Quality improvement initiative: improving obstetric triaging practices in a rural maternal hospital in central India.

Triaging of obstetric patients by emergency care providers is paramount. It helps provide appropriate and timely management to prevent further injury and complications. Standardised trauma acuity scales have limited applicability in obstetric triage. Specific obstetric triage index tools improve maternal and neonatal outcomes but remain underused. The aim was to introduce a validity-tested obstetric triage tool to improve the percentage of correctly triaged patients (correctly colour-coded in accordance with triage index tool and attended to within the stipulated time interval mandated by the tool) from the baseline of 49% to more than 90% through a quality improvement (QI) process.A team of nurses, obstetricians and postgraduates did a root cause analysis to identify the possible reasons for incorrect triaging of obstetric patients using process flow mapping and fish bone analysis. Various change ideas were tested through sequential Plan-Do-Study-Act (PDSA) cycles to address issues identified.The interventions included introduction and application of an obstetric triage index tool, training of triage nurses and residents. We implemented these interventions in eight PDSA cycles and observed outcomes by using run charts. A set of process, output and outcome indicators were used to track if changes made were leading to improvement.Proportion of correctly triaged women increased from the baseline of 49% to more than 95% over a period of 8 months from February to September 2020, and the results have been sustained in the last PDSA cycle, and the triage system is still sustained with similar results. The median triage waiting time reduced from the baseline of 40 min to less than 10 min. There was reduction in complications attributable to improper triaging such as preterm delivery, prolonged intensive care unit stay and overall morbidity. It can be thus concluded that a QI approach improved obstetric triaging in a rural maternity hospital in India.

AlphaFold2 structures guide prospective ligand discovery.

AlphaFold2 (AF2) models have had wide impact, but they have had mixed success in retrospective ligand recognition. We prospectively docked large libraries against unrefined AF2 models of the σ2 and 5-HT2A receptors, testing hundreds of new molecules and comparing results to docking against the experimental structures. Hit rates were high and similar for the experimental and the AF2 structures, as were affinities. The success of docking against the AF2 models was achieved despite differences in orthosteric residue conformations versus the experimental structures. Determination of the cryo-electron microscopy structure for one of the more potent 5HT2A ligands from the AF2 docking revealed residue accommodations that resembled the AF2 prediction. AF2 models may sample conformations that differ from experimental structures but remain low energy and relevant for ligand discovery, extending the domain of structure-based ligand discovery.

Quantum fluctuations lead to glassy electron dynamics in the good metal regime of electron doped KTaO3.

One of the central challenges in condensed matter physics is to comprehend systems that have strong disorder and strong interactions. In the strongly localized regime, their subtle competition leads to glassy electron dynamics which ceases to exist well before the insulator-to-metal transition is approached as a function of doping. Here, we report on the discovery of glassy electron dynamics deep inside the good metal regime of an electron-doped quantum paraelectric system: KTaO3. We reveal that upon excitation of electrons from defect states to the conduction band, the excess injected carriers in the conduction band relax in a stretched exponential manner with a large relaxation time, and the system evinces simple aging phenomena-a telltale sign of glassy dynamics. Most significantly, we observe a critical slowing down of carrier dynamics below 35 K, concomitant with the onset of quantum paraelectricity in the undoped KTaO3. Our combined investigation using second harmonic generation technique, density functional theory and phenomenological modeling demonstrates quantum fluctuation-stabilized soft polar modes as the impetus for the glassy behavior. This study addresses one of the most fundamental questions regarding the potential promotion of glassiness by quantum fluctuations and opens a route for exploring glassy dynamics of electrons in a well-delocalized regime.

Bitter taste receptor activation by cholesterol and an intracellular tastant.

Bitter taste sensing is mediated by type 2 taste receptors (TAS2Rs (also known as T2Rs)), which represent a distinct class of G-protein-coupled receptors1. Among the 26 members of the TAS2Rs, TAS2R14 is highly expressed in extraoral tissues and mediates the responses to more than 100 structurally diverse tastants2-6, although the molecular mechanisms for recognizing diverse chemicals and initiating cellular signalling are still poorly understood. Here we report two cryo-electron microscopy structures for TAS2R14 complexed with Ggust (also known as gustducin) and Gi1. Both structures have an orthosteric binding pocket occupied by endogenous cholesterol as well as an intracellular allosteric site bound by the bitter tastant cmpd28.1, including a direct interaction with the α5 helix of Ggust and Gi1. Computational and biochemical studies validate both ligand interactions. Our functional analysis identified cholesterol as an orthosteric agonist and the bitter tastant cmpd28.1 as a positive allosteric modulator with direct agonist activity at TAS2R14. Moreover, the orthosteric pocket is connected to the allosteric site via an elongated cavity, which has a hydrophobic core rich in aromatic residues. Our findings provide insights into the ligand recognition of bitter taste receptors and suggest activities of TAS2R14 beyond bitter taste perception via intracellular allosteric tastants.

Functionally selective dopamine D1 receptor endocytosis and signaling by catechol and non-catechol agonists.

The dopamine D1 receptor (D1R) has fundamental roles in voluntary movement and memory and is a validated drug target for neurodegenerative and neuropsychiatric disorders. However, previously developed D1R selective agonists possess a catechol moiety which displays poor pharmacokinetic properties. The first selective non-catechol D1R agonists were recently discovered and unexpectedly many of these ligands showed G protein biased signaling. Here, we investigate both catechol and non-catechol D1R agonists to validate potential biased signaling and examine if this impacts agonist-induced D1R endocytosis. We determined that most, but not all, non-catechol agonists display G protein biased signaling at the D1R and have reduced or absent Beta-arrestin recruitment. A notable exception was compound (Cmpd) 19, a non-catechol agonist with full efficacy at both D1R-G protein or D1R Beta-arrestin pathways. In addition, the catechol ligand A-77636 was a highly potent, super agonist for D1R Beta-arrestin activity. When examined for agonist-induced D1R endocytosis, balanced agonists SKF-81297 and Cmpd 19 induced robust D1R endocytosis while the G protein biased agonists did not. The Beta-arrestin super agonist, A-77636, showed significantly increased D1R endocytosis. Moreover, Beta-arrestin recruitment efficacy of tested agonists strongly correlated with total D1R endocytosis. Taken together, these results indicate the degree of D1R signaling functional selectivity profoundly impacts D1R endocytosis regardless of pharmacophore. The range of functional selectivity of these D1R agonists will provide valuable tools to further investigate D1R signaling, trafficking and therapeutic potential.

Implementation of a quality improvement initiative for standardising essential newborn care in a teaching public hospital in rural central India.

OBJECTIVE: Our aim was to refine the essential newborn care practices by employing the multidisciplinary peer team-led quality improvement (QI) projects. DESIGN: In 2017, concerning the same, the department focused on early initiation of breast feeding, prevention of hypothermia within an hour of life and rational usage of antibiotics among babies admitted to neonatal intensive care unit (NICU). Baseline data reported the rate of initiation of breast feeding, hypothermia and antibiotic exposure rate as 35%, 78% and 75%, respectively. Root causes were analysed and a series of Plan-Do-Study-Act cycles were conducted to test the changes. The process of change was studied through run charts (whereas control charts were used for study purpose). RESULT: After the implementation of the QI projects, the rate of initiation of breast feeding was found to be improved from 35% to 90%, the incidence of hypothermia got reduced from 78% to 10% and the antibiotic exposure rate declined from 75% to 20%. Along with the improvement in indicators related to essential newborn care, down the stream we found a decrease in the percentage of culture-positive sepsis rate in the NICU. CONCLUSION: Peer team-led QI initiatives in a resource-limited setting proved beneficial in improving essential newborn care practices.

New Approach to Equitable Intervention Planning to Improve Engagement and Outcomes in a Digital Health Program: Simulation Study.

BACKGROUND: Digital health programs provide individualized support to patients with chronic diseases and their effectiveness is measured by the extent to which patients achieve target individual clinical outcomes and the program's ability to sustain patient engagement. However, patient dropout and inequitable intervention delivery strategies, which may unintentionally penalize certain patient subgroups, represent challenges to maximizing effectiveness. Therefore, methodologies that optimize the balance between success factors (achievement of target clinical outcomes and sustained engagement) equitably would be desirable, particularly when there are resource constraints. OBJECTIVE: Our objectives were to propose a model for digital health program resource management that accounts jointly for the interaction between individual clinical outcomes and patient engagement, ensures equitable allocation as well as allows for capacity planning, and conducts extensive simulations using publicly available data on type 2 diabetes, a chronic disease. METHODS: We propose a restless multiarmed bandit (RMAB) model to plan interventions that jointly optimize long-term engagement and individual clinical outcomes (in this case measured as the achievement of target healthy glucose levels). To mitigate the tendency of RMAB to achieve good aggregate performance by exacerbating disparities between groups, we propose new equitable objectives for RMAB and apply bilevel optimization algorithms to solve them. We formulated a model for the joint evolution of patient engagement and individual clinical outcome trajectory to capture the key dynamics of interest in digital chronic disease management programs. RESULTS: In simulation exercises, our optimized intervention policies lead to up to 10% more patients reaching healthy glucose levels after 12 months, with a 10% reduction in dropout compared to standard-of-care baselines. Further, our new equitable policies reduce the mean absolute difference of engagement and health outcomes across 6 demographic groups by up to 85% compared to the state-of-the-art. CONCLUSIONS: Planning digital health interventions with individual clinical outcome objectives and long-term engagement dynamics as considerations can be both feasible and effective. We propose using an RMAB sequential decision-making framework, which may offer additional capabilities in capacity planning as well. The integration of an equitable RMAB algorithm further enhances the potential for reaching equitable solutions. This approach provides program designers with the flexibility to switch between different priorities and balance trade-offs across various objectives according to their preferences.

Efficacy and safety of Once-Daily Vilanterol/Fluticasone furoate MDI in persistent asthma: Phase 3 OD-INHALE Study.

INTRODUCTION: Once-daily inhalers have been shown to improve adherence leading to lesser discontinuation compared to twice- or thrice-daily inhalers in management of asthma. Combination of Vilanterol and Fluticasone Furoate (VI/FF) is approved for management of asthma and COPD and is available as a dry powder inhaler. Pressurized-Metered Dose Inhalers (pMDIs) offer ease-of-use and therapy alternatives for patients with low inspiratory flow. This study assessed the efficacy and safety of a new once-daily pMDI containing VI/FF in individuals diagnosed with persistent asthma. METHODS: This phase 3, double-blind, randomized controlled study assessed the non-inferiority of VI/FF (12.5 mcg/50 mcg & 12.5 mcg/100 mcg; 2 puffs once-daily) over Formoterol Fumarate and Fluticasone Propionate (FOR/FP, 6 mcg/125 mcg & 6 mcg/250 mcg; 2 puffs twice-daily) in patients with persistent asthma. Primary outcome was change from baseline in trough FEV1 at the end of study (12 weeks). Adverse events and number of exacerbations were used to evaluate safety. RESULTS: A total of 330 patients were randomized into VI/FF (165) and FOR/FP (165). Trough FEV1 significantly improved in both the groups at week 12, with a mean difference (VI/FF minus FOR/FP) being 54.75 mL (95% CI, 8.42-101.08 mL, p = 0.02). The low dose VI/FF had similar efficacy to that of low dose FOR/FP and high dose VI/FF had similar efficacy to high dose FOR/FP. No serious adverse events were reported during the study. CONCLUSION: Once daily VI/FF pMDI was non-inferior to twice daily FOR/FP pMDI in patients with persistent asthma.

Higher order gaps in the renormalized band structure of doubly aligned hBN/bilayer graphene moiré superlattice.

This paper presents our findings on the recursive band gap engineering of chiral fermions in bilayer graphene doubly aligned with hBN. Using two interfering moiré potentials, we generate a supermoiré pattern that renormalizes the electronic bands of the pristine bilayer graphene, resulting in higher order fractal gaps even at very low energies. These Bragg gaps can be mapped using a unique linear combination of periodic areas within the system. To validate our findings, we use electronic transport measurements to identify the position of these gaps as a function of the carrier density. We establish their agreement with the predicted carrier densities and corresponding quantum numbers obtained using the continuum model. Our study provides strong evidence of the quantization of the momentum-space area of quasi-Brillouin zones in a minimally incommensurate lattice. It fills important gaps in the understanding of band structure engineering of Dirac fermions with a doubly periodic superlattice spinor potential.

Impact of heavy alcohol consumption on cortical bone mechanical properties in male rhesus macaques.

Chronic heavy alcohol consumption may influence the skeleton by suppressing intracortical bone remodeling which may impact the quality of bone and its mechanical properties. However, this aspect has not been thoroughly assessed in either humans or animal models whose cortical bone microstructure resembles the microstructure of human cortical bone. The current study is the first to investigate the effects of chronic heavy alcohol consumption on various mechanical properties of bone in a non-human primate model with intracortical remodeling. Male rhesus macaques (5.3 years old at the initiation of treatment) were induced to drink alcohol and then given the choice to voluntarily self-administer water or ethanol (4 % w/v) for approximately 14 months, followed by three abstinence phases (lasting 34, 41, and 39-46 days) with approximately 3 months of ethanol access in between. During the initial 14 months of open-access, monkeys in the alcohol group consumed an average of 2.9 ± 0.8 g/kg/d ethanol (mean ± SD) resulting in a blood ethanol concentration of 89 ± 47 mg/dl in longitudinal samples taken at 7 h after the daily sessions began. To understand the impact of alcohol consumption on material properties, various mechanical tests were conducted on the distal tibia diaphysis of 2-5 monkeys per test group, including dynamic mechanical analysis (DMA) testing, nano-indentation, microhardness testing, compression testing, and fracture resistance curve (R-curve) testing. Additionally, compositional analyses were performed using Fourier-transform infrared (FTIR) spectroscopy. Significant differences in microhardness, compressive stress-strain response, and composition were not observed with alcohol consumption, and only minor differences were detected in hardness and elastic modulus of the matrix and osteons from nanoindentation. Furthermore, the R-curves of both groups overlapped, with similar crack initiation toughness, despite a significant decrease in crack growth toughness (p = 0.032) with alcohol consumption. However, storage modulus (p = 0.029) and loss factor (p = 0.015) from DMA testing were significantly increased in the alcohol group compared to the control group, while loss modulus remained unchanged. These results indicate that heavy alcohol consumption may have only a minor influence on the material properties and the composition of cortical bone in young adult male rhesus macaques.

Controlling Umklapp Scattering in a Bilayer Graphene Moiré Superlattice.

We present experimental findings on electron-electron scattering in two-dimensional moiré heterostructures with a tunable Fermi wave vector, reciprocal lattice vector, and band gap. We achieve this in high-mobility aligned heterostructures of bilayer graphene (BLG) and hBN. Around the half-full point, the primary contribution to the resistance of these devices arises from Umklapp electron-electron (Uee) scattering, making the resistance of graphene/hBN moiré devices significantly larger than that of non-aligned devices (where Uee is forbidden). We find that the strength of Uee scattering follows a universal scaling with Fermi energy and is nonmonotonically dependent on the superlattice period. The Uee scattering can be tuned with the electric field and is affected by layer polarization of BLG. It has a strong particle-hole asymmetry; the resistance when the chemical potential is in the conduction band is significantly lower than when it is in the valence band, making the electron-doped regime more practical for potential applications.

AlphaFold2 structures template ligand discovery.

AlphaFold2 (AF2) and RosettaFold have greatly expanded the number of structures available for structure-based ligand discovery, even though retrospective studies have cast doubt on their direct usefulness for that goal. Here, we tested unrefined AF2 models prospectively, comparing experimental hit-rates and affinities from large library docking against AF2 models vs the same screens targeting experimental structures of the same receptors. In retrospective docking screens against the σ2 and the 5-HT2A receptors, the AF2 structures struggled to recapitulate ligands that we had previously found docking against the receptors' experimental structures, consistent with published results. Prospective large library docking against the AF2 models, however, yielded similar hit rates for both receptors versus docking against experimentally-derived structures; hundreds of molecules were prioritized and tested against each model and each structure of each receptor. The success of the AF2 models was achieved despite differences in orthosteric pocket residue conformations for both targets versus the experimental structures. Intriguingly, against the 5-HT2A receptor the most potent, subtype-selective agonists were discovered via docking against the AF2 model, not the experimental structure. To understand this from a molecular perspective, a cryoEM structure was determined for one of the more potent and selective ligands to emerge from docking against the AF2 model of the 5-HT2A receptor. Our findings suggest that AF2 models may sample conformations that are relevant for ligand discovery, much extending the domain of applicability of structure-based ligand discovery.

Outcomes of an expedited same-day discharge protocol following cardiac implantable electronic device (CIED) implantation.

BACKGROUND: With increasing constraints on healthcare resources, greater attention is being focused on improved resource utilization. Prior studies have demonstrated safety of same-day discharge following CIED implantation but are limited by vague protocols with long observation periods. In this study, we evaluate the safety of an expedited 2 hour same-day discharge protocol following CIED implantation. METHODS: Patients undergoing CIED implantation at three centers between 2015 and 2021 were included. Procedural, demographic, and adverse event data were abstracted from the electronic health record. Patients were divided into same-day discharge (SDD) and delayed discharge (DD) cohorts. The primary outcome was complications including lead malfunction requiring revision, pneumothorax, hemothorax, lead dislodgement, lead perforation with tamponade, and mortality within 30 days of procedure. Outcomes were compared between the two cohorts using the χ2 test. RESULTS: A total of 4543 CIED implantation procedures were included with 1557 patients (34%) in the SDD cohort. SDD patients were comparatively younger, were more likely to be male, and had fewer comorbidities than DD patients. Among SDD patients, the mean time to post-operative chest X-ray was 2.6 h. SDD had lower rates of complications (1.3% vs 2.1%, p = 0.0487) and acute care utilization post-discharge (9.6% vs 14.0%, p < 0.0001). There was no difference in the 90-day infection rate between the cohorts. CONCLUSIONS: An expedited 2 hour same-day discharge protocol is safe and effective with low rates of complications, infection, and post-operative acute care utilization.

Gamut of glycolytic enzymes in vascular smooth muscle cell proliferation: Implications for vascular proliferative diseases.

Vascular smooth muscle cells (VSMCs) are the predominant cell type in the media of the blood vessels and are responsible for maintaining vascular tone. Emerging evidence confirms that VSMCs possess high plasticity. During vascular injury, VSMCs switch from a "contractile" phenotype to an extremely proliferative "synthetic" phenotype. The balance between both strongly affects the progression of vascular remodeling in many cardiovascular pathologies such as restenosis, atherosclerosis and aortic aneurism. Proliferating cells demand high energy requirements and to meet this necessity, alteration in cellular bioenergetics seems to be essential. Glycolysis, fatty acid metabolism, and amino acid metabolism act as a fuel for VSMC proliferation. Metabolic reprogramming of VSMCs is dynamically variable that involves multiple mechanisms and encompasses the coordination of various signaling molecules, proteins, and enzymes. Here, we systemically reviewed the metabolic changes together with the possible treatments that are still under investigation underlying VSMC plasticity which provides a promising direction for the treatment of diseases associated with VSMC proliferation. A better understanding of the interaction between metabolism with associated signaling may uncover additional targets for better therapeutic strategies in vascular disorders.

Venetoclax-based low intensity therapy in molecular failure of NPM1-mutated AML.

ABSTRACT: Molecular failure in NPM1-mutated acute myeloid leukemia (AML) inevitably progresses to frank relapse if untreated. Recently published small case series show that venetoclax combined with low-dose cytarabine or azacitidine can reduce or eliminate measurable residual disease (MRD). Here, we report on an international multicenter cohort of 79 patients treated for molecular failure with venetoclax combinations and report an overall molecular response (≥1-log reduction in MRD) in 66 patients (84%) and MRD negativity in 56 (71%). Eighteen of 79 patients (23%) required hospitalization, and no deaths were reported during treatment. Forty-one patients were bridged to allogeneic transplant with no further therapy, and 25 of 41 were MRD negative assessed by reverse transcription quantitative polymerase chain reaction before transplant. Overall survival (OS) for the whole cohort at 2 years was 67%, event-free survival (EFS) was 45%, and in responding patients, there was no difference in survival in those who received a transplant using time-dependent analysis. Presence of FLT3-ITD mutation was associated with a lower response rate (64 vs 91%; P < .01), worse OS (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06-5.86; P = .036), and EFS (HR, 1.87; 95% CI, 1.06-3.28; P = .03). Eighteen of 35 patients who did not undergo transplant became MRD negative and stopped treatment after a median of 10 months, with 2-year molecular relapse free survival of 62% from the end of treatment. Venetoclax-based low intensive chemotherapy is a potentially effective treatment for molecular relapse in NPM1-mutated AML, either as a bridge to transplant or as definitive therapy.

Dyschromatopsia and contrast sensitivity changes in COVID-19 patients.

PURPOSE: To evaluate the alterations in the psycho-physical tests, contrast sensitivity (CS) and hue discrimination (total estimation score, TES) in COVID-19 patients. METHODS: A prospective case-control study was undertaken in 2021-22 to look at CS and TES among COVID-19 patients and RT-PCR negative normal subjects by a mobile app "smart optometry" and X-Rite's free online version of Farnsworth-Munsell 100 hue test. Strict visual acuity (minimum of 6/9 equivalent on Snellen) and other clinical parameters were used as exclusion criteria to filter potentially confounding pre-receptoral co-morbid conditions. The effect of mismatch in recruiting age and sex matched controls during the pandemic were analyzed by multivariate linear regression. RESULT: One-way ANOVA ruled out any influence of gender on CS and TES; however, there was significant difference in the TES on Mann Whitney U test (TES- 2.95 +/- 3.8 for cases; 0.30 +/- 1.1 for controls; p <0.001) and it persisted after accounting for age. Six controls with breakthrough infections had a significant deterioration in TES (Mean scores -3.0; 95% CI = -5.89 to -0.11; p = 0.04) on paired t test. Qualitative analysis showed that S-cone mediated deficiencies outnumber those affecting M-L cone mediated deficiencies. Among 53 subjects exhibiting three sensory features, anosmia, loss of taste and dyschromatopsia, nine (16.98%) had all features concurrently. CONCLUSION: The study demonstrates that COVID-19 infection leads to altered TES representing dyschromatopsia -an ocular counterpart of anosmia, with little difference on CS.

Diagnostic Performance Between Chest CT Severity Score and Initial Reverse Transcription-Polymerase Chain Reaction (RT-PCR) Cycle Values in COVID-19 Patients and Their Relation With the Clinical Status of Patients.

INTRODUCTION: Reverse transcription-polymerase chain reaction (RT-PCR) is used as a standard test for the diagnosis of SARS-CoV-2 viral RNA from nasopharyngeal aspirates. However, this method lacks sensitivity and cannot assess disease severity. A CT scan of the thorax provides a CT severity score (CT-SS), which depicts lung involvement and disease severity. This study aims to investigate the diagnostic value of chest CT compared with RT-PCR cycle threshold (Ct) values in COVID-19 and relate it clinically with the disease severity of patients. METHODS: This retrospective observational study was conducted in a tertiary center from April 2021 to March 2022. We included 511 patients who had tested RT-PCR positive for COVID-19, were hospitalized, and had undergone high-resolution CT (HRCT) thorax. Data was collected from patient records regarding name, age, sex, admission data, baseline investigations including Ct value, management, and outcome. HRCT was reviewed to assess lung involvement and calculate CT-SS. Data was analyzed using SPSS Statistics version 25 (IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp.). RESULT: The mean age of patients was 50.4 ± 13.7 years, and the majority (67.5%) were male. Gender-wise, there was no difference in RT-PCR cycle threshold (Ct) values; however, CT-SS was significantly higher in males (17.5 ± 4.8 vs.10.5 ± 6.6, t=-13.6, p<0.0001). ICU admission was needed for 34.8% of patients, and they had a significantly lower Ct value (21.7 ± 3.3 vs. 22.8 ± 3.7, t=21.10, p<0.0001) and higher CT-SS (16.3 ± 4.5 vs. 6.7 ± 5.1, t=-3.32, p=0.001). CONCLUSION: Ct values could not differentiate between moderate and severe patients. CT-SS was not related to the viral load at admission. Patients who succumbed had significantly lower Ct values and higher CT-SS.

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.

Serum anti-Müllerian hormone: A potential biomarker for polycystic ovary syndrome.

BACKGROUND OBJECTIVES: Polycystic ovary syndrome (PCOS) is characterized by chronic ovulatory dysfunction, hyperandrogenism and polycystic ovary morphology (PCOM). Although hyperandrogenism is one of the major features of PCOS, it is rarely observed in southeast Asia. Recently, however, there has been growing evidence on association of anti-Müllerian hormone (AMH) with PCOS. The objective of this study was to investigate the diagnostic potentials of AMH in PCOS individuals. METHODS: This case-control study included a total of 131 women with PCOS and 49 healthy controls who were enrolled after the exclusion of secondary causes of PCOS. Serum AMH was measured using an ultra-sensitive AMH ELISA kit in addition to other diagnostic biomarkers. Statistical analyses was carried out using the Student's t test, Wilcoxon rank-sum test, receiver operating characteristic (ROC) curve analysis, Spearman's rank correlation test and multivariable binary logistic regression analysis. RESULTS: The median AMH values were 8.5 ng/ml and 2.5 ng/ml in the study group and controls, respectively ( P <0.001). The normal cutoff value of 4.1 ng/ml for AMH was derived from ROC curve analysis. With a 4.1 ng/ml cut-off value, high levels of AMH was found in about 84 per cent of PCOS cases. However, no significant difference in AMH level was noted between age groups (<20 vs . ≥20 yr), body mass index (BMI) (<25 vs . ≥25 kg/m 2 ) and PCOM types. The area under the ROC curve (AUC) for AMH yielded diagnostic range values. In total PCOS cases, AUC was 0.93 (95% CI: 0.88 and 0.96), and in phenotype A PCOS cases, AUC was 0.96 (95% CI: 0.91 and 0.98). The correlation test also showed no association with BMI, the FG score, PCOM, free androgen index, androstenedione, dehydroepiandrosterone sulphate and luteinizing hormone. However, a weak correlation was observed with testosterone in total PCOS cases and with DHT as well as age in phenotype A PCOS cases. The prediction model for PCOS using multivariable binary logistic regression analysis showed AMH as the best marker. INTERPRETATION CONCLUSIONS: The results of this study suggest that AMH can be considered as the most promising biomarker in PCOS women, particularly with phenotype A and phenotype D.