Showing papers by "Icahn School of Medicine at Mount Sinai published in 2023"

Agitation in cognitive disorders: Progress in the International Psychogeriatric Association consensus clinical and research definition

Abstract: The International Psychogeriatric Association (IPA) published a provisional consensus definition of agitation in cognitive disorders in 2015. As proposed by the original work group, we summarize the use and validation of criteria in order to remove "provisional" from the definition.This report summarizes information from the academic literature, research resources, clinical guidelines, expert surveys, and patient and family advocates on the experience of use of the IPA definition. The information was reviewed by a working group of topic experts to create a finalized definition.We present a final definition which closely resembles the provisional definition with modifications to address special circumstances. We also summarize the development of tools for diagnosis and assessment of agitation and propose strategies for dissemination and integration into precision diagnosis and agitation interventions.The IPA definition of agitation captures a common and important entity that is recognized by many stakeholders. Dissemination of the definition will permit broader detection and can advance research and best practices for care of patients with agitation.

Concurrent Administration of Immune Checkpoint Inhibitors and Single Fraction Stereotactic Radiosurgery in Patients With Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma Brain Metastases

Abstract: Purpose Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases, particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting. Methods and Materials Patients with brain metastases from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Time-to-event analyses were conducted for any grade RN and symptomatic RN (SRN) with death incorporated as a competing risk. As a secondary analysis, recursive partitioning analysis (RPA) was used for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected. Brain V12 Gy thresholds identified on RPA were then incorporated into the competing risks analysis. Concurrent SRS and ICI administration. Results Six hundred fifty-seven patients with 4182 brain metastases across 11 international institutions were analyzed. The median follow-up for all patients was 13.4 months. The median follow-up was 12.8 months and 14.1 months for the concurrent and nonconcurrent groups, respectively (P = .03). The median patient age was 66 years, and the median Karnofsky Performance Status was 90. In patients with any grade RN, 1- and 2-year rates were 6.4% and 9.9%, respectively. In patients with SRN, 1- and 2-year rates were 4.8% and 7.2%, respectively. On RPA, the highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified by V12 Gy: (1) < 12 cm3; (2) 20 cm3 ≥ V12 Gy ≥ 12 cm3; (3) V12 Gy > 20 cm3. In patients with any grade RN, 1-year rates were 3.7% (V12 Gy < 12 cm3), 10.3% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 12.6% (V12 Gy > 20 cm3); the 2-year rates were 7.5% (V12 Gy < 12 cm3), 13.8% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 15.4% (V12 Gy > 20 cm3) (P < 0.001). In patients with any SRN, 1-year rates were 2.4% (V12 Gy < 12 cm3), 8.9% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 10.3% (V12 Gy > 20 cm3); the 2-year rates were 4.4% (V12 Gy < 12 cm3), 12.4% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 13.1% (V12 Gy > 20 cm3; P < 0.001). There were no statistically significant differences in rates of any grade RN or SRN when accounting for therapy timing for all patients and by V12 risk group identified on RPA. Conclusions The use of SRS and ICI results in a low risk of any grade RN and SRN. This risk is not increased with concurrent administration. Therefore, ICI can safely be administered within 4-weeks of SRS. Three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN. Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases, particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting. Patients with brain metastases from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Time-to-event analyses were conducted for any grade RN and symptomatic RN (SRN) with death incorporated as a competing risk. As a secondary analysis, recursive partitioning analysis (RPA) was used for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected. Brain V12 Gy thresholds identified on RPA were then incorporated into the competing risks analysis. Concurrent SRS and ICI administration. Six hundred fifty-seven patients with 4182 brain metastases across 11 international institutions were analyzed. The median follow-up for all patients was 13.4 months. The median follow-up was 12.8 months and 14.1 months for the concurrent and nonconcurrent groups, respectively (P = .03). The median patient age was 66 years, and the median Karnofsky Performance Status was 90. In patients with any grade RN, 1- and 2-year rates were 6.4% and 9.9%, respectively. In patients with SRN, 1- and 2-year rates were 4.8% and 7.2%, respectively. On RPA, the highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified by V12 Gy: (1) < 12 cm3; (2) 20 cm3 ≥ V12 Gy ≥ 12 cm3; (3) V12 Gy > 20 cm3. In patients with any grade RN, 1-year rates were 3.7% (V12 Gy < 12 cm3), 10.3% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 12.6% (V12 Gy > 20 cm3); the 2-year rates were 7.5% (V12 Gy < 12 cm3), 13.8% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 15.4% (V12 Gy > 20 cm3) (P < 0.001). In patients with any SRN, 1-year rates were 2.4% (V12 Gy < 12 cm3), 8.9% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 10.3% (V12 Gy > 20 cm3); the 2-year rates were 4.4% (V12 Gy < 12 cm3), 12.4% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 13.1% (V12 Gy > 20 cm3; P < 0.001). There were no statistically significant differences in rates of any grade RN or SRN when accounting for therapy timing for all patients and by V12 risk group identified on RPA. The use of SRS and ICI results in a low risk of any grade RN and SRN. This risk is not increased with concurrent administration. Therefore, ICI can safely be administered within 4-weeks of SRS. Three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN.

Association of Traumatic Brain Injury with Late Life Neuropathological Outcomes in a Community-Based Cohort

Abstract: Prior studies into the association of head trauma with neuropathology have been limited by incomplete lifetime neurotrauma exposure characterization.To investigate the neuropathological sequelae of traumatic brain injury (TBI) in an autopsy sample using three sources of TBI ascertainment, weighting findings to reflect associations in the larger, community-based cohort.Self-reported head trauma with loss of consciousness (LOC) exposure was collected in biennial clinic visits from 780 older adults from the Adult Changes in Thought study who later died and donated their brain for research. Self-report data were supplemented with medical record abstraction, and, for 244 people, structured interviews on lifetime head trauma. Neuropathology outcomes included Braak stage, CERAD neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral/cortical atrophy. Exposures were TBI with or without LOC. Modified Poisson regressions adjusting for age, sex, education, and APOE ɛ4 genotype were weighted back to the full cohort of 5,546 participants.TBI with LOC was associated with the presence of cerebral cortical atrophy (Relative Risk 1.22, 95% CI 1.02, 1.42). None of the other outcomes was associated with TBI with or without LOC.TBI with LOC was associated with increased risk of cerebral cortical atrophy. Despite our enhanced TBI ascertainment, we found no association with the Alzheimer's disease-related neuropathologic outcomes among people who survived to at least age 65 without dementia. This suggests the pathophysiological processes underlying post-traumatic neurodegeneration are distinct from the hallmark pathologies of Alzheimer's disease.

Shifting reaction path for levulinic acid aqueous-phase hydrogenation by Pt-TiO2 metal-support interaction

Abstract: Levulinic acid (LA) aqueous-phase hydrogenation into γ-valerolactone (GVL) is considered one of the pivotal reactions to convert biomass into renewable chemicals. Here we have deposited Pt on TiO2 nanofilm coated α-Al2O3 via atomic layer deposition (ALD) to synthesize Pt-TiO2/α-Al2O3. This catalyst shows excellent activity and stability (1000 h) in LA hydrogenation compared to Pt/α-Al2O3. By excluding the effect of Pt particle size, lattice plane, support morphology, pore structure, and electronic state, the critical role of Pt-TiO2 interaction is revealed by various characterization methods. CO diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) and in-situ Fourier transform Infrared spectra (FTIR) results indicate that Pt-TiO2 interaction provides new interfacial Pt sites for LA and intermediate adsorption and Ti-OH active sites for LA dehydration cyclization to α-angelica lactone intermediate, which leads to the shift of reaction pathways from direct LA CO hydrogenation lactonization on Pt/α-Al2O3 to LA dehydration cyclization and hydrogenation on Pt-TiO2/α-Al2O3。It provides insight into the design of high-efficient catalysts for aqueous-phase hydrogenation.

Prenatal Lead Exposure is Negatively Associated with the Gut Microbiome in Childhood

Abstract: Metal exposures are associated with gut microbiome (GM) composition and function, and exposures early in development may be particularly important. Considering the role of the GM in association with many adverse health outcomes, understanding the relationship between prenatal metal exposures and the GM is critically important. However, there is sparse knowledge of the association between prenatal metal exposure and GM later in childhood.This analysis aims to identify associations between prenatal lead (Pb) exposure and GM composition and function in children 9-11 years old.Data come from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) cohort based in Mexico City, Mexico. Prenatal metal concentrations were measured in maternal whole blood drawn during the second and third trimesters of pregnancy. Stool samples collected at 9-11 years old underwent metagenomic sequencing to assess the GM. This analysis uses multiple statistical modeling approaches, including linear regression, permutational analysis of variance, weighted quantile sum regression (WQS), and individual taxa regressions, to estimate the association between maternal blood Pb during pregnancy and multiple aspects of the child GM at 9-11 years old, adjusting for relevant confounders.Of the 123 child participants in this pilot data analysis, 74 were male and 49 were female. Mean prenatal maternal blood Pb was 33.6(SE=2.1) ug/L and 34.9(SE=2.1) ug/L at second and third trimesters, respectively. Analysis suggests a consistent negative relationship between prenatal maternal blood Pb and the GM at age 9-11, including measures of alpha and beta diversity, microbiome mixture analysis, and individual taxa. The WQS analysis showed a negative association between prenatal Pb exposure and the gut microbiome, for both second and third trimester exposures (2Tβ=-0.17,95%CI=[-0.46,0.11]; 3Tβ=-0.17,95%CI=[-0.44,0.10]). Ruminococcus gnavus, Bifidobacterium longum, Alistipes indistinctus, Bacteroides caccae, and Bifidobacterium bifidum all had weights above the importance threshold from 80% or more of the WQS repeated holdouts in association with both second and third trimester Pb exposure.Pilot data analysis suggests a negative association between prenatal Pb exposure and the gut microbiome later in childhood; however, additional investigation is needed.

Examining Daily Associations Among Sleep, Stress, and Blood Pressure Across Adulthood

Abstract: Abstract Background Sleep can have consequential effects on people’s health and well-being, and these effects may vary among younger and older adults. Purpose The goal of the present study was to investigate how sleep relates to physiologic and stress responses in daily life across adulthood. Methods We used an Ecological Momentary Assessment method in a large sample of participants (N = 4,359; Mage = 46.75, SD = 12.39; 69.30% male, 29.85% female) who completed morning sleep diaries, reported subjective stress, and recorded their heart rate and blood pressure for 21 days. Sleep was assessed with self-reports of duration, efficiency, and quality. Results Using multilevel modeling, between-person analyses showed that sleep duration, efficiency, and quality were negatively related to morning heart rate and stress, such that people who slept longer, more efficiently, or better experienced lower heart rate and stress compared to those who slept shorter, less efficiently, or worse. Within-person analyses showed that sleep duration, efficiency, and quality predicted morning heart rate, blood pressure (though less consistently), and stress. That is, people experienced lower heart, blood pressure, and stress following nights when they slept longer, more efficiently, or better than they typically did. These within-person relationships were moderated by age, such that the effects of better and longer sleep on lower morning heart rate, blood pressure, and stress were stronger among younger than older adults. Conclusion These findings suggest that daily variations in sleep show immediate associations with stress and physiologic responses, but these daily variations have a stronger relationship among younger compared to older adults.

Diurnal and Seasonal Variations of Aerosol Optical Depth Observed by MEDA/TIRS at Jezero Crater, Mars

Abstract: The two upward-looking Thermal InfraRed Sensor (TIRS) channels from the Mars Environmental Dynamics Analyzer (MEDA) instrument suite on board the Perseverance rover enable the retrieval of total aerosol optical depth (dust plus water ice cloud) above the rover for all observations when TIRS is taken. Because TIRS observes at thermal infrared wavelengths, the retrievals are possible during both the day and night and thus, they provide an excellent way to monitor both the diurnal and seasonal variations of aerosols above Jezero Crater. A retrieval algorithm has been developed for this purpose and here, we describe that algorithm along with our results for the first 400 sols of the Perseverance mission covering nearly the entire aphelion season as well as a regional dust storm and the beginning of the perihelion season. We find systematic diurnal variations in aerosol optical depth that can be associated with dust and water ice clouds as well as a clear change from a cloud-filled aphelion season to a perihelion season where dust is the dominant aerosol. A comparison of retrieved optical depths between TIRS and the SkyCam camera that is also part of MEDA indicates evidence of possible diurnal variations in cloud height or particle size.

Progressive excitability changes in the medial entorhinal cortex in the 3xTg mouse model of Alzheimer's disease pathology

Abstract: ABSTRACT Alzheimer’s disease (AD) is a chronic neurodegenerative disorder that is characterized by memory loss and progressive cognitive impairments. In mouse models of AD pathology, studies have found neuronal and synaptic deficits in the hippocampus, but less is known about what happens in the medial entorhinal cortex (MEC), which is the primary spatial input to the hippocampus and an early site of AD pathology. Here, we measured the neuronal intrinsic excitability and synaptic activity in MEC layer II (MECII) stellate cells, MECII pyramidal cells, and MEC layer III (MECIII) excitatory neurons at early (3 months) and late (10 months) time points in the 3xTg mouse model of AD pathology. At 3 months of age, prior to the onset of memory impairments, we found early hyperexcitability in MECII stellate and pyramidal cells’ intrinsic properties, but this was balanced by a relative reduction in synaptic excitation (E) compared to inhibition (I), suggesting intact homeostatic mechanisms regulating activity in MECII. Conversely, MECIII neurons had reduced intrinsic excitability at this early time point with no change in the synaptic E/I ratio. By 10 months of age, after the onset of memory deficits, neuronal excitability of MECII pyramidal cells and MECIII excitatory neurons was largely normalized in 3xTg mice. However, MECII stellate cells remained hyperexcitable and this was further exacerbated by an increased synaptic E/I ratio. This observed combination of increased intrinsically and synaptically generated excitability suggests a breakdown in homeostatic mechanisms specifically in MECII stellate cells at this post-symptomatic time point. Together, these data suggest that the breakdown in homeostatic excitability mechanisms in MECII stellate cells may contribute to the emergence of memory deficits in AD.

Gene–environment interactions in the associations of PFAS exposure with insulin sensitivity and beta-cell function in a Faroese cohort followed from birth to adulthood

Abstract: Exposure to perfluoroalkyl substances (PFAS) has been associated with changes in insulin sensitivity and pancreatic beta-cell function in humans. Genetic predisposition to diabetes may modify these associations; however, this hypothesis has not been yet studied.To evaluate genetic heterogeneity as a modifier in the PFAS association with insulin sensitivity and pancreatic beta-cell function, using a targeted gene-environment (GxE) approach.We studied 85 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes, in 665 Faroese adults born in 1986-1987. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) were measured in cord whole blood at birth and in participants' serum from age 28 years. We calculated the Matsuda-insulin sensitivity index (ISI) and the insulinogenic index (IGI) based on a 2 h-oral glucose tolerance test performed at age 28. Effect modification was evaluated in linear regression models adjusted for cross-product terms (PFAS*SNP) and important covariates.Prenatal and adult PFOS exposures were significantly associated with decreased insulin sensitivity and increased beta-cell function. PFOA associations were in the same direction but attenuated compared to PFOS. A total of 58 SNPs were associated with at least one PFAS exposure variable and/or Matsuda-ISI or IGI in the Faroese population and were subsequently tested as modifiers in the PFAS-clinical outcome associations. Eighteen SNPs showed interaction p-values (PGxE) < 0.05 in at least one PFAS-clinical outcome association, five of which passed False Discovery Rate (FDR) correction (PGxE-FDR<0.20). SNPs for which we found stronger evidence for GxE interactions included ABCA1 rs3890182, FTO rs9939609, FTO rs3751812, PPARG rs170036314 and SLC12A3 rs2289116 and were more clearly shown to modify the PFAS associations with insulin sensitivity, rather than with beta-cell function.Findings from this study suggest that PFAS-associated changes in insulin sensitivity could vary between individuals as a result of genetic predisposition and warrant replication in independent larger populations.

Acute Severe Ulcerative Colitis Is Associated With an Increased Risk of Acute Pouchitis

Abstract: Abstract Background Pouchitis occurs in up to 80% of patients after total proctocolectomy (TPC) with ileal pouch–anal anastomosis (IPAA) and has been associated with microbial and host-related immunological factors. We hypothesized that a more robust immune response at the time of colectomy, manifested by acute severe ulcerative colitis (ASUC), may be associated with subsequent acute pouchitis. Methods This was a retrospective cohort analysis of all patients with UC or indeterminate colitis complicated by medically refractory disease or dysplasia who underwent TPC with IPAA at Mount Sinai Hospital between 2008 and 2017 and at least 1 subsequent pouchoscopy. Acute pouchitis was defined according to the Pouchitis Disease Activity Index. Cox regression was used to assess unadjusted relationships between hypothesized risk factors and acute pouchitis. Results A total of 416 patients met inclusion criteria. Of the 165 (39.7%) patients who underwent urgent colectomy, 77 (46.7%) were admitted with ASUC. Acute pouchitis occurred in 228 (54.8%) patients a median of 1.3 (interquartile range, 0.6-3.1) years after the final surgical stage. On multivariable analysis, ASUC (hazard ratio [HR], 1.50; 95% confidence interval [CI], 1.04-2.17) and a greater number of biologics precolectomy (HR, 1.57; 95% CI, 1.06-2.31) were associated with an increased probability of acute pouchitis, while older age at colectomy (HR, 0.98; 95% CI, 0.97-0.99) was associated with a decreased probability. Time to pouchitis was significantly less in patients admitted with ASUC compared with those not (P = .002). Conclusion A severe UC disease phenotype at the time of colectomy was associated with an increased probability of acute pouchitis.

Human Tracheal Transplantation

Abstract: Long-segment tracheal airway defects may be congenital or result from burns, trauma, iatrogenic intubation damage, or tumor invasion. Although airway defects <6 cm in length may be reconstructed using existing end-to-end reconstructive techniques, defects >6 cm continue to challenge surgeons worldwide. The reconstruction of long-segment tracheal defects has long been a reconstructive dilemma, and these defects are associated with significant morbidity and mortality. Many of these defects are not compatible with life or require a permanent extended-length tracheostomy that is fraught with complications including mucus plugging and tracheoesophageal fistula. Extensive circumferential tracheal defects require a reconstructive technique that provides a rigid structure able to withstand the inspiratory pressures, a structure that will biologically integrate, and contain functional ciliated epithelium to allow for normal mucociliary clearance. Tracheal transplantation has been considered the reconstructive "Holy Grail;" however, there has been a long-held scientific dogma that revascularization of the trachea was not possible. This dogma stifled research to achieve single-staged vascularized tracheal transplantation and prompted the introduction of many creative and inventive alternatives. Throughout history, alloplastic material, nonvascularized allografts, and homografts have been used to address this dilemma. However, these techniques have largely been unsuccessful. The recent introduction of a technique for single-staged vascularized tracheal transplantation may offer a solution to this dilemma and potentially a solution to management of the fatal tracheoesophageal fistula.

TMAO Destabilizes RNA Secondary Structure via Direct Hydrogen Bond Interactions

Abstract: Trimethylamine N-oxide (TMAO) is an osmolyte that accumulates in cells in response to osmotic stress. TMAO stabilizes proteins by the entropic stabilization mechanism, which pictures TMAO as a nanocrowder that predominantly destabilizes the unfolded state. However, the mechanism of action of TMAO on RNA is much less understood. Here, we use all-atom molecular dynamics simulations to investigate how TMAO interacts with a 12-nt RNA hairpin with a high melting temperature, and an 8-nt RNA hairpin, which has a relatively fluid native basin in the absence of TMAO. The use of the two hairpins with different free energy of stabilization allows us to probe the origin of the destabilization effect of TMAO on RNA molecules without the possibility of forming tertiary interactions. We generated multiple trajectories using all-atom molecular dynamics (MD) simulations in explicit water by employing AMBER and CHARMM force fields, both in the absence and presence of TMAO. We observed qualitatively similar RNA-TMAO interaction profiles from the simulations using the two force fields. TMAO hydrogen bond interactions are largely depleted around the paired RNA bases and ribose sugars. In contrast, we show that the oxygen atom in TMAO, the hydrogen bond acceptor, preferentially interacts with the hydrogen bond donors in the solvent exposed bases, such as those in the stem-loop and the destabilized base stacks in the unfolded state, especially in the marginally stable 8-nt RNA hairpin. The predicted destabilization mechanism through TMAO-RNA hydrogen bond interactions could be tested using two-dimensional IR spectroscopy. Since TMAO does not significantly interact with the hydroxyl group of the ribose sugars, we predict that similar results must also hold for DNA.

Comparision of Bayesian methods for incorporating adult clinical trial data to improve certainty of treatment effect estimates in children.

Abstract: Abstract There are challenges associated with recruiting children to take part in randomised clinical trials and as a result, compared to adults, in many disease areas we are less certain about which treatments are most safe and effective. This can lead to weaker recommendations about which treatments to prescribe in practice. However, it may be possible to ‘borrow strength’ from adult evidence to improve our understanding of which treatments work best in children, and many different statistical methods are available to conduct these analyses. In this paper we discuss Bayesian methods for extrapolating adult clinical trial evidence to children. Using an exemplar dataset, we compare the effect of modelling assumptions on the estimated treatment effect and associated heterogeneity. We finally discuss the appropriateness of different modelling assumptions in the context of estimating treatment effect in children.

Becoming an inner ally: the compassionate minds approach to self-compassion − an online programme

Abstract: A rapidly growing body of evidence indicates the enormous psychological burden of working in health care on nurses and other health professionals that is resulting in high levels of psychological problems. These will have profound effects on individuals and long-term ramifications for healthcare systems. Effective interventions that can counter the adverse psychological effects of caring during the COVID-19 pandemic and beyond are urgently required. With this in mind, the authors have created an online self-compassion programme to advance the health and wellbeing of the nursing workforce through developing proactive evidence-based preventive teaching and learning strategies to promote compassion satisfaction and prevent compassion fatigue by improving self-compassion. The online programme is underpinned by compassionate minds theories and research.

Patient-Derived iPSCs Faithfully Represent the Genetic Diversity and Cellular Architecture of Human Acute Myeloid Leukemia

Abstract: The reprogramming of human acute myeloid leukemia (AML) cells into induced pluripotent stem cell (iPSC) lines could provide new faithful genetic models of AML, but is currently hindered by low success rates and uncertainty about whether iPSC-derived cells resemble their primary counterparts. Here we developed a reprogramming method tailored to cancer cells, with which we generated iPSCs from 15 patients representing all major genetic groups of AML. These AML-iPSCs retain genetic fidelity and produce transplantable hematopoietic cells with hallmark phenotypic leukemic features. Critically, single-cell transcriptomics reveal that, upon xenotransplantation, iPSC-derived leukemias faithfully mimic the primary patient-matched xenografts. Transplantation of iPSC-derived leukemias capturing a clone and subclone from the same patient allowed us to isolate the contribution of a FLT3-ITD mutation to the AML phenotype. The results and resources reported here can transform basic and preclinical cancer research of AML and other human cancers.We report the generation of patient-derived iPSC models of all major genetic groups of human AML. These exhibit phenotypic hallmarks of AML in vitro and in vivo, inform the clonal hierarchy and clonal dynamics of human AML, and exhibit striking similarity to patient-matched primary leukemias upon xenotransplantation. See related commentary by Doulatov, p. 252. This article is highlighted in the In This Issue feature, p. 247.

Boldine modulates glial transcription and functional recovery in a murine model of contusion spinal cord injury

Abstract: Membrane channels such as connexins (Cx), pannexins (Panx) and P2X 7 receptors (P2X 7 R) are permeable to calcium ions and other small molecules such as ATP and glutamate. Release of ATP and glutamate through these channels is a key mechanism driving tissue response to traumas such as spinal cord injury (SCI). Boldine, an alkaloid isolated from the Chilean boldo tree, blocks both Cx hemichannels (HC) and Panx. To test if boldine could improve function after SCI, boldine or vehicle was administered to treat mice with a moderate severity contusion-induced SCI. Boldine led to greater spared white matter and increased locomotor function as determined by the Basso Mouse Scale and horizontal ladder rung walk tests. Boldine treatment reduced immunostaining for markers of activated microglia (Iba1) and astrocytic (GFAP) markers while increasing that for axon growth and neuroplasticity (GAP-43). Cell culture studies demonstrated that boldine blocked glial HC, specifically Cx26 and Cx30, in cultured astrocytes and blocked calcium entry through activated P2X 7 R. RT-qPCR studies showed that boldine treatment reduced expression of the chemokine Ccl2, cytokine IL-6 and microglial gene CD68, while increasing expression of the neurotransmission genes Snap25 and Grin2b, and Gap-43. Bulk RNA sequencing (of the spinal cord revealed that boldine modulated a large number of genes involved in neurotransmission in in spinal cord tissue just below the lesion epicenter at 14 days after SCI. Numbers of genes regulated by boldine was much lower at 28 days after injury. These results indicate that boldine treatment ameliorates injury and spares tissue to increase locomotor function.

Joint Modeling of Clinical and Biomarker Data in Acute Kidney Injury Defines Unique Subphenotypes with Differing Outcomes

Abstract: Background AKI is a heterogeneous syndrome. Current subphenotyping approaches have only used limited laboratory data to understand a much more complex condition. Methods We focused on patients with AKI from the Assessment, Serial Evaluation, and Subsequent Sequelae in AKI (ASSESS-AKI). We used hierarchical clustering with Ward linkage on biomarkers of inflammation, injury, and repair/health. We then evaluated clinical differences between subphenotypes and examined their associations with cardiorenal events and death using Cox proportional hazard models. Results We included 748 patients with AKI: 543 (73%) of them had AKI stage 1, 112 (15%) had AKI stage 2, and 93 (12%) had AKI stage 3. The mean age (±SD) was 64 (13) years; 508 (68%) were men; and the median follow-up was 4.7 (Q1: 2.9, Q3: 5.7) years. Patients with AKI subphenotype 1 (N=181) had the highest kidney injury molecule (KIM-1) and troponin T levels. Subphenotype 2 (N=250) had the highest levels of uromodulin. AKI subphenotype 3 (N=159) comprised patients with markedly high pro–brain natriuretic peptide and plasma tumor necrosis factor receptor-1 and -2 and low concentrations of KIM-1 and neutrophil gelatinase–associated lipocalin. Finally, patients with subphenotype 4 (N=158) predominantly had sepsis-AKI and the highest levels of vascular/kidney inflammation (YKL-40, MCP-1) and injury (neutrophil gelatinase–associated lipocalin, KIM-1). AKI subphenotypes 3 and 4 were independently associated with a higher risk of death compared with subphenotype 2 and had adjusted hazard ratios of 2.9 (95% confidence interval, 1.8 to 4.6) and 1.6 (95% CI, 1.01 to 2.6, P = 0.04), respectively. Subphenotype 3 was also independently associated with a three-fold risk of CKD and cardiovascular events. Conclusions We discovered four AKI subphenotypes with differing clinical features and biomarker profiles that are associated with longitudinal clinical outcomes. Visual Abstract Export

Discussion: National Undervaluation of Cleft Surgical Services: Evidence from a Comparative Analysis of 50,450 Cases

Abstract: New York, NY From the Division of Plastic and Reconstructive Surgery, Icahn School of Medicine at Mount Sinai. Received for publication September 29, 2022; accepted October 10, 2022. Disclosure:The author has no financial interest to declare in relation to the content of this Discussion or of the associated article. Peter J. Taub, MD, MS, Division of Plastic and Reconstructive Surgery, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, Box 1259, New York, NY 10128, [email protected]

Neuronal activity in the human amygdala and hippocampus enhances emotional memory encoding

Abstract: Emotional events comprise our strongest and most valuable memories. Here we examined how the brain prioritizes emotional information for storage using direct brain recording and deep brain stimulation. First, 148 participants undergoing intracranial electroencephalographic (iEEG) recording performed an episodic memory task. Participants were most successful at remembering emotionally arousing stimuli. High-frequency activity (HFA), a correlate of neuronal spiking activity, increased in both the hippocampus and the amygdala when participants successfully encoded emotional stimuli. Next, in a subset of participants (N = 19), we show that applying high-frequency electrical stimulation to the hippocampus selectively diminished memory for emotional stimuli and specifically decreased HFA. Finally, we show that individuals with depression (N = 19) also exhibit diminished emotion-mediated memory and HFA. By demonstrating how direct stimulation and symptoms of depression unlink HFA, emotion and memory, we show the causal and translational potential of neural activity in the amygdalohippocampal circuit for prioritizing emotionally arousing memories.

Prognostic Factors Among Colonic Adenocarcinomas Invading Into the Muscularis Propria

Abstract: Depth of invasion through the intestinal wall, categorized as primary tumor stage (pT), is an important prognostic factor in colorectal cancer. However, additional variables that may affect clinical behavior among tumors involving the muscularis propria (pT2) have not been examined at length. We evaluated 109 patients with pT2 colonic adenocarcinomas (median age: 71 y, interquartile range: 59 to 79 y) along various clinicopathologic parameters, including invasion depth, regional lymph node involvement, and disease progression after resection. Tumors extending to the outer muscularis propria (termed pT2b) were associated in multivariate analysis with older patient age (P=0.04), larger tumor size (P<0.001), higher likelihood of lymphovascular invasion (LVI; P=0.03) and higher lymph node stage (pN; P=0.04), compared with tumors limited to the inner muscle layer (pT2a), and LVI was the single most important variable predicting regional lymph node metastasis at resection in these tumors (P=0.001). The Kaplan-Meier analysis during a median clinical follow-up of 59.7 months (interquartile range: 31.5 to 91.2) revealed that disease progression was more likely in pT2 tumors that exhibited, at the time of staging: size >2.5 cm (P=0.039), perineural invasion (PNI; P=0.047), high-grade tumor budding (P=0.036), higher pN stage (P=0.002), and distant metastasis (P<0.001). Proportional hazards (Cox) regression identified high-grade tumor budding (P=0.02) as independently predicting shorter progression-free survival in pT2 tumors. Finally, among cases that would not ordinarily be candidates for adjuvant treatment (ie, pT2N0M0), the presence of high-grade tumor budding was significantly associated with disease progression (P=0.04). These data suggest that, during the diagnosis of pT2 tumors, pathologists may wish to pay particular attention and ensure adequate reporting of certain variables such as tumor size, depth of invasion within the muscularis propria (ie, pT2a vs. pT2b), LVI, PNI, and, especially, tumor budding, as these may affect clinical treatment decisions and proper patient prognostication.

CQCF: A Cyclic Queuing Cluster Forwarding Based Transmission Mechanism for Large-Scale Deterministic Network

Abstract: AbstractWith the increase of time-sensitive applications, the traditional networks using Best Effort approach can no longer meet the needs of the network applications. For satisfying the demand for high-quality, low delay, and low jitter transmission, IETF establishes the TSN and DetNet Working Group. However, there is no DetNet mechanism specifically designed for time synchronization scenarios. In this paper, we propose a time synchronization cross-domain transmission mechanism for a large-scale Deterministic Network, which is named CQCF (Cyclic Queuing Cluster Forwarding). CQCF adopts the queuing cluster module to cache and forward time-sensitive traffic, making sure that packets can be received at the specified time. Meanwhile, we propose the mapping principle on the Cycle and Hypercycle between access networks and core networks to improve the feasibility of cross-domain transmission. The experimental results show that the CQCF mechanism can schedule more flows than DIP under the time synchronization scenario. The runtime of the scheduling algorithm using CQCF improves by 27.9% compared with the algorithm using DIP under scheduling 2000 flows.KeywordsTime sensitive networkDeterministic networkQuality of serviceQueuing clusters