Persistent enhancement of exciton diffusivity in CsPbBr3 nanocrystal solids.

In semiconductors, exciton or charge carrier diffusivity is typically described as an inherent material property. Here, we show that the transport of excitons among CsPbBr3 perovskite nanocrystals (NCs) depends markedly on how recently those NCs were occupied by a previous exciton. Using transient photoluminescence microscopy, we observe a striking dependence of the apparent exciton diffusivity on excitation laser power that does not arise from nonlinear exciton-exciton interactions or thermal heating. We interpret our observations with a model in which excitons cause NCs to transition to a long-lived metastable configuration that markedly increases exciton transport. The exciton diffusivity observed here (>0.15 square centimeters per second) is considerably higher than that observed in other NC systems, revealing unusually strong excitonic coupling between NCs. The finding of a persistent enhancement in excitonic coupling may help explain other photophysical behaviors observed in CsPbBr3 NCs, such as superfluorescence, and inform the design of optoelectronic devices.

Light Emission in 2D Silver Phenylchalcogenolates.

Silver phenylselenolate (AgSePh, also known as "mithrene") and silver phenyltellurolate (AgTePh, also known as "tethrene") are two-dimensional (2D) van der Waals semiconductors belonging to an emerging class of hybrid organic-inorganic materials called metal-organic chalcogenolates. Despite having the same crystal structure, AgSePh and AgTePh exhibit a strikingly different excitonic behavior. Whereas AgSePh exhibits narrow, fast luminescence with a minimal Stokes shift, AgTePh exhibits comparatively slow luminescence that is significantly broadened and red-shifted from its absorption minimum. Using time-resolved and temperature-dependent absorption and emission microspectroscopy, combined with subgap photoexcitation studies, we show that exciton dynamics in AgTePh films are dominated by an intrinsic self-trapping behavior, whereas dynamics in AgSePh films are dominated by the interaction of band-edge excitons with a finite number of extrinsic defect/trap states. Density functional theory calculations reveal that AgSePh has simple parabolic band edges with a direct gap at Γ, whereas AgTePh has a saddle point at Γ with a horizontal splitting along the Γ-N1 direction. The correlation between the unique band structure of AgTePh and exciton self-trapping behavior is unclear, prompting further exploration of excitonic phenomena in this emerging class of hybrid 2D semiconductors.

Predicting future left anterior descending artery events from non-culprit lesions: insights from the Lipid-Rich Plaque study.

AIMS: The left anterior descending (LAD) artery is the most frequently affected site by coronary artery disease. The prospective Lipid Rich Plaque (LRP) study, which enrolled patients undergoing imaging of non-culprits followed over 2 years, reported the successful identification of coronary segments at risk of future events based on near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS) lipid signals. We aimed to characterize the plaque events involving the LAD vs. non-LAD segments. METHODS AND RESULTS: LRP enrolled 1563 patients from 2014 to 2016. All adjudicated plaque events defined by the composite of cardiac death, cardiac arrest, non-fatal myocardial infarction, acute coronary syndrome, revascularization by coronary bypass or percutaneous coronary intervention, and rehospitalization for angina with >20% stenosis progression and reported as non-culprit lesion-related major adverse cardiac events (NC-MACE) were classified by NIRS-IVUS maxLCBI4 mm (maximum 4-mm Lipid Core Burden Index) ≤400 or >400 and association with high-risk-plaque characteristics, plaque burden ≥70%, and minimum lumen area (MLA) ≤4 mm2. Fifty-seven events were recorded with more lipid-rich plaques in the LAD vs. left circumflex and right coronary artery; 12.5% vs. 10.4% vs. 11.3%, P = 0.097. Unequivocally, a maxLCBI4 mm >400 in the LAD was more predictive of NC-MACE [hazard ratio (HR) 4.32, 95% confidence interval (CI) (1.93-9.69); P = 0.0004] vs. [HR 2.56, 95% CI (1.06-6.17); P = 0.0354] in non-LAD segments. MLA ≤4 mm2 within the maxLCBI4 mm was significantly higher in the LAD (34.1% vs. 25.9% vs. 13.7%, P < 0.001). CONCLUSION: Non-culprit lipid-rich segments in the LAD were more frequently associated with plaque-level events. LAD NIRS-IVUS screening may help identify patients requiring intensive surveillance and medical treatment.

Power-Dependent Photoluminescence Efficiency in Manganese-Doped 2D Hybrid Perovskite Nanoplatelets.

Substitutional metal doping is a powerful strategy for manipulating the emission spectra and excited state dynamics of semiconductor nanomaterials. Here, we demonstrate the synthesis of colloidal manganese (Mn2+)-doped organic-inorganic hybrid perovskite nanoplatelets (chemical formula: L2[APb1-xMnxBr3]n-1Pb1-xMnxBr4; L, butylammonium; A, methylammonium or formamidinium; n (= 1 or 2), number of Pb1-xMnxBr64- octahedral layers in thickness) via a ligand-assisted reprecipitation method. Substitutional doping of manganese for lead introduces bright (approaching 100% efficiency) and long-lived (>500 µs) midgap Mn2+ atomic states, and the doped nanoplatelets exhibit dual emission from both the band edge and the dopant state. Photoluminescence quantum yields and band-edge-to-Mn intensity ratios exhibit strong excitation power dependence, even at a very low incident intensity (<100 µW/cm2). Surprisingly, we find that the saturation of long-lived Mn2+ dopant sites cannot explain our observation. Instead, we propose an alternative mechanism involving the cross-relaxation of long-lived Mn-site excitations by freely diffusing band-edge excitons. We formulate a kinetic model based on this cross-relaxation mechanism that quantitatively reproduces all of the experimental observations and validate the model using time-resolved absorption and emission spectroscopy. Finally, we extract a concentration-normalized microscopic rate constant for band edge-to-dopant excitation transfer that is ∼10× faster in methylammonium-containing nanoplatelets than in formamidinium-containing nanoplatelets. This work provides fundamental insight into the interaction of mobile band edge excitons with localized dopant sites in 2D semiconductors and expands the toolbox for manipulating light emission in perovskite nanomaterials.

Predictive Value of Combining Biomarkers for Clinical Outcomes in Advanced Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

INTRODUCTION: A high tumor mutational burden (TMB) (≥10 mut/Mb) has been associated with improved clinical benefit in non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICI) and is a tumor agnostic indication for pembrolizumab across tumor types. We explored whether combining TMB with programmed cell death ligand 1 (PD-L1) and pretreatment neutrophil-lymphocyte ratio (NLR) was associated with improved outcomes in ICI-treated NSCLC. METHODS: We retrospectively analyzed patients treated with ICI with Foundation One genomic testing, including TMB. Optimal cutoff for prediction of response by TMB was determined by receiver operating characteristic analysis, and area under the curve (AUC) was calculated for all 3 biomarkers and combinations. Cox model was used to assess prognostic factors of overall survival (OS) and time to progression (TTP). Survival cutoffs calculated with Kaplan-Meier survival curves were TMB ≥10 mut/Mb, PD-L1 ≥50%, NLR <5, and combined biomarkers. RESULTS: Data from 88 patients treated were analyzed. The optimal TMB cutoff was 9.24 mut/Mb (AUC, 0.62), improving to 0.74 combining all 3 biomarkers. Adjusted Cox model showed that TMB ≥10 mut/Mb was an independent factor of OS (hazard ratio [HR], 0.31; 95% confidence interval; 0.14-0.69; P = .004) and TTP (HR, 0.46; 95% CI, 0.27-0.77; P = .003). The combination of high TMB with positive PD-L1 and low NLR was significantly associated with OS (P = .038) but not TTP. CONCLUSIONS: TMB has modest predictive and prognostic power for clinical outcomes after ICI treatment. The combination of TMB, PD-L1, and NLR status improves this power.

Feasibility of point-of-care cardiac ultrasound performed by clinicians at health centers in Tanzania.

BACKGROUND: Point-of-care cardiac ultrasound (cardiac POCUS) has potential to become a useful tool for improving cardiovascular care in Tanzania. We conducted a pilot program to train clinicians at peripheral health centers to obtain and interpret focused cardiac POCUS examinations using a hand-held portable device. METHODS: Over a 5-day period, didactic and experiential methods were used to train clinicians to conduct a pre-specified scanning protocol and recognize key pathologies. Pre- and post-training knowledge and post-training image acquisition competency were assessed. In their usual clinical practices, trainees then scanned patients with cardiovascular signs/symptoms, recorded a pre-specified set of images for each scan, and documented their interpretation as to presence or absence of key pathologies on a case report form. A cardiologist subsequently reviewed all images, graded them for image quality, and then documented their interpretation of key pathologies in a blinded fashion; the cardiologist interpretation was considered the gold standard. RESULTS: 8 trainees (6 Clinical Officers, 1 Assistant Medical Officer, and 1 Medical Doctor) initiated and completed the training. Trainees subsequently performed a total of 429 cardiac POCUS examinations in their clinical practices over a 9 week period. Stratified by trainee, the median percent of images that were of sufficient quality to be interpretable was 76.7% (range 18.0-94.2%). For five of eight trainees, 75% or more of images were interpretable. For detection of pre-specified key pathologies, kappa statistics for agreement between trainee and cardiologist ranged from - 0.03 (no agreement) for detection of pericardial effusion to 0.42 (moderate agreement) for detection of tricuspid valve regurgitation. Mean kappa values across the key pathologies varied by trainee from 0 (no agreement) to 0.32 (fair agreement). CONCLUSIONS: The 5-day training program was sufficient to train most clinicians to obtain basic cardiac images but not to accurately interpret them. Proficiency in image interpretation may require a more intensive training program.

Novel therapies are changing treatment paradigms in metastatic prostate cancer.

Metastatic castration-resistant prostate cancer (mCRPC) remains a terminal diagnosis with an aggressive disease course despite currently approved therapeutics. The recent successful development of poly ADP-ribose polymerase (PARP) inhibitors for patients with mCRPC and mutations in DNA damage repair genes has added to the treatment armamentarium and improved personalized treatments for prostate cancer. Other promising therapeutic agents currently in clinical development include the radiotherapeutic 177-lutetium-prostate-specific membrane antigen (PSMA)-617 targeting PSMA-expressing prostate cancer and combinations of immunotherapy with currently effective treatment options for prostate cancer. Herein, we have highlighted the progress in systemic treatments for mCRPC and the promising agents currently in ongoing clinical trials.

Two Origins of Broadband Emission in Multilayered 2D Lead Iodide Perovskites.

Broadband emission in lead iodide 2D perovskites has been alternately attributed to self-trapped excitons (STEs) or permanent structural defects and/or impurities. Here, we investigate six different multilayered (n > 1) 2D lead iodide perovskites as a function of sample temperature from 5 to 300 K. We distinguish shallow defect-associated emission from a broad near-infrared (NIR) spectral feature, which we assign to an STE through subgap photoexcitation experiments. When we varied the thickness (n = 2, 3, 4), A-site cation (methylammonium vs formamidinium), and organic spacer (butylammonium vs hexylammonium vs phenylethylammonium), we found that the temperature dependence of broad NIR emission was strongly correlated with both the strength of electron-phonon coupling and the extent of structural deformation of the ground-state lattice, strongly supporting the assignment of this spectral feature to an STE. However, the extent to which formation of these STEs is intrinsic versus defect-assisted remains open to debate.

2-Year Outcomes After Stenting of Lipid-Rich and Nonrich Coronary Plaques.

BACKGROUND: Autopsy studies suggest that implanting stents in lipid-rich plaque (LRP) may be associated with adverse outcomes. OBJECTIVES: The purpose of this study was to evaluate the association between LRP detected by near-infrared spectroscopy (NIRS) and clinical outcomes in patients with coronary artery disease treated with contemporary drug-eluting stents. METHODS: In this prospective, multicenter registry, NIRS was performed in patients undergoing coronary angiography and possible percutaneous coronary intervention (PCI). Lipid core burden index (LCBI) was calculated as the fraction of pixels with the probability of LRP >0.6 within a region of interest. MaxLCBI4mm was defined as the maximum LCBI within any 4-mm-long segment. Major adverse cardiac events (MACE) included cardiac death, myocardial infarction, definite or probable stent thrombosis, or unplanned revascularization or rehospitalization for progressive angina or unstable angina. Events were subcategorized as culprit (treated) lesion-related, nonculprit (untreated) lesion-related, or indeterminate. RESULTS: Among 1,999 patients who were enrolled in the COLOR (Chemometric Observations of Lipid Core Plaques of Interest in Native Coronary Arteries Registry), PCI was performed in 1,621 patients and MACE occurred in 18.0% of patients, of which 8.3% were culprit lesion-related, 10.7% were nonculprit lesion-related, and 3.1% were indeterminate during 2-year follow-up. Complications from NIRS imaging occurred in 9 patients (0.45%), which resulted in 1 peri-procedural myocardial infarction and 1 emergent coronary bypass. Pre-PCI NIRS imaging was obtained in 1,189 patients, and the 2-year rate of culprit lesion-related MACE was not significantly associated with maxLCBI4mm (hazard ratio of maxLCBI4mm per 100: 1.06; 95% confidence interval: 0.96 to 1.17; p = 0.28) after adjusting clinical and procedural factors. CONCLUSIONS: Following PCI with contemporary drug-eluting stents, stent implantation in NIRS-defined LRPs was not associated with increased periprocedural or late adverse outcomes compared with those without significant lipid.

Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging: a prospective, cohort study.

BACKGROUND: Near-infrared spectroscopy (NIRS) intravascular ultrasound imaging can detect lipid-rich plaques (LRPs). LRPs are associated with acute coronary syndromes or myocardial infarction, which can result in revascularisation or cardiac death. In this study, we aimed to establish the relationship between LRPs detected by NIRS-intravascular ultrasound imaging at unstented sites and subsequent coronary events from new culprit lesions. METHODS: In this prospective, cohort study (LRP), patients from 44 medical centres were enrolled in Italy, Latvia, Netherlands, Slovakia, UK, and the USA. Patients with suspected coronary artery disease who underwent cardiac catheterisation with possible ad hoc percutaneous coronary intervention were eligible to be enrolled. Enrolled patients underwent scanning of non-culprit segments using NIRS-intravascular ultrasound imaging. The study had two hierarchal primary hypotheses, patient and plaque, each testing the association between maximum 4 mm Lipid Core Burden Index (maxLCBI4mm) and non-culprit major adverse cardiovascular events (NC-MACE). Enrolled patients with large LRPs (≥250 maxLCBI4mm) and a randomly selected half of patients with small LRPs (<250 maxLCBI4mm) were followed up for 24 months. This study is registered with ClinicalTrials.gov, NCT02033694. FINDINGS: Between Feb 21, 2014, and March 30, 2016, 1563 patients were enrolled. NIRS-intravascular ultrasound device-related events were seen in six (0·4%) patients. 1271 patients (mean age 64 years, SD 10, 883 [69%] men, 388 [31%]women) with analysable maxLCBI4mm were allocated to follow-up. The 2-year cumulative incidence of NC-MACE was 9% (n=103). Both hierarchical primary hypotheses were met. On a patient level, the unadjusted hazard ratio (HR) for NC-MACE was 1·21 (95% CI 1·09-1·35; p=0·0004) for each 100-unit increase maxLCBI4mm) and adjusted HR 1·18 (1·05-1·32; p=0·0043). In patients with a maxLCBI4mm more than 400, the unadjusted HR for NC-MACE was 2·18 (1·48-3·22; p<0·0001) and adjusted HR was 1·89 (1·26-2·83; p=0·0021). At the plaque level, the unadjusted HR was 1·45 (1·30-1·60; p<0·0001) for each 100-unit increase in maxLCBI4mm. For segments with a maxLCBI4mm more than 400, the unadjusted HR for NC-MACE was 4·22 (2·39-7·45; p<0·0001) and adjusted HR was 3·39 (1·85-6·20; p<0·0001). INTERPRETATION: NIRS imaging of non-obstructive territories in patients undergoing cardiac catheterisation and possible percutaneous coronary intervention was safe and can aid in identifying patients and segments at higher risk for subsequent NC-MACE. NIRS-intravascular ultrasound imaging adds to the armamentarium as the first diagnostic tool able to detect vulnerable patients and plaques in clinical practice. FUNDING: Infraredx.

Relation of Lymphangiogenic Factor Vascular Endothelial Growth Factor-D to Elevated Pulmonary Artery Wedge Pressure.

Lymphatic flow is augmented in states of chronic heart failure (cHF). However, the biological mechanism driving increased lymphatic flow capacity (lymphangiogenesis) in cHF is unknown. Recent studies have indicated that vascular endothelial growth factors (VEGF-A, -C, and -D) are involved in lymphangiogenesis. This study examined the association between VEGF-A, -C, and -D levels, invasively measured hemodynamics, and heart failure symptoms. Subjects who underwent clinically indicated right heart catheterization at Medical University of South Carolina between 12/2016 and 7/2018 were eligible for inclusion. These subjects underwent clinical assessment of cHF severity (including 6MWT and KCCQ), hemodynamic assessment with right heart catheterization, laboratory studies including B-type natriuretic peptide, and concomitant measurement of VEGF-A, -C, and -D. Fifty-six patients were included for analysis. Subjects with elevated pulmonary artery wedge pressure (PAWP) had significantly higher VEGF-D levels (263 ± 415 pg/ml vs 65 ± 101 pg/ml; p = 0.02). PAWP was not associated with VEGF-A or VEGF-C levels. When stratified by VEGF-D, subjects with elevated VEGF-D had clinical and hemodynamic characteristics associated with worse HF severity (lower ejection fraction, higher b-type natriuretic peptide, higher PAWP, lower cardiac output), but were not more symptomatic by Kansas City Cardiomyopathy Questionnaire scores and had similar 6-minute walk test distance compared with subjects with lower VEGF-D. Subjects with an elevated VEGF-D were more likely to have a diagnosis of heart failure for >3 years. In conclusion, VEGF-D is associated with elevated PAWP in cHF, and elevated VEGF-D may mitigate cHF symptoms.

Practical Successes in Telepathology Experiences in Africa.

Across much of Africa, there is a critical shortage of pathology services necessary for clinical care. Even in settings where specialty-level clinical care, such as medical oncology, is available, access to anatomic pathology services has often lagged behind. Pathology laboratories in the region are challenging to establish and maintain. This article describes the successful implementation of telepathology services in Malawi and reviews other successful programs developed to support diagnostic pathology in resource-limited settings.

Lymphoma and Pathology in Sub-Saharan Africa: Current Approaches and Future Directions.

The care of patients with lymphoma relies heavily on accurate tissue diagnosis and classification. In sub-Saharan Africa, where lymphoma burden is increasing because of population growth, aging, and continued epidemic levels of human immunodeficiency virus infection, diagnostic pathology services are limited. This article summarizes lymphoma epidemiology, current diagnostic capacity, and obstacles and opportunities for improving practice in the region.

Extranodal natural killer/T-cell lymphoma in Malawi: a report of three cases.

BACKGROUND: Extranodal NK/T-cell lymphoma (ENKTCL) reports from sub-Saharan Africa (SSA) are remarkably rare, despite early childhood acquisition and high prevalence of the causative infectious agent, Epstein-Barr virus (EBV), and frequent occurrence of other lymphoproliferative disorders causally associated with EBV. CASE PRESENTATIONS: At a national teaching hospital in Malawi, three patients of African descent were seen with ENKTCL between 2013 and 2014. Patients were aged between 29 and 60 years, two with craniofacial involvement and one with a primary abdominal tumor, and all were HIV-negative. All had systemic B symptoms, and two severely impaired performance status. On histologic review, morphology and immunophenotyping demonstrated classical ENKTCL features in all cases, including diffuse proliferations of intermediate-to-large atypical lymphocytes with high mitotic activity and extensive background necrosis, positivity for CD3 and CD56, and negativity for CD20. By in situ hybridization, all three tumors were positive for EBV-encoded RNA (EBER). Baseline plasma EBV DNA was also markedly elevated for all three patients. Due to radiotherapy and chemotherapy limitations, patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) with rapid disease progression. All three patients died from progressive lymphoma within 3 months of initial diagnosis. CONCLUSIONS: Our experience with these three patients in Malawi can highlight that ENKTCL does indeed occur in SSA, increase familiarity with ENKTCL among clinicians and pathologists throughout the region, and emphasize the need for better diagnosis and treatment for this neglected population.

Higher Maximum Doses and Infusion Rates Compared with Standard Unfractionated Heparin Therapy Are Associated with Adequate Anticoagulation without Increased Bleeding in Both Obese and Nonobese Patients with Cardiovascular Indications.

STUDY OBJECTIVE: To evaluate the time to achieve therapeutic activated partial thromboplastin time (aPTT) values and occurrence of bleeding based on standard unfractionated heparin (UFH) weight-based dosing recommendations compared with an aggressive weight-based UFH dosing strategy using higher maximum doses and infusion rates in both obese and nonobese patients who presented with non-ST-segment elevation myocardial infarction or unstable angina (NSTEMI/UA) or atrial fibrillation. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: A total of 197 adults were included who were admitted for NSTEMI/UA, atrial fibrillation, or other cardiac indications and received at least 6 hours of a continuous UFH infusion. Of those patients, 71 were treated with standard UFH dosing (60-unit/kg bolus [or maximum 4000 units] followed by an infusion of 12 units/kg/hour [or maximum 1000 units/hr]) between September 2013 and February 2014, and 126 patients received an aggressive UFH dosing strategy (60-unit/kg bolus [or maximum 10,000 units] followed by an infusion of 12 units/kg/hr [or maximum 2250 units/hr]) between October 2014 and March 2015. Patients in the standard dosing and aggressive strategy cohorts were further classified by body mass index status (normal, overweight, obese, and morbidly obese) and weight status. MEASUREMENTS AND MAIN RESULTS: A time-to-event analysis for achievement of therapeutic aPTT range (60-80 sec) was assessed. A significantly higher proportion of patients treated with the aggressive strategy achieved a therapeutic aPTT within 6 hours (23% vs 11%, p=0.043). The delay or failure to achieve therapeutic anticoagulation was particularly evident in obese patients in the standard dosing group. The mean ± SD initial infusion rate was 10.8 ± 1.4 units/kg/hour in the standard dosing group versus 12 ± 0.02 units/kg/hour in the aggressive strategy group (p=<0.0005). The occurrence of supratherapeutic aPTT values and the highest aPTT achieved were similar between the two dosing groups (p=0.817 and p=0.348, respectively). No bleeding events were reported in either group. CONCLUSION: Patients who had higher UFH maximum bolus doses and infusion rates achieved therapeutic anticoagulation more rapidly, without increased bleeding, and these doses can be adjusted for obese as well as nonobese patients. However, despite use of the higher doses, only 23% of patients achieved therapeutic aPTT values within 6 hours, suggesting that an even higher bolus dose and infusion rate may still be warranted.

Advances in transcatheter valve therapies.

The surgical treatment for valvular heart disease is well established with excellent long-term outcomes in appropriately selected patients. For patients at elevated risk for surgical intervention, options have traditionally been limited to medical therapy with disappointing results. The advent of transcatheter techniques of valvular repair or replacement has revolutionized treatment options for these patients at significantly elevated risk for surgery. In both the aortic and mitral realms, landmark clinical trials and real-world registries have begun to define the roles of these therapies, and the development of multidisciplinary heart teams have helped optimize patient treatment pathways and outcomes. Transcatheter treatment of aortic stenosis and mitral regurgitation has emerged as an approved option for properly selected patients, and guidelines have evolved to include these therapies. Further procedural refinement, device development, and clinical trials will continue to evolve this field.