Phthalate and phthalate replacement concentrations in relationship to adiposity in a multi-racial cohort of children.

BACKGROUND/OBJECTIVE: Phthalates and phthalate replacements are used in multiple everyday products, making many of them bioavailable to children. Experimental studies suggest that phthalates and their replacements may be obesogenic, however, epidemiologic studies remain inconsistent. Therefore, our objective was to examine the association between phthalates, phthalate replacements and childhood adiposity/obesity markers in children. SUBJECTS/METHODS: A cross-sectional study was conducted in 630 racial/ethnically diverse children ages 4-8 years. Urinary oxidative metabolites of DINCH and DEHTP, three low molecular weight (LMW) phthalates, and eleven high molecular weight (HMW) phthalates were measured. Weight, height, waist circumference and % body fat were measured. Composite molar sum groups (nmol/ml) were natural log-transformed. Linear regression models adjusted for urine specific gravity, sex, age, race-ethnicity, birthweight, breastfeeding, reported activity level, mother's education and pre-pregnancy BMI. RESULTS: All children had LMW and HMW phthalate metabolites and 88% had DINCH levels above the limit of detection. One unit higher in the log of DINCH was associated with 0.106 units lower BMI z-score [ß = -0.106 (95% CI: -0.181, -0.031)], 0.119 units lower waist circumference z-score [ß = -0.119 (95% CI: -0.189, -0.050)], and 0.012 units lower percent body fat [ß = -0.012 (95% CI: -0.019, -0.005)]. LMW and HMW group values were not associated with adiposity/obesity. CONCLUSIONS: We report an inverse association between child urinary DINCH levels, a non-phthalate plasticizer that has replaced DEHP in several applications, and BMI z-score, waist circumference z-score and % body fat in children. Few prior studies of phthalates and their replacements in children have been conducted in diverse populations. Moreover, DINCH has not received a great deal of attention or regulation, but it is a common exposure. In summary, understanding the ubiquitous nature of these chemical exposures and ultimately their sources will contribute to our understanding of their relationship with obesity.

Online corrections can occur within movement imagery: An investigation of the motor-cognitive model.

The motor-cognitive model proposes that movement imagery additionally requires conscious monitoring owing to an absence of veridical online sensory feedback. Therefore, it is predicted that there would be a comparatively limited ability for individuals to update or correct movement imagery as they could within execution. To investigate, participants executed and imagined target-directed aiming movements featuring either an unexpected target perturbation (Exp. 1) or removal of visual sensory feedback (Exp. 2). The results of both experiments indicated that the time-course of executed and imagined movements was equally influenced by each of these online visual manipulations. Thus, contrary to some of the tenets of the motor-cognitive model, movement imagery holds the capacity to interpolate online corrections despite the absence of veridical sensory feedback. The further theoretical implications of these findings are discussed.

Aspirin for preeclampsia prevention in low- and middle-income countries: mind the gaps.

Preeclampsia is a syndrome that continues to be a major contributor to maternal and neonatal mortality, especially in low-income countries. Low-dose aspirin reduces the risk of preeclampsia, but the mechanism is still unknown. Risk factors to identify women at risk of preeclampsia are based on clinical characteristics. Women identified as high-risk would benefit from aspirin treatment initiated, preferably at the end of the first trimester. Current efforts have largely focused on developing screening algorithms that incorporate clinical risk factors, maternal biomarkers, and uterine artery Doppler evaluated in the first trimester. However, most studies on preeclampsia are conducted in high-income settings, raising uncertainties about whether the information gained can be totally applied in low-resource settings. In low- and middle-income countries, lack of adequate antenatal care and late commencement of antenatal care visits pose significant challenges for both screening for preeclampsia and initiating aspirin treatment. Furthermore, the preventive effect of first-trimester screening based on algorithms and subsequent aspirin treatment is primarily seen for preterm preeclampsia, and reviews indicate minimal or no impact on reducing the risk of term preeclampsia. The lack of evidence regarding the effectiveness of aspirin in preventing term preeclampsia is a crucial concern, as 75% of women will develop this subtype of the syndrome. Regarding adverse outcomes, low-dose aspirin has been linked to a possible higher risk of postpartum hemorrhage, a condition as deadly as preeclampsia in many low- and middle-income countries. The increased risk of postpartum hemorrhage among women in low-income settings should be taken into consideration when discussing which pregnant women would benefit from the use of aspirin and the ideal aspirin dosage for preventing preeclampsia. In addition, women's adherence to aspirin during pregnancy is crucial for determining its effectiveness and complications, an aspect often overlooked in trials. In this review, we analyze the knowledge gaps that must be addressed to safely increase low-dose aspirin use in low- and middle-income countries, and we propose directions for future research.

Identification and characterisation of functional Kir6.1-containing ATP-sensitive potassium channels in the cardiac ventricular sarcolemmal membrane.

BACKGROUND AND PURPOSE: The canonical Kir6.2/SUR2A ventricular KATP channel is highly ATP-sensitive and remains closed under normal physiological conditions. These channels activate only when prolonged metabolic compromise causes significant ATP depletion and then shortens the action potential to reduce contractile activity. Pharmacological activation of KATP channels is cardioprotective, but physiologically, it is difficult to understand how these channels protect the heart if they only open under extreme metabolic stress. The presence of a second KATP channel population could help explain this. Here, we characterise the biophysical and pharmacological behaviours of a constitutively active Kir6.1-containing KATP channel in ventricular cardiomyocytes. EXPERIMENTAL APPROACH: Patch-clamp recordings from rat ventricular myocytes in combination with well-defined pharmacological modulators was used to characterise these newly identified K+ channels. Action potential recording, calcium (Fluo-4) fluorescence measurements and video edge detection of contractile function were used to assess functional consequences of channel modulation. KEY RESULTS: Our data show a ventricular K+ conductance whose biophysical characteristics and response to pharmacological modulation were consistent with Kir6.1-containing channels. These Kir6.1-containing channels lack the ATP-sensitivity of the canonical channels and are constitutively active. CONCLUSION AND IMPLICATIONS: We conclude there are two functionally distinct populations of ventricular KATP channels: constitutively active Kir6.1-containing channels that play an important role in fine-tuning the action potential and Kir6.2/SUR2A channels that activate with prolonged ischaemia to impart late-stage protection against catastrophic ATP depletion. Further research is required to determine whether Kir6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens.

Atrophic changes in thyroid tumors are strong indicators of underlying DICER1 mutations: a bi-institutional genotype-phenotype correlation study.

Somatic and biallelic DICER1 mutations are reported in subsets of thyroid tumors, supporting the role of this gene in thyroid tumor development. As recent studies have brought attention to macrofollicular patterns, atrophic changes, and papillary structures as being associated with DICER1 mutations, we sought to explore these observations in a bi-institutional cohort. A total of 61 thyroid lesions (54 tumors and 7 cases of thyroid follicular nodular disease; TFND), including 26 DICER1 mutated and 35 DICER1 wildtype controls were subjected to histological re-investigation and clinical follow-up. DICER1-mutated lesions showed a statistically significant association with younger age at surgery (29.2 ± 12.5 versus 51.3 ± 18.8, p = 0.0001), a predominant macrofollicular growth pattern (20/26 mutated cases versus 18/35 wildtype; p = 0.01) and atrophic changes (20/26 mutated cases versus 2/35 wildtype; p = 0.0001). Similar results were obtained when excluding TFND cases. We also present clinical and histological triaging criteria for DICER1 sequencing of thyroid lesions, which led to the identification of DICER1 variants in 16 out of 26 cases (62%) when followed. Among these, 3 out of 12 cases with available data were found to carry a constitutional DICER1 mutation. This observation suggests that the majority of DICER1 mutations are somatic-however implies that sequencing of constitutional tissues could be clinically motivated. We conclude that DICER1 mutations are amassed in younger patients with macrofollicular-patterned tumors and, most strikingly, atrophic changes. Given the rate of constitutional involvement, our findings could be of clinical value, allowing the pathologist to triage cases for genetic testing based on histological findings.

Preeclampsia epidemiology(ies) and pathophysiology(ies).

Preeclampsia/eclampsia was first described 2000 years ago. Concepts guiding diagnosis have changed over time making longitudinal studies challenging. Similarly, concepts of pathophysiology have evolved from eclampsia as a pregnancy seizure disorder to preeclampsia as a hypertensive and renal disorder to our current concept of a preeclampsia as a pregnancy specific, multisystemic inflammatory disorder. Although preeclampsia is pregnancy specific and many pathophysiologic findings begin to resolve with delivery, its impact extends beyond pregnancy. The risk of cardiovascular and neurological disease is increased after pregnancy in women who have had preeclampsia. The disorder is not a disease, but a syndrome and emerging data indicate multiple pathways to the syndrome. It is likely that our failure to have a major impact on prediction and prevention despite a large increase in understanding is due to the existence of multiple subtypes of preeclampsia. This concept should guide future research.

Comprehensive evaluation of cytomorphologic, histologic, and molecular features of DICER1-altered thyroid lesions on FNA: A multipractice experience.

BACKGROUND: DICER1 mutations, though infrequent, are encountered on preoperative molecular testing of indeterminate adult and pediatric thyroid fine-needle aspiration (FNA) specimens. Yet, published cytomorphologic features of DICER1-altered thyroid lesions are limited. Cytomorphological features of DICER1-altered thyroid lesions were examined in a multipractice FNA cohort with clinical, radiological, and histologic data. METHODS: The cohort comprised 18 DICER1-altered thyroid FNAs, with 14 having slides available and eight having corresponding surgical resections. Smears, ThinPrep, and formalin-fixed cell block slides were reviewed and correlated with histology, when available. Clinical and radiologic data were obtained from the medical record. RESULTS: Most DICER1-altered FNAs were classified as atypia of undetermined significance (94.4%). DICER1 mutations occurred in codons 1709 (50%), 1810 (27.8%), and 1813 (22.2%). One patient had an additional DICER1 p.D1822N variant in both of their FNAs. Lesions were often hypoechoic (35.3%) and solid (47.1%) on ultrasound. Notable cytomorphologic features include mixed but prominent microfollicular or crowded component, variable colloid, and insignificant nuclear atypia. On resection (n = 10), histologic diagnoses ranged from benign follicular adenoma and low-risk follicular thyroid carcinoma to high-grade follicular-derived nonanaplastic thyroid carcinoma. Subcapsular infarct-type change was the most common histologic change. There was no evidence of recurrence or metastasis in eight patients on limited follow-up. CONCLUSION: DICER1-altered thyroid lesions occurred frequently in young females and FNAs show RAS-like cytomorphology including crowded, mixed macro-/microfollicular pattern, and bland nuclear features. On resection, DICER1-altered thyroid lesions include benign (50%), low-risk lesions (30%), or high-risk malignancies (20%).

A growth chart of brain function from infancy to adolescence based on EEG.

BACKGROUND: In children, objective, quantitative tools that determine functional neurodevelopment are scarce and rarely scalable for clinical use. Direct recordings of cortical activity using routinely acquired electroencephalography (EEG) offer reliable measures of brain function. METHODS: We developed and validated a measure of functional brain age (FBA) using a residual neural network-based interpretation of the paediatric EEG. In this cross-sectional study, we included 1056 children with typical development ranging in age from 1 month to 18 years. We analysed a 10- to 15-min segment of 18-channel EEG recorded during light sleep (N1 and N2 states). FINDINGS: The FBA had a weighted mean absolute error (wMAE) of 0.85 years (95% CI: 0.69-1.02; n = 1056). A two-channel version of the FBA had a wMAE of 1.51 years (95% CI: 1.30-1.73; n = 1056) and was validated on an independent set of EEG recordings (wMAE = 2.27 years, 95% CI: 1.90-2.65; n = 723). Group-level maturational delays were also detected in a small cohort of children with Trisomy 21 (Cohen's d = 0.36, p = 0.028). INTERPRETATION: A FBA, based on EEG, is an accurate, practical and scalable automated tool to track brain function maturation throughout childhood with accuracy comparable to widely used physical growth charts. FUNDING: This research was supported by the National Health and Medical Research Council, Australia, Helsinki University Diagnostic Center Research Funds, Finnish Academy, Finnish Paediatric Foundation, and Sigrid Juselius Foundation.

Theoretical explanations and the availability of information for learning via combined action observation and motor imagery: a commentary on Eaves et al. (2022).

The recent review by Eaves et al. (Psychological Research/Psychologische Forschung, 2022) outlines the research conducted to-date on combined action-observation and motor imagery (AOMI), and more specifically, its added benefit to learning. Of interest, these findings have been primarily attributed to the dual action simulation hypothesis, whereby AO and MI activate separable representations for action that may be later merged when they are congruent with one another. The present commentary more closely evaluates this explanation. What's more, we offer an alternative information-based argument where the benefit to learning may be served instead by the availability of key information. Along these lines, we speculate on possible future directions including the need for a transfer design.

Factors associated with parental human papillomavirus vaccination intentions among adolescents from socioeconomically advantaged versus deprived households: a nationwide, cross-sectional survey.

Background: In the USA, HPV vaccine coverage is substantially lower among adolescents from high-income households compared to their low-income counterparts. We examined and compared the factors associated with parental HPV vaccination intentions between socioeconomically divergent groups. Methods: Data from unvaccinated and not fully HPV-vaccinated adolescents from the 2017-2021 National Immunization Survey (NIS)-Teen were analyzed. Socioeconomically advantaged vs. deprived groups were identified based on dichotomized income (material capital) and education (social capital). Parental intent to initiate and complete the HPV vaccine series was compared using bivariable analysis and the factors associated with lacking intent were identified. Findings: The 2017-2021 NIS-Teen included a total of 212,643 participants; the final analytical sample consisted of 105,958 adolescents (an estimated 10.3 million adolescents) who were unvaccinated or not fully vaccinated. In the advantaged group, 64.7% of parents of unvaccinated adolescents (equating to 2.4 million US adolescents) had no intention to initiate the HPV vaccine compared to 40.9% of parents in the deprived group (equating to 0.2 million adolescents) (P < 0.0001; S > 13.29). The most frequent reason for lacking intent in the advantaged group was 'safety concerns' (25.5%). In the deprived group, 'lack of knowledge', 'not recommended', and 'not needed' were common reasons (nearly 15% each). Lack of intent to complete the HPV vaccine series was higher in the advantaged group (43.9%; 1.1 million adolescents) compared to the deprived group (25.2%; 0.08 million adolescents) (P < 0.0001; S > 13.29). More than half in the advantaged group (58.4%) and over a third (37.1%) in the deprived group cited 'already up to date' as the main reason for not completing the HPV vaccine series. Interpretation: Lack of intent to initiate and complete the HPV vaccination series, particularly among socioeconomically advantaged parents is a significant barrier to achieving the national goal in the USA. Funding: The US National Institute on Minority Health and Health Disparities, the National Center for Advancing Translational Sciences, MUSC Hollings Cancer Center Seed funding, and the US National Cancer Institutes.

The type 1 submovement conundrum: an investigation into the function of velocity zero-crossings within two-component aiming movements.

In rapid manual aiming, traditional wisdom would have it that two components manifest from feedback-based processes, where error accumulated within the primary submovement can be corrected within the secondary submovement courtesy of online sensory feedback. In some aiming contexts, there are more type 1 submovements (overshooting) compared to types 2 and 3 submovements (undershooting), particularly for more rapid movements. These particular submovements have also been attributed to a mechanical artefact involving movement termination and stabilisation. Hence, the goal of our study was to more closely examine the function of type 1 submovements by revisiting some of our previous datasets. We categorised these submovements according to whether the secondary submovement moved the limb closer (functional), or not (non-functional), to the target. Overall, there were both functional and non-functional submovements with a significantly higher proportion for the former. The displacement at the primary and secondary submovements, and negative velocity peak were significantly greater in the functional compared to non-functional. The influence of submovement type on other movement characteristics, including movement time, was somewhat less clear. These findings indicate that the majority of type 1 submovements are related to intended feedforward- and/or feedback-based processes, although there are a portion that can be attributed an indirect manifestation of a mechanical artefact. As a result, we suggest that submovements should be further categorised by their error-reducing function.

Study protocol for clinical trial of the FIT Families multicomponent obesity intervention for African American adolescents and their caregivers: Next step from the ORBIT initiative.

INTRODUCTION: This study will test the effectiveness of FIT Families (FIT), a multicomponent family-based behavioural intervention, against a credible attention control condition, Home-Based Family Support (HBFS). This protocol paper describes the design of a randomised clinical trial testing the efficacy of the FIT intervention. The protocol will assess the efficacy of FIT to improve health status in African American adolescents with obesity (AAAO) and their primary caregivers on primary (percent body fat) and secondary (physical activity, metabolic control, weight loss) outcomes and its cost-effectiveness. METHODS: 180 youth/caregiver dyads are randomised into FIT or HBFS, stratified by age, gender and baseline per cent overweight. The proposed study follows a two condition (FIT, HBFS) by four assessment time points. Tests will be conducted to identify potential relationship of baseline demographic and clinical variables to our dependent variables and see whether they are balanced between groups. It is hypothesised that youth/caregiver dyads randomised to FIT will show significantly greater reductions in percent body fat over a 12-month follow-up period compared with AAAO receiving HBFS. Preliminary findings are expected by November 2023. ETHICS: This protocol received IRB approval from the Medical University of South Carolina (Pro00106021; see 'MUSC IRB 106021 Main Approval.doxc' in online supplemental materials). DISSEMINATION: Dissemination activities will include summary documents designed for distribution to the broader medical community/family audience and submission of manuscripts, based on study results, to relevant peer-reviewed scientific high-impact journals. TRIAL REGISTRATION NUMBER: NCT04974554.

Consumption of Health-Related Videos and Human Papillomavirus Awareness: Cross-Sectional Analyses of a US National Survey and YouTube From the Urban-Rural Context.

BACKGROUND: Nearly 70% of Americans use the internet as their first source of information for health-related questions. Contemporary data on the consumption of web-based videos containing health information among American adults by urbanity or rurality is currently unavailable, and its link with health topic awareness, particularly for human papillomavirus (HPV), is not known. OBJECTIVE: We aim to describe trends and patterns in the consumption of health-related videos on social media from an urban-rural context, examine the association between exposure to health-related videos on social media and awareness of health topics (ie, HPV and HPV vaccine), and understand public interest in HPV-related video content through search terms and engagement analytics. METHODS: We conducted a cross-sectional analysis of the US Health Information National Trends Survey 6, a nationally representative survey that collects data from civilian, noninstitutionalized adults aged 18 years or older residing in the United States. Bivariable analyses were used to estimate the prevalence of consumption of health-related videos on social media among US adults overall and by urbanity or rurality. Multivariable logistic regression models were used to examine the association between the consumption of health-related videos and HPV awareness among urban and rural adults. To provide additional context on the public's interest in HPV-specific video content, we examined search volumes (quantitative) and related query searches (qualitative) for the terms "HPV" and "HPV vaccine" on YouTube. RESULTS: In 2022, 59.6% of US adults (152.3 million) consumed health-related videos on social media, an increase of nearly 100% from 2017 to 2022. Prevalence increased among adults living in both urban (from 31.4% in 2017 to 59.8% in 2022; P<.001) and rural (from 22.4% in 2017 to 58% in 2022; P<.001) regions. Within the urban and rural groups, consumption of health-related videos on social media was most prevalent among adults aged between 18 and 40 years and college graduates or higher-educated adults. Among both urban and rural groups, adults who consumed health-related videos had a significantly higher probability of being aware of HPV and the HPV vaccine compared with those who did not watch health videos on the internet. The term "HPV" was more frequently searched on YouTube compared with "HPV vaccine." Individuals were most commonly searching for videos that covered content about the HPV vaccine, HPV in males, and side effects of the HPV vaccine. CONCLUSIONS: The consumption of health-related videos on social media in the United States increased dramatically between 2017 and 2022. The rise was prominent among both urban and rural adults. Watching a health-related video on social media was associated with a greater probability of being aware of HPV and the HPV vaccine. Additional research on designing and developing social media strategies is needed to increase public awareness of health topics.

Early EEG-burst sharpness and 2-year disability in extremely preterm infants.

BACKGROUND: Automated computational measures of EEG have the potential for large-scale application. We hypothesised that a predefined measure of early EEG-burst shape (increased burst sharpness) could predict neurodevelopmental impairment (NDI) and mental developmental index (MDI) at 2 years of age over-and-above that of brain ultrasound. METHODS: We carried out a secondary analysis of data from extremely preterm infants collected for an RCT (SafeBoosC-II). Two hours of single-channel cross-brain EEG was used to analyse burst sharpness with an automated algorithm. The co-primary outcomes were moderate-or-severe NDI and MDI. Complete data were available from 58 infants. A predefined statistical analysis was adjusted for GA, sex and no, mild-moderate, and severe brain injury as detected by cranial ultrasound. RESULTS: Nine infants had moderate-or-severe NDI and the mean MDI was 87 ± 17.3 SD. The typical burst sharpness was low (negative values) and varied relatively little (mean -0.81 ± 0.11 SD), but the odds ratio for NDI was increased by 3.8 (p = 0.008) and the MDI was reduced by -3.2 points (p = 0.14) per 0.1 burst sharpness units increase (+1 SD) in the adjusted analysis. CONCLUSION: This study confirms the association between EEG-burst measures in preterm infants and neurodevelopment in childhood. Importantly, this was by a priori defined analysis. IMPACT: A fully automated, computational measure of EEG in the first week of life was predictive of neurodevelopmental impairment at 2 years of age. This confirms many previous studies using expert reading of EEG. Only single-channel EEG data were used, adding to the applicability. EEG was recorded by several different devices thus this measure appears to be robust to differences in electrodes, amplifiers and filters. The likelihood ratio of a positive EEG test, however, was only about 2, suggesting little immediate clinical value.

The Dual Nature of Social Media: Examining the Direction of Causal Flow Between Fear of Missing Out and Social Media Use.

The dual (bidirectional) nature of social media suggests that fear-of-missing-out (FOMO) leads to greater social media use (SMU). In turn, higher levels of SMU lead to heightened FOMO. Ironically, individuals use social media to assuage their FOMO but end up with higher levels of FOMO after being exposed to a wide variety of social opportunities, where they may not have been included. The present research examines the hypothesized bidirectional causal flow between FOMO and SMU. Extant research involving FOMO has been largely correlational. In Study 1, FOMO was manipulated and found to increase reported levels of SMU. Study 2 manipulated SMU, which led to higher levels of FOMO. It appears that, regarding FOMO, social media does exhibit a dual (bidirectional) nature.

Optimization of time series features to estimate brain age in children from electroencephalography.

Functional brain age measures in children, derived from the electroencephalogram (EEG), offer direct and objective measures in assessing neurodevelopmental status. Here we explored the effectiveness of 32 preselected 'handcrafted' EEG features in predicting brain age in children. These features were benchmarked against a large library of highly comparative multivariate time series features (>7000 features). Results showed that age predictors based on handcrafted EEG features consistently outperformed a generic set of time series features. These findings suggest that optimization of brain age estimation in children benefits from careful preselection of EEG features that are related to age and neurodevelopmental trajectory. This approach shows potential for clinical translation in the future.Clinical Relevance-Handcrafted EEG features provide an accurate functional neurodevelopmental biomarker that tracks brain function maturity in children.

Underreported and underrecognized: a comprehensive imaging review of breast injury.

Breast injury is commonly encountered yet it remains significantly underreported. Injury to the breast may arise from either primary mechanisms or secondary or iatrogenic mechanisms. Primary mechanisms of breast injury include blunt force, seat-belt, penetrating, and thermal injury. Secondary or iatrogenic mechanisms of breast injury include breast biopsy or intervention as well as operative intervention and cardiopulmonary resuscitation. The severity of breast injury arising from these mechanisms is broad, ranging from breast contusion to avulsion. Sequelae of breast injury include fat necrosis and Mondor's disease. Radiologists play an integral role in the evaluation and management of breast injury both in the acute and non-acute settings. In the acute setting, radiologists must be able to recognize breast injury arising from primary mechanisms or iatrogenic or secondary mechanisms and to identify rare but potentially life-threatening complications promptly to ensure timely, appropriate management. In the non-acute setting, radiologists must be able to discern the sequalae of breast injury from other processes to prevent potentially unnecessary further evaluation and intervention. Nonetheless, though breast injury is commonly encountered there remain few guidelines and a lack of established recommendations for the evaluation and management of breast injury. We provide a comprehensive multi-modality imaging review of breast injury arising in the acute setting as well as the sequela of breast injury arising in the non-acute setting. Moreover, we provide an overview of the management of breast injury.

Tamoxifen for the treatment of myeloproliferative neoplasms: A Phase II clinical trial and exploratory analysis.

Current therapies for myeloproliferative neoplasms (MPNs) improve symptoms but have limited effect on tumor size. In preclinical studies, tamoxifen restored normal apoptosis in mutated hematopoietic stem/progenitor cells (HSPCs). TAMARIN Phase-II, multicenter, single-arm clinical trial assessed tamoxifen's safety and activity in patients with stable MPNs, no prior thrombotic events and mutated JAK2V617F, CALRins5 or CALRdel52 peripheral blood allele burden ≥20% (EudraCT 2015-005497-38). 38 patients were recruited over 112w and 32 completed 24w-treatment. The study's A'herns success criteria were met as the primary outcome ( ≥ 50% reduction in mutant allele burden at 24w) was observed in 3/38 patients. Secondary outcomes included ≥25% reduction at 24w (5/38), ≥50% reduction at 12w (0/38), thrombotic events (2/38), toxicities, hematological response, proportion of patients in each IWG-MRT response category and ELN response criteria. As exploratory outcomes, baseline analysis of HSPC transcriptome segregates responders and non-responders, suggesting a predictive signature. In responder HSPCs, longitudinal analysis shows high baseline expression of JAK-STAT signaling and oxidative phosphorylation genes, which are downregulated by tamoxifen. We further demonstrate in preclinical studies that in JAK2V617F+ cells, 4-hydroxytamoxifen inhibits mitochondrial complex-I, activates integrated stress response and decreases pathogenic JAK2-signaling. These results warrant further investigation of tamoxifen in MPN, with careful consideration of thrombotic risk.