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Background/aim: Previous studies have demonstrated that breast cancer cells secrete exosomes into the tumor microenvironment, promoting tumor progression. However, the paracrine influence of noncancerous breast epithelial cells on the growth of triple-negative breast cancer (TNBC) cells has largely been overlooked. We hypothesize that exosomes from noncancerous breast epithelial cells are secreted into the tumor microenvironment, stimulating TNBC growth., Materials and Methods: Exosome-containing media were prepared using exosomes isolated from triple-negative patient-derived xenografts (PDX) or noncancerous MCF-10A breast epithelial cells and used to treat MCF-7 or TNBC cells. Exosome-containing media from MCF-10A cells were characterized using ELISA. Subsequently, MDA-MB-231 and MDA-MB-468 cells treated with the MCF-10A exosome-containing media, and their impact on proliferation, migration, protein expression and gene expression were analyzed using Alamar blue assays, wound healing assays, western blotting, immunofluorescence, and gene expression arrays, respectively., Results: Exosomes extracted from the PDX and MCF-10A cells stimulated the growth of all examined cell lines. The MCF-10A exosome-containing media expressed CD9 and CD63; however, the MDA-MB-231 and MDA-MB-468 cells treated with these media exhibited differential expression of these proteins. Exposure of MDA-MB-231 and MDA-MB-468 cells to the MCF-10A exosome-containing media stimulated their growth and migration. Exposure of MDA-MB-231 cells to MCF-10A exosome-containing media caused down-regulation of genes involved in cell-cell adhesion, DNA damage response, epithelial-mesenchymal transition drivers, tumor suppression, and up-regulation of the MYC oncogene., Conclusion: Secreted factors from noncancerous cells, identified as exosomes, induce cancer cell proliferation and prime the tumor microenvironment by enhancing disease progression-associated pathways., (Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Electronic medical records (EMRs) have the potential to improve and streamline the quality and safety of patient care. Harnessing the full benefits of EMR implementation depends on the utilisation of advanced features, defined as "mature usage." At present, little is known about the maturity of EMR usage by allied health professionals (AHPs)., Objective: To examine current maturity of EMR use by AHPs and explore perceived barriers to mature EMR utilisation and optimisation., Method: AHPs were recruited from three health services. Participants completed a 27-question electronic questionnaire based on the EMR Adoption Framework, which measures clinician EMR utilisation (0 =  paper chart , 5 =  theoretical maximum ) across 10 EMR feature categories. Interviews were conducted with both clinicians and managers to explore the nature of current EMR utilisation and perceived facilitators and barriers to mature usage., Results: Questionnaire responses were obtained from 193 participants AHPs. The majority of questions (74%) showed a mean score of <3, indicating a lack of mature EMR use. Pockets of mature usage were identified in the categories of health information, referrals and administration processes. Interviews with 21 clinicians and managers revealed barriers to optimisation across three themes: (1) limited understanding of EMR opportunities; (2) complexity of the EMR change process and (3) end-user and environmental factors., Conclusion: Mature usage across EMR feature categories of the EMR Adoption Framework was low. However, questionnaire and qualitative interview data suggested pockets of mature utilisation., Implications: Achieving mature allied health EMR use will require strategies implemented at the clinician, EMR support, and service levels., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Renal infarcts are uncommon, difficult to diagnose, and can lead to long-term kidney disease. Because they have numerous etiologies and patients may present with nonspecific symptoms, renal infarcts may be mistaken for other common conditions. A 50-year-old woman presented to the emergency department (ED) with flank pain, nausea, and vomiting. Computed tomography (CT) revealed multiple right kidney infarcts, transthoracic echocardiography revealed mitral valve stenosis with no evidence of atrial fibrillation, and hypercoagulability tests were negative. High-intensity anticoagulation therapy resolved the infarcts and she was discharged on warfarin. Six years later, at the age of 56, the woman again presented to the ED with back pain, nausea, vomiting, and fever. She had undergone valvuloplasty to repair the mitral valve stenosis 1 month before this ED visit, and warfarin had been discontinued shortly after the procedure. CT imaging and ultrasonography showed no evidence of infarcts and electrocardiogram was normal. Although urinalysis was negative for infection, pyelonephritis was suspected per CT results. However, renal function and leukocytosis did not improve after 2 days of antibiotic therapy. Radioisotope renal scan then revealed infarcts in the left kidney. Anticoagulation therapy again led to recovery, and the patient was discharged back on warfarin. After the recurrent infarct, monitoring and cardiac care have led to adequate long-term management, and no evidence of atrial fibrillation has ever been observed. This case illustrates the challenging diagnosis of an unusual presentation of recurrent renal infarct, where each infarct was suspected to have a unique and independent etiology: mitral valve stenosis in the first and hypercoagulability from withdrawal of warfarin in the second. Because no clear risk or symptom profiles exist for renal infarcts, this unusual condition should be considered when patients do not respond to treatment for other renal problems, especially those with cardiovascular disease., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Kaitlyn Perkins et al.)

Background: Transplantation of human-induced pluripotent stem cell (hiPSC)-derived islet organoids is a promising cell replacement therapy for type 1 diabetes (T1D). It is important to improve the efficacy of islet organoids transplantation by identifying new transplantation sites with high vascularization and sufficient accommodation to support graft survival with a high capacity for oxygen delivery., Methods: A human-induced pluripotent stem cell line (hiPSCs-L1) was generated constitutively expressing luciferase. Luciferase-expressing hiPSCs were differentiated into islet organoids. The islet organoids were transplanted into the scapular brown adipose tissue (BAT) of nonobese diabetic/severe combined immunodeficiency disease (NOD/SCID) mice as the BAT group and under the left kidney capsule (KC) of NOD/SCID mice as a control group, respectively. Bioluminescence imaging (BLI) of the organoid grafts was performed on days 1, 7, 14, 28, 35, 42, 49, 56, and 63 posttransplantation., Results: BLI signals were detected in all recipients, including both the BAT and control groups. The BLI signal gradually decreased in both BAT and KC groups. However, the graft BLI signal intensity under the left KC decreased substantially faster than that of the BAT. Furthermore, our data show that islet organoids transplanted into streptozotocin-induced diabetic mice restored normoglycemia. Positron emission tomography/MRI verified that the islet organoids were transplanted at the intended location in these diabetic mice. Immunofluorescence staining revealed the presence of functional organoid grafts, as confirmed by insulin and glucagon staining., Conclusions: Our results demonstrate that BAT is a potentially desirable site for islet organoid transplantation for T1D therapy., (Copyright © 2024 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Treatment of candidemia may be complicated by hematogenous dissemination. Limited data exist to guide decision-making regarding the evaluation for disseminated disease. We sought to describe the epidemiology of invasive disease after candidemia, report the diagnostic evaluations performed and identify risk factors for disseminated disease., Methods: We performed a retrospective single-center study of candidemia from January 1, 2012 to December 31, 2022. Disseminated candidiasis was defined as radiologic findings consistent with end-organ disease, abnormal ophthalmologic exam or growth of Candida spp. from a sterile site after an episode of candidemia. A multilevel regression model was used to identify risk factors for dissemination., Results: The cohort included 124 patients with 144 episodes of candidemia. Twelve patients died before an evaluation for dissemination occurred. Only 107/132 patients underwent evaluation for dissemination. Tests obtained included abdominal imaging (93/132), echocardiography (91/132), neuroimaging (45/132) and chest imaging (38/132). A retinal examination was performed in 90/132 patients. Overall, 27/107 patients (25%) had disseminated disease. Frequently identified sites of dissemination were lungs and abdominal organs. Regression modeling identified prematurity [adjusted odds ratio (aOR): 11.88; 95% confidence interval (CI): 1.72-81.90] and mitochondrial and genetic disease (aOR: 5.66; 95% CI: 1.06-30.17) as risk factors for disseminated candidiasis. Each additional day of candidemia increased the odds of dissemination (aOR: 1.36; 95% CI: 1.12-1.66)., Discussion: In a heterogeneous cohort of patients, disseminated candidiasis was common. Evaluation for disseminated disease was variable. Those with persistent candidemia had significantly increased risk of dissemination and should undergo a standardized evaluation for disseminated disease., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

The Medical and Pharmacy Student Collaboration (MAPSC) student organization at the University of Southern California, Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, created an extracurricular, peer-led, virtual group mock objective structured clinical examination (MOSCE) to expose first-year pharmacy students (P1s) to the Pharmacists' Patient Care Process (PPCP). The purpose of this study is to evaluate the impact of a MAPSC MOSCE on P1s self-reported confidence in applying the PPCP and on patient communication, medication knowledge, and clinical skills. An anonymous, optional, self-reported survey was administered to P1s before and after the event, where they rated their confidence on a scale of 0-100 (0 = not confident, 100 = certainly confident). The statistical analysis was a paired two-tailed t-test with a significance level of p < 0.05. A total of 152 P1s and 30 facilitators attended the MOSCE. One hundred thirty-nine students met the inclusion criteria and were included in the data analysis. There was a statistically significant difference in the change in self-reported confidence for all PPCP components and learning outcomes. The results of our study strongly indicate that introducing P1 students to the PPCP through a MAPSC MOSCE format is a valuable experience.

Objective: Differences in how impulsivity is conceptualized, along with a myopic focus on impulsivity's relationship with historical suicidal behaviors, have resulted in limited implications made from prior research regarding impulsivity and suicidal thoughts and behaviors. The current study investigated the indirect effect facets of impulsivity may have on suicidal ideation, specifically, through thwarted interpersonal needs., Methods: Participants were N  = 424 undergraduate students who completed a cross-sectional survey. Participants completed the Urgency, Premeditation, Perseverance, Sensation Seeking, Impulsive Behavior Scale (UPPS), the Adult Suicide Ideation Questionnaire (ASIQ), and the Interpersonal Needs Questionnaire (INQ). Parallel mediation models were run to examine the relation between facets of impulsivity, perceived burdensomeness, thwarted belongingness, and suicidal ideation., Results: Thwarted belonginess and perceived burdensomeness significantly accounted for the variance in the relation between negative urgency and suicidal ideation. Neither thwarted belongingness nor perceived burdensomeness significantly explained variance in the relation between (lack of) premeditation and suicidal ideation. Conversely, perceived burdensomeness and thwarted belonginess significantly explained the inverse relation between sensation seeking and suicidal ideation (i.e., greater sensation seeking was related to lower perceived burdensomeness and thwarted belongingness and in turn lower suicidal ideation)., Conclusion: Negative urgency, in particular, is related to suicidal ideation through thwarted interpersonal needs. Future research should continue to differentiate between various types of impulsivity and its relationship with both suicidal ideation and behaviors utilizing both cross-sectional and ambulatory assessments of these constructs.HIGHLIGHTSNegative urgency is related to suicidal ideation.Negative urgency is related to thwarted interpersonal needs.Thwarted interpersonal needs partially explain the relation between negative urgency and suicidal ideation.

Awareness of welfare issues within animal collections is increasing as information becomes more accessible for staff and the public. A knowledge gap remains when considering the welfare of invertebrates, particularly when housed in public aquaria. TripAdvisor comments were analyzed for 485 worldwide aquariums. The public focused on anthropogenic features or charismatic organisms within collections. Invertebrate welfare was only presented in 18% of negative welfare comments compared with the 51% of represented vertebrates and 31% of negative general welfare comments. The UK and USA reported a greater number of perceived invertebrate welfare issues. Greater dissemination of information between aquarists and scientists should be encouraged to drive welfare standards and improve husbandry. In addition, incorporating input from invertebrate aquarists while utilizing welfare toolkits are vital for improving overall standards if we are to have greater representation of invertebrate welfare in public aquaria.

Importance: Live vaccines (measles-mumps-rubella [MMR] and varicella-zoster virus [VZV]) have not been recommended after solid organ transplant due to concern for inciting vaccine strain infection in an immunocompromised host. However, the rates of measles, mumps, and varicella are rising nationally and internationally, leaving susceptible immunocompromised children at risk for life-threating conditions., Objective: To determine the safety and immunogenicity of live vaccines in pediatric liver and kidney transplant recipients., Design, Setting, and Participants: This cohort study included select pediatric liver and kidney transplant recipients who had not completed their primary MMR and VZV vaccine series and/or who displayed nonprotective serum antibody levels at enrollment between January 1, 2002, and February 28, 2023. Eligibility for live vaccine was determined by individual US pediatric solid organ transplant center protocols., Exposures: Exposure was defined as receipt of a posttransplant live vaccine. Transplant recipients received 1 to 3 doses of MMR vaccine and/or 1 to 3 doses of VZV vaccine., Main Outcome and Measure: Safety data were collected following each vaccination, and antibody levels were obtained at 0 to 3 months and 1 year following vaccination. Comparisons were performed using Mann-Whitney U test, and factors associated with development of postvaccination protective antibodies were explored using univariate analysis., Results: The cohort included 281 children (270 [96%] liver, 9 [3%] kidney, 2 [1%] liver-kidney recipients) from 18 centers. The median time from transplant to enrollment was 6.3 years (IQR, 3.4-11.1 years). The median age at first posttransplant vaccine was 8.9 years (IQR, 4.7-13.8 years). A total of 202 of 275 (73%) children were receiving low-level monotherapy immunosuppression at the time of vaccination. The majority of children developed protective antibodies following vaccination (107 of 149 [72%] varicella, 130 of 152 [86%] measles, 100 of 120 [83%] mumps, and 124 of 125 [99%] rubella). One year post vaccination, the majority of children who initially mounted protective antibodies maintained this protection (34 of 44 [77%] varicella, 45 of 49 [92%] measles, 35 of 42 [83%] mumps, 51 of 54 [94%] rubella). Five children developed clinical varicella, all of which resolved within 1 week. There were no cases of measles or rubella and no episodes of graft rejection within 1 month of vaccination. There was no association between antibody response and immunosuppression level at the time of vaccination., Conclusions and Relevance: The findings suggest that live vaccinations may be safe and immunogenic after solid organ transplant in select pediatric recipients and can offer protection against circulating measles, mumps, and varicella.

The potential impact of human presence on captive animal behavior has recently been the focus of considerable research interest, especially following 2020 and 2021 periods of enforced closure as a result of COVID-19 opening restrictions. It is important to investigate whether human presence represents an enriching or stressful stimulus to a range of zoo-housed species. In 2020, during an easing of lockdown restrictions, investigations of the "visitor effect" and "observer effect" were carried out, using the giant otter (Pteronura brasiliensis) as a model species. To investigate the impact of both visitor and observer presence, otter behavior and space use was recorded for a pair of on-show and a pair of off-show otters. Observations were conducted using either a human observer, or cameras, allowing the researchers to investigate otter behavior when no one was present at the exhibits. The Electivity Index was used to assess the otters' use of four enclosure zones. Overall, otter behavior was significantly impacted by observer presence, though the impact of an observer differed between individual otters. Visitors had a minimal effect on otter enclosure use, whereas observers had a greater impact, whereby otters used their pools less frequently and houses more frequently when observers were present. However, this change in zone use differed between individuals, with more dominant otters tending to make use of indoor zones more often when observers were present. Zoos should consider the potential impact of human presence on their animals and use both behavior and space use when conducting their investigations., (© 2023 Wiley Periodicals LLC.)

Objective To utilise a concept mapping process to identify key opportunities for electronic medical record (EMR) optimisation for allied health professionals (AHPs). Methods A total of 26 participants (allied health managers, clinicians and healthcare consumers) completed the concept mapping process, which included generating statements, and then subsequently sorting all statements into groups, and also ranking each statement for importance and changeability (0 = not important/changeable, 4 extremely important/changeable). Multivariate analysis and multidimensional scaling were then used to identify core priorities for digital optimisation. Results Participants generated 98 discrete statements that were grouped into 13 conceptual clusters. Of these, 36 statements were subsequently determined to fall within the 'green zone' on the Go-Zone plot of importance and changeability (changeability ≥2.44, importance ≥2.79), and formed the set of key optimisation priorities. Clusters with the most items in the Go-Zone plot were 'training and business rules ' and 'service statistics .' Conclusion Concept mapping facilitated identification of 36 key optimisation priorities considered both changeable and important to assist EMR optimisation for AHPs. Addressing these priorities requires action related to end-user skills and training, EMR system capacity, and streamlining of governance and collaboration for the optimisation process.

Background: Bemnifosbuvir, a novel, oral, nonmutagenic, nonteratogenic nucleotide analogue inhibits SARS-CoV-2 replication in vitro ., Materials & Methods: Adults in hospital settings with moderate COVID-19 were randomized 1:1 bemnifosbuvir/placebo. Study amended to two parts after interim analysis; part B enrollment limited owing to evolving standard of care., Results: Although the study ended early and did not meet the primary efficacy end point, bemnifosbuvir was well tolerated and did not contribute to all-cause mortality. Compared with placebo, bemnifosbuvir treatment resulted in 0.61 log 10 greater viral load mean change on day 2; trend sustained through day 8. Treatment-emergent adverse events were similar in both groups; most were mild/moderate, unrelated to study drug., Conclusion: Our results suggest a potential role for bemnifosbuvir in blunting COVID-19 progression., Clinical Trial Registration: NCT04396106 (ClinicalTrials.gov)., Competing Interests: The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (© 2023 The Authors.)

Introduction: Acute severe behavioural disturbance (ASBD) is a condition seen with increasing frequency in emergency departments (EDs) in adults and young people. Despite the increasing number of presentations and significant associated risks to patients, families and caregivers, there is limited evidence to guide the most effective pharmacological management in children and adolescents. The aim of this study is to determine whether a single dose of oral olanzapine is more effective than a dose of oral diazepam at successfully sedating young people with ASBD., Methods and Analysis: This study is a multicentre, open-label, superiority randomised controlled trial. Young people aged between 9 years and 17 years and 364 days presenting to an ED with ASBD who are deemed to require medication for behavioural containment will be recruited to the study. Participants will be randomised in a 1:1 allocation between a single weight-based dose of oral olanzapine and oral diazepam. The primary outcome is the proportion of participants who achieve successful sedation at 1-hour post randomisation without the need for additional sedation. Secondary outcomes will include assessing for adverse events, additional medications provided in the ED, further episodes of ASBD, length of stay in the ED and hospital and satisfaction with management.Effectiveness will be determined using an intention-to-treat analysis, with medication efficacy determined as part of the secondary outcomes using a per-protocol analysis. The primary outcome of successful sedation at 1 hour will be presented as a percentage within each treatment group, with comparisons presented as a risk difference with its 95% CIs., Ethics and Dissemination: Ethics approval was received from the Royal Children's Hospital Human Research Ethics Committee (HREC/66478/RCHM-2020). This incorporated a waiver of informed consent for the study. The findings will be disseminated in a peer-reviewed journal and at academic conferences., Trial Registration Number: ACTRN12621001236886., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Acute severe behavioural disturbance (ASBD) is a condition seen with increasing frequency in emergency departments (EDs) in adults and young people. Despite the increasing number of presentations and significant associated risks to patients, families and caregivers, there is limited evidence to guide the most effective pharmacological management in children and adolescents. The aim of this study is to determine whether a single dose of intramuscular olanzapine is more effective than intramuscular droperidol at successfully sedating young people with ASBD requiring intramuscular sedation., Methods and Analysis: This study is a multicentre, open-label, superiority randomised controlled trial. Young people aged between 9 and 17 years and 364 days presenting to an ED with ASBD who are deemed to require medication for behavioural containment will be recruited to the study. Participants will be randomised in a 1:1 allocation between a single weight-based dose of intramuscular olanzapine and intramuscular droperidol. The primary outcome is the proportion of participants who achieve successful sedation at 1-hour post randomisation without the need for additional sedation. Secondary outcomes will include assessing for adverse events, additional medications provided in the ED, further episodes of ASBD, length of stay in the ED and hospital and satisfaction with management.Effectiveness will be determined using an intention-to-treat analysis, with medication efficacy determined as part of the secondary outcomes using a per-protocol analysis. The primary outcome of successful sedation at 1 hour will be presented as a percentage within each treatment group, with comparisons presented as a risk difference with its 95% CIs., Ethics and Dissemination: Ethics approval was received from the Royal Children's Hospital Human Research Ethics Committee (HREC/69948/RCHM-2021). This incorporated a waiver of informed consent for the study. The findings will be disseminated in a peer-reviewed journal and at academic conferences., Trial Registration Number: ACTRN12621001238864., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The mTOR inhibitor sirolimus is prescribed to treat children with varying diseases, ranging from vascular anomalies to sporadic lymphangioleiomyomatosis to transplantation (solid organ or hematopoietic cell). Precision dosing of sirolimus using therapeutic drug monitoring (TDM) of sirolimus concentrations in whole blood drawn at the trough (before the next dose) time-point is the current standard of care. For sirolimus, trough concentrations are only modestly correlated with the area under the curve, with R 2 values ranging from 0.52 to 0.84. Thus, it should not be surprising, even with the use of sirolimus TDM, that patients treated with sirolimus have variable pharmacokinetics, toxicity, and effectiveness. Model-informed precision dosing (MIPD) will be beneficial and should be implemented. The data do not suggest dried blood spots point-of-care sampling of sirolimus concentrations for precision dosing of sirolimus. Future research on precision dosing of sirolimus should focus on pharmacogenomic and pharmacometabolomic tools to predict sirolimus pharmacokinetics and wearables for point-of-care quantitation and MIPD., 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 © 2023 Shen, Moua, Perkins, Johnson, Li, Curtin, Gao and McCune.)

Reading disability (RD) can manifest itself as a word decoding problem or a reading comprehension problem. In the current study, we identified 3 subtypes of RD: poor decoders (PD), poor comprehenders (PC), and poor-in-both (PB). We found that PD had greater deficits in meta-linguistic skills such as phonological awareness, orthographic skills, and morphological skills than PC, whereas PC had greater deficits in listening comprehension than PD. In the brain, we also found different patterns of deficits during an auditory rhyming judgment task using functional magnetic resonance imaging. PD showed less activation than PC and age controls in the left dorsal inferior frontal gyrus (IFG) and pre-supplementary motor area (SMA), brain activation of which was correlated with phonological awareness and working memory. In contrast, PC showed less activation in the left fusiform gyrus than PD and age controls, which was correlated with reading comprehension fluency and morphological skill. Last, PB showed both PD's and PC's deficits, as well as additional deficits in the bilateral lingual gyri. Our findings contribute to revealing different neural signatures of poor decoding and poor comprehension, which are distinct disorders but co-occur very often. These findings implicate possibility and necessity of precise diagnosis and individualized intervention., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Monkeypox (mpox) cases in the 2022 outbreak have primarily occurred among adult gay, bisexual, and other men who have sex with men (MSM); however, other populations have also been affected (1). To date, data on mpox in cisgender women and pregnant persons have been limited. Understanding transmission in these populations is critical for mpox prevention. In addition, among pregnant persons, Monkeypox virus can be transmitted to the fetus during pregnancy or to the neonate through close contact during or after birth (2-5). Adverse pregnancy outcomes, including spontaneous abortion and stillbirth, have been reported in previous mpox outbreaks (3). During May 11-November 7, 2022, CDC and U.S. jurisdictional health departments identified mpox in 769 cisgender women aged ≥15 years, representing 2.7% of all reported mpox cases. † Among cases with available data, 44% occurred in cisgender women who were non-Hispanic Black or African American (Black), 25% who were non-Hispanic White (White), and 23% who were Hispanic or Latino (Hispanic). Among cisgender women with available data, 73% reported sexual activity or close intimate contact as the likely route of exposure, with mpox lesions most frequently reported on the legs, arms, and genitals. Twenty-three mpox cases were reported in persons who were pregnant or recently pregnant § ; all identified as cisgender women based on the mpox case report form. ¶ Four pregnant persons required hospitalization for mpox. Eleven pregnant persons received tecovirimat, and no adverse reactions were reported. Continued studies on mpox transmission risks in populations less commonly affected during the outbreak, including cisgender women and pregnant persons, are important to assess and understand the impact of mpox on sexual, reproductive, and overall health., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Intra-individual variability of neural response has been found to be negatively associated with cognitive proficiency and automaticity. However, whether developmental dyslexia (DD) is marked by greater intra-individual neural variability remains unclear. Using a multivariate approach and dual-control group design, the current study aims to examine whether the pattern similarity of brain activation during a visual spelling task is abnormal in children with DD compared to age control and reading control children. We found that there was reduced intra-subject pattern similarity at the left occipito-temporal regions in children with DD than both control groups, suggesting a neural signature of DD. Furthermore, we found that pattern similarity was positively associated with stability of reaction time and reading fluency in both children with DD and typical control children, suggesting that neural stability supports behavioral stability and automaticity during reading., 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 © 2022 Elsevier Inc. All rights reserved.)

Over seventy percent of marketed monoclonal antibody therapeutics contain between 0.001% and 0.1% (w/v) polysorbate, as it has a generally beneficial stabilizing effect that increases drug product shelf life. However, polysorbate has also been shown to contribute to particle formation due to auto-oxidation and hydrolysis, 1 which results in free fatty acids and subsequent fatty acid particle formation. Although the impact of fatty acid particles on the safety and efficacy of drug products has not been fully evaluated, it is advantageous to mitigate particle formation due to degradation of polysorbate, improving the consistency of a product's quality attributes (in this case particulate levels) throughout its lifecycle. In this report, we describe a simple experimental assay to rapidly generate fatty acid particles. Further, we show that the presence of human serum albumin (HSA) is sufficient to prevent the formation of fatty acid particles. Separately, we demonstrate that HSA can also rapidly and completely solubilize pre-formed particles. These results point to a highly plausible mechanistic explanation of previous observations and diminishes concern regarding low levels of particles in the final drug product., 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 © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Considering both biological and non-biological polygonal shape organizations, in this paper we introduce a quantitative method which is able to determine informational entropy as spatial differences between heterogeneity of internal areas from simulation and experimental samples. According to these data (i.e., heterogeneity), we are able to establish levels of informational entropy using statistical insights of spatial orders using discrete and continuous values. Given a particular state of entropy, we establish levels of information as a novel approach which can unveil general principles of biological organization. Thirty-five geometric aggregates are tested (biological, non-biological, and polygonal simulations) in order to obtain the theoretical and experimental results of their spatial heterogeneity. Geometrical aggregates (meshes) include a spectrum of organizations ranging from cell meshes to ecological patterns. Experimental results for discrete entropy using a bin width of 0.5 show that a particular range of informational entropy (0.08 to 0.27 bits) is intrinsically associated with low rates of heterogeneity, which indicates a high degree of uncertainty in finding non-homogeneous configurations. In contrast, differential entropy (continuous) results reflect negative entropy within a particular range (-0.4 to -0.9) for all bin widths. We conclude that the differential entropy of geometrical organizations is an important source of neglected information in biological systems.

Objective: To evaluate the field performance of a multiplex PCR (M-PCR) assay for detection of herpes simplex virus (HSV)-1 and HSV-2, Treponema pallidum ( T. pallidum ) and Haemophilus ducreyi ( H. ducreyi ) in genital ulcer disease (GUD) specimens., Methods: GUD M-PCR was performed on 186 remnant specimens, previously collected for HSV testing, by four public health laboratories (PHLs) and the Laboratory Reference and Research Branch (LRRB) at the Centers for Disease Control and Prevention. The results from the PHLs were compared with those of LRRB, which served as the reference testing method, and percentage agreement was calculated., Results: HSV was detected in 31 of 52 (59.6%), 20 of 40 (50%), 43 of 44 (97.7%) and 19 of 50 (38.0%) specimens from PHL1, PHL2, PHL3 and PHL4, respectively. There were seven discrepant results for HSV, and the overall percent agreement between the PHLs and the LRRB was 94%-100%, with a kappa value of 0.922, which demonstrates high agreement. T. pallidum was identified in 7 of 51 (13.7%) specimens from PHL1 with 94.1% agreement and in 2 of 40 (5.0%) specimens from PHL2 with 100% agreement. The LRRB identified three additional T. pallidum -positive specimens from PHL1. The kappa value (0.849) for T. pallidum testing suggests good agreement. Consistent with the LRRB results, no T. pallidum was detected in specimens from PHL3 and PHL4, and H. ducreyi was not detected at any of the study sites., Conclusions: The GUD M-PCR assay performed well in four independent PHLs and 12 suspected syphilis cases were identified in this study. The M-PCR assay could provide improved diagnostic options for GUD infections in state and local PHLs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Izencitinib (TD-1473), an oral, gut-selective pan-Janus kinase (JAK) inhibitor under investigation for treatment of inflammatory bowel diseases, was designed for optimal efficacy in the gastrointestinal tract while minimizing systemic exposures and JAK-related safety findings. The nonclinical safety of izencitinib was evaluated in rat and dog repeat-dose and rat and rabbit reproductive and developmental toxicity studies. Systemic exposures were compared with JAK inhibitory potency to determine effects at or above pharmacologic plasma concentrations (≥1× plasma average plasma concentration [Cave]:JAK 50% inhibitory concentration [IC50] ratio). In rats and dogs, 1000 and 30 mg/kg/day izencitinib, respectively, produced minimal systemic findings (ie, red/white cell changes) and low systemic concentrations (approximately 1× plasma Cave:JAK IC50 ratio) with an 8× nonclinical:clinical systemic area under the curve (AUC) margin compared with exposures at the highest clinically tested dose (300 mg, quaque die, once daily, phase 1 study in healthy volunteers). In dogs, it was possible to attain sufficient systemic exposures to result in immunosuppression characteristic of systemic JAK inhibition, but at high AUC margins (43×) compared with systemic exposures observed at the highest tested dose in humans. No adverse findings were observed in the gastrointestinal tract or systemic tissues. Izencitinib did not affect male or female fertility. Izencitinib did not affect embryonic development in rats and rabbits as commonly reported with systemic JAK inhibition, consistent with low maternal systemic concentrations (2-6× plasma Cave:JAK IC50 ratio, 10-33× nonclinical:clinical AUC margin) and negligible fetal exposures. In conclusion, the izencitinib gut-selective approach resulted in minimal systemic findings in nonclinical species at pharmacologic, clinically relevant systemic exposures, highlighting the impact of organ-selectivity in reducing systemic safety findings., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology.)

Systemic therapies targeting transforming growth factor beta (TGFβ) or TGFβR1 kinase (ALK5) have been plagued by toxicities including cardiac valvulopathy and bone physeal dysplasia in animals, posing a significant challenge for clinical development in pulmonary indications. The current work aims to demonstrate that systemic ALK5-associated toxicities can be mitigated through localized lung delivery. Lung-selective (THRX-144644) and systemically bioavailable (galunisertib) ALK5 inhibitors were compared to determine whether lung selectivity is sufficient to maintain local tissue concentrations while mitigating systemic exposure and consequent pathway-related findings. Both molecules demonstrated potent ALK5 activity in rat precision cut lung slices (PCLS; p-SMAD3 half-maximal inhibitory concentration [IC50], 141 nM and 1070 nM for THRX-144644 and galunisertib, respectively). In 14-day repeat-dose studies in rats, dose-related cardiac valvulopathy was recapitulated with oral galunisertib at doses ≥150 mg/kg/day. In contrast, inhaled nebulized THRX-144644 did not cause similar systemic findings up to the maximally tolerated doses in rats or dogs (10 and 1.5 mg/kg/day, respectively). THRX-144644 lung-to-plasma ratios ranged from 100- to 1200-fold in rats and dogs across dose levels. THRX-144644 lung trough (24 h) concentrations in rats and dogs ranged from 3- to 17-fold above the PCLS IC50 across tolerated doses. At a dose level exceeding tolerability (60 mg/kg/day; 76-fold above PCLS IC50) minimal heart and bone changes were observed when systemic drug concentrations reached pharmacologic levels. In conclusion, the current preclinical work demonstrates that localized pulmonary delivery of an ALK5 inhibitor leads to favorable TGFβ pathway pharmacodynamic inhibition in lung while minimizing key systemic toxicities., (Copyright © 2022 Theravance Biopharma Ireland Limited. Published by Elsevier Inc. All rights reserved.)