association between fluoride and primary bone cancer. One study including 88 participants reported a positive association between water fluoridation and osteosarcoma development (in young males between 0 and 20 years of age), and the second study, with an unreported number of participants, reported this positive association with bone cancers in males. No association between fluoridation and bone cancer development was reported in the remaining studies. Across all 14 studies, data was presented in a narrative synthesis with subgroup analysis conducted on study design, age, sex, fluoride level and quality score. Both studies reporting a positive association between fluoride and bone cancer identified this association in males, however, both studies concluded that further research is needed. Here we report the most comprehensive systematic review to date examining associations between fluoride exposure and primary bone cancer. We also highlight some of the methodological limitations of some studies, and identify the need, and opportunity, to conduct a large, prospective study to address this and other health issues associated with fluoride., 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 © 2024 Elsevier Inc. All rights reserved.)

Carcinus spp. are global aquatic invaders and carriers of several parasites, including a taxonomically unrecognised microsporidian recently observed from Argentina. We provide genome drafts for two parasite isolates, one from Carcinus maenas and one from Carcinus aestuarii, and use multi-gene phylogenetics and genome comparison methods to outline their similarities. Their SSU genes are 100 % similar and other genes have an average similarity of 99.31 %. We informally name the parasite Agmasoma carcini, terming the isolates Ac. var. aestuarii and Ac. var. maenas, following the wealth of genomic data available for each. This study follows on from Frizzera et al. (2021), where this parasite was first histologically identified., 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 The Author(s). Published by Elsevier Inc. All rights reserved.)

Classic Hodgkin lymphoma (cHL) has a rich immune infiltrate, which is an intrinsic component of the neoplastic process. Malignant Hodgkin Reed-Sternberg cells (HRSCs) create an immunosuppressive microenvironment by the expression of regulatory molecules, preventing T-cell activation. It has also been demonstrated that mononuclear phagocytes (MNPs) in the vicinity of HRSCs express similar regulatory mechanisms in parallel, and their presence in tissue is associated with inferior patient outcomes. MNPs in cHL have hitherto been identified by a small number of canonical markers and are usually described as tumor-associated macrophages. The organization of MNP networks and interactions with HRSCs remains unexplored at high resolution. Here, we defined the global immune-cell composition of cHL and nonlymphoma lymph nodes, integrating data across single-cell RNA sequencing, spatial transcriptomics, and multiplexed immunofluorescence. We observed that MNPs comprise multiple subsets of monocytes, macrophages, and dendritic cells (DCs). Classical monocytes, macrophages and conventional DC2s were enriched in the vicinity of HRSCs, but plasmacytoid DCs and activated DCs were excluded. Unexpectedly, cDCs and monocytes expressed immunoregulatory checkpoints PD-L1, TIM-3, and the tryptophan-catabolizing protein IDO, at the same level as macrophages. Expression of these molecules increased with age. We also found that classical monocytes are important signaling hubs, potentially controlling the retention of cDC2 and ThExh via CCR1-, CCR4-, CCR5-, and CXCR3-dependent signaling. Enrichment of the cDC2-monocyte-macrophage network in diagnostic biopsies is associated with early treatment failure. These results reveal unanticipated complexity and spatial polarization within the MNP compartment, further demonstrating their potential roles in immune evasion by cHL., (© 2023 by The American Society of Hematology.)

A common problem in the study of human malignancy is the elucidation of cancer driver mechanisms associated with recurrent deletion of regions containing multiple genes. Taking B-cell acute lymphoblastic leukaemia (B-ALL) and large deletions of 6q [del(6q)] as a model, we integrated analysis of functional cDNA clone tracking assays with patient genomic and transcriptomic data, to identify the transcription factors FOXO3 and PRDM1 as candidate tumour suppressor genes (TSG). Analysis of cell cycle and transcriptomic changes following overexpression of FOXO3 or PRDM1 indicated that they co-operate to promote cell cycle exit at the pre-B cell stage. FOXO1 abnormalities are absent in B-ALL, but like FOXO3, FOXO1 expression suppressed growth of TCF3::PBX1 and ETV6::RUNX1 B-ALL in-vitro. While both FOXOs induced PRDM1 and other genes contributing to late pre-B cell development, FOXO1 alone induced the key transcription factor, IRF4, and chemokine, CXCR4. CRISPR-Cas9 screening identified FOXO3 as a TSG, while FOXO1 emerged as essential for B-ALL growth. We relate this FOXO3-specific leukaemia-protective role to suppression of glycolysis based on integrated analysis of CRISPR-data and gene sets induced or suppressed by FOXO1 and FOXO3. Pan-FOXO agonist Selinexor induced the glycolysis inhibitor TXNIP and suppressed B-ALL growth at low dose (ID 50  < 50 nM)., (© 2023. The Author(s).)

We reconstructed the natural history and temporal evolution of the most common childhood brain malignancy, medulloblastoma, by single-cell whole-genome sequencing (sc-WGS) of tumours representing its major molecular sub-classes and clinical risk groups. Favourable-risk disease sub-types assessed (MB WNT and infant desmoplastic/nodular MB SHH ) typically comprised a single clone with no evidence of further evolution. In contrast, highest risk sub-classes (MYC-amplified MB Group3 and TP53-mutated MB SHH ) were most clonally diverse and displayed gradual evolutionary trajectories. Clinically adopted biomarkers (e.g. chromosome 6/17 aberrations; CTNNB1/TP53 mutations) were typically early-clonal/initiating events, exploitable as targets for early-disease detection; in analyses of spatially distinct tumour regions, a single biopsy was sufficient to assess their status. Importantly, sc-WGS revealed novel events which arise later and/or sub-clonally and more commonly display spatial diversity; their clinical significance and role in disease evolution post-diagnosis now require establishment. These findings reveal diverse modes of tumour initiation and evolution in the major medulloblastoma sub-classes, with pathogenic relevance and clinical potential., (© 2022. The Author(s).)

Children with B-cell non-Hodgkin lymphoma (B-NHL) have an excellent chance of survival, however, current clinical risk stratification places as many as half of patients in a high-risk group receiving very intensive chemo-immunotherapy. TP53 alterations are associated with adverse outcome in many malignancies; however, whilst common in paediatric B-NHL, their utility as a risk classifier is unknown. We evaluated the clinical significance of TP53 abnormalities (mutations, deletion and/or copy number neutral loss of heterozygosity) in a large UK paediatric B-NHL cohort and determined their impact on survival. TP53 abnormalities were present in 54.7% of cases and were independently associated with a significantly inferior survival compared to those without a TP53 abnormality (PFS 70.0% vs 100%, p < 0.001, OS 78.0% vs 100%, p = 0.002). Moreover, amongst patients clinically defined as high-risk (stage III with high LDH or stage IV), those without a TP53 abnormality have superior survival compared to those with TP53 abnormalities (PFS 100% vs 55.6%, p = 0.005, OS 100% vs 66.7%, p = 0.019). Biallelic TP53 abnormalities were either maintained from the presentation or acquired at progression in all paired diagnosis/progression Burkitt lymphoma cases. TP53 abnormalities thus define clinical risk groups within paediatric B-NHL and offer a novel molecular risk stratifier, allowing more personalised treatment protocols., (© 2021. The Author(s).)

Chronic lymphocytic leukaemia (CLL) is a heterogeneous disease with a highly variable clinical outcome. There are well-established CLL prognostic biomarkers that have transformed treatment and improved the understanding of CLL biology. Here, we have studied the clinical significance of two crucial B cell regulators, BACH2 (BTB and CNC homology 1, basic leucine zipper transcription factor 2) and BCL6 (B-cell CLL/lymphoma 6), in a cohort of 102 CLL patients and determined the protein interaction networks that they participate in using MEC-1 CLL cells. We observed that CLL patients expressing low levels of BCL6 and BACH2 RNA had significantly shorter overall survival (OS) than high BCL6 - and BACH2 -expressing cases. Notably, their low expression specifically decreased the OS of immunoglobulin heavy chain variable region-mutated (IGHV-M) CLL patients, as well as those with 11q and 13q deletions. Similar to the RNA data, a low BACH2 protein expression was associated with a significantly shorter OS than a high expression. There was no direct interaction observed between BACH2 and BCL6 in MEC-1 CLL cells, but they shared protein networks that included fifty different proteins. Interestingly, a prognostic index (PI) model that we generated, using integrative risk score values of BACH2 RNA expression, age, and 17p deletion status, predicted patient outcomes in our cohort. Taken together, these data have shown for the first time a possible prognostic role for BACH2 in CLL and have revealed protein interaction networks shared by BCL6 and BACH2, indicating a significant role for BACH2 and BCL6 in key cellular processes, including ubiquitination mediated B-cell receptor functions, nucleic acid metabolism, protein degradation, and homeostasis in CLL biology.

DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also enriched in MYC-translocated diffuse large B cell lymphoma and reveal functional cooperation between mutant DDX3X and MYC. DDX3X promotes the translation of mRNA encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y chromosome homolog, the expression of which is normally restricted to the testis. These findings show that DDX3X loss of function can buffer MYC-driven proteotoxic stress and highlight the capacity of male B cell lymphomas to then compensate for this loss by ectopic DDX3Y expression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Children undergoing heart transplant are at higher risk of developing post-transplant lymphoproliferative disorder (PTLD) than other solid organ recipients. The factors driving that risk are unclear. This study investigated risk factors for PTLD in children transplanted at 1 of 2 United Kingdom pediatric cardiac transplantation centers., Methods: All children (<18 years, n = 200) transplanted at our institution over a 16-year period were analyzed. Freedom from PTLD was assessed using the Kaplan-Meier method and Cox proportional regression., Results: PTLD occurred in 17 of 71 children transplanted for congenital heart disease (CHD) and 18 of 129 transplanted for acquired cardiomyopathy (ACM). The cumulative incidence of all PTLD was 21.1% at 5 years after transplant. Median time from transplant to PTLD was 2.9 years (interquartile range: 0.9-4.6). Negative Epstein-Barr virus (EBV) serostatus pre-transplant (adjusted hazard ratio [HR]: 2.7, 95% CI: 1.3-5.6, p = 0.01) and underlying CHD (adjusted HR: 3.2, 95% CI: 1.4-7.4, p = 0.007) were independently associated with higher risk of PTLD. Age at thymectomy was significantly different between children with CHD and ACM (0.4 vs 5.5 years, p < 0.01). Median CD4 + and CD8 + T lymphocyte counts at 2 years after transplant were significantly lower in children transplanted for CHD vs ACM (CD4 + : 391/µl vs 644/µl, p = 0.01; CD8 + : 382/µl vs 500/µl, p = 0.01). At 5 years after transplant, those differences persisted among patients who developed PTLD (CD4 + , 430/µl vs 963/µl, p < 0.01 and CD8 + , 367/µl vs 765/µl, p < 0.01)., Conclusion: Underlying CHD is an independent risk factor for PTLD and is associated with a younger age at thymectomy. A persistent association with altered T lymphocyte subsets may contribute to the impaired response to primary EBV infection and increase the risk of PTLD., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

The goal of this qualitative study was to assess physicians' perceptions around features of key screens within a prominent commercial EHR, and to solicit end-user recommendations for improved retrieval of high-priority clinical information. We conducted a qualitative, descriptive study of 25 physicians in a medical ICU setting. at a tertiary academic medical center. An in-depth, semi-structured interview guide was developed to elicit physician perceptions on information retrieval as well as favorable and unfavorable features of specific EHR screens. Transcripts were independently coded in a qualitative software management tool by at least two trained coders using a common code book. We successfully obtained vendor permission to map physicians perception's on full Epic© screenshots. Among the 25 physician participants (13 female; 5 attending physicians, 9 fellows, 11 residents), the majority of participants reported experiencing challenges finding clinical information in the EHR. We present the most favorable and unfavorable screen-level features for four central EHR screens: Flowsheet, Notes/Chart Review, Results Review, and Vital Signs. We also compiled participants' recommendations for a comprehensive EHR dashboard screen to better support clinical workflow and information retrieval in the medical ICU through User-Centered Design. ICU physicians demonstrated a mix of positive and negative attitudes toward specific screen-level features in a major vendor-based EHR system. Physician perceptions of information overload emerged as a theme across multiple EHR screens. Our findings underscore the importance of qualitative research and end-user feedback in EHR software design and interface optimization at both the vendor and institutional level.

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western World and it is characterized by a marked degree of clinical heterogeneity. An impaired balance between pro- and anti-apoptotic stimuli determines chemorefractoriness and outcome. The low proliferation rate of CLL cells indicates that one of the primary mechanisms involved in disease development may be an apoptotic failure. Here, we study the clinical and functional significance of DRAK2, a novel stress response kinase that plays a critical role in apoptosis, T-cell biology, and B-cell activation in CLL. We have analyzed CLL patient samples and showed that low expression levels of DRAK2 were significantly associated with unfavorable outcome in our CLL cohort. DRAK2 expression levels showed a positive correlation with the expression of DAPK1 , and TGFBR1 . Consistent with clinical data, the downregulation of DRAK2 in MEC-1 CLL cells strongly increased cell viability and proliferation. Further, our transcriptome data from MEC-1 cells highlighted MAPK, NF-κB, and Akt and as critical signaling hubs upon DRAK2 knockdown. Taken together, our results indicate DRAK2 as a novel marker of CLL survival that plays key regulatory roles in CLL prognosis.

FOXO1 has an oncogenic role in adult germinal center-derived lymphomas, in which mutations, predominately within the AKT recognition motif, cause nuclear retention of FOXO1, resulting in increased cell proliferation. To determine the prevalence and distribution of FOXO1 mutations in pediatric Burkitt lymphoma (BL), we sequenced a large number of sporadic and endemic BL patient samples. We report a high frequency of FOXO1 mutations in both sporadic and endemic BL at diagnosis, occurring in 23/78 (29%) and 48/89 (54%) samples, respectively, as well as 8/16 (50%) cases at relapse. Mutations of T24 were the most common in sporadic BL but were rare in endemic cases, in which mutations of residue S22, also within the AKT recognition motif, were the most frequent. FOXO1 mutations were almost always present in the major tumor cell clone but were not associated with outcome. Analysis of other recurrent mutations reported in BL revealed that FOXO1 mutations were associated with mutations of DDX3X and ARID1A, but not MYC , TCF3 / ID3, or members of the phosphatidylinositol 3-kinase signaling pathway. We further show common nuclear retention of the FOXO1 protein, irrespective of mutation status, suggesting alternative unknown mechanisms for maintaining FOXO1 transcriptional activity in BL. CRISPR/Cas9 knockout of FOXO1 in an endemic cell line produced a significant decrease in cell proliferation, supporting an oncogenic role for FOXO1 in endemic BL. Thus, FOXO1 is frequently mutated in both sporadic and endemic BL and may offer a potential therapeutic target for pediatric BL patients worldwide., (© 2019 by The American Society of Hematology.)

The Electronic Health Record has become a staple today in every hospital and clinic, thanks to policy changes advocating its use. However, its full potential can be realized only when it is easy to use and compliant to the needs of the different user subgroups. This study uses a novel approach of eye tracking to assess and differentiate EHR usability based on gender. Though the findings were not suggestive of a significant gender-based difference, they did indicate that the design and layout of screen elements have a significant influence on the search efficiency for both user groups and this point could be relevant for future EHR design.

Electronic health records usability creates challenges to the delivery of care. This paper presents a novel approach to user analysis. Fixation counts have been analyzed to identify differences among physicians of 3 experience levels - residents, fellows and attending physicians. The findings indicate that users with different training levels had varied experiences while interacting with the same interface. EHRs will always be used by a variety of user groups, each with their own unique characteristics and therefore user analysis must be an important component of EHR usability testing. Eye tracking technology could serve as a valuable tool in this context.

Background: Poor EHR design adds further challenges, especially in the areas of order entry and information visualization, with a net effect of increased rates of incidents, accidents, and mortality in ICU settings., Objective: The purpose of this study was to propose a novel, mixed-methods framework to understand EHR-related information overload by identifying and characterizing areas of suboptimal usability and clinician frustration within a vendor-based, provider-facing EHR interface., Methods: A mixed-methods, live observational usability study was conducted at a single, large, tertiary academic medical center in the Southeastern US utilizing a commercial, vendor based EHR. Physicians were asked to complete usability patient cases, provide responses to three surveys, and participant in a semi-structured interview., Results: Of the 25 enrolled ICU physician participants, there were 5(20%) attending physicians, 9 (36%) fellows, and 11 (44%) residents; 52% of participants were females. On average, residents were the quickest in completing the tasks while attending physician took the longest to complete the same task. Poor usability, complex interface screens, and difficulty to navigate the EHR significantly correlated with high frustration levels. Significant association were found between the occurrence of error messages and temporal demand such that more error messages resulted in longer completion time (p = .03)., Discussion: Physicians remain frustrated with the EHR due to difficulty in finding patient information. EHR usability remains a critical challenge in healthcare, with implications for medical errors, patient safety, and clinician burnout. There is a need for scientific findings on current information needs and ways to improve EHR-related information overload., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Information overload is a significant problem in the digital age of healthcare and plays key a role in diagnostic errors, near misses, and patient safety, especially in critical care settings. Because of this, we propose a new mixed-methods approach for evaluating EHR-related information overload on clinicians in the ICU. We describe a three-part approach to better understand ICU clinicians' information needs and workflow as they relate to the EHR, and to explore the effects of the EHR on provider workload, performance, and satisfaction. Based on discussions with ICU providers, key areas of information needs have been identified and a preliminary model of EHR workflow has been established.