Search

Objective: This study aimed to assess whether information from AI chatbots on benefits and harms of breast and prostate cancer screening were concordant with evidence-based cancer screening recommendations., Methods: Seven unique prompts (four breast cancer; three prostate cancer) were presented to ChatGPT in March 2024. A total of 60 criteria (30 breast; 30 prostate) were used to assess the concordance of information. Concordance was scored between 0 and 2 against the United States Preventive Services Task Force (USPSTF) breast and prostate cancer screening recommendations independently by international cancer screening experts., Results: 43 of 60 (71.7 %) criteria were completely concordant, 3 (5 %) were moderately concordant and 14 (23.3 %) were not concordant or not present, with most of the non-concordant criteria (9 of 14, 64.3 %) being from prompts for the oldest age groups. ChatGPT hallucinations (i.e., completely made up, non-sensical or irrelevant information) were found in 9 of 60 criteria (15 %)., Conclusions: ChatGPT provided information mostly concordant with USPSTF breast and prostate cancer screening recommendations, however, important gaps exist. These findings provide insights into the role of AI to communicate cancer screening benefits and harms and hold increased relevance for periods of guideline change., Practice Implications: AI generated information on cancer screening should be taken in conjunction with official screening recommendations and/or information from clinicians., Competing Interests: Declaration of Competing Interest BN and KM are current members of the International Scientific Committee of Preventing Overdiagnosis. CIL receives textbook royalties from UpToDate, Inc., McGraw Hill, Inc., and Oxford University Press; personal fees from the American College of Radiology for journal editorial board work; and research consulting fees from DeepHealth/RadNet for work outside of the submitted work. KM is the company director of Health Literacy Solutions pty, a consultancy that holds the sub-licence to the SHeLL Health Literacy Editor and takes no personal income for this role outside of the submitted work. All other authors declare no conflicts of interest., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Abiotic stresses arising as consequences of climate change pose a serious threat to agricultural productivity on a global scale. Most cultivated crop varieties exhibit susceptibility to such environmental pressures as drought, salinity, and waterlogging. Addressing these abiotic stresses through agronomic means is not only financially burdensome but also often impractical, particularly in the case of abiotic stresses like heat stress. Cultivating resilient varieties that can withstand such pressures emerges as an economically feasible strategy to mitigate these challenges. Nevertheless, the development of stress-tolerant cultivars is hindered by the intricate nature of abiotic stress tolerance, often characterized by low heritability values. Compounding this complexity is the dynamic and multifaceted nature of these stresses, which impede conventional breeding efforts, rendering them painstakingly slow. The identification of molecular markers has emerged as a pivotal advancement in this arena. By pinpointing genomic regions associated with tolerance to abiotic stresses, these markers serve as effective tools for selection and trait introgression. In the post-genomic era, the proliferation of high-density SNP markers has revolutionized breeding strategies. Genomic selection, leveraging these markers, has become the method of choice for addressing polygenic traits with low heritability, such as abiotic stress tolerance. With the functional characterization of many genes being done, precise manipulation through genome editing techniques is gaining significant traction. This review delves into the application of molecular markers in breeding stress-tolerant crop varieties, alongside role of recent genomic techniques in enhancing abiotic stress tolerance. It also explores success stories and identifies potential targets for marker-assisted selection., Competing Interests: Declaration of competing interest 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 © 2024 Elsevier Ltd. All rights reserved.)

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin-blistering disorder that often progresses to metastatic cutaneous squamous cell carcinoma (cSCC) at chronic wound sites. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell-surface proteoglycan that is an oncoantigen in multiple malignancies, where it modulates oncogenic signalling, drives epithelial-to-mesenchymal transition (EMT) and enables cell motility., Objectives: To evaluate CSPG4 expression and function in RDEB cSCC., Methods: RDEB cSCC cell lines were used to assess CSPG4-dependent changes in invasive potential, transforming growth factor (TGF)-β1-stimulated signal activation and clinically relevant cytopathology metrics in an in vitro full-thickness tumour model. CSPG4 expression in RDEB cSCC and non-RDEB cSCC tumours was analysed via immunohistochemistry and single-cell RNA sequencing (scRNA-Seq), respectively., Results: Inhibiting CSPG4 expression reduced invasive potential in multiple RDEB cSCC cell lines and altered membrane-proximal TGF-β signal activation via changes in SMAD3 phosphorylation. CSPG4 expression was uniformly localized to basal layer keratinocytes in fibrotic RDEB skin and tumour cells at the tumour-stroma interface at the invasive front in RDEB cSCC tumours in vivo. Analysis of published scRNA-Seq data revealed that CSPG4 expression was correlated with an enhanced EMT transcriptomic signature in cells at the tumour-stroma interface of non-RDEB cSCC tumours. Cytopathological metrics, for example nucleus : cell area ratio, were influenced by CSPG4 expression in in vitro tumour models., Conclusions: We determined that CSPG4 expression in RDEB cSCC cell lines enhanced the invasive potential of tumours. Mechanistically, CSPG4 was found to enhance membrane-proximal TGF-β-stimulated signalling via SMAD3, which is a key mediator of EMT in RDEB cSCC. The implication of these studies is that CSPG4 may represent a therapeutic target that can be leveraged for the clinical management of patients with RDEB cSCC., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. 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.)

Objectives: Treatment with tumour necrosis factor inhibitors (TNFi) has significantly improved outcomes in uveitis associated with juvenile idiopathic arthritis (JIA-U). This study examines a CARRA Registry cohort of JIA-U patients on TNFi to analyse utilisation patterns and identify factors associated with response., Methods: This retrospective cohort study used CARRA Registry data for subjects aged 0-25 with JIA-U who had uveitis onset before the age of 19, and ever used TNFi. We collected data about demographics, uveitis courses, and treatment. We defined TNFi response and identified associated characteristics. As appropriate, comparisons between factors were tested using t-test, Chi-square, and Fisher's exact test. Multivariable logistic regression was used to model TNFi response., Results: Among 871 JIA-U subjects, 616 (70.7%) used TNFi; 558 met inclusion criteria; 418 (74.9%) had successful treatment under TNFi. Among the 140 (25.1%) TNFi non-responders, 117 remained on TNFi and 23 discontinued. Multivariate analysis found significant TNFi success associations with White race (OR=2.08, p=0.005) and non-oligoarticular JIA (OR=1.58, p=0.044)., Conclusions: In this CARRA Registry cohort of patients with JIA-U, a large proportion used a TNFi for uveitis. The percentage successfully treated with TNFi is consistent with the current literature. White race and non-oligoarticular JIA were associated with a successful response to TNFi.

The ESCRT (Endosomal Sorting Complex Required for Transport) machinery comprising protein complexes ESCRT-0 to ESCRT-III and Vps4 plays a pivotal role in intracellular trafficking, a process of endocytosing cell surface proteins into the cell for various biological activities. The ESCRT protein complexes are sequentially assembled which interact amongst each other to form a functional ESCRT machinery. Deregulation of these events are shown to be involved in various disease development including tumor formation and viral infections. Recently upregulation of a crucial ESCRT protein, Vps28 has been shown to be implicated in tumor formation. However, Vps28 in ESCRT-I interacts with Vps36 in ESCRT-II to function as a connecting protein during ESCRT machinery formation. Until now biomolecular approaches to inhibit the formation/assembly of ESCRT machinery have not been developed. Hence, we hypothesized that disrupting Vps28/Vps36 interaction would prevent assembly of ESCRT machinery and offer therapeutic potential to restrict disease development and progression. To address this, we utilized a virtual screening approach using a flavonoid-based library to identify potential small molecule inhibitors that can bind to Vps28 active site. Based on the binding affinity, top-hit compounds were identified. Molecular dynamics simulations set over a 500 ns timescale demonstrated the stability of the Vps28-small molecule complexes. Per-residue decomposition analysis using Molecular Mechanics/Poisson-Boltzmann surface area highlighted the significant contributions of active site residues Asn189, Arg190, Arg193 and Asn210 in Vps28 for interaction with small molecules. Absorption, Distribution, Metabolism, Excretion, and Toxicity analysis for toxicity evaluation indicates that molecules Z0131, H0194, Z0199 and DQ00112 exhibited physicochemical properties suitable for drug development.

Background and Aims: High-throughput in vitro pharmacological toxicity testing is essential for drug discovery. Precision-cut liver slices (PCLS) provide a robust system for screening that is more representative of the complex 3D structure of the whole liver than isolated hepatocytes. However, PCLS are not available as off-the-shelf products, significantly limiting their translational potential. Cryopreservation could solve this bottleneck by effectively preserving PCLS indefinitely until their time of use. Conventional cryopreservation (slow cooling in DMSO-forming ice) results in poor PCLS viability and function and, therefore, has proven unsuitable. Here, we explore an "ice-free" cryopreservation approach called vitrification and focus on culturing and assessing PCLS for 3 days post-vitrification and rewarming, given that most acute drug toxicity tests are conducted over 24h., Methods: Rat liver slices were diffusively loaded with a cryoprotective agent (CPA) cocktail consisting of EG and Sucrose. The CPA-loaded PCLS were placed on a polymer cryomesh, vitrified in liquid nitrogen (LN2), and rapidly rewarmed in CPA. The vitrified and rewarmed PCLS were subsequently cultured in a controlled volume of serum-free, chemically defined media for 3 days., Results: The cryopreserved PCLS maintained high viability, morphology, function, enzymatic activity, and drug toxicity response. Results show that the vitrified PCLS perform comparably to untreated controls and significantly outperform conventionally cryopreserved PCLS in all assessments ( p < 0.05)., Conclusions: Rapid vitrification and rewarming of PCLS using cryomesh enabled successful preservation and culture. This approach maintained high viability, function, enzymatic activity, and drug response for 3 days in culture, similar to controls., Competing Interests: Conflict of interest J.B., E.F. and M.E. disclose equity in a start-up which is commercializing the cryomesh platform technology and related intellectual property (NorthStar Cryo, Inc.).

Background: The long-term survival of liver transplant (LT) recipients is essential for optimizing organ allocation and estimating mortality outcomes. While models like the Model-for-End-Stage-Liver-Disease (MELD) predict 90-day mortality on the waiting list, they do not predict post-LT survival accurately. There is a need for predictive models that can forecast post-LT survival beyond the immediate period after transplantation., Method: This study introduces new temporal variation features for predicting post-LT survival during the waiting list period. Cox Proportional-Hazards regression (CoxPH), Random Survival Forest (RSF), and Extreme Gradient Boosting (XGB) models are utilized, along with patient demographics and waiting list duration. Data from 716 LT patients from the University of Minnesota CTSI (2011-2021) are used to develop, evaluate, and compare post-LT survival prediction models., Results: The temporal variation features, particularly when combined with the RSF model, proved most effective in predicting post-LT survival, with a C-index of 0.71 and an IBS of 0.151. This outperformed the predictive capability of the most recent MELD score, which had a C-index of <0.51 in the same cohort., Conclusions: Incorporating temporal variation features with the RSF model enhances long-term post-LT survival predictions. These insights can assist clinicians and patients in making more informed decisions about organ allocation and understanding the utility of LT, ultimately leading to improved patient outcomes., Competing Interests: Declaration of competing interest Authors declare no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Assessment of cardiac structure and function improves risk prediction of new-onset atrial fibrillation (AF) in different populations. We aimed to comprehensively compare standard and newer measures of cardiac structure and function in improving prediction of AF in a cohort of older adults without history of AF and stroke., Methods and Results: We included 5050 participants without prevalent AF and stroke (mean age 75 ± 5 years, 59% women, and 22% Black) from the Atherosclerosis Risk in Communities (ARIC) study who underwent complete two-dimensional echocardiography, including speckle-tracking analysis of the left ventricle (LV) and left atrium (LA). We assessed the association of cardiac measures with incident AF (including atrial flutter) and quantified the extent to which these measures improved model discrimination and risk classification of AF compared with the CHARGE-AF score. Over a median follow-up time of 7 years, 676 participants developed AF (incidence rate 2.13 per 100 person-years). LV mass index and wall thickness, E/e', and measures of LA structure and function, but not LV systolic function, were associated with incident AF, after accounting for confounders. Above all, LA reservoir strain, contraction strain, and LA minimal volume index (C-statistics [95% confidence interval]: 0.73 [0.70, 0.75], 0.72 [0.70, 0.75], and 0.72 [0.69, 0.75], respectively) significantly improved the risk discrimination of the CHARGE-AF score (baseline C-statistic: 0.68 [0.65, 0.70]) and achieved the highest category-based net reclassification improvement (29%, 24%, and 20%, respectively)., Conclusion: In a large cohort of older adults without prevalent AF and stroke, measures of LA function improved the prediction of AF more than other conventional cardiac measures., Competing Interests: Conflict of interest: A.M.S. reported funding from the NIH/National Heart, Lung, and Blood Institute (NHLBI), Philips Ultrasound grant to BWH, personal fees from Philips Ultrasound advisory board, grants from Novartis grant to BWH, personal fees from Edwards Life Sciences consultant, and personal fees from Janssen advisory board outside the submitted work. S.D.S. reported funding from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI grant to institution, outside scope of manuscript and personal fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and PureHealth consulting, outside scope of manuscript outside the submitted work. L.Y.C. reported funding from the NIH. No other disclosures were reported., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Anthropogenic activities can significantly impact wildlife in natural water bodies, affecting not only the host's physiology but also its microbiome. This study aimed to analyze the gut microbiome and antimicrobial resistance gene profile (i.e., the resistome) of yellow perch living in lakes subjected to different levels of anthropogenic pressure: wastewater effluent-impacted lakes and undeveloped lakes. Total DNA and RNA from gut content samples were extracted and sequenced for analysis. Results indicate that the gut resistome and microbiome of yellow perch differ between lakes, perhaps due to varying anthropogenic pressure. The resistome was predominated by macrolide resistance genes, particularly the MLS23S group, making up 53 % of resistome sequences from effluent-impacted lakes and 73 % from undeveloped lakes. The colistin resistance gene group ( mcr ) was detected in numerous samples, including variants associated with Aeromonas and the family Enterobacteriaceae . The gut microbiome across all samples was dominated by the phyla Proteobacteria, Firmicutes, and Actinobacteria, with the opportunistic pathogens Plesiomonas shigelloides and Aeromonas veronii more abundant in effluent-impacted lakes. Metagenomic analysis of wild fish samples offers valuable insights into the effects of anthropogenic pressures on microbial communities, including antimicrobial resistance genes, in water bodies., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: I have nothing to declare. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Background: Vascular risk factors seem to contribute to disease progression in Multiple Sclerosis (MS), but the mechanistic connection between vascular risk and MS is unknown. Understanding cerebrovascular hemodynamics (CVH) in MS may help advance our understanding of the link between vascular risk and MS., Objectives: Examine the relationship between CVH [dynamic cerebral autoregulation (dCA) and vasoreactivity (VR)] and brain structure (MRI) and function (cognition, and gait) in individuals with MS., Methods: Transcranial Doppler ultrasound (TCD) was utilized to assess two key markers of CVH: dCA and VR. dCA (reported as phase and gain) is calculated from the spontaneous blood pressure and flow velocity oscillations. VR is calculated as the slope of change in cerebral blood flow velocity in response to end-tidal CO 2 . Global gray matter (GM), white matter (WM), WM hyperintensity (WMH) volumes and WM lesion counts were measured from brain MRI. All participants underwent detailed cognitive and gait assessments., Results: Eighty participants were included (age 44 ± 11, 26 % male); 75 had relapsing-remitting MS (94 %), with disease duration of 8 (11) years [median (IQR)] since MS diagnosis and an Expanded Disability Status Scale (EDSS) of 2.0 (4.0). Higher phase (better dCA) was associated with greater GM volume, lower WHM burden and higher cognitive scores in the memory and global cognitive domains (all P values <0.05). There was no relationship between CVH and gait speed in our study participants. There was no relationship between VR and any measures of brain structure and function., Conclusions: More efficient cerebral autoregulation is associated with better brain structure (larger GM and lower WMH volumes) and function (cognition, but not gait) in patients with MS., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Objective: To develop an ultrasound (US)-guided ventral approach to the brachial plexus (BP) and evaluate nerve anatomy and staining in barred owl cadavers., Study Design: Prospective, cadaveric study., Animals: Eleven adult male and female barred owl cadavers with a body mass of 0.43-0.98 kg., Methods: Eleven frozen cadavers were thawed for 48 hours, weighed and assigned a body condition score. Ten cadavers were placed in dorsal recumbency with wings abducted. US-guided visualization of the BP was achieved by placing a 13-6 MHz linear probe over the ventral aspect of the scapulohumeral joint, parallel to the sternum. A 22 gauge, 50 mm insulated needle was advanced in-plane in a caudal-to-cranial direction. In each owl, injection targeting one BP was performed with 0.4 mL kg -1 of a 1:1 0.5% ropivacaine and 1% methylene blue solution. Dissection was performed 15 minutes postinjection. Nerve staining was deemed successful if ≥ 1 cm of circumferential staining was achieved. The eleventh owl cadaver was injected with a 1:1 solution of 1% methylene blue and 74% ioversol contrast into both wings, and computed tomography (CT) was performed just before and 15 minutes after injection., Results: The BP was clearly identified ultrasonographically in cadavers weighing > 0.5 kg. An injectate volume of 0.4 mL kg -1 provided complete staining of the BP branches in all cadavers. CT scan revealed no contrast within the coelomic cavity., Conclusions and Clinical Relevance: The US-guided BP injection using a ventral approach was easily performed in barred owl cadavers weighing > 0.5 kg. The injection of 0.4 mL kg -1 of a ropivacaine-dye solution resulted in complete staining of the BP branches in all wings, suggesting that this technique could provide analgesia for structures distal to the scapulohumeral joint. Clinical studies are necessary to confirm the safety and efficacy of this technique in barred owls and other bird species., (Published by Elsevier Ltd.)

Outcomes from cholesteatoma surgery are improved by using endoscopes to guide dissection as the wide-angled view facilitates more complete removal of cholesteatoma matrix, reducing the risk of residual disease. Furthermore, surgery can often be completed transcanal, reducing postoperative morbidity. The decision to complete cholesteatoma removal endoscopically transcanal is made from a combination of preoperative imaging and intraoperative findings. A one-handed approach to operating is required as the other hand is used to optimize endoscope positioning. Aspects of technique and instrumentation particular to endoscopic cholesteatoma surgery are presented., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cryptococcal meningitis is a fungal infection that is typically caused by Cryptococcus neoformans and most commonly seen in severely immunosuppressed patient. This disease causes severe neurologic disease due to elevated intracranial pressures. In this case report, we describe a patient with newly diagnosed HIV presenting to the hospital with cryptococcal meningitis complicated by sudden vision loss. We highlight the role of prompt diagnosis and treatment in the reversal of vision loss, with subsequent monitoring using a handheld, non-mydriatic fundus imaging device., Competing Interests: No potential conflicts of interest to report., (© 2024 The Authors.)

Background: Magnesium administration is a common practice in cardiovascular surgeries utilizing cardiopulmonary bypass (CPB). However, concerns persist regarding the risk of hypermagnesemia, particularly in patients with kidney dysfunction. This study aims to determine the incidence of postoperative hypermagnesemia in CPB-assisted cardiovascular surgeries and identify the associated risk factors., Methods: This was a retrospective cohort study conducted at a tertiary medical center. Data from adult patients undergoing open-heart surgery utilizing CPB between 2018 and 2020 were analyzed. Sociodemographic, perioperative, and clinical variables were collected from electronic medical records. Logistic regression was utilized to identify independent risk factors for hypermagnesemia., Results: Of 278 patients analyzed, 53.2% developed postoperative hypermagnesemia (Mg ≥2.5 mg/dL). Mild hypermagnesemia (Mg 2.5-3.9 mg/dL) was most common, with no significant impact on clinical outcomes observed. Patients with hypermagnesemia were older, with higher comorbidity burdens and lower baseline estimated glomerular filtration rate (eGFR). Cardioplegic solutions with higher magnesium content and lower baseline eGFR were independently associated with hypermagnesemia (OR 64.3; 95% CI 12.9-501.1 and OR 1.3; 95% CI, 1.1-1.5 respectively). Notably, ultrafiltration on CPB was associated with low risk of hypermagnesemia (OR 0.4, 95% CI 0.1-1.0, P value 0.048)., Conclusions: This study highlights the importance of mindful magnesium supplementation strategies in those with advanced kidney disease. Future large-scale prospective multicenter studies should validate these findings and explore the extended effects of hypermagnesemia on clinical outcomes in patients with advanced CKD undergoing CPB surgeries., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

The endogenous opioid system regulates pain through local release of neuropeptides and modulation of their action on opioid receptors. However, the effect of opioid peptides, the enkephalins, is short-lived due to their rapid hydrolysis by enkephalin-degrading enzymes. In turn, an innovative approach to the management of pain would be to increase the local concentration and prolong the stability of enkephalins by preventing their inactivation by neural enkephalinases such as puromycin-sensitive aminopeptidase (PSA). Our previous structure-activity relationship studies offered the S-diphenylmethyl cysteinyl derivative of puromycin (20) as a nanomolar inhibitor of PSA. This chemical class, however, suffered from undesirable metabolism to nephrotoxic puromycin aminonucleoside (PAN). To prevent such toxicity, we designed and synthesized 5'-chloro substituted derivatives. The compounds retained the PSA inhibitory potency of the corresponding 5'-hydroxy analogs and had improved selectivity toward PSA. In vivo treatment with the lead compound 19 caused significantly reduced pain response in antinociception assays, alone and in combination with Met-enkephalin. The analgesic effect was reversed by the opioid antagonist naloxone, suggesting the involvement of opioid receptors. Further, PSA inhibition by compound 19 in brain slices caused local increase in endogenous enkephalin levels, corroborating our rationale. Pharmacokinetic assessment of compound 19 showed desirable plasma stability and identified the cysteinyl sulfur as the principal site of metabolic liability. We gained additional insight into inhibitor-PSA interactions by molecular modeling, which underscored the importance of bulky aromatic amino acid in puromycin scaffold. The results of this study strongly support our rationale for the development of PSA inhibitors for effective pain management., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Robert Vince, Swati S. More, and Rohit Singh have a patent pending to the University of Minnesota. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Background: Almost all acquired severe aplastic anaemia is immune mediated and characterised by hypocellular bone marrow and ≥2 affected haematopoietic lineages. The optimal preparartive regimen for unrelated donor transplantation remains to be established. We aimed to study long-term outcomes after unrelated donor transplantation for severe aplastic anaemia with de-escalation of cyclophosphamide (Cy) dose in steps of 50 mg/kg (150, 100, 50, 0 mg/kg) in combination with total body irradiation (TBI) 2 Gy, anti-thymocyte globulin (ATG) and fludarabine., Methods: Ninety-six patients with severe aplastic anaemia aged ≤65 years with adequate organ function enrolled on a trial of human leukocyte antigen (HLA)-matched or 1 HLA-locus mismatched unrelated donor marrow transplantation conducted between 02/2006 and 12/2013 in the United States (NCT00326417). Exclusion criteria were Karnofsky performance status of less than 60, clonal cytogenetic abnormalities and inherited marrow failure syndormes. The primary outcome was day-100 engraftment (achievement of absolute neutrophil recovery to at least 0.5 × 10 9 /L without subsequent decline) and day-100 survival. The trial determined the lowest effective Cy dose as 50 mg/kg (n = 38) for day-100 engraftment and survival. Cy dose 100 mg/kg (n = 41) was also acceptable. Accrual to Cy doses 150 mg/kg (n = 15) and 0 mg/kg (n = 3) was terminated early for toxicities. The current study is an extended follow up of patients enrolled on the trial (NCT00326477) and includes 76 of 96 patients alive ≥1 year after transplantation. There were 20 deaths in the first year after transplantation (Cy 0 mg/kg [n = 2], Cy 50 mg/kg [n = 1], Cy 100 mg/kg [n = 10], Cy 150 mg/kg [n = 7]). Patients were followed prospectively from transplantation and data reported using standardized data collection forms until death, loss to follow up or last contact through November 2023. The incidence of graft failure was calculated using the cumulative incidence estimator and the probability of survival using the Kaplan-Meier estimator., Findings: The median follow up of the cohort is 8.02 (IQR) 5.16-10.12) years. With Cy 50 mg/kg, there was one graft failure and five deaths ≥1 year after transplantation. With Cy 100 mg/kg there was only one late death and no graft failure. The 8-year probabilities of survival were 85.0% (95% CI 67.3-93.5) and 75.6% (95% CI 59.4-86.1) after Cy 50 mg/kg and 100 mg/kg, respectively, P = 0.31. With Cy 0 mg/kg and 150 mg/kg, there were no graft failures or death ≥1 year after transplantation. Regardless of Cy dose 12 of 15 patients aged ≥50 years died., Interpretation: Cy 50 mg/kg or 100 mg/kg with TBI 2 Gy, ATG and fludarabine are effective conditioning regimens for unrelated donor marrow transplants for aplastic anaemia. Identification of an optimized transplantation approach for patients aged ≥50 years is needed., Funding: US National Institutes of Health., Competing Interests: MAP: Consulting fees from Pfizer, Cargo, Noavartis, Bluebird Bio, Vertex, Medexus, Equillium. Honoraria serving as DSMB member (Autlolos). SDR: Serves on the Community Advisory Board (SIRPant Immunotherapeutics) and stock options (SIRPant Immunotherapeutics). Other authors declare no competing interest., (© 2024 The Author(s).)

Partial trisomy of the long arm of chromosome 17 (17q) is a rare but clinically recognized syndrome that involves facial dysmorphisms, skeletal abnormalities, and global developmental delay, as well as various reports of cardiovascular, renal, and central nervous system abnormalities. This report presents a novel neuroradiologic finding of diffuse enlarged, tortuous cortical veins with physiological antegrade flow in a child with a microduplication of the distal end of 17q. To our knowledge, this finding has not been described previously. Although the exact cause for the cortical vascular anomaly is currently unknown, this duplicated region contains genes of interest for future studies that focus on normal and abnormal angiogenesis.

Background: Major barriers to addressing SARS-CoV-2 vaccine hesitancy include limited knowledge of what causes delay/refusal of SARS-CoV-2 vaccination and limited ability to predict who will remain unvaccinated over significant time periods despite vaccine availability. The present study begins to address these barriers by developing a machine learning model that prospectively predicts who will persist in not vaccinating against SARS-CoV-2., Method: Unvaccinated individuals (n = 325) who completed a baseline survey were followed over the six-month period when vaccines against SARS-CoV-2 were first widely available (April-October 2021). A random forest model was used to predict who would remain unvaccinated against SARS-CoV-2 from their baseline measures, including demographic information (e.g., age), medical history (e.g., of influenza vaccination), Health-Belief Model constructs (e.g., perceived vaccine dangerousness), conspiracist ideation, and task-based metrics of vulnerability to conspiracist ideation (e.g., tendency toward illusory pattern perception)., Results: The resulting model significantly predicted vaccination status (AUC-PR = 0.77, 95%CI [0.56 0.90]). At the optimal probability threshold determined by the Generalized Threshold Shifting Protocol, the model was moderately precise (0.83) when identifying individuals who remained unvaccinated (n = 80), and had a very low rate (0.04) of false-positives (incorrectly suggesting that individuals remained unvaccinated). Permutational importance tests suggested that baseline SARS-CoV-2 vaccine intentions conveyed the most information about future SARS-CoV-2 vaccination status. Conspiracist ideation was the second most informative predictor, suggesting that misinformation influences vaccination behavior. Other important predictors included perceived vaccine dangerousness, as expected under the Health Belief Model, and influenza vaccination history., Conclusions: The model we developed can accurately and prospectively identify individuals who remain unvaccinated against SARS-CoV-2. It could therefore facilitate empirically-informed allocation of interventions that encourage vaccine uptake. The predictive value of conspiracist ideation, perceived vaccine dangerousness, and vaccine intentions in our model is consistent with potential causal relations between these variables and SARS-CoV-2 vaccine uptake., 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., (Published by Elsevier Ltd.)

Circulating tumor DNA assays are promising tools for the prediction of cancer treatment response. Here, we build a framework for the design of ctDNA biomarkers of therapy response that incorporate variations in ctDNA dynamics driven by specific treatment mechanisms. We develop mathematical models of ctDNA kinetics driven by tumor response to several therapy classes, and utilize them to simulate randomized virtual patient cohorts to test candidate biomarkers. Using this approach, we propose specific biomarkers, based on ctDNA longitudinal features, for targeted therapy, chemotherapy and radiation therapy. We evaluate and demonstrate the efficacy of these biomarkers in predicting treatment response within a randomized virtual patient cohort dataset. These biomarkers are based on novel proposals for ctDNA sampling protocols, consisting of frequent sampling within a compact time window surrounding therapy initiation - which we hypothesize to hold valuable prognostic information on longer-term treatment response. This study highlights a need for tailoring ctDNA sampling protocols and interpretation methodology to specific biological mechanisms of therapy response, and it provides a novel modeling and simulation framework for doing so. In addition, it highlights the potential of ctDNA assays for making early, rapid predictions of treatment response within the first days or weeks of treatment, and generates hypotheses for further clinical testing.

TP53 mutational status in myeloid neoplasms is prognostic and in acute myeloid leukaemia (AML) may lead to alternative induction therapy; therefore, rapid assessment is necessary for precision treatment. Assessment of multiple prognostic genes by next generation sequencing in AML is standard of care, but the turn-around time often cannot support rapid clinical decision making. Studies in haematological neoplasms suggest p53 immunohistochemistry (IHC) correlates with TP53 mutational status, but they have used variable criteria to define TP53 overexpression. p53 IHC was performed and interpreted on AZF-fixed, acid decalcified bone marrow biopsies on 47 cases of clonal myeloid neoplasms with TP53 mutations between 2016 and 2019 and 16 control samples. Results were scored by manual and digital analysis. Most TP53-mutated cases (81%) overexpressed p53 by digital analysis and manual analysis gave similar results. Among the nine TP53-mutated IHC-negative cases, seven (78%) were truncating mutations and two (22%) were single-hit missense mutations. Using a digital cut-off of at least 3% ≥1+ positive nuclei, the sensitivity and specificity are 81% and 100%; cases with loss-of-function mutations were more likely to be negative. In this cohort, p53 immunopositivity correlated with TP53 mutational status, especially missense mutations, with excellent specificity. Truncating TP53 mutations explain most IHC-negative cases, impacting the sensitivity. We demonstrate that p53 IHC can screen for TP53 mutations allowing quicker treatment decisions for most patients. However, not all patients will be identified, so molecular studies are required. Furthermore, cut-offs for positivity vary in the literature, consequently laboratories should independently validate their processes before adopting p53 IHC for clinical use. p53 IHC performs well to screen for TP53 mutations in AZF-fixed bone marrow. Performance in our setting differs from the literature, which shows variability of pre-analytic factors and cut-offs used to screen for TP53 mutations. Each laboratory should validate p53 IHC to screen for TP53 mutations in their unique setting., (Copyright © 2024 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Background: Social cognition training (SCT) can improve social cognition deficits in schizophrenia. However, little is known about patterns of response to SCT or individual characteristics that predict response., Methods: 76 adults with schizophrenia randomized to receive 8-12 weeks of remotely-delivered SCT were included in this analysis. Social cognition was measured with a composite of six assessments. Latent class growth analyses identified trajectories of social cognitive response to SCT. Random forest and logistic regression models were trained to predict membership in the trajectory group that showed improvement from baseline measures including symptoms, functioning, motivation, and cognition., Results: Five trajectory groups were identified: Group 1 (29 %) began with slightly above average social cognition, and this ability significantly improved with SCT. Group 2 (9 %) had baseline social cognition approximately one standard deviation above the sample mean and did not improve with training. Groups 3 (18 %) and 4 (36 %) began with average to slightly below-average social cognition and showed non-significant trends toward improvement. Group 5 (8 %) began with social cognition approximately one standard deviation below the sample mean, and experienced significant deterioration in social cognition. The random forest model had the best performance, predicting Group 1 membership with an area under the curve of 0.73 (SD 0.24; 95 % CI [0.51-0.87])., Conclusions: Findings suggest that there are distinct patterns of response to SCT in schizophrenia and that those with slightly above average social cognition at baseline may be most likely to experience gains. Results may inform future research seeking to individualize SCT treatment for schizophrenia., Competing Interests: Declaration of competing interest Hyunku Lee, PhD is a paid employee of Posit Science, the company which holds rights for the computerized SocialVille training, which is described in the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with older age, inflammation and with risk of coronary artery disease (CAD). We aimed to characterize the burden of CHIP, and to explore the association between CHIP, inflammatory markers, and CAD in older persons with HIV (PWH)., Methods: From the Copenhagen Comorbidity in HIV Infection (COCOMO) study, we included 190 individuals older than 55 years of age. We defined CHIP as variant allele fraction at least 2%. CAD was categorized according to the most severe coronary artery lesion on coronary computed tomography (CT) angiography as no coronary atherosclerosis; any atherosclerosis defined as at least 1% stenosis and obstructive CAD defined as at least 50% stenosis., Results: In the entire population (median age 66 years, 87% men), we identified a total of 62 mutations distributed among 49 (26%) participants. The three most mutated genes were DNMT3A , TET2 , and ASXL1 , accounting for 49, 25, and 16% of mutations, respectively. Age and sex were the only variables associated with CHIP. IL-1β, IL-1Ra, IL-2, IL-6, IL-10, soluble CD14, soluble CD163 and TNF-α were not associated with CHIP, and CHIP was not associated with any atherosclerosis or with obstructive CAD in adjusted analyses., Conclusion: In older, well treated, Scandinavian PWH, more than one in four had at least one CHIP mutation. We did not find evidence of an association between CHIP and inflammatory markers or between CHIP and CAD. CHIP is an unlikely underlying mechanism to explain the association between inflammation and CAD in treated HIV disease., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for NAFLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using NAFLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of NAFLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for NAFLD., Approach & Results: We used the UK Biobank to explore the associations of our novel NAFLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study NAFLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of NAFLD., Conclusions: Complementary genetic and genomic approaches are useful for the identification of NAFLD genes. Our data supports VKORC1 as a bona fide NAFLD gene. We have established a functional genomic framework to study at scale putative novel NAFLD genes from human genetic association studies.

Many recent studies have demonstrated that environmental contexts, both social and physical, have an important impact on child and adolescent neural and behavioral development. The adoption of geospatial methods, such as in the Adolescent Brain Cognitive Development (ABCD) Study, has facilitated the exploration of many environmental contexts surrounding participants' residential locations without creating additional burdens for research participants (i.e., youth and families) in neuroscience studies. However, as the number of linked databases increases, developing a framework that considers the various domains related to child and adolescent environments external to their home becomes crucial. Such a framework needs to identify structural contextual factors that may yield inequalities in children's built and natural environments; these differences may, in turn, result in downstream negative effects on children from historically minoritized groups. In this paper, we develop such a framework - which we describe as the "adolescent neural urbanome" - and use it to categorize newly geocoded information incorporated into the ABCD Study by the Linked External Data (LED) Environment & Policy Working Group. We also highlight important relationships between the linked measures and describe possible applications of the Adolescent Neural Urbanome. Finally, we provide a number of recommendations and considerations regarding the responsible use and communication of these data, highlighting the potential harm to historically minoritized groups through their misuse., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Telerehabilitation, or the delivery of rehabilitation services through telehealth platforms, has existed since the late 1990 s. Telerehabilitation was characterized by unprecedented, exponential growth at the beginning of the novel coronavirus-2019 (COVID-19) pandemic. Medical systems sought to reduce the likelihood of disease transmission by using telerehabilitation to limit physical proximity during routine care. This dramatic change in how medical care was delivered forced many professions to adapt processes and practices. Following the change, debates sparked regarding the best path to move forward for the betterment of patients, clinicians, systems, and society. Long COVID has emerged as a complex chronic health condition arising from COVID-19. The unique needs and dynamic disease process of Long COVID has incentivized medical systems to create equitable ways for patients to safely access interdisciplinary care., Objectives: The purpose of this commentary is to describe what medical systems must consider when deploying high-quality telerehabilitation to deliver rehabilitation through asynchronous (e.g., text, portal) and synchronous modalities (e.g., phone or video). We highlight lessons learned to help guide decision-makers on key actions to support their patients and clinicians., Methods: Not applicable., Results: Not applicable., Conclusions: Key action steps from our lessons learned may be used to address complex chronic health conditions such as Long COVID and prepare for future challenges that may disrupt medical systems.

In small series, third-party fecal microbiota transplantation (FMT) has been successful in decolonizing the gut from clinically relevant antibiotic resistance genes (ARGs). Less is known about the short- and long-term effects of FMT on larger panels of ARGs. We analyzed 226 pre- and post-treatment stool samples from a randomized placebo-controlled trial of FMT in 100 patients undergoing allogeneic hematopoietic cell transplantation or receiving anti-leukemia induction chemotherapy for 47 ARGs. These patients have heavy antibiotic exposure and a high incidence of colonization with multidrug-resistant organisms. Samples from each patient spanned a period of up to 9 months, allowing us to describe both short- and long-term effects of FMT on ARGs, while the randomized design allowed us to distinguish between spontaneous changes vs. FMT effect. We find an overall bimodal pattern. In the first phase (days to weeks after FMT), low-level transfer of ARGs largely associated with commensal healthy donor microbiota occurs. This phase is followed by long-term resistance to new ARGs as stable communities with colonization resistance are formed after FMT. The clinical implications of these findings are likely context-dependent and require further research. In the setting of cancer and intensive therapy, long-term ARG decolonization could translate into fewer downstream infections.

Interpretation biases and inflexibility (i.e., difficulties revising interpretations) have been linked to increased internalizing symptoms. Although adolescence is a developmental period characterized by novel social situations and increased vulnerability to internalizing disorders, no studies have examined interpretation inflexibility in adolescents. Additionally, no studies (on adolescents or adults) have examined interpretation flexibility as a protective factor against adverse outcomes of interpersonal events. Using a novel task and a 28-day diary we examined relations among interpretation bias and inflexibility, internalizing symptoms, and negative interpersonal events in a sample of children and adolescents ( N = 159, ages 9-18). At baseline, negative interpretation bias was positively correlated with social anxiety symptoms, and positive interpretation bias negatively correlated with social anxiety and depressive symptoms. Inflexible positive interpretations were correlated with higher social anxiety and depressive symptoms, while inflexible negative interpretations were correlated with higher social anxiety. Finally, interpretation inflexibility moderated daily associations between negative interpersonal events and depressive symptoms in daily life, such that higher inflexibility was associated with stronger associations between interpersonal events and subsequent depressive symptoms, potentially increasing depressive symptom instability. These results suggest that interpretation biases and inflexibility may act as both risk and protective factors for adolescent anxiety and depression.

Background: Severe mucopolysaccharidosis type I, (MPS IH) is a rare inherited lysosomal disorder resulting in progressive storage of proteoglycans (GAGs) in central nervous system and somatic tissues and, if left untreated, causing death within the first decade of life. Hematopoietic cell transplantation (HCT) arrests many of the features of MPS IH but carries a 10-15% risk of mortality. Decreased cardiac function can occur in MPS IH and increase the risk of HCT., Methods: Retrospective chart review was performed to determine the long-term outcome of individuals evaluated for HCT with MPS IH who had decreased cardiac function as measured by cardiac echocardiogram (echo) and ejection fraction (EF) of <50% at the time of initial evaluation., Results: Six patients ranging in age from 1 week to 21 months (median: 4 months) had EFs ranging from 25 to 47% (median: 32%) at diagnosis and were initiated on enzyme replacement therapy (ERT) with improvement in EF in three patients by 5 months. The remaining three patients continued to have EFs <50% and continuous milrinone infusion was added in the pre-HCT period. On average, milrinone infusion was able to be discontinued post-HCT, prior to hospital discharge, within a mean of 37 days. Five patients survived HCT and are alive today with normal EFs. One patient receiving milrinone died of sepsis during HCT with a normal EF., Conclusion: Decreased cardiac systolic function in infants with MPS IH that fails to normalize with ERT alone may benefit from the addition of continuous milrinone infusion during HCT., Competing Interests: Declaration of Competing Interest The authors have no relevant conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Transcranial alternating current stimulation (tACS) is a widely used noninvasive brain stimulation (NIBS) technique to affect neural activity. TACS experiments have been coupled with computational simulations to predict the electromagnetic fields within the brain. However, existing simulations are focused on the magnitude of the field. As the possibility of inducing the phase gradient in the brain using multiple tACS electrodes arises, a simulation framework is necessary to investigate and predict the phase gradient of electric fields during multi-channel tACS., Objective: Here, we develop such a framework for phasor simulation using phasor algebra and evaluate its accuracy using in vivo recordings in monkeys., Methods: We extract the phase and amplitude of electric fields from intracranial recordings in two monkeys during multi-channel tACS and compare them to those calculated by phasor analysis using finite element models., Results: Our findings demonstrate that simulated phases correspond well to measured phases (r = 0.9). Further, we systematically evaluated the impact of accurate electrode placement on modeling and data agreement. Finally, our framework can predict the amplitude distribution in measurements given calibrated tissues' conductivity., Conclusions: Our validated general framework for simulating multi-phase, multi-electrode tACS provides a streamlined tool for principled planning of multi-channel tACS experiments., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background and Objectives: Pompe disease (PD) results from a deficiency of lysosomal acid α-glucosidase that leads to glycogen accumulation in lysosomes in multiple tissues. There are two phenotypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The objective was to evaluate the diagnostic and follow-up outcomes of children identified with PD through newborn screening (NBS) in the state of Minnesota over a 4-year period., Methods: This study is a retrospective analysis of infants born in Minnesota between August 1, 2017, and July 31, 2021, by the Minnesota Department of Health NBS Program for Pompe disease. Newborn screening and clinical diagnostic data are summarized for all newborns with positive newborn screens for Pompe disease., Results: Children with IOPD had abnormal biomarkers necessitating immediate initiation of treatment. Children with LOPD are asymptomatic to date (1.25-4.58 years) with normal biomarkers including creatine kinase, urine glucotetrasaccharides, liver function tests, and echocardiogram. The estimated birth prevalence of PD is 1:15,160. The positive predictive value for PD was 81% with a false positive rate of 1.9 per 10 positive screens. 32% of the children with LOPD were lost to follow up among which 66% were from minority ethnic groups., Conclusion: This emphasizes the disparity in access to health care among specific demographics, as well as the importance of a primary care provider's early involvement in educating these families. To accomplish this, and ensure equality in follow-up care, the Minnesota Pompe Disease Consortium has been formed., Competing Interests: Declaration of Competing Interest The authors have no relevant conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Temporal interference stimulation (TIS) is a neuromodulation technique that could stimulate deep brain regions by inducing interfering electrical signals based on high-frequency electrical stimulations of multiple electrode pairs from outside the brain. Despite numerous TIS studies, however, there has been limited investigation into the neurochemical effects of TIS., Objective: We performed two experiments to investigate the effect of TIS on the medial forebrain bundle (MFB)-evoked phasic dopamine (DA) response., Methods: In the first experiment, we applied TIS next to a carbon fiber microelectrode (CFM) to examine the modulation of the MFB-evoked phasic DA response in the striatum (STr). Beat frequencies and intensities of TIS were 0, 2, 6, 10, 20, 60, 130 Hz and 0, 100, 200, 300, 400, 500 μA. In the second experiment, we examined the effect of TIS with a 2 Hz beat frequency (based on the first experiment) on MFB-evoked phasic DA release when applied above the cortex (with a simulation-based stimulation site targeting the striatum). We employed 0 Hz and 2 Hz beat frequencies and a control condition without stimulation., Results: In the first experiment, TIS with a beat frequency of 2 Hz and an intensity of 400 μA or greater decreased MFB-evoked phasic DA release by roughly 40%, which continued until the experiment's end. In contrast, TIS at beat frequencies other than 2 Hz and intensities less than 400 μA did not affect MFB-evoked phasic DA release. In the second experiment, TIS with a 2 Hz beat frequency decreased only the MFB-evoked phasic DA response, but the reduction in DA release was not sustained., Conclusions: STr-applied and cortex-applied TIS with delta frequency dampens evoked phasic DA release in the STr. These findings demonstrate that TIS could influence the neurochemical modulation of the brain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background: Accumulating evidence indicates that an early, robust type 1 interferon (IFN) response to SARS-CoV-2 is important in determining COVID-19 outcomes, with an inadequate IFN response associated with disease severity. Our objective was to examine the prophylactic potential of IFN administration to limit viral transmission., Methods: A cluster randomised open label clinical trial was undertaken to determine the effects of pegylated IFNβ-1a administration on SARS-CoV-2 household transmission between December 3rd, 2020 and June 29th, 2021. Index cases were identified from databases of confirmed SARS-CoV-2 individuals in Santiago, Chile. Households were cluster randomised (stratified by household size and age of index cases) to receive 3 doses of 125 μg subcutaneous pegylated IFNβ-1a (172 households, 607 participants), or standard care (169 households, 565 participants). The statistical team was blinded to treatment assignment until the analysis plan was finalised. Analyses were undertaken to determine effects of treatment on viral shedding and viral transmission. Safety analyses included incidence and severity of adverse events in all treatment eligible participants in the standard care arm, or in the treatment arm with at least one dose administered. Clinicaltrials.gov identifier: NCT04552379., Findings: 5154 index cases were assessed for eligibility, 1372 index cases invited to participate, and 341 index cases and their household contacts (n = 831) enrolled. 1172 participants in 341 households underwent randomisation, with 607 assigned to receive IFNβ-1a and 565 to standard care. Based on intention to treat (ITT) and per protocol (PP) analyses for the primary endpoints, IFNβ-1a treatment did not affect duration of viral shedding in index cases (absolute risk reduction = -0.2%, 95% CI = -8.46% to 8.06%) and transmission of SARS-CoV-2 to household contacts (absolute risk reduction = 3.87%, 95% CI = -3.6% to 11.3%). Treatment with IFNβ-1a resulted in significantly more treatment-related adverse events, but no increase in overall adverse events or serious adverse events., Interpretation: Based upon the primary analyses, IFNβ-1a treatment did not affect duration of viral shedding or the probability of SARS-CoV-2 transmission to uninfected contacts within a household., Funding: Biogen PTY Ltd. Supply of interferon as 'Plegridy (peginterferon beta-1a).' The study was substantially funded by BHP Holdings Pty Ltd., Competing Interests: Authors Castro-Rodriguez, Kollman, and Stick received funding from BHP Holdings Pty Ltd and Biogen Pty Ltd to conduct this study. Balshaw was paid consulting fees to advise on this study. Castro-Rodriguez received honoraria from AstraZeneca and GlaxoSmithKline to speak at symposia and Eurofarma for participation on advisory board. Kollmann has received research funding from NIH, Medical Research Future Fund, and Bill and Melinda Gates Foundation, honoraria from the Human Immunome Project to attend a conference, and holds two patents unrelated to this study. Montgomery received funding from NHMRC and TSANZ to present findings from this study at conferences. Authors Aniba, Borzutzky, Chen, Fish, Garcia-Huidobro, Gigi-Yunge, Hancock, Hartnell, Ho, Iturriaga, Karpievitch, Othman, Perret, Shannon, Tebbutt, and Urzua have no declared conflicts of interest., (© 2023 The Author(s).)