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A significant proportion of men with prostate cancer will experience biochemical recurrence (BCR), which is characterized by an elevation in prostate-specific antigen (PSA) levels after receiving treatment with curative intent. Imaging plays an important role in the management of patients with BCR. It can help identify sites of recurrence to determine the most appropriate management strategies, ranging from salvage treatment for local recurrences to systemic treatments for those with advanced, distant disease. PET/CT with prostate-specific membrane antigen (PSMA)-radioligands is the most sensitive method for the detection of prostate cancer recurrence, with significantly higher cancer detection rates compared to conventional imaging techniques such as bone scan and computed tomography, even at lower PSA levels. Nevertheless, interpretation of PSMA PET/CT images can be challenging, particularly for the evaluation of local recurrence due to urinary activity that can mimic or mask the presence of cancer. Furthermore, some prostate cancers may not express PSMA and have false negative results. Multiparametric prostate MRI is an excellent method for the evaluation of local recurrence and can overcome some of the limitations of PSMA PET/CT. In this review, we discuss the role of imaging in managing patients with prostate cancer BCR and describe the potential benefits of MRI in the PSMA-radioligand imaging era, emphasizing the assessment of local recurrence., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Tuberculosis (TB) is the leading cause of death from a single infectious agent. The burden is highest in some low- and middle-income countries. One-quarter of the world's population is estimated to have been infected with TB, which is the seedbed for progressing from TB infection to the deadly and contagious disease itself. Although some individuals may clear their infections through innate and acquired immunity, many do not. People living with HIV, TB-exposed household contacts, other individuals recently infected, and immunosuppressed individuals are at especially high risk of progressing to TB disease. There have been major advances in recent years to support the programmatic management of TB infection. New tests of infection, including those that predict progression to TB disease, have become available. Numerous World Health Organization-recommended TB preventive treatment (TPT) regimens are available for all ages and for both drug-susceptible and drug-resistant TB infection. All regimens are generally safe, efficacious, and cost effective and have a low risk of generating resistance. TPT is recommended for pregnant women who are at risk for developing TB, but some regimens are associated with an increased likelihood of poor obstetric and fetal outcomes, and newer regimens have not yet been tested in pregnancy. New formulations of rifapentine-based TPT have been developed, and the cost has been radically reduced. Innovative models of delivery to support the scale up of TPT have been developed. Modeling suggests that scaling up TPT, especially regimens with optimal target product profile characteristics, can contribute substantially to ending the TB epidemic. The global uptake of TPT has increased substantially, especially for people living with HIV. Implementation gaps remain, particularly for children, pregnant women, and other household contacts. Further innovation is required to support the continued scale up of TPT and to contribute to ending the TB epidemic., Competing Interests: Declarations. Funding: GC and VC were supported by Unitaid through the IMPAACT4TB project (2017-20-IMPAACT4TB). GC is supported by an NIH grant UM1AI068636 for the PHOENIx MDR TB trial. REC was supported by Unitaid through the IMPAACT4TB project (2017-20-IMPAACT4TB) and NIH grant P30AI18436. KED is supported by NIH/NIAID K24AI150349. MG, AG, NSA, TR, CJH, SL, JSM, and VM have not received funding. Conflict of interest: VC, MG, AG, NSA, TR, CJM, JSM, VM, and KED have no relevant financial or non-financial interests to disclose. SML is funded by Merck through her institution for C19-related research and declares UpToDate—royalties for a chapter on TB infection in pregnancy. REC’s spouse owns stock in Merck. RC and GC have consulted for Johnson & Johnson. Availability of data and material: No data are available as this was a review. Ethics approval: Not applicable. The manuscript is a review and does not report results of a study that involved human participants, their data, or biological material. Consent for publication: Not applicable. The manuscript does not contain identifiable patient data. Consent for publication: Not applicable. The article does not contain clinical photos of patients or patient data that could be identifiable. Author contributions: VC and GC conceptualized and designed the outline of the paper. All authors (VC, MG, AG, NSA, TR, CJM, SL, JSM, VM, KED, REC, GC) contributed to specific sections of the manuscript and reviewed the paper. All authors read and approved the final version., (© 2024. The Author(s).)

Well-preserved specimens of a new species of arthrodiran placoderm, Groenlandaspis howittensis sp. nov. (Middle Devonian of Victoria, Australia), reveals previously unknown information on the dermal skeleton, body-shape and dentition of the wide-spread genus Groenlandaspis . The new material includes dual pineal plates, extrascapular plates, and cheek bones showing the presence of cutaneous sensory organs. The anterior supragnathal, usually a paired element in arthrodires, is a fused median bone in G. howittensis sp. nov. It is positioned anterior to the occlusion of the mouth between the lower jaw (infragnathals) and upper jaw (posterior supragnathals) bones, indicating a specialised feeding mechanism and broadening the known diversity of placoderm dental morphologies. G. howittensis sp. nov. differs from all other groenlandaspidids by a less pronounced posterior expansion of the nuchal plate; the shape of the posterior dorsolateral plate and the presence of a short accessory canal on the anterior dorsolateral plate. A new phylogenetic analysis positions Groenlandaspididae in a monophyly with the phlyctaeniid families Arctolepidae and Arctaspididae, however, the specific intrarelationships of groenlandaspidids remain poorly resolved., Competing Interests: The authors declare that they have no competing interests., (© 2024 Fitzpatrick et al.)

Competing Interests: We declare no competing interests.

Background: Stereotactic radiosurgery (SRS) is an effective treatment for essential tremor (ET) and Parkinsonian tremor (PT). However, current treatment methods can be time-consuming and expose patients to unnecessary radiation. This study investigates the use of the Varian TrueBeam system with FFF beam modes as a potential solution for these issues., Methods: We recreated and evaluated treatment plans using the Varian TrueBeam and Eclipse Cone Planning system for ten patients previously treated for tremor cessation using a Novalis Tx linear accelerator with Brainlab planning system prescribed a maximum dose of 160 Gy. Analyses included beam-on delivery time, total MU, dose to brain and brainstem tissues, and confirmation of SRS cone accuracy., Results: The TrueBeam cone delivery system is highly accurate. Our results demonstrated a significant reduction in monitor units (MU) and treatment delivery time shortened to 17-26 min beam-on time for all-Varian plans compared to 39 min for non-Varian (iPlan) plans (p < 0.0001). Furthermore, the Varian plans showed improved or similar dose fall-off and radiation dose to brainstem normal tissue., Conclusion: Our findings suggest that the Varian TrueBeam system offers a safe and effective option for SRS tremor treatment, providing similar or superior treatment parameters compared to other LINAC-based SRS treatments. The reduced treatment times and improved patient comfort offered by this system make it a promising solution for future tremor treatments., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: A.N. Kirschner, M.J. Price, G. Luo, and G.X. Ding reports receiving commercial research funds from Varian Medical Systems, Inc. The other authors declare no potential conflicts of interest., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

The microtubule cytoskeleton regulates microglial morphology, motility, and effector functions. The microtubule-severing enzyme, fidgetin-like 2 (FL2), negatively regulates cell motility and nerve regeneration, making it a promising therapeutic target for central nervous system injury. Microglia perform important functions in response to inflammation and injury, but how FL2 affects microglia is unclear. In this study, we investigated the role of FL2 in microglial morphology and injury responses in vitro. We first determined that the pro-inflammatory stimulus, lipopolysaccharide (LPS), induced a dose- and time-dependent reduction in FL2 expression associated with reduced microglial ramification. We then administered nanoparticle-encapuslated FL2 siRNA to knockdown FL2 and assess microglial functions compared to negative control siRNA and vehicle controls. Time-lapse live-cell microscopy showed that FL2 knockdown increased the velocity of microglial motility. After incubation with fluorescently labeled IgG-opsonized beads, FL2 knockdown increased phagocytosis. Microglia were exposed to low-dose LPS after nanoparticle treatment to model injury-induced cytokine secretion. FL2 knockdown enhanced LPS-induced cytokine secretion of IL-1α, IL-1β, and TNFα. These results identify FL2 as a regulator of microglial morphology and suggest that FL2 can be targeted to increase or accelerate microglial injury responses., Competing Interests: Declarations. Ethics Approval and Consent to Participate: All experiments complied fully with the principles set forth in the “Guide for the Care and Use of Laboratory Animals” and were approved by the Uniformed Services University. Consent for Publication: Not applicable. Competing Interests: LB is a senior scientist at MicroCures Inc., and DJS is the Chief Scientific Officer of MicroCures Inc. DJS holds stock in MicroCures, Inc., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The relationship between socioeconomic status and colorectal cancer (CRC) screening in Canada remains poorly understood. This study aims to measure and explain the extent of socioeconomic inequalities in CRC screening participation in Ontario, Canada., Methods: This study assesses socioeconomic inequalities in CRC screening uptake in Ontario among adults aged 50 to 74 years (n=12,039) utilizing cross-sectional data from the 2017-2018 Canadian Community Health Survey (CCHS). The Wagstaff Index (WI) and the Erreygers Index (EI) were used to quantify and decompose income-related inequality in CRC screening participation., Results: The results revealed an overall CRC screening rate of 71.7%, with higher rates among females (78.4%) compared to males (69.4%). The positive values of the WI (0.193; 95% confidence interval [CI]: 0.170 to 0.215) and the EI (0.156; 95% CI: 0.138 to 0.174) indicated a pro-rich inequality in CRC screening participation in Ontario (i.e., screening is more concentrated among wealthier individuals). The decomposition analysis identified income (71.61%), education (8.61%), and language barriers with healthcare providers (5.76%) as the primary factors contributing to the observed income-related inequality in CRC screening participation., Conclusion: Income is the primary driver of socioeconomic inequality, requiring targeted strategies to boost screening rates among low-income residents. Addressing education and language barriers through awareness initiatives and language support can reduce socioeconomic inequalities in cancer screening uptake in Ontario., Impact: Our study reveals significant socioeconomic inequality in colorectal cancer screening in Ontario, driven by income, education, and language barriers, underscoring the need for targeted interventions to promote equitable access.

Breast cancer (BC) is defined by distinct molecular subtypes with different cells of origin. The transcriptional networks that characterize the subtype-specific tumor-normal lineages are not established. In this work, we applied bulk, single-cell and single-nucleus multi-omic techniques as well as spatial transcriptomics and multiplex imaging on 61 samples from 37 patients with BC to show characteristic links in gene expression and chromatin accessibility between BC subtypes and their putative cells of origin. Regulatory network analysis of transcription factors underscored the importance of BHLHE40 in luminal BC and luminal mature cells and KLF5 in basal-like tumors and luminal progenitor cells. Furthermore, we identify key genes defining the basal-like (SOX6 and KCNQ3) and luminal A/B (FAM155A and LRP1B) lineages. Exhausted CTLA4-expressing CD8 +  T cells were enriched in basal-like BC, suggesting an altered means of immune dysfunction. These findings demonstrate analysis of paired transcription and chromatin accessibility at the single-cell level is a powerful tool for investigating cancer lineage and highlight transcriptional networks that define basal and luminal BC lineages., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

To study the spatial interactions among cancer and non-cancer cells 1 , we here examined a cohort of 131 tumour sections from 78 cases across 6 cancer types by Visium spatial transcriptomics (ST). This was combined with 48 matched single-nucleus RNA sequencing samples and 22 matched co-detection by indexing (CODEX) samples. To describe tumour structures and habitats, we defined 'tumour microregions' as spatially distinct cancer cell clusters separated by stromal components. They varied in size and density among cancer types, with the largest microregions observed in metastatic samples. We further grouped microregions with shared genetic alterations into 'spatial subclones'. Thirty five tumour sections exhibited subclonal structures. Spatial subclones with distinct copy number variations and mutations displayed differential oncogenic activities. We identified increased metabolic activity at the centre and increased antigen presentation along the leading edges of microregions. We also observed variable T cell infiltrations within microregions and macrophages predominantly residing at tumour boundaries. We reconstructed 3D tumour structures by co-registering 48 serial ST sections from 16 samples, which provided insights into the spatial organization and heterogeneity of tumours. Additionally, using an unsupervised deep-learning algorithm and integrating ST and CODEX data, we identified both immune hot and cold neighbourhoods and enhanced immune exhaustion markers surrounding the 3D subclones. These findings contribute to the understanding of spatial tumour evolution through interactions with the local microenvironment in 2D and 3D space, providing valuable insights into tumour biology., (© 2024. The Author(s).)

Objective: To evaluate the clinical performance and financial costs of breast-specific gamma imaging (BSGI) as a biopsy-reducing problem-solving strategy in patients with inconclusive diagnostic imaging findings., Methods: A retrospective analysis of all patients for whom BSGI was utilized for inconclusive imaging findings following complete diagnostic mammographic and sonographic evaluation between January 2013 and December 2018 was performed. Positive BSGI findings were correlated and biopsied with either US or stereotactic technique with confirmation by clip location and pathology. After a negative BSGI result, patients were followed for a minimum of 24 months or considered lost to follow-up and excluded (22 patients). Results of further imaging studies, biopsies, and pathology results were analyzed. Net savings of avoided biopsies were calculated based on average Medicare charges., Results: Four hundred and forty female patients from 30 to 95 years (mean 55 years) of age were included in our study. BSGI demonstrated a negative predictive value (NPV) of 98.4% (314/319) and a positive predictive value for biopsy of 35.5% (43/121). The overall sensitivity was 89.6% (43/48), and the specificity was 80.1% (314/392). In total, 78 false positive but only 5 false negative BSGI findings were identified. Six hundred and twenty-one inconclusive imaging findings were analyzed with BSGI and a total of 309 biopsies were avoided. Estimated net financial savings from avoided biopsies were $646 897., Conclusion: In the management of patients with inconclusive imaging findings on mammography or ultrasonography, BSGI is a problem-solving imaging modality with high NPV that helps avoid costs of image-guided biopsies., (© Society of Breast Imaging 2024. 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.)

Background: Tuberculosis (TB) preventive treatment (TPT) is a long-standing recommendation for children exposed to TB but remains poorly implemented. Home-based contact management may increase access and coverage of TPT among children exposed to TB in their households., Methods: Sixty in-depth interviews were conducted with key informants including program managers, TB providers (known as TB focal persons), health extension workers and caregivers whose children had recently engaged with TB prevention services in Oromia, Ethiopia in 2021 to understand the barriers and facilitators to providing home-based TB prevention services for children aged < 15 years. Thematic content analysis was conducted including systematically coding each interview., Results: Home-based services were considered a family-centered intervention, addressing the time and financial constraints of clients. Stakeholders proposed a task-shared intervention between health extension workers and facility-based TB focal persons. They recommended that TB services be integrated into other home-based services, including HIV, nutrition, and vaccination services to reduce workload on the already overstretched health extension workers. Community awareness was considered essential to improve acceptability of home-based services and TPT in general among community members., Conclusions: Decentralization of TPT should be supported by task-sharing initiation and follow up between health extension workers and facility-based TB focal persons and integration of home-based services. Active community engagement through several existing mechanisms can help improve acceptability for both home-based interventions and TPT promotion overall for children., Trial Registration: The results presented here were from formative research related to the CHIP-TB Trial (Identifier NCT04369326) registered on April 30, 2020. This qualitative study was separately registered at NCT04494516 on 27 July 2020., (© 2024. The Author(s).)

Competing Interests: GC and NS-A report a grant from Unitaid to the Aurum Institute for the IMPAACT4TB project.

Competing Interests: Declaration of Competing Interest Phoebe Long Franco and Krista Gregory wrote the Resiliency Training Curriculum described in the manuscript.

Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas., Competing Interests: Declaration of interests T.M.Y. is a co-founder, stockholder, and member of the board of directors of DESTROKE, Inc., an early stage start-up developing mobile technology for automated clinical stroke detection. J.L.J. has received consulting fees from Scorpion Therapeutics and Volastra Therapeutics. L.C.C. is a founder and member of the board of directors of Agios Pharmaceuticals and is a founder of Petra Pharmaceuticals. L.C.C. is an inventor on patents (pending) for Combination Therapy for PI3K-associated Disease or Disorder, and The Identification of Therapeutic Interventions to Improve Response to PI3K Inhibitors for Cancer Treatment. L.C.C. is a co-founder and shareholder in Faeth Therapeutics. P.W. is a statistical consultant for Sema4. M.G.C. receives research support from Merck, Orbus Therapeutics, and NeoimmuneTech Inc, and royalties from UpToDate., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Competing Interests: TSR reports funding from Unitaid for research on the cost-effectiveness of short-course TPT outside of the submitted manuscript. NS-A declares no competing interests.

Diabetic wound healing is uniquely challenging to manage due to chronic inflammation and heightened microbial growth from elevated interstitial glucose. Carbon monoxide (CO), widely acknowledged as a toxic gas, is also known to provide unique therapeutic immune modulating effects. To facilitate delivery of CO, we have designed hyaluronic acid-based CO-gas-entrapping materials (CO-GEMs) for topical and prolonged gas delivery to the wound bed. We demonstrate that CO-GEMs promote the healing response in murine diabetic wound models (full-thickness wounds and pressure ulcers) compared to N 2 -GEMs and untreated controls.

Background: The risk factors for tuberculosis (TB) disease development in children remained understudied, particularly in low-income countries like Ethiopia. The objective of this study was to identify determinants of TB disease development in general and in relation to BCG vaccination in children in central Ethiopia., Methods: We employed a 1:1 age-matched case-control design to compare the characteristics of children who developed TB (cases) with those who did not (controls). Data were collected in healthcare facilities in Addis Ababa city, Adama, and Bishoftu towns between September 25, 2021, and June 24, 2022. Two hundred and fifty-six cases were drawn at random from a list of childhood TB patients entered into SPSS software, and 256 controls were selected sequentially at triage from the same healthcare facilities where the cases were treated. A bivariate conditional logistic regression analysis was performed first to select candidate variables with p-values less than or equal to 0.20 for the multivariable model. Finally, variables with a p-value less than 0.05 for a matched adjusted odds ratio (mORadj) were reported as independent determinants of TB disease development., Results: The mean age of the cases was nine years, while that of the controls was 10 years. Males comprised 126 cases (49.2%) and 119 controls (46.5%), with the remainder being females. Ninety-nine (38.7%) of the cases were not BCG-vaccinated, compared to 58 (22.7%) of the controls. Household TB contact was experienced by 43 (16.8%) of the cases and 10 (3.9%) of the controls. Twenty-two (8.6%) of the cases and six (2.3%) of the controls were exposed to a cigarette smoker in their household. Twenty-two (8.6%) of the cases and three (1.2%) of the controls were positive for HIV. Children who were not vaccinated with BCG at birth or within two weeks of birth had more than twice the odds (mORadj = 2.11, 95% CI = 1.28-3.48) of developing TB compared to those who were. Children who ever lived with a TB-sick family member (mORadj = 4.28, 95% CI = 1.95-9.39), smoking family members (mORadj = 3.15, 95% CI = 1.07-9.27), and HIV-infected children (mORadj = 8.71, 95% CI = 1.96-38.66) also had higher odds of developing TB disease than their counterparts., Conclusions: Being BCG-unvaccinated, having household TB contact, having a smoker in the household, and being HIV-infected were found to be independent determinants of TB disease development among children., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Infants born to mothers with tuberculosis disease are at increased risk of developing tuberculosis disease themselves. We reviewed published studies and guidelines on the management of these infants to inform the development of a consensus practice guideline. We searched MEDLINE, CINAHL, and Cochrane Library from database inception to Dec 1, 2022, for original studies reporting the management and outcome of infants born to mothers with tuberculosis. Of the 521 published papers identified, only three met inclusion criteria and no evidence-based conclusions could be drawn from these studies, given their narrow scope, variable aims, descriptive nature, inconsistent data collection, and high attrition rates. We also assessed a collection of national and international guidelines to inform a consensus practice guideline developed by an international panel of experts from different epidemiological contexts. The 16 guidelines reviewed had consistent features to inform the expert consultation process. Two management algorithms were developed-one for infants born to mothers considered potentially infectious at the time of delivery and another for mothers not considered infectious at the time of delivery-with different guidance for high and low tuberculosis incidence settings. This systematic review and consensus practice guideline should facilitate more consistent clinical management, support the collection of better data, and encourage the development of more studies to improve evidence-based care., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: One of the global key indicators for monitoring the implementation of the World Health Organization's End Tuberculosis (TB) Strategy is the treatment outcome rate., Objective: This study aims to assess the magnitude of unfavorable treatment outcomes and estimate their relationship with baseline undernutrition and sustained undernutrition among children receiving TB treatment in central Ethiopia., Methods: This retrospective cohort study included children treated for drug-susceptible TB between June 2014 and February 2022. The study comprised children aged 16 and younger who were treated in 32 randomly selected healthcare facilities. A log-binomial model was used to compute adjusted risk ratios (aRR) with 95% confidence intervals (CIs)., Results: Of 640 children, 42 (6.6%; 95% CI = 4.8-8.8%) had an unfavorable TB treatment outcomes, with 31 (73.8%; 95% CI = 58.0-86.1%) occurring during the continuation phase of TB treatment. We confirmed that baseline undernutrition (aRR = 2.68; 95% CI = 1.53-4.71), age less than 10 years (aRR = 2.69; 95% CI = 1.56-4.61), HIV infection (aRR = 2.62; 95% CI = 1.50-4.59), and relapsed TB (aRR = 3.19; 95% CI = 1.79-4.71) were independent predictors of unfavorable TB treatment outcomes. When we looked separately at children who had been on TB treatment for two months or more, we found that sustained undernutrition (aRR = 3.76; 95% CI = 1.90-7.43), age below ten years (aRR = 2.60; 95% CI = 1.31-5.15), and HIV infection (aRR = 2.26; 95% CI = 1.11-4.59) remained predictors of unfavorable outcomes, just as they had in the first two months. However, the effect of relapsed TB became insignificant (aRR = 2.81; 95% CI = 0.96-8.22) after the first two months TB treatment., Conclusions: The magnitude of unfavorable TB treatment outcomes among children in central Ethiopia met the World Health Organization's 2025 milestone. Nearly three-quarters of unfavorable TB treatment outcomes occurred during the continuation phase of TB treatment. Baseline undernutrition, sustained undernutrition, younger age, HIV infection, and relapsed TB were found to be independent predictors of unfavorable TB treatment outcomes among children receiving TB treatment in central Ethiopia., 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 Published by Elsevier Ltd.)

Competing Interests: None disclosed.

Objective: Healthcare consumers and providers are increasingly turning to digital solutions, such as curated websites. Knowing who accesses/benefits from these may improve design and development. This study investigated website usage of informal caregivers of people with multiple sclerosis and shifts in outcome plausibly associated with usage., Methods: Secondary analysis of data from a randomized clinical trial of 148 caregivers compared effectiveness of a website + tele-coaching to a website only intervention for caregivers. Groupwise differences in means/proportions were tested using t-tests and chi-square. Modified Poisson regression with a robust variance estimator and ordinal logistic regression tested the relationship between group and likelihood of website log-in. Ordinal logistic regression models examined whether caregiver characteristics were associated with website use. Generalized estimating equations (GEE) with an autoregressive correlation structure modeled the relationship between website usage and outcomes., Results: Females were more likely to access the website than males (60% vs. 43%; p = 0.05). Though not statistically significant, a possible association (POR: .85, 95% CI: .69, 1.03) between caregiver burden and website access emerged; caregivers experiencing highest levels of burden appeared less likely to engage. Usage patterns differed by treatment arm: the website-only group accessed the Caring for yourself topic significantly more (61.67% vs. 38.33%: p = .04) with similar, but insignificant, trends for other topics., Conclusions: Clinicians can be confident referring females with moderate levels of burden to website-based interventions. By contrast, male caregivers and those experiencing high levels of burden may be less likely to access these resources, pointing to the need for alternative interventions., Trial Registration: Clinicaltrials.gov, registration number: NCT0466208., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Michelle Lehman and Dr Tanya Packer are co-founders and shareholders of Think Self-Management Inc., an incorporated company that disseminates evidence-based self-management interventions. The remaining authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

BACKGROUND Myositis is an inflammatory myopathy that can be caused by a variety of drugs, diseases, and toxins. The U.S. military uses chemoprophylaxis with intramuscular penicillin G to prevent group A streptococcal infection. We present a case of penicillin G-induced myositis, a rare cause of drug-induced myositis with limited discussion in the medical literature. CASE REPORT A 25-year-old man with no pertinent medical history presented to the Emergency Department with right hip and leg pain after receiving a single dose of intramuscular penicillin G as part of standard prophylaxis for group A streptococcal infection during basic military training. He reported pain and leg weakness that was exacerbated by physical exertion and weight bearing but had no systemic symptoms, such as fevers or chills. Initial radiographs of the hip were normal; however, subsequent magnetic resonance imaging of the hip revealed intramuscular edema and features consistent with myositis of the right proximal thigh and hip musculature. He was admitted for isolated right gluteal myositis, attributed to his preceding local penicillin injection. He recovered with symptomatic care over the following 2 weeks, with return to baseline function. CONCLUSIONS This case highlights a rare complication of intramuscular penicillin G as a cause of acute isolated myositis. It serves to inform physicians of this rare complication and to recommend the consideration of intramuscular penicillin G as a causative etiology in individuals presenting with myositis and recent penicillin G exposure.

Prior work has demonstrated that a novel programme involving dermatologist-led, team-based education of student athletes (SAs), coaches, and athletic trainers termed Stanford University Network for Sun Protection, Outreach, Research, and Teamwork (SUNSPORT) improved photoprotective behaviours in National Collegiate Athletic Association (NCAA) SAs. Our current study investigated the use of an alternative, video-based form of SUNSPORT at Cal and UCLA. We demonstrate a trend for increasing sunscreen use amongst SAs with a more feasible programme., Competing Interests: None to declare., (© 2023 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The blood-brain barrier (BBB) is a unique and selective feature of the central nervous system's vasculature. BBB dysfunction has been observed as an early sign of Alzheimer's Disease (AD) before the onset of dementia or neurodegeneration. The intricate relationship between the BBB and the pathogenesis of AD, especially in the context of neurovascular coupling and the overlap of pathophysiology in neurodegenerative and cerebrovascular diseases, underscores the urgency to understand the BBB's role more deeply. Preserving or restoring the BBB function emerges as a potentially promising strategy for mitigating the progression and severity of AD. Molecular and genetic changes, such as the isoform ε4 of apolipoprotein E (ApoEε4), a significant genetic risk factor and a promoter of the BBB dysfunction, have been shown to mediate the BBB disruption. Additionally, receptors and transporters like the low-density lipoprotein receptor-related protein 1 (LRP1), P-glycoprotein (P-gp), and the receptor for advanced glycation end products (RAGEs) have been implicated in AD's pathogenesis. In this comprehensive review, we endeavor to shed light on the intricate pathogenic and therapeutic connections between AD and the BBB. We also delve into the latest developments and pioneering strategies targeting the BBB for therapeutic interventions, addressing its potential as a barrier and a carrier. By providing an integrative perspective, we anticipate paving the way for future research and treatments focused on exploiting the BBB's role in AD pathogenesis and therapy.

Objective: To evaluate if access to team-based primary care is related to medication management outcomes for older adults., Methods: We completed two retrospective cohort studies using administrative health data for older adults (66+) in Ontario (n = 428,852) and Québec (n = 310,198) who were rostered with a family physician (FP) between the 2001/02 and 2017/18 fiscal years. We generated matched comparison groups of older adults rostered to an FP practicing in a team-based model, and older adults rostered to an FP in a non-team model. We compared the following outcomes between these groups: any adverse drug reactions (ADRs), any potentially inappropriate prescription (PIP), and polypharmacy. Average treatment effects of access to team-based care were estimated using a difference-in-differences estimator., Results: The risk of an ADR was 22 % higher (RR = 1.22, 95 % CI = 1.18, 1.26) for older adults rostered to a team-based FP in Québec and 6 % lower (RR = 0.943, 95 % CI = 0.907, 0.978) in Ontario. However, absolute risk differences were less than 0.5 %. Differences in the risk of polypharmacy were small in Québec (RR = 1.005, 95 % CI = 1.001, 1.009) and Ontario (RR = 1.004, 95 % CI = 1.001, 1.007) and had absolute risk differences of less than 1 % in both provinces. Effects on PIP were not statistically or clinically significant in adjusted models., Interpretation: We did not find evidence that access to team-based primary care in Ontario or Québec meaningfully improved medication management outcomes for older adults., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors have no conflict of interest to declare. The Quebec component of this work was completed through a traineeship at Institut national d’excellence en santé et services sociaux (INESSS). We thank INESSS for their guidance and support throughout the analytical process. The Ontario component of this study was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health (MOH) and the Ministry of Long-Term Care (MLTC). Parts of this material are based on data and information compiled and provided by the Ontario Ministry of Health and the Canadian Institute for Health Information. The analyses, conclusions, opinions and statements expressed herein are solely those of the authors and do not reflect those of the funding or data sources; no endorsement is intended or should be inferred. We thank IQVIA Solutions Canada Inc. for use of their Drug Information File. Parts of this material are based on data and/or information from the Canadian Drug Product Database and Data Extract, compiled and provided by Health Canada, and used by ICES with the permission of the Minister of Health Canada, 2017. This work was supported by the Canadian Institutes of Health Information (CIHR) (PJT156326)., (© 2023 The Authors.)

Breast cancer is a heterogeneous disease, and treatment is guided by biomarker profiles representing distinct molecular subtypes. Breast cancer arises from the breast ductal epithelium, and experimental data suggests breast cancer subtypes have different cells of origin within that lineage. The precise cells of origin for each subtype and the transcriptional networks that characterize these tumor-normal lineages are not established. In this work, we applied bulk, single-cell (sc), and single-nucleus (sn) multi-omic techniques as well as spatial transcriptomics and multiplex imaging on 61 samples from 37 breast cancer patients to show characteristic links in gene expression and chromatin accessibility between breast cancer subtypes and their putative cells of origin. We applied the PAM50 subtyping algorithm in tandem with bulk RNA-seq and snRNA-seq to reliably subtype even low-purity tumor samples and confirm promoter accessibility using snATAC. Trajectory analysis of chromatin accessibility and differentially accessible motifs clearly connected progenitor populations with breast cancer subtypes supporting the cell of origin for basal-like and luminal A and B tumors. Regulatory network analysis of transcription factors underscored the importance of BHLHE40 in luminal breast cancer and luminal mature cells, and KLF5 in basal-like tumors and luminal progenitor cells. Furthermore, we identify key genes defining the basal-like ( PRKCA , SOX6 , RGS6 , KCNQ3 ) and luminal A/B ( FAM155A , LRP1B ) lineages, with expression in both precursor and cancer cells and further upregulation in tumors. Exhausted CTLA4-expressing CD8+ T cells were enriched in basal-like breast cancer, suggesting altered means of immune dysfunction among breast cancer subtypes. We used spatial transcriptomics and multiplex imaging to provide spatial detail for key markers of benign and malignant cell types and immune cell colocation. These findings demonstrate analysis of paired transcription and chromatin accessibility at the single cell level is a powerful tool for investigating breast cancer lineage development and highlight transcriptional networks that define basal and luminal breast cancer lineages.

The scale-up of rifampicin-based prevention regimens is an essential part of the global leprosy strategy. Daily rifampicin may reduce the effectiveness of the oral contraceptive pill (OCP), but little is known about the effects of rifampicin at the less frequent dosing intervals used for leprosy prophylaxis. As many women of reproductive age rely on OCP for family planning, evaluating the interaction with less-than-daily rifampicin regimens would enhance the scalability and acceptability of leprosy prophylaxis. Using a semi-mechanistic pharmacokinetic model of rifampicin induction, we simulated predicted changes in OCP clearance when coadministered with varying rifampicin dosing schedules. Rifampicin given as a single dose (600 or 1200 mg) or 600 mg every 4 weeks was not predicted to result in a clinically relevant interaction with OCP, defined as a >25% increase in clearance. Simulations of daily rifampicin were predicted to increase OCP clearance within the range of observed changes previously reported in the literature. Therefore, our findings suggest that OCP efficacy will be maintained when coadministered with rifampicin-based leprosy prophylaxis regimens of 600 mg once, 1200 mg once, and 600 mg every 4 weeks. This work provides reassurance to stakeholders that leprosy prophylaxis can be used with OCP without any additional recommendations for contraception prevention., (© 2023 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis 1-4 . Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions., (© 2023. The Author(s).)

Aim: Very preterm (VPT) birth is a known early vulnerability factor, impacting both physical and mental health over the life-span. The additional burden of psychiatric illness in VPT adolescents is likely to adversely affect critical developmental tasks and personal, social and academic/vocational trajectories. Our aim was to examine the magnitude and extent of the risk of psychological burden by determining the prevalence of psychiatric disorders in our prospectively followed-up VPT and full-term (FT) control cohorts, in this period of developmental transition at age 17 years., Methods: Rates of psychiatric disorder in the VPT and FT control cohorts were ascertained at clinical interview of the adolescents and their care giver(s) by an adolescent psychiatrist., Results: VPT birth was associated with a greater risk of generalised anxiety disorder (VPT vs. FT risk ratio (RR) 2.33; 95% confidence interval (CI): 1.16, 4.67, P = 0.02), as well as attentional problems (VPT vs. FT RR 3.46; 95% CI: 1.01, 11.88, P = 0.03). Although care givers of VPT adolescents reported many social and communication difficulties, and observation at clinical interview supported this, our data did not reach clinical threshold for group differences in autistic spectrum disorder. For all other psychiatric disorders, there was no difference between VPT and FT control adolescents., Conclusion: Our longitudinal cohort follow-up study examining the late effects of VPT birth has demonstrated increased rates of clinically significant psychiatric disorder in this period of important developmental transition. Families and health professionals need to be aware of the increased risk so they can monitor for symptoms and seek effective mental health treatments and support., (© 2023 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Objectives: To test if intravesical instillation of both an anti-programmed cell death protein 1 (PD-1) inhibitor and an oncolytic reovirus would demonstrate a greater effect than either treatment alone, as non-muscle-invasive bladder cancer that is refractory to intravesical bacillus Calmette-Guérin can be treated by systemic anti-PD-1 immunotherapy and we previously demonstrated improved overall survival (OS) with six once-weekly instillations of intravesical anti-PD-1 in a murine model., Materials and Methods: Using an orthotopic syngeneic C3H murine model of MBT2 urothelial bladder cancer, groups of 10 mice were compared between no treatment, intravesical anti-PD-1, intravesical oncolytic reovirus, or intravesical reovirus + anti-PD-1. A single intravesical treatment session was given. The primary outcome was OS, and the secondary outcomes included long-term immunity and tumour-immune profile., Results: With a median follow-up of 9 months, all mice that received no treatment died with a median survival of 41 days, while the comparison median OS was not reached for reovirus (hazard ratio [HR] 14.4, 95% confidence interval [CI] 3.9-32.6; P < 0.001), anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001), and reovirus + anti-PD-1 (HR 28.4, 95% CI 7.0-115.9; P < 0.001). Monotherapy with anti-PD-1 or reovirus demonstrated no significant differences in survival (P = 0.067). Mass cytometry showed that reovirus + anti-PD-1 treatment enriched monocytes and decreased myeloid-derived suppressor cells, generating an immuno-responsive tumour microenvironment. Depletion of CD8 + T cells eliminated the survival advantage provided by the intravesical treatment., Conclusions: Treatment of murine orthotopic bladder tumours with a single instillation of intravesical reovirus, anti-PD-1 antibody, or the combination confers superior survival compared to controls. Tumour-immune microenvironment differences indicated myeloid-derived suppressor cells and CD8 + T cells mediate the treatment response., (© 2023 BJU International.)

Background: Each year, 1 million children develop TB resulting in over 200,000 child deaths. TB preventive treatment (TPT) is highly effective in preventing TB but remains poorly implemented for household child contacts. Home-based child contact management and TPT services may improve access to care. In this study, we aim to evaluate the effectiveness and cost-effectiveness of home-based contact management with TPT initiation in two TB high-burden African countries, Ethiopia and South Africa., Methods: This pragmatic cluster randomized trial compares home-based versus facility-based care delivery models for contact management. Thirty-six clinics with decentralized TB services (18 in Ethiopia and 18 in South Africa) were randomized in a 1:1 ratio to conduct either home-based or facility-based contact management. The study will attempt to enroll all eligible close child contacts of infectious drug-sensitive TB index patients diagnosed and treated for TB by one of the study clinics. Child TB contact management, including contact tracing, child evaluation, and TPT initiation and follow-up, will take place in the child's home for the intervention arm and at the clinic for the control arm. The primary outcome is the cluster-level ratio of the number of household child contacts less than 15 years of age in Ethiopia and less than 5 years of age in South Africa initiated on TPT per index patient, comparing the intervention to the control arm. Secondary outcomes include child contact identification and the TB prevention continuum of care. Other implementation outcomes include acceptability, feasibility, fidelity, cost, and cost-effectiveness of the intervention., Discussion: This implementation research trial will determine whether home-based contact management identifies and initiates more household child contacts on TPT than facility-based contact management., Trial Registration: NCT04369326 . Registered on April 30, 2020., (© 2023. The Author(s).)

Background: Childhood tuberculosis (TB) was poorly studied in Ethiopia. This study aimed to describe the epidemiology of childhood TB and identify predictors of death among children on TB treatment., Methods: This is a retrospective cohort study of children aged 16 and younger who were treated for TB between 2014 and 2022. Data were extracted from TB registers of 32 healthcare facilities in central Ethiopia. Phone interview was also conducted to measure variables without a space and not recorded in the registers. Frequency tables and a graph were used to describe the epidemiology of childhood TB. To perform survival analysis, we used a Cox proportional hazards model, which was then challenged with an extended Cox model., Results: We enrolled 640 children with TB, 80 (12.5%) of whom were under the age of two. Five hundred and fifty-seven (87.0%) of the enrolled children had not had known household TB contact. Thirty-six (5.6%) children died while being treated for TB. Nine (25%) of those who died were under the age of two. HIV infection (aHR = 4.2; 95% CI = 1.9-9.3), under nutrition (aHR = 4.2; 95% CI = 2.2-10.48), being under 10 years old (aHR = 4.1; 95% CI = 1.7-9.7), and relapsed TB (aHR = 3.7; 95% CI = 1.1-13.1) were all independent predictors of death. Children who were found to be still undernourished two months after starting TB treatment also had a higher risk of death (aHR = 5.64, 95% CI = 2.42-13.14) than normally nourished children., Conclusions: The majority of children had no known pulmonary TB household contact implying that they contracted TB from the community. The death rate among children on TB treatment was unacceptably high, with children under the age of two being disproportionately impacted. HIV infection, baseline as well as persistent under nutrition, age < 10 years, and relapsed TB all increased the risk of death in children undergoing TB treatment., (© 2023. The Author(s).)

Droplet-based single-cell RNA-seq (scRNA-seq) data are plagued by ambient contaminations caused by nucleic acid material released by dead and dying cells. This material is mixed into the buffer and is co-encapsulated with cells, leading to a lower signal-to-noise ratio. Although there exist computational methods to remove ambient contaminations post-hoc, the reliability of algorithms in generating high-quality data from low-quality sources remains uncertain. Here, we assess data quality before data filtering by a set of quantitative, contamination-based metrics that assess data quality more effectively than standard metrics. Through a series of controlled experiments, we report improvements that can minimize ambient contamination outside of tissue dissociation, via cell fixation, improved cell loading, microfluidic dilution, and nuclei versus cell preparation; many of these parameters are inaccessible on commercial platforms. We provide end-users with insights on factors that can guide their decision-making regarding optimizations that minimize ambient contamination, and metrics to assess data quality., Competing Interests: The authors declare no competing interest., (© 2023 The Author(s).)

The role of intratumor heterogeneity is becoming increasingly apparent in part due to expansion in single cell technologies. Clinically, tumor heterogeneity poses several obstacles to effective cancer therapy dealing with biomarker variability and treatment responses. Matrix stiffening is known to occur during tumor progression and contribute to pathogenesis in several cancer hallmarks, including tumor angiogenesis and metastasis. However, the effects of matrix stiffening on intratumor heterogeneity have not been thoroughly studied. In this study, we applied single-cell RNA sequencing to investigate the differences in the transcriptional landscapes between stiff and compliant MMTV-PyMT mouse mammary tumors. We found similar compositions of cancer and stromal subpopulations in compliant and stiff tumors but differential intercellular communication and a significantly higher concentration of tumor-promoting, M2-like macrophages in the stiffer tumor microenvironments. Interestingly, we found that cancer cells seeded on stiffer substrates recruited more macrophages. Furthermore, elevated matrix stiffness increased Colony Stimulating Factor 1 (CSF-1) expression in breast cancer cells and reduction of CSF-1 expression on stiffer substrates reduced macrophage recruitment. Thus, our results demonstrate that tissue phenotypes were conserved between stiff and compliant tumors but matrix stiffening altered cell-cell interactions which may be responsible for shifting the phenotypic balance of macrophages residing in the tumor microenvironment towards a pro-tumor progression M2 phenotype. STATEMENT OF SIGNIFICANCE: Cells within tumors are highly heterogeneous, posing challenges with treatment and recurrence. While increased tissue stiffness can promote several hallmarks of cancer, its effects on tumor heterogeneity are unclear. We used single-cell RNA sequencing to investigate the differences in the transcriptional landscapes between stiff and compliant MMTV-PyMT mouse mammary tumors. We found similar compositions of cancer and stromal subpopulations in compliant and stiff tumors but differential intercellular communication and a significantly higher concentration of tumor-promoting, M2-like macrophages in the stiffer tumor microenvironments. Using a biomaterial-based platform, we found that cancer cells seeded on stiffer substrates recruited more macrophages, supporting our in vivo findings. Together, our results demonstrate a key role of matrix stiffness in affecting cell-cell communication and macrophage recruitment., 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. Published by Elsevier Ltd.)

Mitochondrial DNA (mtDNA) deletion mutations cause many human diseases and are linked to age-induced mitochondrial dysfunction. Mapping the mutation spectrum and quantifying mtDNA deletion mutation frequency is challenging with next-generation sequencing methods. We hypothesized that long-read sequencing of human mtDNA across the lifespan would detect a broader spectrum of mtDNA rearrangements and provide a more accurate measurement of their frequency. We employed nanopore Cas9-targeted sequencing (nCATS) to map and quantitate mtDNA deletion mutations and develop analyses that are fit-for-purpose. We analyzed total DNA from vastus lateralis muscle in 15 males ranging from 20 to 81 years of age and substantia nigra from three 20-year-old and three 79-year-old men. We found that mtDNA deletion mutations detected by nCATS increased exponentially with age and mapped to a wider region of the mitochondrial genome than previously reported. Using simulated data, we observed that large deletions are often reported as chimeric alignments. To address this, we developed two algorithms for deletion identification which yield consistent deletion mapping and identify both previously reported and novel mtDNA deletion breakpoints. The identified mtDNA deletion frequency measured by nCATS correlates strongly with chronological age and predicts the deletion frequency as measured by digital PCR approaches. In substantia nigra, we observed a similar frequency of age-related mtDNA deletions to those observed in muscle samples, but noted a distinct spectrum of deletion breakpoints. NCATS-mtDNA sequencing allows the identification of mtDNA deletions on a single-molecule level, characterizing the strong relationship between mtDNA deletion frequency and chronological aging., (© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

Stretch-injured microglia display significantly altered morphology, function and inflammatory-associated gene expression when cultured on a synthetic fibronectin substrate. However, the mechanism by which stretch induces these changes is unknown. Integrins, such as α5β1, mediate microglial attachment to fibronectin via the RGD binding peptide; following integrin ligation the integrin-associated signaling enzyme, focal adhesion kinase (FAK), autophosphorylates tyrosine residue 397 and mediates multiple downstream cellular processes. We therefore hypothesize that blocking the RGD binding/integrin pathway with a commercially available RGD peptide will mimic the stretch-induced morphological alterations and functional deficits in microglia. Further, we hypothesize that upregulation of stretch-inhibited downstream integrin signaling will reverse these effects. Using primary rat microglia, we tested the effects of RGD binding peptide and a FAK activator on cellular function and structure and response to stretch-injury. Similar to injured cells, RGD peptide administration significantly decreases media nitric oxide (NO) levels and iNOS expression and induced morphological alterations and migratory deficits. While stretch-injury and RGD peptide administration decreased phosphorylation of the tyrosine 397 residue on FAK, 20 nM of ZINC 40099027, an activator specific to the tyrosine 397 residue, rescued the stretch-induced decrease in FAK phosphorylation and ameliorated the injury-induced decrease in media NO levels, iNOS expression and inflammatory associated gene expression. Additionally, treatment alleviated morphological changes observed after stretch-injury and restored normal migratory behavior to control levels. Taken together, these data suggest that the integrin/FAK pathway partially mediates the stretch-injured phenotype in microglia, and may serve as a pathway to modulate microglial responses., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

BACKGROUND: Each year more than 200,000 pregnant people become sick with TB, but little is known about how to optimize their diagnosis and therapy. Although there is a need for further research in this population, it is important to recognize that much can be done to improve the services they currently receive. METHODS: Following a systematic review of the literature and the input of a global team of health professionals, a series of best practices for the diagnosis, prevention and treatment of TB during pregnancy were developed. RESULTS: Best practices were developed for each of the following areas: 1) screening and diagnosis; 2) reproductive health services and family planning; 3) treatment of drug-susceptible TB; 4) treatment of rifampicin-resistant/multidrug-resistant TB; 5) compassionate infection control practices; 6) feeding considerations; 7) counseling and support; 8) treatment of TB infection/TB preventive therapy; and 9) research considerations. CONCLUSION: Effective strategies for the care of pregnant people across the TB spectrum are readily achievable and will greatly improve the lives and health of this under-served population.

Context: Improving detection of pediatric tuberculosis (TB) is critical to reducing morbidity and mortality among children., Objective: We conducted a systematic review to estimate the number of children needed to screen (NNS) to detect a single case of active TB using different active case finding (ACF) screening approaches and across different settings., Data Sources: We searched 4 databases (PubMed, Embase, Scopus, and the Cochrane Library) for articles published from November 2010 to February 2020., Study Selection: We included studies of TB ACF in children using symptom-based screening, clinical indicators, chest x-ray, and Xpert., Data Extraction: We indirectly estimated the weighted mean NNS for a given modality, location, and population using the inverse of the weighted prevalence. We assessed risk of bias using a modified AXIS tool., Results: We screened 27 221 titles and abstracts, of which we included 31 studies of ACF in children < 15 years old. Symptom-based screening was the most common screening modality (weighted mean NNS: 257 [range, 5-undefined], 19 studies). The weighted mean NNS was lower in both inpatient (216 [18-241]) and outpatient (67 [5-undefined]) settings (107 [5-undefined]) compared with community (1117 [28-5146]) and school settings (464 [118-665]). Risk of bias was low., Limitations: Heterogeneity in the screening modalities and populations make it difficult to draw conclusions., Conclusions: We identified a potential opportunity to increase TB detection by screening children presenting in health care settings. Pediatric TB case finding interventions should incorporate evidence-based interventions and local contextual information in an effort to detect as many children with TB as possible., (Copyright © 2023 by the American Academy of Pediatrics.)

Mandibular arteriovenous malformations (AVMs) are high flow vascular malformations that can cause pain, hypertrophy, deformity, malocclusion, jaw asymmetry, bone destruction, tooth loss, and severe bleeding [1]. Although general principles apply, the rarity of mandibular AVMs limits definitive agreement on the best course of treatment. Current treatment options include embolization, sclerotherapy, surgical resection, or some combination of techniques [2]. [3]. An alternative multidisciplinary technique of embolization with mandibular-sparing resection is presented. This technique aims to mitigate bleeding with effective removal of the AVM, while preserving mandibular form, function, dentition, and occlusion., Competing Interests: Declarations of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Tumor hypoxia drives resistance to many cancer therapies, including radiotherapy and chemotherapy. Methods that increase tumor oxygen pressures, such as hyperbaric oxygen therapy and microbubble infusion, are utilized to improve the responses to current standard-of-care therapies. However, key obstacles remain, in particular delivery of oxygen at the appropriate dose and with optimal pharmacokinetics. Toward overcoming these hurdles, gas-entrapping materials (GeMs) that are capable of tunable oxygen release are formulated. It is shown that injection or implantation of these materials into tumors can mitigate tumor hypoxia by delivering oxygen locally and that these GeMs enhance responsiveness to radiation and chemotherapy in multiple tumor types. This paper also demonstrates, by comparing an oxygen (O 2 )-GeM to a sham GeM, that the former generates an antitumorigenic and immunogenic tumor microenvironment in malignant peripheral nerve sheath tumors. Collectively the results indicate that the use of O 2 -GeMs is promising as an adjunctive strategy for the treatment of solid tumors., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

HTL0041178 ( 1 ), a potent GPR52 agonist with a promising pharmacokinetic profile and exhibiting oral activity in preclinical models, has been identified. This molecule was the outcome of a judicious molecular property-based optimization approach, focusing on balancing potency against metabolic stability, solubility, permeability, and P-gp efflux., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Background: The left and right ventricles of the human heart differ in embryology, shape, thickness, and function. Ventricular dyssynchrony often occurs in cases of heart failure. Our objectives were to assess whether differences in contractile properties exist between the left and right ventricles and to evaluate signs of left/right ventricular mechanical synchrony in isolated healthy and diseased human myocardium., Methods: Myocardial left and right ventricular trabeculae were dissected from nonfailing and end-stage failing human hearts. Baseline contractile force and contraction/relaxation kinetics of the left ventricle were compared to those of the right ventricle in the nonfailing group (n=41) and in the failing group (n=29). Correlation analysis was performed to assess the mechanical synchrony between left and right ventricular myocardium isolated from the same heart, in nonfailing (n=41) and failing hearts (n=29)., Results: The failing right ventricular myocardium showed significantly higher developed force (Fdev; P =0.001; d=0.98), prolonged time to peak ( P <0.001; d=1.14), and higher rate of force development ( P =0.002; d=0.89) and force decline ( P =0.003; d=0.82) compared to corresponding left ventricular myocardium. In healthy myocardium, a strong positive relationship was present between the left and right ventricles in time to peak (r=0.58, P <0.001) and maximal kinetic rate of contraction (r=0.63, P <0.001). These coefficients were much weaker, often nearly absent, in failing myocardium., Conclusions: At the level of isolated cardiac trabeculae, contractile performance, specifically of contractile kinetics, is correlated in the nonfailing myocardium between the left and right ventricles' but this correlation is significantly weaker, or even absent, in end-stage heart failure, suggesting an interventricular mechanical dyssynchrony.

Beta-guanidinopropionic acid (GPA) is a creatine analog suggested as a treatment for hypertension, diabetes, and obesity, which manifest primarily in older adults. A notable side effect of GPA is the induction of mitochondrial DNA deletion mutations. We hypothesized that mtDNA deletions contribute to muscle aging and used the mutation promoting effect of GPA to examine the impact of mtDNA deletions on muscles with differential vulnerability to aging. Rats were treated with GPA for up to 4 months starting at 14 or 30 months of age. We examined quadriceps and adductor longus muscles as the quadriceps exhibits profound age-induced deterioration, while adductor longus is maintained. GPA decreased body and muscle mass and mtDNA copy number while increasing mtDNA deletion frequency. The interactions between age and GPA treatment observed in the quadriceps were not observed in the adductor longus. GPA had negative mitochondrial effects in as little as 4 weeks. GPA treatment exacerbated mtDNA deletions and muscle aging phenotypes in the quadriceps, an age-sensitive muscle, while the adductor longus was spared. GPA has been proposed for use in age-associated diseases, yet the pharmacodynamics of GPA differ with age and include the detrimental induction of mtDNA deletions, a mitochondrial genotoxic stress that is pronounced in muscles that are most vulnerable to aging. Further research is needed to determine if the proposed benefits of GPA on hypertension, diabetes, and obesity outweigh the detrimental mitochondrial and myopathic side effects., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

B cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein-protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate 58 (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and an excellent oral pharmacokinetic profile. Based on its overall favorable preclinical profile, OICR12694 is a highly potent, orally bioavailable candidate for testing BCL6 inhibition in DLBCL and other neoplasms, particularly in combination with other therapies., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)