Macromolecular condensation organizes nucleolar sub-phases to set up a pH gradient.

Nucleoli are multicomponent condensates defined by coexisting sub-phases. We identified distinct intrinsically disordered regions (IDRs), including acidic (D/E) tracts and K-blocks interspersed by E-rich regions, as defining features of nucleolar proteins. We show that the localization preferences of nucleolar proteins are determined by their IDRs and the types of RNA or DNA binding domains they encompass. In vitro reconstitutions and studies in cells showed how condensation, which combines binding and complex coacervation of nucleolar components, contributes to nucleolar organization. D/E tracts of nucleolar proteins contribute to lowering the pH of co-condensates formed with nucleolar RNAs in vitro. In cells, this sets up a pH gradient between nucleoli and the nucleoplasm. By contrast, juxta-nucleolar bodies, which have different macromolecular compositions, featuring protein IDRs with very different charge profiles, have pH values that are equivalent to or higher than the nucleoplasm. Our findings show that distinct compositional specificities generate distinct physicochemical properties for condensates.

Sensory encoding and memory in the mushroom body: signals, noise, and variability.

To survive in changing environments, animals need to learn to associate specific sensory stimuli with positive or negative valence. How do they form stimulus-specific memories to distinguish between positively/negatively associated stimuli and other irrelevant stimuli? Solving this task is one of the functions of the mushroom body, the associative memory center in insect brains. Here we summarize recent work on sensory encoding and memory in the Drosophila mushroom body, highlighting general principles such as pattern separation, sparse coding, noise and variability, coincidence detection, and spatially localized neuromodulation, and placing the mushroom body in comparative perspective with mammalian memory systems.

Can non-invasive brain stimulation modulate peak alpha frequency in the human brain? A systematic review and meta-analysis.

Peak alpha frequency (PAF), the dominant oscillatory frequency within the alpha range (8-12 Hz), is associated with cognitive function and several neurological conditions, including chronic pain. Manipulating PAF could offer valuable insight into the relationship between PAF and various functions and conditions, potentially providing new treatment avenues. This systematic review aimed to comprehensively synthesise effects of non-invasive brain stimulation (NIBS) on PAF speed. Relevant studies assessing PAF pre- and post-NIBS in healthy adults were identified through systematic searches of electronic databases (Embase, PubMed, PsychINFO, Scopus, The Cochrane Library) and trial registers. The Cochrane risk-of-bias tool was employed for assessing study quality. Quantitative analysis was conducted through pairwise meta-analysis when possible; otherwise, qualitative synthesis was performed. The review protocol was registered with PROSPERO (CRD42020190512) and the Open Science Framework (https://osf.io/2yaxz/). Eleven NIBS studies were included, all with a low risk-of-bias, comprising seven transcranial alternating current stimulation (tACS), three repetitive transcranial magnetic stimulation (rTMS), and one transcranial direct current stimulation (tDCS) study. Meta-analysis of active tACS conditions (eight conditions from five studies) revealed no significant effects on PAF (mean difference [MD] = -0.12, 95% CI = -0.32 to 0.08, p = 0.24). Qualitative synthesis provided no evidence that tDCS altered PAF and moderate evidence for transient increases in PAF with 10 Hz rTMS. However, it is crucial to note that small sample sizes were used, there was substantial variation in stimulation protocols, and most studies did not specifically target PAF alteration. Further studies are needed to determine NIBS's potential for modulating PAF.

Genome-wide loss of heterozygosity predicts aggressive, treatment-refractory behavior in pituitary neuroendocrine tumors.

Pituitary neuroendocrine tumors (PitNETs) exhibiting aggressive, treatment-refractory behavior are the rare subset that progress after surgery, conventional medical therapies, and an initial course of radiation and are characterized by unrelenting growth and/or metastatic dissemination. Two groups of patients with PitNETs were sequenced: a prospective group of patients (n = 66) who consented to sequencing prior to surgery and a retrospective group (n = 26) comprised of aggressive/higher risk PitNETs. A higher mutational burden and fraction of loss of heterozygosity (LOH) was found in the aggressive, treatment-refractory PitNETs compared to the benign tumors (p = 1.3 × 10-10 and p = 8.5 × 10-9, respectively). Within the corticotroph lineage, a characteristic pattern of recurrent chromosomal LOH in 12 specific chromosomes was associated with treatment-refractoriness (occurring in 11 of 14 treatment-refractory versus 1 of 14 benign corticotroph PitNETs, p = 1.7 × 10-4). Across the cohort, a higher fraction of LOH was identified in tumors with TP53 mutations (p = 3.3 × 10-8). A machine learning approach identified loss of heterozygosity as the most predictive variable for aggressive, treatment-refractory behavior, outperforming the most common gene-level alteration, TP53, with an accuracy of 0.88 (95% CI: 0.70-0.96). Aggressive, treatment-refractory PitNETs are characterized by significant aneuploidy due to widespread chromosomal LOH, most prominently in the corticotroph tumors. This LOH predicts treatment-refractoriness with high accuracy and represents a novel biomarker for this poorly defined PitNET category.

Noninvasive Atherosclerotic Phenotyping: The Next Frontier into Understanding the Pathobiology of Coronary Artery Disease.

PURPOSE OF REVIEW: Despite recent advances, coronary artery disease remains one of the leading causes of mortality worldwide. Noninvasive imaging allows atherosclerotic phenotyping by measurement of plaque burden, morphology, activity and inflammation, which has the potential to refine patient risk stratification and guide personalized therapy. This review describes the current and emerging roles of advanced noninvasive cardiovascular imaging methods for the assessment of coronary artery disease. RECENT FINDINGS: Cardiac computed tomography enables comprehensive, noninvasive imaging of the coronary vasculature, and is used to assess luminal stenoses, coronary calcifications, and distinct adverse plaque characteristics, helping to identify patients prone to future events. Novel software tools, implementing artificial intelligence solutions, can automatically quantify and characterize atherosclerotic plaque from standard computed tomography datasets. These quantitative imaging biomarkers have been shown to improve patient risk stratification beyond clinical risk scores and current clinical interpretation of cardiac computed tomography. In addition, noninvasive molecular imaging in higher risk patients can be used to assess plaque activity and plaque thrombosis. Noninvasive imaging allows unique insight into the burden, morphology and activity of atherosclerotic coronary plaques. Such phenotyping of atherosclerosis can potentially improve individual patient risk prediction, and in the near future has the potential for clinical implementation.

Real-World Use of Hypofractionated Radiotherapy for Primary CNS Tumors in the Elderly, and Implications on Medicare Spending.

BACKGROUND: For elderly patients with high-grade gliomas, 3-week hypofractionated radiotherapy (HFRT) is noninferior to standard long-course radiotherapy (LCRT). We analyzed real-world utilization of HFRT with and without systemic therapy in Medicare beneficiaries treated with RT for primary central nervous system (CNS) tumors using Centers for Medicare & Medicaid Services data. METHODS: Radiation modality, year, age (65-74, 75-84, or ≥85 years), and site of care (freestanding vs hospital-affiliated) were evaluated. Utilization of HFRT (11-20 fractions) versus LCRT (21-30 or 31-40 fractions) and systemic therapy was evaluated by multivariable logistic regression. Medicare spending over the 90-day episode after RT planning initiation was analyzed using multivariable linear regression. RESULTS: From 2015 to 2019, a total of 10,702 RT courses (ie, episodes) were included (28% HFRT; 65% of patients aged 65-74 years). A considerable minority died within 90 days of RT planning initiation (n=1,251; 12%), and 765 (61%) of those received HFRT. HFRT utilization increased (24% in 2015 to 31% in 2019; odds ratio [OR], 1.2 per year; 95% CI, 1.1-1.2) and was associated with older age (≥85 vs 65-74 years; OR, 6.8; 95% CI, 5.5-8.4), death within 90 days of RT planning initiation (OR, 5.0; 95% CI, 4.4-5.8), hospital-affiliated sites (OR, 1.4; 95% CI, 1.3-1.6), conventional external-beam RT (vs intensity-modulated RT; OR, 2.7; 95% CI, 2.3-3.1), and no systemic therapy (OR, 1.2; 95% CI, 1.1-1.3; P<.001 for all). Increasing use of HFRT was concentrated in hospital-affiliated sites (P=.002 for interaction). Most patients (69%) received systemic therapy with no differences by site of care (P=.12). Systemic therapy utilization increased (67% in 2015 to 71% in 2019; OR, 1.1 per year; 95% CI, 1.0-1.1) and was less likely for older patients, patients who died within 90 days of RT planning initiation, those who received conventional external-beam RT, and those who received HFRT. HFRT significantly reduced spending compared with LCRT (adjusted ß for LCRT = +$8,649; 95% CI, $8,544-$8,755), whereas spending modestly increased with systemic therapy (adjusted ß for systemic therapy = +$270; 95% CI, $176-$365). CONCLUSIONS: Although most Medicare beneficiaries received LCRT for primary brain tumors, HFRT utilization increased in hospital-affiliated centers. Despite high-level evidence for elderly patients, discrepancy in HFRT implementation by site of care persists. Further investigation is needed to understand why patients with short survival may still receive LCRT, because this has major quality-of-life and Medicare spending implications.

Different patient versus provider perspectives on living with Cushing's disease.

CONTEXT: Patients with Cushing's disease (CD) face challenges living with and receiving appropriate care for this rare, chronic condition. Even with successful treatment, many patients experience ongoing symptoms and impaired quality of life (QoL). Different perspectives and expectations between patients and healthcare providers (HCPs) may also impair well-being. OBJECTIVE: To examine differences in perspectives on living with CD between patients and HCPs, and to compare care goals and unmet needs. DESIGN: Memorial Sloan Kettering Pituitary Center established an annual pituitary symposium for pituitary patients and HCPs. Through anonymous pre-program surveys distributed at the 2020 and 2022 symposia, patients and HCPs answered questions related to their own sense, or perception of their patients' sense, of hope, choice, and loneliness in the context of living with CD. PARTICIPANTS: From 655 participants over two educational events, 46 patients with CD and 116 HCPs were included. Median age of both groups was 51 years. 78.3% of the patients were female vs. 53.0% of the HCPs. RESULTS: More patients than HCPs reported they had no choices in their treatment (21.7% vs. 0.9%, P < 0.001). More patients reported feeling alone living with CD than HCPs' perception of such (60.9% vs. 45.5%, P = 0.08). The most common personal care goal concern for patients was 'QoL/mental health,' vs. 'medical therapies/tumor control' for HCPs. The most common CD unmet need reported by patients was 'education/awareness' vs. 'medical therapies/tumor control' for HCPs. CONCLUSIONS: CD patients experience long term symptoms and impaired QoL which may in part be due to a perception of lack of effective treatment options and little hope for improvement. Communicating experiences and care goals may improve long term outcomes for CD patients.

Compensatory variability in network parameters enhances memory performance in the Drosophila mushroom body.

Neural circuits use homeostatic compensation to achieve consistent behavior despite variability in underlying intrinsic and network parameters. However, it remains unclear how compensation regulates variability across a population of the same type of neurons within an individual and what computational benefits might result from such compensation. We address these questions in the Drosophila mushroom body, the fly's olfactory memory center. In a computational model, we show that under sparse coding conditions, memory performance is degraded when the mushroom body's principal neurons, Kenyon cells (KCs), vary realistically in key parameters governing their excitability. However, memory performance is rescued while maintaining realistic variability if parameters compensate for each other to equalize KC average activity. Such compensation can be achieved through both activity-dependent and activity-independent mechanisms. Finally, we show that correlations predicted by our model's compensatory mechanisms appear in the Drosophila hemibrain connectome. These findings reveal compensatory variability in the mushroom body and describe its computational benefits for associative memory.

Impact of virtual monoenergetic levels on coronary plaque volume components using photon-counting computed tomography.

OBJECTIVES: Virtual monoenergetic images (VMIs) from photon-counting CT (PCCT) may change quantitative coronary plaque volumes. We aimed to assess how plaque component volumes change with respect to VMIs. METHODS: Coronary CT angiography (CTA) images were acquired using a dual-source PCCT and VMIs were reconstructed between 40 and 180 keV in 10-keV increments. Polychromatic images at 120 kVp (T3D) were used as reference. Quantitative plaque analysis was performed on T3D images and segmentation masks were copied to VMI reconstructions. Calcified plaque (CP; > 350 Hounsfield units, HU), non-calcified plaque (NCP; 30 to 350 HU), and low-attenuation NCP (LAP; - 100 to 30 HU) volumes were calculated using fixed thresholds. RESULTS: We analyzed 51 plaques from 51 patients (67% male, mean age 65 ± 12 years). Average attenuation and contrast-to-noise ratio (CNR) decreased significantly with increasing keV levels, with similar values observed between T3D and 70 keV images (299 ± 209 vs. 303 ± 225 HU, p = 0.15 for mean HU; 15.5 ± 3.7 vs. 15.8 ± 3.5, p = 0.32 for CNR). Mean NCP volume was comparable between T3D and 100-180-keV reconstructions. There was a monotonic decrease in mean CP volume, with a significant difference between all VMIs and T3D (p < 0.05). LAP volume increased with increasing keV levels and all VMIs showed a significant difference compared to T3D, except for 50 keV (28.0 ± 30.8 mm3 and 28.6 ± 30.1 mm3, respectively, p = 0.63). CONCLUSIONS: Estimated coronary plaque volumes significantly differ between VMIs. Normalization protocols are needed to have comparable results between future studies, especially for LAP volume which is currently defined using a fixed HU threshold. CLINICAL RELEVANCE STATEMENT: Different virtual monoenergetic images from photon-counting CT alter attenuation values and therefore corresponding plaque component volumes. New clinical standards and protocols are required to determine the optimal thresholds to derive plaque volumes from photon-counting CT. KEY POINTS: • Utilizing different VMI energy levels from photon-counting CT for the analysis of coronary artery plaques leads to substantial changes in attenuation values and corresponding plaque component volumes. • Low-energy images (40-70 keV) improved contrast-to-noise ratio, however also increased image noise. • Normalization protocols are needed to have comparable results between future studies, especially for low-attenuation plaque volume which is currently defined using a fixed HU threshold.

Relationship between impaired myocardial blood flow by positron emission tomography and low-attenuation plaque burden and pericoronary adipose tissue attenuation from coronary computed tomography: From the prospective PACIFIC trial.

BACKGROUND: Positron emission tomography (PET) is the clinical gold standard for quantifying myocardial blood flow (MBF). Pericoronary adipose tissue (PCAT) attenuation may detect vascular inflammation indirectly. We examined the relationship between MBF by PET and plaque burden and PCAT on coronary CT angiography (CCTA). METHODS: This post hoc analysis of the PACIFIC trial included 208 patients with suspected coronary artery disease (CAD) who underwent [15O]H2O PET and CCTA. Low-attenuation plaque (LAP, < 30HU), non-calcified plaque (NCP), and PCAT attenuation were measured by CCTA. RESULTS: In 582 vessels, 211 (36.3%) had impaired per-vessel hyperemic MBF (≤ 2.30 mL/min/g). In multivariable analysis, LAP burden was independently and consistently associated with impaired hyperemic MBF (P = 0.016); over NCP burden (P = 0.997). Addition of LAP burden improved predictive performance for impaired hyperemic MBF from a model with CAD severity and calcified plaque burden (P < 0.001). There was no correlation between PCAT attenuation and hyperemic MBF (r = - 0.11), and PCAT attenuation was not associated with impaired hyperemic MBF in univariable or multivariable analysis of all vessels (P > 0.1). CONCLUSION: In patients with stable CAD, LAP burden was independently associated with impaired hyperemic MBF and a stronger predictor of impaired hyperemic MBF than NCP burden. There was no association between PCAT attenuation and hyperemic MBF.

Dabrafenib as a diagnostic and therapeutic strategy for the non-surgical management of papillary craniopharyngioma.

PURPOSE: Papillary craniopharyngiomas can cause considerable morbidity due to mass effect and potential surgical complications. These tumors are known to harbor BRAF V600 mutations, which make them exquisitely sensitive to BRAF inhibitors. METHODS: The patient is a 59 year old man with a progressive suprasellar lesion that was radiographically consistent with a papillary craniopharyngioma. He was consented to an Institution Review Board-approved protocol, which permits sequencing of cell free DNA in plasma and the collection and reporting of clinical data. RESULTS: The patient declined surgical resection and was empirically treated with dabrafenib at 150 mg twice daily. Treatment response was demonstrated after 19 days, confirming the diagnosis. After achieving a near complete response after 6.5 months on drug, a decision was made to deescalate treatment to dabrafenib 75 mg twice daily with subsequent tumor stability for 2.5 months. CONCLUSION: Patients with a suspected papillary craniopharyngioma can be challenged with dabrafenib as a potentially effective diagnostic and therapeutic strategy, given that rapid regression with dabrafenib is only observed in tumors harboring a BRAF V600 mutation. Further work is needed to explore the optimal regimen and dose of the targeted therapy.

The treatment of aggressive prolactinomas with everolimus.

INTRODUCTION: Aggressive prolactinomas are life-limiting tumors without a standard of care treatment option after the oral alkylator, temozolomide, fails to provide tumor control. METHODS: We reviewed an institutional database of pituitary tumors for patients with aggressive prolactinomas who progressed following treatment with a dopamine receptor agonist, radiotherapy and temozolomide. Within this cohort, we identified four patients who were treated with everolimus and we report their response to this therapy. Treatment response was determined by a neuroradiologist, who manually performed volumetric assessment and determined treatment response by Response Assessments in Neuro-Oncology (RANO) criteria. RESULTS: Three of four patients who were treated with everolimus had a biochemical response to therapy and all patients derived a clinically meaningful benefit based upon suppression of tumor growth. While the best overall response as assessed by RANO criteria was stable disease for the four patients, a minor regression in tumor size was appreciated in two of the four patients. CONCLUSION: Everolimus is an active agent in the treatment of prolactinomas that warrants further investigation.

Performance evaluation and model of spacesuit cooling by hydrophobic hollow fiber-membrane based water evaporation through pores.

A comprehensive mathematical model is presented that accurately estimates and predicts failure modes through the computations of heat rejection, temperature drop and lumen side pressure drop of the hollow fiber (HF) membrane-based NASA Spacesuit Water Membrane Evaporator (SWME). The model is based on mass and energy balances in terms of the physical properties of water and membrane transport properties. The mass flux of water vapor through the pores is calculated based on Knudsen diffusion with a membrane structure parameter that accounts for effective mean pore diameter, porosity, thickness, and tortuosity. Lumen-side convective heat transfer coefficients are calculated from laminar flow boundary layer theory using the Nusselt correlation. Lumen side pressure drop is estimated using the Hagen-Poiseuille equation. The coupled ordinary differential equations for mass flow rate, water temperature and lumen side pressure are solved simultaneously with the equations for mass flux and convective heat transfer to determine overall heat rejection, water temperature and lumen side pressure drop. A sensitivity analysis is performed to quantify the effect of input variability on SWME response and identify critical failure modes. The analysis includes the potential effect of organic and/or inorganic contaminants and foulants, partial pore entry due to hydrophilization, and other unexpected operational failures such as bursting or fiber damage. The model can be applied to other hollow fiber membrane-based applications such as low temperature separation and concentration of valuable biomolecules from solution.

Mechanisms underlying homeostatic plasticity in the Drosophila mushroom body in vivo.

Neural network function requires an appropriate balance of excitation and inhibition to be maintained by homeostatic plasticity. However, little is known about homeostatic mechanisms in the intact central brain in vivo. Here, we study homeostatic plasticity in the Drosophila mushroom body, where Kenyon cells receive feedforward excitation from olfactory projection neurons and feedback inhibition from the anterior paired lateral neuron (APL). We show that prolonged (4-d) artificial activation of the inhibitory APL causes increased Kenyon cell odor responses after the artificial inhibition is removed, suggesting that the mushroom body compensates for excess inhibition. In contrast, there is little compensation for lack of inhibition (blockade of APL). The compensation occurs through a combination of increased excitation of Kenyon cells and decreased activation of APL, with differing relative contributions for different Kenyon cell subtypes. Our findings establish the fly mushroom body as a model for homeostatic plasticity in vivo.

A prospective study of dysgeusia and related symptoms in patients with multiple myeloma after autologous hematopoietic cell transplantation.

BACKGROUND: Dysgeusia is a common but understudied complication in patients undergoing autologous hematopoietic cell transplantation (auto-HCT). We assessed the feasibility of using chemical gustometry (CG) to measure dysgeusia and explored its associations with symptom burden, nutrition, chemotherapy pharmacokinetics (PK), and the oral microbiome. METHODS: We conducted a single-center, prospective feasibility study (NCT03276481) of patients with multiple myeloma undergoing auto-HCT. CG was performed longitudinally testing five flavors (sweet, sour, salty, bitter, umami) to calculate a total taste score (maximum score, 30). We measured caloric intake and patient-reported symptoms, assessing their correlation with oral microbiota composition and salivary and blood melphalan PK exposure. RESULTS: Among all 45 patients, 39 (87%) completed at least four (>60%) and 22 (49%) completed all six CG assessments. Median total CG scores remained stable over time but were lowest at day +7 (27, range 24-30) with recovery by day +100. Symptom burden was highest by day +10 (area under the curve, 2.9; range, 1.0-4.6) corresponding with the lowest median overall caloric intake (1624 kcal; range, 1345-2267). Higher serum/salivary melphalan levels correlated with higher patient-reported dysgeusia and lower caloric intake. Oral microbiota α-diversity was stable early and increased slightly by day +100. CONCLUSIONS: Assessment of dysgeusia by CG is feasible after auto-HCT. Most dysgeusia, symptom burden, and lowest caloric intake occurred during the blood count nadir. Higher melphalan concentrations correlated with more dysgeusia and poorer caloric intake. Future studies will aim to modulate melphalan exposure by PK-targeted dosing and characterize patient taste preferences to personalize diets for improved nutritional intake. LAY SUMMARY: Taste changes after cancer treatments are very common. We used chemical gustometry (taste testing) to study taste changes and to better understand why patients with multiple myeloma experience this symptom after autologous hematopoietic cell transplantation. We found that taste testing was feasible, taste changes peaked when blood counts were lowest, and most patients recovered their taste by 100 days after transplantation. Taste changes correlated with lower food intake and with higher levels of chemotherapy in the body. Future work will focus on using personalized chemotherapy doses to reduce taste changes and to match patients' individual taste preferences with their diets.

Cardiac Transplantation in Danon Disease.

BACKGROUND: Danon disease (DD) is a rare X-linked dominant cardioskeletal myopathy caused by mutations in the lysosome-associated membrane protein-2 (LAMP-2) gene that is usually lethal without cardiac transplantation. The purpose of this study was to characterize post-transplant outcomes in a large cohort of patients with DD who underwent cardiac transplantation. METHODS: The clinical phenotype and outcome data of patients with DD who underwent cardiac transplantation (n = 38; 19 males and 19 females) were obtained from 8 centers. Study outcomes included graft survival, defined as death or retransplantation, and episodes of acute cellular and antibody-mediated rejection and cardiac allograft vasculopathy at 1 year. RESULTS: Median follow-up time after transplantation for the entire cohort was 4.4 years (IQR: 1.5-12.8 years). The median age at transplant for the cohort was 20.2 years (15.8-27.9 years), with no difference in age between sexes. Median pretransplant left-ventricular ejection fraction for the entire cohort was 30% (range 11%-84%). Males had higher pretransplant aspartate aminotransferase, alanine aminotransferase and creatine phosphokinase levels than females (P < 0.001). There were 2 deaths in the entire cohort and 2 retransplants. There was no difference in actuarial graft survival between males and females (P = 0.8965); the estimated graft survival was 87.1% (95%CI: 63.6%-95.9%) at 5 years. One episode (2.7%) of antibody-mediated rejection, grade 2, and 7 episodes (19%) of acute cellular rejection, grade 2 or 3, were reported in patients who survived to discharge (6 females and 1 male; P = 0.172). CONCLUSIONS: Heart transplantation outcomes are acceptable in DD with high probabilities of 5-year graft survival for males and females suggesting that cardiac transplantation is an effective treatment option for DD patients.

Low mortality in SARS-CoV-2 infected heart transplant recipients at a single center.

Immunosuppressed heart transplant (HT) recipients are thought to be at higher risk of infection and mortality from SARS-CoV-2 infection coronavirus disease 2019 (COVID-19); however, evidence guiding management of HT patients are limited. Retrospective search of electronic health records from February 2020 to February 2021, identified 28 HT recipients out of 400 followed by UC San Diego who tested positive for SARS-CoV-2. Patient demographics, COVID-19 directed therapies, hospital course and outcomes were compared to control HT recipients who tested negative for SARS-CoV-2 during the same period (n = 80). Among 28 HT recipients who tested positive for SARS-CoV-2, 15 were admitted to the hospital and 13 were monitored closely as outpatients. Among inpatients, five developed severe illness and two died (7% mortality). Nine patients were treated with remdesivir, and four received dexamethasone and remdesivir. Two outpatients received neutralizing monoclonal antibody therapy and one outpatient received dexamethasone for persistent dyspnea. Immunosuppressed HT recipients, especially Hispanic patients and patients with higher body mass index, were at greater risk of infection and mortality from COVID-19 than the general population. Use of remdesivir and dexamethasone may have improved outcomes in our HT recipients compared to HT recipients at other centers.

Cardiac Manifestations of Post-Acute COVID-19 Infection.

PURPOSE OF REVIEW: There is emerging evidence that the post-acute and chronic phases of COVID-19 infection are associated with various significant cardiovascular sequelae. RECENT FINDINGS: Long COVID has been shown to be associated with multiple cardiovascular sequelae including direct myocardial injury, arrhythmias, and cardiomyopathies. Hypotheses on the mechanism of myocardial injury include direct viral infiltration and autoimmune dysregulation. Long COVID is associated with persistent cardiac ischemia in patients with no previous history of coronary disease, atrial and ventricular arrhythmias, and the development of new-onset heart failure in previously healthy patients. Onset of long COVID may be related to severity of the initial SARS-CoV2 infection. Cardiac MRI is a valuable tool in assessing myocarditis and the development of cardiomyopathies in the setting of long COVID. Both patients with and without pre-existing cardiovascular disease are at risk of developing myocardial injury in the setting of long COVID. Future studies will elucidate both cardiovascular mortality and cardiac rehabilitation in the post-acute and chronic phases of COVID-19.

Phase 1b trial of an ibrutinib-based combination therapy in recurrent/refractory CNS lymphoma.

Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase (BTK) and has shown single-agent activity in recurrent/refractory central nervous system (CNS) lymphoma. Clinical responses are often transient or incomplete, suggesting a need for a combination therapy approach. We conducted a phase 1b clinical trial to explore the sequential combination of ibrutinib (560 or 840 mg daily dosing) with high-dose methotrexate (HD-MTX) and rituximab in patients with CNS lymphoma (CNSL). HD-MTX was given at 3.5 g/m2 every 2 weeks for a total of 8 doses (4 cycles; 1 cycle = 28 days). Ibrutinib was held on days of HD-MTX infusion and resumed 5 days after HD-MTX infusion or after HD-MTX clearance. Single-agent daily ibrutinib was administered continuously after completion of induction therapy until disease progression, intolerable toxicity, or death. We also explored next-generation sequencing of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF) before and during treatment. The combination of ibrutinib, HD-MTX, and rituximab was tolerated with an acceptable safety profile (no grade 5 events, 3 grade 4 events). No dose-limiting toxicity was observed. Eleven of 15 patients proceeded to maintenance ibrutinib after completing 4 cycles of the ibrutinib/HD-MTX/rituximab combination. Clinical responses occurred in 12 of 15 patients (80%). Sustained tumor responses were associated with clearance of ctDNA from the CSF. This trial was registered at www.clinicaltrials.gov as #NCT02315326.

Metabolic syndrome, fatty liver, and artificial intelligence-based epicardial adipose tissue measures predict long-term risk of cardiac events: a prospective study.

BACKGROUND: We sought to evaluate the association of metabolic syndrome (MetS) and computed tomography (CT)-derived cardiometabolic biomarkers (non-alcoholic fatty liver disease [NAFLD] and epicardial adipose tissue [EAT] measures) with long-term risk of major adverse cardiovascular events (MACE) in asymptomatic individuals. METHODS: This was a post-hoc analysis of the prospective EISNER (Early-Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) study of participants who underwent baseline coronary artery calcium (CAC) scoring CT and 14-year follow-up for MACE (myocardial infarction, late revascularization, or cardiac death). EAT volume (cm3) and attenuation (Hounsfield units [HU]) were quantified from CT using fully automated deep learning software (< 30 s per case). NAFLD was defined as liver-to-spleen attenuation ratio < 1.0 and/or average liver attenuation < 40 HU. RESULTS: In the final population of 2068 participants (59% males, 56 ± 9 years), those with MetS (n = 280;13.5%) had a greater prevalence of NAFLD (26.0% vs. 9.9%), higher EAT volume (114.1 cm3 vs. 73.7 cm3), and lower EAT attenuation (-76.9 HU vs. -73.4 HU; all p < 0.001) compared to those without MetS. At 14 ± 3 years, MACE occurred in 223 (10.8%) participants. In multivariable Cox regression, MetS was associated with increased risk of MACE (HR 1.58 [95% CI 1.10-2.27], p = 0.01) independently of CAC score; however, not after adjustment for EAT measures (p = 0.27). In a separate Cox analysis, NAFLD predicted MACE (HR 1.78 [95% CI 1.21-2.61], p = 0.003) independently of MetS, CAC score, and EAT measures. Addition of EAT volume to current risk assessment tools resulted in significant net reclassification improvement for MACE (22% over ASCVD risk score; 17% over ASCVD risk score plus CAC score). CONCLUSIONS: MetS, NAFLD, and artificial intelligence-based EAT measures predict long-term MACE risk in asymptomatic individuals. Imaging biomarkers of cardiometabolic disease have the potential for integration into routine reporting of CAC scoring CT to enhance cardiovascular risk stratification. Trial registration NCT00927693.